University of Groningen
Placental lesions and outcome in preterm born children
Roescher, Annemiek
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Placental lesions and outcome
in preterm born children
The relation between placental lesions,
neonatal morbidity and neurological development
Annemiek Roescher
Placental lesions and outcome in preterm born children.
The relation between placental lesions, neonatal morbidity and neurological development.
© Copyright 2014, A. M. Roescher, the Netherlands
All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system,
or transmitted in any form or by any means, without the written permission from the
author or, when appropriate, from the publishers of the publications.
ISBN: 978-90-367-7394-2
ISBN Ebook: 978-90-367-7393-5
The printing of this thesis was financially supported by:
AbbVie, Alexion, Chiesi Pharmaceuticals B.V., Nutricia Nederland B.V., Rijksuniversiteit
Groningen, Universitair Medisch Centrum Groningen, postgraduate school for Behavioral
and Cognitive Neurosciences, Covidien, Mead Johnson Nutrition
Cover:
Cover design and lay-out:
Printed by:
Jan van Rymsdyk, in William Hunter’s Anatomy
of the Human Gravid Uterus, 1774
Peter IJdel - Ydel Design
Gildeprint – Enschede
Placental lesions and outcome
in preterm born children
The relation between placental lesions, neonatal morbidity
and neurological development
Proefschrift
ter verkrijging van de graad van doctor aan de
Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 26 november 2014 om 12.45 uur
door
Annemiek Maria Roescher
geboren op 4 augustus 1985
te Raalte
Promotores
Prof. dr. A.F. Bos
Prof. dr. J.J.H.M. Erwich
Copromotor
Dr. A. Timmer
Beoordelingscommissie
Prof. dr. R. de Krijger, Erasmus Medisch Centrum Rotterdam
Prof. dr. S.A. Scherjon, Universitair Medisch Centrum Groningen
Prof. dr. L. Zimmermann, Maastricht Universitair Medisch Centrum
Paranimfen
Marrit Hitzert
Lenneke Roescher
Table of Contents
Chapter 1
General Introduction and Outline of the Thesis
Part 1
Chapter 2
Literature Overview of the Relationship between Placental Lesions and Outcome
Placental lesions, perinatal mortality, neonatal morbidity, and neurological outcome: a systematic review
PLOS ONE 2014;9(2):e89419
Part 2
Chapter 3
Placental Lesions and Short-Term Neonatal Outcome
Placental pathology is associated with illness severity in preterm infants
in the first twenty-four hours after birth
Early Human Development 2011:87:315-319
Placental pathology and neurological morbidity in preterm infants during
the first two weeks after birth
Early Human Development 2014;90:21-25
Chapter 4
Part 3
Chapter 5
Chapter 6
Placental Lesions and Long-Term Outcome
placental lesions and neurodevelopmental outcome at toddler age
Submitted
Placental lesions and functional outcomes at early school age of children
born between 32 and 35 weeks’ gestational age
Submitted
Part 4
Disease Mechanisms of Placental Lesions Leading to Neurological
Morbidity
Chapter 7In preterm infants ascending intrauterine infection is associated with
lower cerebral tissue oxygen saturation and higher oxygen extraction
Provisionally accepted, Pediatric Research
Chapter 8Cytokine response in preterm infants with placental lesions
Submitted
Chapter 9 General Discussion
Chapter 10Summary in English and Dutch
General introduction and outline of the thesis
1
8
1
General introduction and outline of the thesis
Chapter 1
1
General introduction and outline of the thesis
Annemiek Roescher
9
General introduction and outline of the thesis
Placenta
Except for marsupials and egg laying mammals, all mammalian life begins with a placenta.
The first common ancestor of all placental mammals is thought to have evolved during
the Paleogene Period dating 66 million years ago, some hundred thousand years after the
extinction of the dinosaurs.1 This tiny ancestral placental mammal gradually evolved and
diverged and today there are more than five thousand species of mammal, including the
human being. After all these millions of years, the placenta is still the single most important
organ for the development of any placental mammalian fetus.
In humans too, the placenta is the link between the mother and the fetus during
pregnancy, and it is an essential organ for the development of the fetus.2 A well-functioning
placenta is a necessary precondition for a healthy outcome of pregnancy. The placenta
has unique characteristics. It is the only organ which is connected to another individual.
The blood of both the mother and the fetus flows through the placenta, each in a separate
circulation. And it is the only organ which enables the exchange of nutrients and oxygen
from the mother to the fetus and removes fetal waste products.2 Less than optimal placental
performance can, therefore, lead to morbidity or even mortality of the fetus.
1
Placental Examination
Because it is present during the entire duration of pregnancy, examining the placenta
can provide insight into the intrauterine environment of the fetus. Useful information can
be obtained on the causes, severity, and timing of superimposed pathology, fetal wellbeing, or neonatal morbidity and mortality. The importance of placental examination was
acknowledged by Ballantyne, an obstetrician, as early as 1892.3 He wrote:
‘A diseased foetus without its placenta is an imperfect specimen, and a description of a
foetal malady, unless accompanied by a notice of the placental condition, is incomplete.
Deductions drawn from such a case cannot be considered as conclusive, for in the
missing placenta or cord may have existed the cause of the disease and death. During
intrauterine life the foetus, the membranes, the cord and the placenta form an organic
whole, and disease of any part must react upon and affect the others.’
To date, however, the added value of placental examination is not generally
acknowledged by pediatricians. The results of placental examination by pathologists
are generally reported back to the obstetrician, but this information rarely reaches the
pediatrician, even though it could provide useful insight into the possible causes of fetal
and neonatal morbidity and mortality.
Placental lesions
The placental lesions we focus on in this thesis can be divided into four categories:
umbilical cord complications, circulatory disorders, inflammatory disorders, and placental
markers. These categories are presented in an overview of the placenta in Figure 1.
11
General introduction and outline of the thesis
The first category consists of complications of the umbilical cord such as obstruction
or disruption of the umbilical cord blood flow.4 The second category consists of circulatory
disorders. These lesions can in turn be divided into maternal and fetal circulatory
disorders. Maternal circulatory disorders are maternal vascular underperfusion (MVU)
due to inadequate spiral artery remodeling or spiral artery pathology. This can lead to
parenchymal pathology such as placental hypoplasia or abnormal villous maturity.5 MVU is
commonly seen in pregnancies complicated with preeclampsia. Fetal circulatory disorders
are characterized by the presence of thrombosis in the umbilical cord, chorionic plate, or
stem villus vessels with secondary degenerative pathology in the fetal vasculature.6 As
a group these lesions are known as fetal thrombotic vasculopathy. The third category is
inflammatory disorders. These can be divided in ascending intrauterine infection (AIUI),
villitis of unknown etiology (VUE), and chronic deciduitis. AIUI is an acute inflammation of
the extraplacental membranes (chorion and amnion) or chorionic plate. AIUI can emerge
as a maternal response (acute chorioamnionitis or chorionitis) or as a fetal response (acute
umbilical or chorionic vasculitis).7 VUE is a chronic lymphohistiocytic inflammation of the
stem and chorionic villi,8 whereas chronic deciduitis is a lymphohistiocytic inflammation
of the decidua.9 The fourth category consists of placental markers for fetal hypoxia and
chronic hypoperfusion. These markers are elevated nucleated red blood cells (NRBCs)
and chorangiosis. Significant fetal hypoxia leads to erythropoietin release and subsequent
release of red blood cell precursors in an attempt to maximize tissue oxygen delivery,
resulting in elevated NRBCs.10,11 Chronic hypoperfusion increases the number of villous
capillaries in the placenta to optimize perfusion, leading to chorangiosis.12
1
Fetal circulation
Fetal circulatory
disorders
Umbilical
vein
Umbilical
arteries
Umbilical cord
complications
Main stem villus
Amnion
Chorion
Ascending
intrauterine
infection
Placental
septum
Villitis
Decidua basalis
Myometrium
Maternal
circulatory
Maternal
circulatory
disorders
disorders
Endometrial Endometrial
veins
arteries
Intervillous space
Maternal circulation
Figure 1: schematic drawing of the placenta, adapted from N.O. Lunell et al, Uteroplacental Blood
Flow13
12
General introduction and outline of the thesis
Aims of the thesis
Placental lesions are known to be associated with fetal death.14-18 Less is known about the
relationship between placental lesions and neonatal and neurological morbidity. Placental
lesions associated with fetal death are also found in live-born infants. The question arises
whether these placental lesions are also associated with morbidity. The primary aim of this
thesis was, therefore, to determine whether placental lesions are associated with neonatal
morbidity and neurological development. There are suggestions that several placental
lesions are associated with outcome. The mechanism of placental lesions leading to
neonatal and neurological morbidity is unclear. Our secondary aim was, therefore, to
determine a possible mechanism of placental lesions leading to neonatal and neurological
morbidity.
1
Outline of the thesis
This thesis consists of four parts. In each part we addressed one or two research
questions.
Part 1 Literature Overview of Placental Lesions and Outcome
Research question 1: What is known in the literature about the relationship between
placental lesions and perinatal death, neonatal morbidity, and neurological outcome?
In Chapter 2 we review what is known about the relationship between placental lesions
and outcome. In the review we address the relationship between placental lesions and
perinatal death, neonatal morbidity, and neurological outcome.
Part 2 Placental Lesions and Short-Term Outcome
Research question 2: What is the relationship between placental lesions and short-term
neonatal outcome and neurological outcome in preterm-born children?
In Part 2 we describe the relationship between placental lesions and short-term neonatal
outcome as well as neurological outcome in preterm infants. In Chapter 3 we assessed the
short-term neonatal outcome during the first 24 hours after birth with the Score of Neonatal
Acute Physiology Perinatal Extension (SNAPPE).This score assesses the illness severity
of infants during the first 24 hours after birth. Another outcome measure we used shortly
after birth was quality of general movements. In Chapter 4 we describe the relationship
between placental lesions and the quality of general movements during the first two weeks
after birth. The quality of the general movements reflects an infant’s neurological condition
shortly after birth and is a predictor of neurological outcome later in life.
13
General introduction and outline of the thesis
Part 3 Placental Lesions and Long-Term Outcome
Research question 3: What is the relationship between placental lesions and
neurodevelopmental outcome at toddler age and early school age in preterm-born
children?
In Part 3 we present the relationship between placental lesions and neurodevelopmental
outcome at toddler and school age. We determined this relationship in two groups of
preterm-born children. The first group was born at less than 32 weeks’ gestational age
(GA), the second group were moderately preterm-born children (born between 32 and
36 weeks’ GA). In Chapter 5 we describe the relationship between placental lesions and
neurodevelopmental outcome at two to three years of age in preterm-born children (<32
weeks’ GA). In Chapter 6 we determine the relationship between placental lesions and
neurodevelopmental outcome at five to six years of age in late preterm-born children.
1
Part 4 Disease Mechanisms of Placental Lesions Leading to Neurological Morbidity
In part 4 we investigate possible mechanisms of placental lesions leading to neurological
problems.
Research question 4: What is the relationship between placental lesions and cerebral tissue
oxygen saturation and extraction in preterm-born children?
The first mechanism we studied concerning placenta-related neurological problems was
cerebral blood flow. In Chapter 7 we present the relationship between placental lesions
and cerebral tissue oxygen saturation and extraction as determined by using near-infrared
spectroscopy (NIRS).
Research question 5: Are placental lesions associated with cytokine responses directly
after birth in preterm-born children?
The second possible mechanism we studied were cytokine responses in the presence of
placental lesions. In Chapter 8 we describe cytokine levels in the presence and absence
placental lesions.
Chapter 9 is a general discussion of the findings presented in this thesis and some future
perspectives concerning placental lesions, placental examination, and neonatal outcome.
In chapter 10 we summarize our findings in English and Dutch.
14
General introduction and outline of the thesis
References
1. O’Leary MA, Bloch JI, Flynn JJ, et al.
The placental mammal ancestor and
the post-K-Pg radiation of placentals.
Science 2013;339:662-7.
2. Larsen W. Human Embryology.
Philadelphia: Churchill livingstone,
2001.
3. Ballantyne JW. The diseases and
deformities of the fetus: an attempt
towards a system of ante-natal
pathology. Edinburgh: Oliver and Boyd,
1892.
4. Wintermark P, Boyd T, Gregas MC,
Labrecque M, Hansen A. Placental
pathology in asphyxiated newborns
meeting the criteria for therapeutic
hypothermia. Am J Obstet Gynecol
2010;203:579.e1,579.e9.
5. Redline RW, Boyd T, Campbell V, et
al. Maternal vascular underperfusion:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2004;7:237-49.
6. Redline RW, Ariel I, Baergen RN, et
al. Fetal vascular obstructive lesions:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2004;7:443-52.
7. Redline RW, Faye-Petersen O, Heller
D, et al. Amniotic infection syndrome:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2003;6:435-48.
8. Redline RW. Villitis of unknown
etiology: noninfectious chronic
villitis in the placenta. Hum Pathol
2007;38:1439-46.
9. Khong TY, Bendon RW, Qureshi
F, et al. Chronic deciduitis in the
placental basal plate: definition and
interobserver reliability. Hum Pathol
2000;31:292-5.
10. Redline RW. Elevated circulating fetal
nucleated red blood cells and placental
pathology in term infants who
develop cerebral palsy. Hum Pathol
2008;39:1378-84.
11. Teramo KA, Widness JA. Increased
fetal plasma and amniotic fluid
erythropoietin concentrations: markers
of intrauterine hypoxia. Neonatology
2009;95:105-16.
12. Ogino S, Redline RW. Villous
capillary lesions of the placenta:
distinctions between chorangioma,
chorangiomatosis, and chorangiosis.
Hum Pathol 2000;31:945-54.
13. Lunell NO, Nylund L. Uteroplacental
blood flow. Clin Obstet Gynecol
1992;35:108-18.
14. Korteweg FJ, Erwich JJ, Holm JP, et
al. Diverse placental pathologies as
the main causes of fetal death. Obstet
Gynecol 2009;114:809-17.
15. Flenady V, Middleton P, Smith GC,
et al. Stillbirths: the way forward
in high-income countries. Lancet
2011;377:1703-17.
16. Tellefsen CH, Vogt C. How important
is placental examination in cases of
perinatal deaths? Pediatr Dev Pathol
2011;14:99-104.
17. VanderWielen B, Zaleski C, Cold C,
McPherson E. Wisconsin stillbirth
services program: a multifocal
approach to stillbirth analysis. Am J
Med Genet A 2011;155A:1073-80.
18. Stillbirth Collaborative Research
Network Writing Group. Causes
of death among stillbirths. JAMA
2011;306:2459-68.
1
15
16
Part I
Literature overview of placental lesions and outcome
Chapter 2: Placental Pathology, Perinatal Death, Neonatal Outcome
and Neurological Development: A Systematic Review
17
General introduction and outline of the thesis
1
18
2
General introduction and outline of the thesis
Chapter 2
1
Placental Pathology, Perinatal Death, Neonatal Outcome, and
Neurological Development: A Systematic Review
Annemiek M Roescher
Albert Timmer
Jan Jaap HM Erwich
Arend F Bos
PLOS ONE 2014;9(2):e89419
19
Abstract
Background: The placenta plays a crucial role during pregnancy for growth and
development of the fetus. Less than optimal placental performance may result in morbidity
or even mortality of both mother and fetus. Awareness among pediatricians, however, of
the benefit of placental findings for neonatal care, is limited.
Objectives: To provide a systematic overview of the relation between placental lesions
and neonatal outcome.
Data sources: Pubmed database, reference lists of selected publications and important
research groups in the field.
Study appraisal and synthesis methods: We systematically searched the Pubmed
database for literature on the relation between placental lesions and fetal and neonatal
mortality, neonatal morbidity and neurological outcome. We conducted three separate
searches starting with a search for placental pathology and fetal and neonatal mortality,
followed by placental pathology and neonatal morbidity, and finally placental pathology
and neurological development.
We limited our search to full-text articles published in English from January 1995 to October
2013. We refined our search results by selecting the appropriate articles from the ones
found during the initial searches. The first selection was based on the title, the second
on the abstract, and the third on the full article. The quality of the selected articles was
determined by using the Newcastle-Ottawa Quality Assessment Scale.
Results: Placental lesions are one of the main causes of fetal death, where placental
lesions consistent with maternal vascular underperfusion are most important. Several
neonatal problems are also associated with placental lesions, whereby ascending
intrauterine infection (with a fetal component) and fetal thrombotic vasculopathy constitute
the greatest problem.
Conclusions: The placenta plays a key role in fetal and neonatal mortality, morbidity,
and outcome. Pediatricians should make an effort to obtain the results of placental
examinations.
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
Introduction
The placenta is the organ that links mother and fetus during pregnancy. It plays a crucial role
in fetal growth and development by enabling the exchange of nutrients and oxygen from
the mother to the fetus and removing fetal waste products.1 The placenta is an endocrine
organ, a site of synthesis and selective transport of hormones and neurotransmitters.
In addition, the placenta forms a barrier to toxins and infective organisms.2,3 In recent
years, findings based on placental lesions have contributed to a better understanding
of how the placenta functions. Less than optimal placental performance may result in
morbidity or even mortality of both mother and fetus. Indeed, there are indications that
placental lesions are the main cause of fetal death.4 It is also becoming increasingly clear
that impaired placental functioning can have major implications for the live-born infant.
Awareness among pediatricians, however, of the benefit of placental findings for neonatal
care, is limited. Usually, the results of placental examinations are only reported back to the
obstetrician instead of also passing it on to the pediatrician. In our opinion, this is a missed
opportunity. Information on placental lesions can often be helpful towards explaining an
abnormal neonatal outcome and might have consequences for treatment.
This article provides a systematic review of the relation between placental lesions
and neonatal mortality, morbidity, and neurological development. We summarized the
literature published on this topic during the past 18 years. Our hypothesis is that placental
examination provides useful information about the pathophysiological mechanisms that
lead to neonatal mortality and morbidity. Should this prove to be the case, this information
is important for the pediatrician who should, therefore, be aware of and take into
consideration the placental findings of their patients.
2
Methods
Literature search
This systematic review was conducted following the PRISMA guidelines for systematic
reviews. A registered systematic review protocol is not available. Two independent
researchers (AMR and AFB) searched the PubMed database for literature on the relation
between placental lesions and perinatal mortality, neonatal morbidity, and neurological
development. We limited our search to full-text articles published in English from January
1st 1995 to October 31st 2013. We conducted three separate searches starting with a
search for placental lesions and fetal and neonatal mortality, followed by placental lesions
and neonatal morbidity, and finally placental lesions and neurological development.
For the search on placental lesions and fetal and neonatal mortality, we used the terms
(“placental pathology” AND “fetal death”) OR (“placental pathology” AND “stillbirth”) OR
(“placental” AND “causes” AND “stillbirth”) OR (“placental pathology” AND “mortality”).
For the search on placental lesions and neonatal morbidity, we used the terms (“placental
pathology” AND “morbidity”) OR (“placental pathology” AND “neonatal outcome”) OR
(“placental lesions” AND “morbidity”) OR (“placental lesions” AND “neonatal outcome”)
OR (“placenta” AND “neonatal implications”) OR (“placental” AND “lesions” AND “risk
21
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
factor”).
For the search on placental lesions and neurological development, we used the terms
(“placental pathology” AND “neurological”) OR (“placental pathology” AND “neurologic”)
OR (“placental pathology” AND “cerebral palsy”) OR (“placental” AND “neurodevelopmental
outcome”) OR (“placental pathology” AND “follow up”).
Subsequently, we refined our search results by selecting the appropriate articles from
the ones found during the initial searches in three stages. The first selection was based on
the title, the second on the abstract, and the third on the full-text article. Review articles
on the subject of placental lesions and outcome were indicated as background articles.
We did not use these articles in the tables, but we did use them in the text of our article.
We were mainly interested in single births, therefore articles focusing primary on multiple
births were excluded. In addition to the database search, we screened the reference lists
of the selected articles, and the publications of important research groups in the field.
2
Quality assessment
We assessed the quality of all the selected studies by means of the Newcastle-Ottawa
Quality Assessment Scale for cohort and case-control studies. This assessment scale
consists of three parts. For cohort studies these parts include selection, comparability, and
outcome, for case-control studies selection, comparability, and exposure. The selection
part consists of 4 items, with a maximum of 1 point per item. The comparability part has
1 item, with a maximum of 2 points for this item. Both the outcome and exposure parts
consist of 3 items, with a maximum of 1 point per item. This provides a score, ranging from
0 - 9 points, with 9 points for the highest quality.
Results
Our first search for placental lesions and perinatal mortality resulted in 135 articles. The
second search for placental lesions and neonatal morbidity resulted in 55 articles. Our
third search for placental lesions and neurological outcome produced 67 articles. After
removing duplicates, we had a total of 221 articles. We excluded 117 articles based on
their titles. Reasons for exclusion were studies with patient populations from developing
countries or studies focusing on multiple births. Abstracts or full-text articles were
assessed of the remaining 104 articles. Sixty-three articles were additionally excluded for
the following reasons: no placental pathology performed, no neonatal outcome, and the
studies being out of scope. By analyzing the reference lists of the remaining 41 articles,
and screening publications from important research groups in the field, we additionally
included 14 articles. Finally, 55 studies were included in our systematic review (Figure 1),
i.e. 18 studies on perinatal death 4-21, 19 on neonatal morbidity 22-40, and 18 on neurological
outcome.41-58 Characteristics and the quality assessment scores of these 55 articles are
presented in Tables 1-3.
22
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review

Figure 1: PRISMA flowchart
Records identified through searching
Pubmed database
Additional records identified through
reference lists of selected publications
and importantresearch groups in the field
(n = 14)
(n = 257)
2
Records after duplicates removed

(n = 235)
Records screened
(n = 235)


Full-text articles assessed for
eligibility
(n = 118)
Records excluded based on title
(developing countries, specific
multiple births)
(n = 117)
Full-text articles excluded:
No placental pathology
No neonatal outcome
Out of scope
(n = 63)
Studies included in
qualitative synthesis:
Perinatal death
(n = 18)
Studies included in
qualitative synthesis:
Neonatal morbidity
(n = 19)
Studies included in
qualitative synthesis:
Neurological morbidity
(n = 18)
Figure 1: PRISMA flowchart of identified articles published between January 1995 and October 2013
23
Country
Germany
Zanconato et al.
(2007)11
Vergani et al.
(2008)12
Heazell et al.
(2009)13
Kidron et al.
(2009)14
Korteweg et al.
(2009)4
Bonetti et al.
(2011)15
Tellefsen et al.
(2011)16
Norway
The
Netherlands
Italy
Israel
UK
Italy
Italy
Italy
Locatelli et al.
(2005)9
Burke et al. (2007)10 Australia
Horn et al. (2004)8
USA
Ogunyemi et al.
(1998)6
Galan-Roosen et al. The
Netherlands
(2002)7
Incerpi et al. (1998)5 USA
Reference
Cohort Retrospective
Single-center
bservational Retrospective
Multi-center
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Prospective Multicenter
Cohort Retrospective
Single-center
Cohort Retroscpective
Single-center
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Case-control Retrospective
Single-center
Descriptive Prospective
Multi-center
Study design
Stillbirth 23-40wk GA.
Singletons
Antepartum death
>20wk GA
Stillbirth ≥22 wk GA,
≥500g BW
Perinatal death ≥22wk
GA – 7d post partum
Stillbirth ≥22wk GA,
≥500g BW
Stillbirth ≥22 wk GA,
≥500g BW
Stillbirths
NS
Stillbirth ≥22wk<43wk GA, ≥500g
BW
Live born / neonatal
death <750g BW
Intrapartum death, all GA
20002006
19952007
20062007
19942005
20022006
20002004
20042008
19982002
NS
19901994
19851995
19831992
Study
period
Stillbirths >20wk GA,
>500g BW
Stillbirths ≥25wk GA.
Case: stillbirth
Stillbirths + neonatal
death, >500g BW
Study population
Table 1: Description of selected studies perinatal mortality
24
N
N
132
104
N
N
N
N
750
120
71
154
N
N
20
59
Y
N
N
Y
Y
N
N
N
N
N
N
N
N
N
Y
N
Definition
placental
lesions
N
NS
Blinding
placental
examiner
59
115 cases, 193
controls
151 stillbirths,
88 neonatal
death
310
745
Sample size
N
N
N
N
N
N
N
N
Y
N
N
Y
N
Corrected for
confounders
4
3
4
4
3
4
4
4
3
3
4
3
2
Quality
assessment
Selection 4pt
0
0
0
0
0
0
0
0
2
0
0
2
3
3
3
3
3
3
2
3
2
3
2
2
Quality
Quality
assessment
assessment
Comparability 2pt Outcome/
exposurea 3pt
0
3
7
6
7
7
6
7
6
7
7
6
6
7
5
Quality
assessment
Total 9pt
Cohort Prospective Multicenter
Case-control Retrospective
Multi-center
Cohort study Prospective
Multi-center
The
Netherlands
Norway
Stillbirth ≥22 wk GA,
≥500g BW
Stillbirth ≥22 wk GA
Stillbirth ≥20 wk GA
Stillbirth ≥20wk GA +
18-19wk GA if GA was
uncertain
Perinatal death +
terminated pregnancies
20022008
19902003
19982009
20062008
NS
N
N
N
377 cases, 1215 Y
controls
1089
NS
1025
≥20wk 330,
≤20wk 73, 24h
pp 13
512
N
N
N
N
N
Abbreviations: wk - weeks; GA - gestational age; BW - birth weight; NS - not stated; pp - post partum
a: ‘outcome’ for cohort studies, ‘exposure’ for case-control studies.
Sweden
Cohort Prospective Multicenter
USA
The stillbirth
collaborative
research writing
group (2011)18
Korteweg et al.
(2012)19
Helgadottir et al
(2013)20
Bring et al (2013)21
Cohort Prospective Multicenter
VanderWielen et al. USA
(2011)17
25
N
Y
N
Y
N
3
2
3
4
4
0
2
0
1
0
3
1
3
3
3
6
5
6
8
7
USA
USA
USA
USA
Beebe et al. (1996)22
Watterberg et al.
(1996)23
Baergen et al (2001)24
Redline et al. (2002)25
USA
Canada
Holcroft et al (2004)28
Richardson et al.
(2006)29
Mehta et al. (2006)30
Switzerland
Beaudet et al. (2007)32
Dix et al. (2010)33
de Laat et al. (2006)31
The
Netherlands
Canada
USA
Israel
Ariel et al. (2004)27
Ogunyemi et al. (2003)26 USA
Country
Reference
Case-control
Retrospective Singlecenter
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Case-control Prospective
Single-center
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Case-control Prospective
Single-center
Case-control
Retrospective Singlecenter
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Prospective
Single-center
Study design
Preterm infants 24-32
wk GA
Infants from pregnancies
with preeclampsia,
placental abruption
or IUGR
Preterm infants admitted
NICU <34wk GA
Preterm infants 25-34wk
GA
Preterm infants admitted
NICU ≤34wk GA
All GA. Cases: overcoiling
/ undercoiling UC
NICU population
placental pathology
report available
Infants with NECb, all GA.
Case: NEC
VLBW infants <32wk GA
High risk population,
all GA
Intubated infants <2000
gram. Case: RDS
All GA. Case: ELUC
Study population
Table 2: Description of selected studies neonatal morbidity
26
19942005
19992002
19952003
19992001
20022003
19961997
19951997
19922000
NS
19891992
19871989
19771995
Study
period
NS
Y
1296
77 cases. 769
controls
Y
Y
NS
NS
Y
NS
Y
Y
Y
Y
Blinding
placental
examiner
885
165
660
259
64
774
371
38 cases, 15
controls
926 cases, 200
controls
1252
Sample size
N
N
Y
Corrected
for GA
Y
NS
Y
N
Y
Y
Y
Subanalyses
GA
Y
Y
Y
Y
Y
N
reference
Y
previous article
Y
Y
Y
Y
Y
Definitions
placental
lesions
2
3
3
3
3
4
3
4
3
3
3
3
Quality
assessment
Selection 4pt
0
2
1
1
2
2
0
2
2
2
0
3
3
3
2
3
3
3
3
3
3
3
Quality
Quality
assessment
assessment
Comparability 2pt Outcome/
exposurea 3pt
2
2
5
8
7
6
8
9
6
9
8
8
6
7
Quality
assessment
Total 9pt
Canada
Wintermark et al.
(2010)35
The
Netherlands
USA
Italy
Roescher et al. (2011)38
Perrone et al. (2012)40
Cohort study
Retrospective Singlecenter
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Prospective
Multi-center
Cohort Prospective
Single-center
Case-control
Retrospective Singlecenter
Cohort Prospective
Single-center
Preterm infants <32wk
GA
Infants with HIE
undergoing induced
hypothermia ≥36wk GA
NICU population
placental pathology
report available
NICU population <30wk
GA
NICU population <32wk
GA
ELGAN 23-27wk GA
Infants with FTV, all GA.
Case: FTV
20022004
20082001
20002008
2006
2007
NS
19902007
105
1064
40
302
122
23
113 cases. 216
controls
NS
Y
Y
NS
NS
Y
Y
Y
Y
N
Y
N
Y
Y
N
Y
N
Y
N
N
Y
4
4
4
3
2
4
3
0
2
0
1
0
0
2
2
3
3
3
3
3
3
6
9
7
7
5
7
8
hypoxic ischemic encephalopathy; ELGAN - extremely low gestational age newborns
- intrauterine growth restriction; NICU - Neonatal Intensive Care Unit; UC - umbilical cord; NEC - necrotizing enterocolitis; FTV - fetal thrombotic vasculopathy; HIE -
Abbreviations: GA - gestational age; RDS - respiratory distress syndrome; ELUC - excessively long umbilical cord; VLBW - very low birth weight; NS - not stated; IUGR
b: Bell stage II and more
a: ‘outcome’ for cohort studies, ‘exposure’ for case-control studies.
Chen et al. (2011)39
Japan
Sato et al. (2011)37
Moscuzza et al. (2011)36 Italy
USA
Saleemuddin et al.
(2010)34
27
Case-control
Retrospective Singlecenter
Case-control
Retrospective Singlecenter
Case-control
Retrospective Singlecenter
Case-control
Retrospective Singlecenter
Case-control
Retrospective Singlecenter
Case-control
Retrospective Singlecenter
Case-control
Retrospective Singlecenter
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Cohort Prospective
Single-center
Cohort Prospective
Multicenter
USA
USA
USA
Redline et al.
(1998)41
Redline et al.
(2000)42
Viscardi et al.
(2001)43
USA
Redline (2005)46
Leviton et al.
(2010)52
Redline et al.
(2007)48
Reiman et al.
(2008)49
Suppiej et al.
(2008)50
Chau et al. (2009)51
USA
Canada
Italy
Finland
USA
Polam et al. (2005)47 USA
Ireland
McDonald et al.
(2004)45
Adams-Chapman et USA
al. (2002)44
Study design
Country
Reference
Study
period
NS
19871998
19901998
19911996
19901997
NICU population ELBW
infants <1kg BW
Preterm infants <32wk
GA or ≤1500g BW
NICU population <32wk
GA
Preterm infants 24-32wk
GA
ELGAN <28wk GA
19921995
20022006
19982001
20062008
20022004
NICU population 22-29wk 1997GA. Cases: AIUI
2000
Term infants. Cases: NI
Term infants. Cases: NE
NICU population <37wk
GA. Cases: MFI
NICU population all GA.
Cases IUGR
Term infants. Cases: NI.
Controls: meconium
NICU population <1500g 1983BW. Cases: NI at 20m
1991
Study population
Table 3: Description of selected studies neurological outcome
28
1246
92
104
121
129
102 cases, 75
controls
125 cases, 250
controls
93 cases, 387
controls
21 cases, 42
controls
94 cases, 145
controls
40 cases, 176
controls
60 cases, 59
controls
Sample size
NS
NS
NS
Y
Y
Y
Nb
NS
N
Y
N
Y
Blinding
placental
examiner
N
N
N
Y
Y
Y
N
Y
N
Y
Y
Y
Definitions
placental
lesions
Y
N
N
Y
Y
Y
N
Y
Y
Y
Y
N
Corrected for GA
4
3
2
3
3
3
2
3
3
2
1
2
Quality
assessment
Selection 4pt
1
2
0
1
2
2
0
2
2
2
2
Quality
assessment
Comparability
2pt
0
3
3
1
3
3
2
3
2
2
3
3
3
8
8
3
7
8
7
5
7
7
7
6
5
Quality assessment Quality
Outcome/exposurea assessment Total
3pt
9pt
Cohort Retrospective
Single-center
Cohort Retrospective
Single-center
Case-control Prospective
Multi-center
Cohort Retrospective
Single-center
Case-control
Retrospective /
prospective Singlecenter
Rovira et al. (2011)54 Spain
Australia
Late preterm+ term
≥35wk GA. Cases: CP
Preterm infants ≤32wk
GA. AIUI+MVU
Term infants ≥36wk GA.
Cases: NE
Term + late preterm
≥34 wk GA. All neonatal
stroke
Preterm infants <32wk
GA, <1500g BW
IUFD 27-41wk GA
445 cases, 497
controls
72
141 cases, 309
controls
20012008
Y
Y
N
Y
NS
NS
N
Y
Y
Y
Y
Y
Y
Y
N
Y
Y
N
2
4
4
3
4
2
2
2
0
1
2
0
3
2
1
3
3
3
7
8
5
7
9
5
age newborns; IUFD - intrauterine fetal death; CP - cerebral palsy; MVU - maternal vascular underperfusion
maternal floor infarction; NE - neonatal encephalopathy; AIUI -ascending intrauterine infection; ELBW - extremely low birth weight; ELGAN - extremely low gestational
Abbreviations: NICU - Neonatal Intensive Care Unit; BW - birth weight; NI - neurologic impairment; GA - gestational age; IUGR - intrauterine growth restriction; MFI -
b: Subgroup of placentas of both cases and controls were blinded re-reviewed.
37
177
12
20022004
20012007
19801995
NS
19922006
a: ‘outcome’ for cohort studies, ‘exposure’ for case-control studies.
The
Van Vliet et al.
Netherlands
(2012)57
Hayes et al. (2012)58 Ireland
Blair et al. (2011)56
Chang et al. (2011)55 Canada
Cohort Retrospective
Multi-center
Elbers et al. (2011)53 Canada
29
↑ illness severity first 24h,38 NI42
↑NEC,32 ROP,26,36,37,39 IVH,26,32,36,37,47 ventriculomegaly,52 CP,52 NE,45,58
Low Apgar score at 1-5 minute,22,26,35 neonatal infection,22,26,30,36 ↓RDS,29,37 BPD,23,26,40 NEC,32 ROP,26,36,39
IVH,26,30,32,36,47 brain lesions,49 NI,42,46,54 NE,45,58 disability in development at 2y54
Intrapartum death,10 Low Apgar score at 1-5 minute,22,26,35 neonatal infection,22,26,30,36 ↓RDS,23,29,37 BPD,23,26,37,40
Neonatal infection,22 NI,42,46 NE45,58
Fetal death,4 asphyxia in diabetic pregnancy68
Stillbirth,34 asphyxia,35 ↑ illness severity first 24h,38 NEC,32,33 fetal cardiac abnormalities,34 ventriculomegaly,52
PVL,43 NI,41,42 CP46
Fetal death ,21,31 fetal anomalies,24 asphyxia,31,35 low Apgar score at 1-5 minutes,24,31 RDS24
Outcome
Fetal death,4,8,14 CP48,56
impairment; NE - neonatal encephalopathy; BPD - bronchopulmonary dysplasia; ROP - retinopathy of prematurity; IVH - intraventricular hemorrhage
Abbreviations: CP - cerebral palsy; RDS - respiratory distress syndrome; NEC - necrotizing enterocolitis; PVL - periventricular leukomalacia; NI - neurological
Chronic deciduitis
Fetal hypoxia
Acute umbilical and chorionic vasculitis (fetal response). The degree of severity can be staged and
graded.61
Chronic lymphohistiocytic inflammation of placental decidua.70
Elevated nucleated red blood cells (NRBCs). Only rare NRBCs are normal after the first trimester.42
Chorangiosis. Diffuse increase in the number of villous capillaries71
Pathology and explanation
Inadequate spiral artery remodeling or spiral artery pathology (decidual vasculopathy). Commonly seen
in pregnancies complicated with pre-eclampsia. Expressed by parenchymal pathology such as placental
hypoplasia, increased syncytial knots, villous agglutination, increased perivillous fibrin, distal villous
hypoplasia, abnormal villous maturity, infarction, retroplacental hematoma.59
Umbilical cord complications
Obstruction or disruption of the umbilical cord blood flow (e.g. umbilical cord prolapse, entanglement,
knots, disrupted velamentous vessels, hyper/hypo-coiling). Can lead to fetal placental vascular stasis
resulting in FTV.35
Fetal thrombotic vasculopathy (FTV) Thrombosis, recent or remote, in the umbilical cord, chorionic plate or stem villus vessels and / or
secondary degenerative pathology in the fetal vasculature distal to by thrombosis obliterated vessels
(e.g. avascular chorionic villi). Expressed by hemorrhagic endovasculopathy, intimal fibrin cushions,
fibromuscular hypertrophy, villous stromal-vascular karyorrhexis.60
Distal villous immaturity / villous
Maturation defect of the third trimester placenta characterized by enlarged chorionic villi with increased
maturation defect
numbers of capillaries, macrophages, and fluid and decreased formation of vasculosyncytial membranes.
As a result the diffusion distance between intervillous space and fetal capillaries is increased.68
Villitis of unknown etiology (VUE)
Chronic lymphohistiocytic inflammation of the stem- and chorionic villi, with or without obliterative
vasculopathy of stem villus vessels.69
Ascending intrauterine infection
Acute chorioamnionitis and chorionitis (maternal response). The degree of severity can be staged and
(AIUI)
graded.61
Diagnosis
Maternal vascular underperfusion
(MVU)
Table 4: Overview of placental pathology relevant for understanding perinatal morbidity and mortality
30
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
Placental pathology
Examination of the placenta can reveal a wide range of pathologies. For good reproducibility
it is necessary that placental lesions are well defined. Committees of the perinatal section
of the Society for Pediatric Pathology have proposed definitions for maternal vascular
underperfusion, fetal vascular obstructive lesions (fetal thrombotic vasculopathy), and the
amniotic infection syndrome.59-61 Definitions and descriptions of additional pathologies can
be found in various textbooks on the pathology of the placenta.62-67
Since we acknowledge the fact that most pediatricians are unfamiliar with placental
lesions and because a wide variety of terminology is used in the literature, we classified
placental lesions according to the underlying pathology as previously proposed together
with their pathological descriptions in Table 4.35,42,59-61,68-71
2
Placental lesions and perinatal mortality
Perinatal mortality is defined as death during the perinatal period. In the 10th Edition of the
World Health Organization’s International Classification of Diseases, the perinatal period
is defined as death from 22 completed weeks of gestation up to 7 days after birth.72 Fetal
deaths form the largest group of perinatal mortality. In high-income countries one in every
200 infants that reaches 22 weeks’ gestation or more, is stillborn.73 Recently, the important
role of the placenta in fetal deaths has become increasingly clear and several studies
suggested that placental pathology is one of the main causes of fetal death (Table 5). This
underscores the importance of examining the placenta, a fact sorely underestimated by
obstetricians and general pathologists.16
In 30% of the cases the cause of stillbirth is unknown.73 In the remainder, i.e. the
proportion of cases with known cause, most stillbirths are caused by placental lesions
(12-65%, Table 5), followed by infections and umbilical cord abnormalities. 73 For lower
gestational ages (GAs) (20 to 24 weeks), an unknown cause of death is most prominent,
followed by placental lesions. At higher GAs, the relative importance of unknown causes
decreases and placental causes increase.73
Placental pathology consistent with maternal vascular underperfusion is the main
contributor to fetal death, ranging from 34 to 38 percent.4,8,14 This is most prominent during
the preterm period, in pregnancies complicated by hypertensive disorders, with a strong
decline thereafter. During the term period, fetal death is mainly caused by developmental
pathology of placenta parenchyma.4 We can conclude that a pathological examination of
the placenta is essential for clarifying causes of stillbirths.5,13,14,19
The older classification systems for perinatal mortality did not address placental
pathology, or specific placental lesions, as a separate group. Only in the more recent
classification systems is placental pathology included as a cause of fetal death. In all
recent stillbirth studies placental pathology is designated as one of the main causes of
fetal death.74,75 The introduction of classification systems with placental pathology included
as a separate group might be one of the reasons why recent studies identify placental
31
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
pathology as one of the main causes of fetal death. Most of the placental lesions found in
stillbirths, however, are also seen regularly after live, preterm or term, births.76 The question
arises whether placental lesions are also related to neonatal and neurological morbidity.
To summarize, in recent years the role of the placenta in fetal deaths has become
increasingly clear. Placental pathology is one of the main causes of fetal death, with placental
pathology consistent with maternal vascular underperfusion as the main contributor.
2
32
[20]
Placenta
AIUI
[10]
[7]
[8]
[5]
Placenta
Placenta
Chronic/progressive
pathology
Ascending
intrauterine
infection
[6]
Placenta
Placenta
[9]
Placenta
[7]
[19]
Placenta
Acute/subacute
pathology
[12]
[4]
[15]
[17]
[18]
Placenta
Placenta
Placenta
Placenta
Placenta
Placenta
[16]
Placenta
Ref.
[11]
[14]
[13]
Placental lesion
Not specified
Placenta
Placenta
Placenta
Placenta
Intrapartum death
Stillbirth + neonatal death
Stillbirth + neonatal death
Stillbirth
Stillbirth
Evaluation Stillbirth
placental pathology in survivors and
neonates who died
Stillbirths
Test determine cause death
Stillbirth
Stillbirth
Stillbirth
Stillbirth
Stillbirth
Explanation perinatal death
Unexplained stillbirth
Outcome measure: Perinatal death
Stillbirth
Stillbirth
Table 5: Results of selected studies on perinatal death
33
Proportion 0.35 (0.18-0.57)
Proportion 0.21 (0.16-0.27)
Proportion 0.32 (27-0.38)
Proportion 0.50 (0.45-0.55)
Proportion 0.62 (0.56-0.67)
Proportion 0.30 (0.26-0.34)
OR: 2.43 (1.12-5.26)
Proportion 0.96 (0.94-0.97)
Proportion 0.73 (0.64-0.81)
Proportion 0.51(0.41-0.66)
Proportion 0.12-0.40 (0.08-0.48)
Proportion 0.65 (0.61-0.69)
Proportion 0.22 (0.15-0.30)
Proportion 0.42 (0.37-0.47)
Proportion 0.24 (0.20-0.28)
Association found proportion*/OR (95% CI)
Proportion 0.42 (0.31-0.55)
Proportion 0.33 (0.25-0.41)
Proportion 0.47 (0.38-0.56)
OR 0.17 (0.04-0.70)
50% other (UC entanglement)
Proportion AIUI in intrapartum death
Remarks
Placenta new insight
Direct cause death
Major contributor
After placental assessment stillbirth less likely to be
unexplained
12% placenta no connection
Could explain death
death
Cause explained by placental examination alone
Different classification systems
Placental lesions main cause fetal death
51% no placental cause
Secondary main condition
19.9% fetal, 13% maternal, 31.9% no cause Proportion placental/cord causes stillbirth
29.3% obstetric condition, 13.7% fetal
Placental second common cause stillbirth. Placenta main
abnormalities, 12.9% infection, 10.4%
cause (26.1%) in antepartum deaths.
umbilical cord abnormalities
72.6% autopsy, 29.0% genetic analysis
Placental examination most valuable test for determination
of cause stillbirth
No differences in placental pathology
between survivors and neonates who died.
Positive placental pathology in 66% of stillbirths versus 44%
in controls.
Leading cause intrauterine death
Most important aspects stillbirth evaluation: placenta and
autopsy
19.4% unknown
Main cause of death. Placenta 18% associated condition
death
23% congenital malformation,
Most probable cause stillbirth
16% infection, 8% prematurity, 7%
unclassifiable
Third most probable cause stillbirth
No association found/ non placental
53% placenta negative
Umbilical cord
lesions
Umbilical cord
complication
Undercoiling umbilical
cord
Overcoiling umbilical
cord
Excessive long UC
Maternal vascular
underperfusion
[24]
[31]
[31]
[21]
[4]
[8]
[15]
[14]
[15]
Fetal/neonatal death
Fetal death
Fetal death
Stillbirth
Stillbirth
Stillbirth
Stillbirth
Stillbirth
Stillbirth
OR 3.35 (1.48-7.63)
Proportion 0.08 (0.06-0.10)
Proportion 0.34 (0.30-0.38)
Proportion 0.38 (0.31-0.45)
Proportion 0.05 (0.02-0.10)
Proportion 0.35 (0.27-0.44)
Proportion 0.23 (0.16-0.31)
Not significant. OR 2.75 (0.65-36.14)
Not significant. OR 2.43 (0.68-8.66)
Abbreviations: AIUI - ascending intrauterine infection; MVU - maternal vascular underperfusion; UC - umbilical cord
* proportion placental lesions in perinatal death
UC
UC
UC
UC
MVU
MVU
UC
MVU
AIUI
34
Significant more in term stillbirths (9.75) compared to
preterm stillbirths (6.4%)
Most important placental lesions in fetal death
Main contributor placental lesions to death
Proportion UC pathology in stillbirth
Major relevant condition associated with death.
Chorioamnionits diagnosed by bacterial cultures
Direct/major contributor fetal death
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
Placental lesions and neonatal morbidity
It has been suggested that placental lesions are also associated with neonatal morbidity,
but the association is less clear than for fetal mortality. Placental lesions are suggested
to be associated with illness severity shortly after birth, and with a wide range of neonatal
problems (Table 6).
Illness severity shortly after birth can be determined by the presence of asphyxia, Apgar
scores during the first minutes after birth, and by several clinical variables during the first
24 hours after birth. Perinatal asphyxia is described to be associated with placental lesions
affecting fetal vascular supply. These lesions were umbilical cord complications (disrupted
velamentous vessels, cord tear, hypercoiled cord, cord hematoma), chorioamnionitis
with fetal vasculitis, and fetal thrombotic vasculopathy.31,35 Low Apgar scores at 1 and
5 minutes are associated with ascending intrauterine infection and maternal vascular
underperfusion.22,26 Higher illness severity during the first 24 hours after birth, determined by
the Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE), is associated with
placental pathological findings of fetal thrombotic vasculopathy and elevated nucleated
red blood cells (a sign of hypoxia).38
Lung development and neonatal respiratory problems, such as neonatal respiratory
distress syndrome (RDS) and bronchopulmonary dysplasia (BPD), are associated with
placental inflammation. There are indications that the incidence of RDS is reduced in infants
exposed to chorioamnionitis (ORs 0.1-0.6, 95% CI: 0.02-0.8).23,29,37,77 This beneficial effect
may be explained in several ways. It can be explained by advanced lung maturation in
terms of an early elevation of interleukin-1 beta (IL-1β) in lung lavage fluid in the presence
of chorioamnionitis, which stimulates the release of corticotrophin-releasing factor and
corticotrophin.78,79 These hormones enhance the production of cortisol which results in
accelerated lung maturation and, therefore, a decrease in the incidence of RDS.80 Lung
maturation is also explained with animal models of fetal inflammation. Chorioamnionitis
in the fetal lung induces elevated IL-1, which in turn increases the amounts of surfactant
proteins in parallel with increases in surfactant lipids in bronchoalveolar lavages. The lung
mesenchymal tissue decreases, which increases the epithelial surface area and airspace
volume of the lung. This results in a more mature lung structure that contains more
surfactant, has increased compliance, and supports better gas exchange.77,81,82
Besides potentially a beneficial effect on lung function immediately after birth, an
ascending intrauterine infection can also have a detrimental effect on the preterm lung,
particularly in the long-term.77 Chorioamnionitis can promote BPD, with ORs ranging from
2.0-7.4 (95% CI: 1.2-31.2).23,26,37,40,77,83 BPD results from multiple antenatal and postnatal
factors (hits) contributing to disease progression.84 Despite a healthier initial condition (less
RDS), the pulmonary status worsens during the postnatal period.83 This is explained by an
increased susceptibility of the lung to postnatal injurious events (second hits).83-86 Even so,
the relation between respiratory problems and chorioamnionitis is difficult to assess, since
it is confounded by a variety of prenatal factors.85
Necrotizing enterocolitis (NEC) is a challenging problem in the neonatal care of,
2
35
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
mainly, preterm infants. The etiology of NEC is still poorly understood, but it is believed
to be multifactorial.87 Several studies found an association between NEC and placental
lesions, in particular fetal vascular obstructive lesions (fetal thrombotic vasculopathy,
congested villi, coagulation-related lesions) with ORs ranging from 2.6 to 9.10 (95% CI:
1.13-15.08).26,32,33 The presence of ischemia has been proposed as an explanation for the
etiology of NEC. Placental vasculopathy, which causes uteroplacental insufficiency, may
cause fetal circulatory adaptive changes to hypoxia, which may result in bowel ischemia
predisposing to NEC.26
Retinopathy of prematurity (ROP) is also associated with placental lesions, in particular
with inflammatory lesions with ORs ranging from 1.8 to 3.1 (95% CI: 1.02-9.5). 26,36,37,39,88
ROP affects preterm infants and is caused by disorganized growth of retinal blood vessels
which may result in scarring and retinal detachment. The etiology of ROP is likely to be a
multihit phenomenon. At least part of the multihit is an inflammation-related pathogenesis,
which is thought to be mediated by cytokines and growth factors present in the newborn’s
systemic circulation.39 The severity of ROP also correlates positively with ascending
intrauterine infection.88
Fetal cardiac abnormalities are also thought to be associated with placental lesions.
A six-fold increase in fetal cardiac abnormalities is reported in the presence of fetal
thrombotic vasculopathy.34 The most common cardiac abnormalities found in its presence
are ventricular and atrial septal defects, cardiomegaly, and coarctation of the aorta. It is
hypothesized that the relation may be explained by a causal link between the two lesions.34
The presence of one lesion may lead to the establishment of the other, through abnormal
blood flow which serves as the common denominator. Another theory is that a common
genetic variation underlies both placental fetal thrombotic vasculopathy and abnormal
development of the heart.34 This theory is supported by studies in mice which have shown
placental and cardiac functions to be intimately linked, both through secretion of placental
factors which affect maternal and fetal circulation and through genes which contribute to
the development of both organ systems.89 In addition, ascending intrauterine infection with
both maternal and fetal response is associated with an increased risk for patent ductus
arteriosus with ORs ranging from 1.7 to 5.53 (95% CI: 1.1-19.27).26,36,40
To summarize, the most important placental lesions in neonatal morbidity seem to
be ascending intrauterine infection and fetal thrombotic vasculopathy. Nevertheless,
caution is required in order to interpret these findings properly. Many studies on neonatal
outcome only focus on infectious placental lesions and fetal thrombotic vasculopathy to
the exclusion of other placental lesions. Thus there may be a bias towards these two
lesions, because chorioamnionitis is a placental lesion well-known to both gynecologists
and pediatricians. Even so, four of the larger studies including a wide range of placental
lesions identified ascending intrauterine infection and fetal thrombotic vasculopathy as the
most important placental finding with respect to neonatal morbidity.22,26,32,40 This may pave
the way for early interventions serving to prevent morbidity. Before such interventions can
be defined, however, detailed knowledge of the pathophysiological mechanisms that lead
to neonatal morbidity is required.
2
36
(not specified)
AIUI
[26,30,32,36,40]
[26,36,39,40]
[26,32,40]
[28]
[22]
[22]
AIUI
AIUI
AIUI
AIUI
AIUI
AIUI
[37]
[37]
[37]
AIUI
AIUI
PDA
ROP
[29,37]
AIUI
NEC
IVH
BPD
[29,37]
AIUI
RDS
Sepsis
[37]
[29,37]
Asphyxia
[35]
Fetal metabolic acidosis
Anomalies*
Liver disorders
Fetal metabolic acidosis
NEC
ROP
PDA
BPD
BPD
RDS
Neonatal infection
Illness severity first 24h
Low Apgar score
Outcome measure
AIUI
AIUI
[28]
[25]
AIUI
AIUI
[23,26,32]
[23,26,32,40]
AIUI
AIUI
[22,26,30,32,36]
AIUI
Maternal response
[22,26,35]
Maternal + fetal response
AIUI
[38]
Ref.
Placental lesion specified
Placental
lesion
Table 6: Results of selected studies on neonatal morbidity
37
OR 0.6 (0.5-0.8)
OR 3.80 (1.67-8.67)
OR 1.8-3.1 (1.02-9.5)
OR 1.7-5.53 (1.1-19.27)
OR 0.7 (0.4-0.9)
OR 2.0-7.4 (1.20-31.16)
OR 0.11 (0.02-0.63)
OR 1.7-1.9 (1.2-3.0)
OR 1.7-2.1 (1.2-3.0)
Associations found OR (95% CI)
62.9% with ROP had AIUI
65.9% with IVH had AIUI37
59% with BPD had AIUI. 37
Proportion BPD 0.26 95% CI
(0.19-0.35)29
Proportion RDS: 0.44 95% CI
(0.35-0.53)29
Proportion: 0.22 95% CI (0.100.42)
Effect size r = 0.5236
Effect size r = 0.25
36
Effect size r = 0.3136
Proportion AIUI: 0.35 95%CI
(0.19-0.55)35
Association found other
No relation
No relation
No relation29
Adjusted for GA not
significant29
No relation
No relation
No relation
No relation
No relation
No relation26,40
No relation40
No relation
32,30
No relation32
No relation
26,32
No relation32
No relation
No association found
Stage AIUI
Adjusted for GA no relation
Stage AIUI
Adjusted for GA no relation [37]
Significant less than control group
Stage AIUI
Proportion AIUI
In combination with microorganisms [39]
Unadjusted GA ns
EOS + LOS + nosocomial infection
Apgar 1 + 5 minutes, asphyxia.
Remarks
[32,33]
[27]
[32]
[32]
[32]
FTV
FTV
FTV
[38]
FTV
FTV
[35]
FTV
FTV
[34]
[34]
[34]
FTV
Fetal thrombotic vasculopathy
FTV
FTV
[22]
[22]
MVU
[22]
[26,40]
MVU
MVU
[26,32,40]
MVU
MVU
[26,32]
MVU
[22]
[25,26,32,40]
MVU
MVU
[26,32,40]
MVU
Placental infarction /abruption
[26]
[26,32]
MVU
[38]
MVU
Maternal vascular
underperfusion
[29, 30]
MVU
[29]
[29]
AIUI
Fetal response
AIUI
AIUI
38
BPD
RDS
Nosocomial infection
Fetal thrombophilia
NEC
Illness severity first 24h
Asphyxia
CNS abnormalities
Fetal cardiac abnormalities
NRFHT
Anomalies*
Neonatal infection
Low Apgar score 1 min
Liver disorders
ROP
PDA
RDS
BPD
NEC
Neonatal infection
Low Apgar score 1 min
Illness severity first 24h
IVH
BPD
RDS
OR 4.34-9.10 (1.80-15.08)
OR 8.02 (3.02-21.26)
OR 3.01 (1.54-5.78)
OR 2.2 (1.2-4.2)
OR 4 (1.7-9.2)
OR 1.4-1.7 (1.02-2.5)
OR 1.95 (1.01-4.21)
Median scores illness severity
significantly ↑
Proportion: 0.26 95% CI (0.130.46)
Proportion 0.47 95% CI (0.400.55)
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation 32,40
No relation
No relation
No relation29
Higher illness severity
Proportion FTV
Only with abruption
Apgar <7 (1 + 5 min)
Significant less than control group
Chronic deciduitis
[30,32]
[30]
Deciduitis
Deciduitis
[36]
[36]
Marker
[38]
Elevated NRBCs
Marker
Marker
[31]
Overcoiling umbilical cord
UC
[36]
[31]
Marker
[24]
Undercoiling umbilical cord
UC
[24]
UC
UC
[24]
[24]
UC
[24]
UC
Excessively long umbilical cord
[30,32]
Deciduitis
UC
[32]
Deciduitis
[35]
[25,30,32]
Deciduitis
Umbilical cord lesions
[32]
Deciduitis
UC
[32]
Deciduitis
[38]
[22]
VUE
Deciduitis
[22]
[22]
VUE
VUE
[38]
VUE
[22]
[32]
Villitis of unknown etiology
FTV
VUE
[32]
FTV
39
ROP
PDA
LOS
Illness severity
Asphyxia
Low Apgar 5 min
Respiratory distress
Fetal anomalies
NRFHS
Apgar 5 min
Apgar 1 min
Asphyxia
ROP
IVH
PDA
NEC
BPD
RDS
Nosocomial infection
Illness severity first 24h
Anomalies*
Liver disorders
Neonatal infection
Illness severity first 24h
Low Apgar score 1 min
IVH
PDA
OR 4.16 (1.30-13.36)
OR 3.14 (1.47-6.70)
OR 2.86 (1.09-8.17)
OR 13.10 (1.95-256.26)
OR 4.91 (1.71-15.91)
OR 2.3 (1.1-5.1)
Median scores illness severity
significantly ↑
Effect size r = - 0.07
Effect size r = - 0.09
Proportion UC: 0.39 95% CI
(0.22-0.59)
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
Higher illness severity
Lower Apgar scores
Lower Apgar scores
Less in control group
[32]
Other
[22]
[22]
Other
Other
[26]
[26]
[26]
[26]
[26]
[26]
Other
Other
Other
Other
Other
Other
[26]
[32]
Other
Coagulation related lesions
[32]
Other
Other
[32]
Other
[35]
[32]
Other
Chorionic plate meconium
[32]
Other
Other
[22,32]
Other
[22]
[32]
Other
Meconium staining
[32]
Other
Other
[32]
Other
[32]
[22]
Marker
Villus edema
[22]
Marker
Other
[22]
Marker
[22]
[38]
Chorangiosis
[36]
Marker
Marker
Marker
40
EOS
ROP
IVH
BPD
RDS
Low Apgar score
NEC
Asphyxia
Anomalies
Liver disorders
IVH
PDA
NEC
BPD
RDS
Neonatal infection
Low Apgar score 1 min
PDA
NEC
RDS
Nosocomial infection
BPD
Anomalies*
Liver disorders
Neonatal infection
Illness severity first 24h
Low Apgar score 1 min
IVH
OR 2.6 (1.13-6.00)
Proportion
OR 0.18 (0.05-0.68)
OR 1.46 (1.04-2.05)
0.30 95% CI (0.16-0.51)
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
No relation
Apgar 1 - 5 minutes
[22]
Other
Anomalies*
Liver disorders
Low Apgar score 1 min
Neonatal infection
PDA
OR 0.54 (0.35-0.84)
No relation
No relation
No relation
No relation
unknown etiology; UC - umbilical cord; NRBCs - elevated nucleated red blood cells.
Abbreviations placental lesions: AIUI - ascending intrauterine infection; MVU - maternal vascular underperfusion; FTV - fetal thrombotic vasculopathy; VUE - villitis of
NRFHS - non-reassuring fetal heart status
- patent duct arteriosus; ROP - retinopathy of prematurity; NEC - necrotizing enterocolitis; NRFHT - non-reassuring fetal heart tracing; CNS - central nervous system;
Abbreviations: EOS - early onset sepsis; LOS - late onset sepsis; RDS - respiratory distress syndrome; BPD - bronchopulmonary dysplasia; GA - gestational age; PDA
* Anomalies: notations of dysmorphia, hydrocephalus, Down syndrome.
[22]
Other
[22]
[22]
Placental ischemic changes
[26]
Other
Other
Other
41
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
Placental lesions and neurological morbidity
Many prospective and retrospective studies have been conducted on placental lesions and
neurological morbidity (Table 7). Some of the studies focused on early brain development,
while others focused on neurological and functional outcome as determined by follow-up
testing. However, it is difficult to conduct correlative studies between placenta lesions
and neurologic or psychiatric outcomes in the child.90 Neurological outcomes are not
evident immediately after birth, but only long after most placentas have been discarded.
Placentas, especially those of term infants, are not routinely sent to the pathologist for
examination.55,90 Unless studied prospectively, infants whose placentas are examined,
form a biased group.90
It is thought that the pathogenesis of neurological impairment has an antenatal as well
as an intra-partum component. An event weeks before delivery can result in a non-optimal
fetal environment. This might result in lowering the threshold required for more recent
events to cause brain injury. Placental lesions can be such an antenatal event.41,42,45
Regarding short-term neurological outcome of preterm infants in particular, most studies
focused on white matter diseases (periventricular leukomalacia, PVL) and intraventricular
hemorrhages (IVH). The results are inconsistent as far as the relation between these short
term neurological outcomes and placental lesions is concerned. Several studies did find
a relation between IVH and histological ascending intrauterine infection (maternal and
fetal response) with ORs ranging from 1.7 to 2.2 (95% CI 1.01-23).26,30,32,36,47 In addition,
the severity of ascending intrauterine infection is significantly higher among infants with
IVH.37 After adjusting for gestational age, however, the severity of ascending intrauterine
infection did not seem to affect the occurrence of IVH. Others were not able to find a
relation between IVH and AIUI.29,40 There are no indications that other placental lesions are
associated with IVH.
Regarding white matter injury, several studies failed to find a relation with histological
AIUI (maternal and fetal response).43,51 Nevertheless, in a meta-analysis, ascending
intrauterine infection (clinical and histological) was indicated as a risk factor for white
matter injury in preterm infants, with a relative risk of approximately 2.1.91 The authors
hypothesized that elevated cytokine levels play a role in the etiology of white matter brain
lesions. The reason for the inconsistency of the results may be ascribed to differences
in adjusting for potential confounders. Wu et al.91 explained the effect of adjusting for
gestational age. Although gestational age appears to be a possible confounder, it may
also lie directly in the causal pathway between maternal infection and cerebral palsy (CP).
Chorioamnionitis is associated with preterm delivery, and low gestational age is in turn
associated with a host of intrinsic vulnerabilities within the brain that have been implicated
in the pathogenesis of cystic PVL and CP. Therefore, if low gestational age resulting from
maternal infection in itself plays a direct role in the pathogenesis of CP, then adjusting
for its effect will falsely diminish the observed association between chorioamnionitis and
CP.91
Neonatal encephalopathy has mainly an antepartum, rather than an intrapartum,
2
42
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
etiology. An important antepartum factor is placental pathology.45,58 Placental lesions
consistent with fetal thrombotic vasculopathy (OR 4.63, 95% CI: 2.01-10.68) and AIUI
with a fetal response (funisitis) (OR 22.54 95% CI: 11.07-45.91) are both associated
with neonatal encephalopathy.45,58 Another less strongly associated placental lesion is
accelerated villous maturation (disturbed uteroplacental flow) with an OR of 3.86 (95% CI:
1.36-10.92).45
Elbers et el. studied placental pathology in relation to neonatal stroke.53 They
systematically described their findings in twelve cases of neonatal stroke, ten of which
had placental lesions. They found the following types of lesions: thromboinflammatory
process in six cases, sudden catastrophic event in five cases, decreased placental reserve
in three cases, and stressful intrauterine environment in two cases. They suggested that
multiple risk factors are involved in neonatal stroke, and that placental pathology may be
a contributing factor.53
The Extremely Low Gestational Age Newborns (ELGAN) investigators studied the
predictive value of placental pathology in regard to white matter damage and later CP.
They found histologic inflammation to be predictive of ventriculomegaly and diplegic CP,
with ORs ranging from 1.4 to 1.5 (95% CI: 1.0-2.4) and ORs 2.3-3.4 (95% CI: 1.1-7.4),
respectively. Placental inflammation was not predictive for echolucent lesions.52 Also
fetal thrombotic vasculopathy is found to be associated with CP. In the presence of FTV
and CP, obstructive umbilical cord abnormalities have been identified. These umbilical
cord abnormalities can lead to fetal placental vascular stasis resulting in fetal thrombotic
vasculopathy.42,46,92 Macroscopic examination of the placenta can also identify an increased
risk of CP. Placental infarction thus identified is associated with an increased risk of the
spastic quadriplegic subtype of CP (OR 2.6, 95% CI: 1.2-5.6).56 The pathophysiological
mechanism of placental infarction leading to CP is not clear. It is stated that because of the
many functions and substantial functional reserve of the placenta, it cannot be assumed
that placental infarction acts mainly by interference with gas exchange. A hypothesis is
that, whatever the underlying process that harmed the vasculature of the placenta causing
infarction, the same process may also have directly harmed either the fetal cerebral
vasculature or the brain.56
Results on the association between placental pathology and long-term neurological
outcome, including developmental tests and functional outcome, are also inconsistent
between studies. In preterm infants it is thought that neurological impairment is associated
with recent non-occlusive thrombi of the chorionic plate vessels in combination with
chorioamnionitis and severe villous edema. Chorioamnionitis alone is not associated with
neurological impairment.41 This was attributed to the strong and consistent relationship
between neurologic impairment and chorionic plate thrombi that occur only in placentas with
chorioamnionitis.41 Placental pathology consistent with maternal vascular underperfusion
was also found to be a risk factor for neurological impairment, with ORs ranging from 7.4
to 10.1 (95% CI: 1.6-46.3).48
For term infants, Redline et al. reported an association between neurological
2
43
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
impairment and ascending intrauterine infection with a fetal response (OR 2.9-13.2, 95%
CI: 1.2-144).42,46 In addition to AIUI with a fetal response, they found that the following
lesions are present significantly more often in placentas of infants with neurological
impairment: meconium associated vascular necrosis, chorionic vessel thrombi, increased
nucleated red blood cells (sign of fetal hypoxia), findings consistent with abruption placenta,
diffuse chronic villitis, extensive avascular villi, diffuse chorioamnionic hemosiderosis, and
perivillous fibrin.42
Neurodevelopmental outcome of preterm-born children at toddler age is also associated
with ascending intrauterine infection with a fetal response (funisitis). In the presence of
funisitis, a higher incidence of moderate to severe disability is present with an OR of 4.08
(95% CI: 1.16-14.44).54 In addition, speech abnormalities and hearing loss are associated
with AIUI (ORs 2.9-5.1, 95% CI: 1.2-19.4 and OR 11.6, 95% CI: 1.3-105.9, respectively. A
study comparing neurodevelopmental outcome at two years of age between very preterm
infants with maternal vascular underperfusion and very preterm infants with histological
chorioamnionitis found poorer mental development in infants with maternal vascular
underperfusion compared to infants with chorioamnionitis.57
Neurocognitive outcome of preterm-born children at school age is associated with
villous edema (OR 4.7, 95% CI: 1.1-19.2). Lower scores on mental processing and on
neuropsychological assessment are found in its presence. In this study, ascending
intrauterine infection is not predictive of impaired neurodevelopmental outcome in
the population as a whole, but a severe funisitis is associated with lower scores on
neurocognitive tests in the subpopulations with ascending intrauterine infection.48
In summary, despite the difficulties in studying the relation between placental lesions
and neurological morbidity, and the inconsistent results, some conclusions can be drawn.
For those studies finding a relation with poor neurological outcome, the placental lesion
is ascending intrauterine infection with a fetal response. Furthermore, in term infants a
larger variety of placental lesions seem to be associated with poor neurological outcome
compared to preterm infants. Knowledge on the pathophysiological mechanisms leading
to long-term neurological deficits may lead to possible interventions to improve outcome.
The fact that the placenta is available for histological examination immediately after birth
and that it may reveal valuable information for pediatricians, leads to an early opportunity
to intervene to the benefit, hopefully, of ill neonates.
2
44
Not specified
AIUI
Fetal response
[51]
[52]
AIUI
AIUI
[29,30,54]
[54]
[48]
AIUI
AIUI
AIUI
[54]
[54]
AIUI
AIUI
[41]
[49]
AIUI
[54]
[45,58]
AIUI
AIUI
[48,52,54]
AIUI
AIUI
[52]
AIUI
[29,54]
[50]
AIUI
AIUI
[50]
[50]
AIUI
[47]
AIUI
AIUI
[43]
[55]
AIUI
AIUI
Maternal response
[26,32,36,40,47]
Maternal + fetal response
AIUI
[51]
Ref.
Placental lesion specified
Placental
lesion
Ventriculomegaly
WMI
IVH
Neurocognitive function
Hearing loss
Speech abnormalities
Any grade disability
Motor abnormalities
Neurolic impairment
Brain lesions
Neonatal encephalopathy
CP
Ventriculomegaly
IVH
Motor development
Hearing loss
Speech abnormalities
Neurodevelopment
Neuronal karyorrhexis or white
matter gliosis
Ultrasound abnormalities
WMI
IVH
Outcome measure
Table 7: Results of selected studies on neurological outcome
45
OR 2.0-2.3 (1.0-5.5)
OR 3.68 (0.95-14.28)
OR 2.02 (1.16-3.74)
OR 2.3-3.4 (1.1-7.4)
OR 1.4-1.5 (1.01-2.4)
OR 2.4 (1.0-5.6)
OR 11.6 (1.3-105.9)
OR: 5.1 (1.35-19.4)
OR 1.7-3.5 (1.2-23)
Associations found OR (95% CI)
RRR 3.3 (1.1-10.4)58
No data (p < 0.05)
r* = 0.7136
Association found other
29
No relation
No relation
No relation29
No relation
No relation
No relation
No relation
No relation
No relation
No relation 48,54
No relation
No relation
No relation
No relation
No relation
No relation40
No association found
OR 1.4 (0.9-2.2)52
Adjusted for GA not significant54
ELBWI follow-up 8y
24months
24months
24months
24m Bayley-II or Brunet-Lezine scale
VLBWI
IVH, cPVL, ventriculomegaly
Adjusted for confounders not
significant45
Adjusted for GA not significant54
18months
18months
18months
Age: 12-24m BSID-II
Neuropathology in stillbirths
IVH, PVL, infarction
Stage/grade AIUI also not associated
WMI
Remarks
Maternal vascular
underperfusion
[42,46]
[41,42,46]
FTV
VUE
[48,52]
FTV
VUE
[52]
[43]
FTV
FTV
[56]
[48,57]
MVU
[32]
[57]
MVU
Macroscopic placental infarct
[48,52]
MVU
FTV
[41]
MVU
MVU
[53]
MVU
FTV
[52]
[45]
MVU
MVU
[26,32,40]
[54]
[48]
AIUI
AIUI
MVU
[54]
[49]
AIUI
[54]
[45,58]
AIUI
AIUI
[41,42,46]
AIUI
AIUI
[48,52,54]
AIUI
46
Neurologic impairment
Neurologic impairment
CP
Ultrasound abnormalities
Ventriculomegaly
IVH
CP
Neurodevelopment 7/8y
Neurodevelopment 2y Bayley-II
MDI + PDI
CP
Neurologic impairment
Neonatal stroke
Neonatal encephalopathy
Ventriculomegaly
IVH
Neurocognitive function
Hearing loss
Speech abnormalities
Moderate to severe disability
Brain lesions
Neonatal encephalopathy
Neurologic impairment
CP
OR 4.1-7.4 (1.3-17.9)
OR 3.7-9.2 (1.0-51)
OR 5.41 (1.42-20.54)
OR 2.1 (1.2-3.9)
OR 2.6 (1.23-5.57)
OR 7.4-10.1 (1.6-46.3)
OR 3.86 (1.36-10.92)
OR 0.5 (0.3-0.96)
OR 2.89 (1.19-7.04)
OR 4.08 (1.16-14.44)
OR 2.46 (1.13-5.41)
OR 22.54 (11.07-45.91)
OR 2.9-13.2 (1.2-144)
OR 4.32 (0.91-20.44)
Cohen’s d: 1.12 MDI
Proportion 0.25 (0.09-0.53)
RRR 20.7-34.6 (1.8-232.9)58
52
Adjusted for GA not
significant42
No relation
No relation
No relation
PDI no relation
No relation
No relation
No relation
No relation
No relation
Adjusted for GA not
significant
No relation
41
No relation48,52
With oblirative fetal vasculopathy46
Only chorionic plate thrombi41
OR 1.9 (0.8-4.3)52
IVH, PVL, infarction
WISC, MABC, CBCL compared to AIUI
Lower MDI scores compared to AIUI
OR 1.5 (0.3-6.6)52
VLBWI
3 placentas of 12 infants with
neonatal stroke
ELBWI follow-up 8y
24months
24months
24months
IVH, cPVL, ventriculomegaly
OR 1.7 (0.8-3.7)52
[48]
[42,46]
[58]
[42]
Meconium-associated
vascular necrosis
Meconium phagocytosis
Chorioamnionic
hemosiderosis
Other
Other
Other
[55]
[32]
Meconium staining
Other
Other
[30,32]
[26]
Coagulation related lesions
Other
Other
[45]
[55]
Other
Other
[41]
Villus edema
Other
Other
[53]
Stressful intrauterine
environment
Marker
[42]
Marker
[36]
[55]
Elevated NRBCs
Marker
Marker
[44]
[44]
MFI
MFI
[32]
[43,44]
Deciduitis
Maternal floor infarction
MFI
Neurologic impairment
Neontal encephalopathy
Neurologic impairment
Gliosis
IVH
IVH
IVH
Neuronal karyorrhexis
Neonatal encephalopathy
Neurologic impairment
Neurocognitive function
Neonatal stroke
Neurologic impairment
Neuronal karyorrhexis or white
matter gliosis
IVH
Neurodevelopment
WMI
Ultrasound abnormalities
IVH
Neuronal karyorrhexis or white
matter gliosis
[55]
Deciduitis
Ultrasound abnormalities
[43]
VUE
Neonatal encephalopathy
[45,58]
VUE
47
OR 74.8 (6.3-894)
OR 4.8-8.2 (2.0-29.0)
OR 2.57-2.19 (1.01-6.58)
OR 4.63 (2.01-10.68)
OR 5.7 (1.5-21.0)
OR 4.7 (1.1-19.2)
OR 22.3 (11-46)
OR 14 (2-163)
OR 3.7 (1.1-12.7)
OR 2.11 (1.16-3.83
RRR 7.2-9.8 (2.3-42.4)
No data (p < .05).
No data (p < 0.05)
Proportion 0.17 (0.05-0.45)
RRR 17.7 (5.0-60.8)58
Adjusted for GA not
significant42
No relation
No relation
Adjusted for GA not
significant
No relation
No relation
No relation
No relation
No relation
No relation
Neuropathology in stillbirths
Neuropathology in stillbirths
ELBWI follow-up 8y
1 case ↑NRBCs and 1 case
chorangiosis
Neuropathology in stillbirths
Age:22-29months
IVH, PVL, infarction
Neuropathology in stillbirths
IVH, PVL, infarction
Adjusted for confounders not
significant45
[53]
Thrombo-inflammatory
process
Other
Neonatal stroke
Neonatal stroke
Proportion 0.5 (0.25-0.75)
Proportion 0.42 (0.19-0.68)
Acute chorioamnionitis, chronic
villitis, chorionic vessel thrombi,
avascular villi
Retroplacental hematoma and
umbilical cord occlusion
unknown etiology; MFI - maternal floor infarction; NRBCs - nucleated red blood cells
Abbreviations placental lesions: AIUI - ascending intrauterine infection; MVU - maternal vascular underperfusion; FTV - fetal thrombotic vasculopathy; VUE - villitis of
children; CBCL - Children Behavior Checklist.
- mental development index; PDI - psychomotor development index; WISC - Wechsler Intelligence Scale for Children; MABC - movement assessment battery for
gestational age; CP - cerebral palsy; cPVL – cystic periventricular leukomalacia; ELBWI - extremely low birth weight infant; VLBWI - very low birth weight infant; MDI
Abbreviations: IVH- intraventricular hemorrhage; WMI - white matter injury; PVL - periventricular leukomalacia; BSID - Bayley scales of infant development; GA -
* r = effect size
[53]
Sudden catastrophic event
Other
48
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
Discussion / Conclusion
The placenta plays a key role in fetal and neonatal mortality, morbidity, and outcome.
Placental lesions are one of the main contributors to fetal death. In these cases placental
lesions consistent with maternal vascular underperfusion are most important. Although
less clear-cut, several neonatal problems are also associated with placental lesions.
Regarding neonatal morbidity and neurological outcome, placental lesions with ascending
intrauterine infection (with a fetal component) and fetal thrombotic vasculopathy, constitute
the greatest problem.
To our surprise we noticed a difference in the description of placental lesions between
studies on perinatal death and studies on neonatal outcome. The majority of studies on
placental pathology and stillbirth only focus on the presence or absence of placental
lesions in general, but they do not examine the relation between specific placental lesions
and stillbirth. Studies concerning placental lesions and neonatal or neurological outcome
do specify the lesions, finding several relations between specific placental lesions and
outcome. Characterizing placental lesions in more detail in stillbirth studies may provide
additional information concerning the cause of death.
Most studies report on associations between placental lesions and outcomes but this
does not necessarily reflect a causal relation. There is still need to clarify pathophysiological
mechanisms. One of these proposed mechanisms include gene-environment interactions.
[92] Placental lesions might already have their onset early in pregnancy, due to changes in
placental genes, leading to epigenetic alterations. Causes for these placental epigenetic
changes may include a non optimal intrauterine environment, due to a maternal disease
or adverse insults to the intrauterine environment.93 This may in turn cause placental
dysfunction and hence adverse neonatal outcome. We thus have to take into account that
multiple interactions from maternal, placental, and fetal health play a role in the etiology
of perinatal death and neonatal morbidity. Future research must consider statistical tools
to better address interactions among these multiple variables, such as a mixed-effect
regression analyses for example.
There are several limitations to our systematic review. Firstly, there is a potential risk of
publication bias. Studies finding negative results regarding placental lesions and outcome
might not be published. This may lead to an overestimation of associations between
placental lesions and outcomes. Secondly, we included studies from the past 18 years.
Earlier studies might have had different results. Finally, most studies included in this review
were conducted in high-risk populations. Studies in a low- or moderate-risk group may
reveal different results.
A final point we would like to address is an urgent need for increasing awareness
among pediatricians for placental lesions and neonatal outcome. The obstetrician sends
the placenta to the pathologist for histological examination. The results of the examination
are reported back to the obstetrician. In most cases the pediatrician is unaware of the
results of the placental examination. In the light of the accumulating evidence, however,
that placental pathology is associated with perinatal mortality, neonatal morbidity, and
2
49
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
neurological outcome, pediatricians should make an effort to obtain the results of placental
examinations. Placental pathology, ascending intrauterine infection and fetal thrombotic
vasculopathy in particular, may help to identify the group of neonates at risk of adverse
neonatal outcome. Monitoring these infants more closely could be helpful. Knowledge
of the pathophysiological mechanisms leading to neonatal mortality and morbidity may
lead the way to finding early intervention strategies to improve infants’ morbidity and
outcome.
2
Acknowledgments
We thank Dr. Titia Brantsma - van Wulfften Palthe for correcting and editing the English
manuscript. Annemiek Roescher received financial support from the Junior Scientific
Master Class of the University of Groningen.
50
Placental Pathology, Perinatal Death, Neonatal Outcome,
and Neurological Development: A Systematic Review
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2
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58
Part II
Placental Lesions and Short -Term Outcome
Chapter 3: Placental pathology is associated with illness severity in preterm
infants in the first twenty-four hours after birth
Chapter 4: Placental pathology and neurological morbidity in preterm infants
during the first two weeks after birth
59
General introduction and outline of the thesis
1
60
3
General introduction and outline of the thesis
Chapter 3
1
Placental pathology is associated with illness severity in preterm
infants in the first twenty-four hours after birth
Annemiek M Roescher
Marrit M Hitzert
Albert Timmer
Elise A Verhagen
Jan Jaap HM Erwich
Arend F Bos
Early Human Development 2011:87:315-319
61
Abstract:
Background: Placental pathology is associated with long-term neurological morbidity.
Little is known about the association of placental pathology and illness severity directly
after birth in preterm infants.
Objective: To determine the association between placental pathology and illness severity
in preterm infants during the first 24 hours after birth.
Study design: Placentas of 40 preterm infants, born after singleton pregnancies (gestational
age 25.4-31.7 weeks, birth weight 560-2250 grams) were assessed for histopathology.
Illness severity was measured using the Score of Neonatal Acute Physiology Perinatal
Extension (SNAPPE). A high SNAPPE reflects high illness severity.
Results: Examination of the 40 placentas revealed: pathology consistent with maternal
vascular underperfusion (MVU) (n=24), ascending intrauterine infection (AIUI) (n=17), villitis
of unknown aetiology (VUE) (n=6), foetal thrombotic vasculopathy (FTV) (n=6), elevated
nucleated red blood cells (NRBCs) (n=6), and chronic deciduitis (n=10). SNAPPE ranged
from 1 to 53 (median 10). Infants with elevated NRBCs had a higher SNAPPE than infants
without elevated NRBCs (median 30 vs. 10, P=0.014). The same was found for the presence
of FTV (median 30 vs. 10, P=0.019). No relation existed between SNAPPE and the other
placental pathologies.
Conclusions: Elevated NRBCs and FTV were associated with higher illness severity during
the first 24 hours after birth in preterm infants. Ascending intrauterine infection was not
associated with high illness severity.
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
Introduction
In industrialised countries, preterm birth is responsible for 75 percent of neonatal morbidity
and contributes to long-term neurodevelopmental problems.1 Placental pathology
may act as a causative factor in preterm birth. The placenta plays a crucial role during
pregnancy, with major implications for the child if its function is impaired. Previous studies
in term infants suggested that several placental lesions are associated with long-term
neurological morbidity.2,3 These lesions include ascending intrauterine infection, chronic
villitis of unknown aetiology, meconium associated vascular necrosis, foetal thrombotic
vasculopathy, and the appearance of elevated nucleated red blood cells.2,3 Recently,
placental pathology was also reported as being the main cause of foetal death.4 The most
common cause of foetal death in the preterm period is maternal hypoperfusion of the
placenta in a pregnancy complicated by hypertensive disorders. In the term period, foetal
death is mainly caused by developmental pathology of placenta parenchyma.4
In the case of preterm infants little is known about the effect of placental pathology on
neonatal morbidity. The question arises whether the same lesions that are associated with
long-term neurological morbidity in term infants are also associated with early morbidity
in preterm infants. If these lesions are associated with early morbidity, the mechanisms
leading to neonatal morbidity may become clear. One way of assessing early morbidity
is to determine illness severity soon after birth by scoring several clinical variables. A
reliable instrument to measure illness severity in the first 24 hours after birth is the Score
of Neonatal Acute Physiology Perinatal Extension (SNAPPE).5 The scores obtained are
associated with both mortality and morbidity.
Our objective was to determine whether placental pathology was associated with
illness severity during the first 24 hours after birth in preterm infants born at < 32 weeks of
gestational age. We hypothesised that in the presence of placental lesions preterm infants
will be more severely ill and physiologically unstable during the first 24 hours after birth.
3
Materials and Methods
Patient population
We carried out a cohort study of 44 preterm, singleton infants. All infants had been admitted
to the NICU of the University Medical Center Groningen. The inclusion criterion was a
gestational age of less than 32 weeks. Exclusion criteria were major chromosomal and
congenital abnormalities. We also excluded infants whose placentas were not available for
pathological examination (n=4). Our final study group consisted of 40 preterm singleton
infants.
Placental pathology
The placentas were examined by a perinatal pathologist (AT) in accordance with the
guidelines published by the Royal College of Obstetricians and Gynaecologists and the
Royal College of Pathologists, and the College of American Pathologists.6,7 We included
63
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
and graded all placental lesions for which an association with neurological impairment
had been suggested previously.2,3 These lesions are placental pathology consistent
with maternal vascular underperfusion (MVU),8 ascending intrauterine infection (AIUI),9
chronic villitis of unknown origin (VUE),10 chronic deciduitis,11 perivillous fibrinoid,12 foetal
thrombotic vasculopathy (FTV),13 meconium associated vascular necrosis,14 chorioamniotic
hemosiderosis,15 increased nucleated red blood cells (NRBCs),2 chorangiosis,16 and
umbilical cord abnormalities.17 We also recorded placental weight, cord length, and coiling
index.
3
Score of Neonatal Acute Physiology Perinatal Extension
To assess the illness severity of the infants during the first 24 hours after birth, we determined
the Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE) from the medical
records and nursing files. SNAPPE consists of 31 clinical and physiological variables, such
as blood pressure, pCO2, temperature, oxygen saturation, Apgar score, and the presence
of apnoea. The most abnormal value of each item during the first 24 hours after birth was
used in the calculation. SNAPPE may range from 0 to 184, a higher SNAPPE reflects higher
illness severiy. SNAPPE is associated with both neonatal morbidity and mortality.5,18
Statistical analysis
SPSS 16.0 software for Windows (SPSS Inc Chicago, IL) was used for the statistical
analyses. To test the associations between placental pathology and SNAPPE, we used the
Mann-Whitney U test for categorical placental pathologies and Spearman’s rho correlation
test for ordinal or continuous variables reflecting placental pathologic measures. For further
analysis, we used a multivariate regression model to test the independent associations
of SNAPPE with the various individual placental pathologies. We used the logarithm of
SNAPPE in this model to meet the conditions of multivariate regression. A P-value of < .05
was considered statistically significant.
Results
Patient characteristics
The patient characteristics are presented in Table 1. Placental characteristics such as
placental weight and umbilical cord length were also included. None of the infants died
within the first 24 hours after birth, however 4 infants died between 6 and 19 days after
birth. Three infants died of respiratory and circulatoiry insufficiency due to sepsis and 1
infant died of gastrointestinal perforation.
64
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
Table 1. Patient characteristics. Data are given as median (range) or numbers.
Study population
40
Gestational age, weteks
29.9 (25.4 – 31.7)
Birth weight, grams
1243 (560 – 2250)
Male/female
20/20
Intracranial haemorrhage (Grade 1-2)
7
Intracranial haemorrhage (Grade 3-4)
2
3
Cause of preterm birth
Preterm due to maternal or foetal reasons (e.g. foetal distress)
16
Spontaneous preterm birth
17
- Preterm due to premature rupturing of
the membranes (PPROM)
7
Caesarean section
22
Placental weight, grams
260.5 (99 – 470)
Cord length, centimeter
28 (15 – 59)
Placental pathology
The distribution of placental pathologies is presented in Figure 1. Only 3 out of the 40
placentas showed no pathology. The largest group of 24 placentas consisted of pathologies
consistent with MVU, followed by 17 placentas with signs of AIUI. The occurrence of
placental pathologies categorised by gestational age and birth weight is presented in table
2. There was no significant association between placental pathologies and gestational age.
A lower birth weight was associated with higher occurrence of NRBCs and FTV (MannWhitney U P<.05).
Twenty-four placentas showed more than one category of placental histopathology.
The most common combinations were placental pathology consistent with MVU plus
elevated NRBCs (n=5) and MVU plus AIUI (n=5). We found no meconium associated
vascular necrosis or complications of the umbilical cord in our group.
65
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
Table 2. Presence of placental pathology specified by gestational age and birth weight.
Placental lesions
MVU (n=24)
AIUI (n=16)
Chronic deciduitis (n=10)
Chronic villitis (n=6)
FTV (n=6)
↑NRBCs (n=6)
Chorangiosis (n=3)
Perivillous fibrinoid (n=1)
Chorioamniotic hemosiderosis (n=1)
3
<28 wk
≥28 wk
<750 gr
750 gr – 1 kg
>1 kg
n=9
n=31
n=4
n=4
n=32
4
5
1
1
1
2
1
0
1
20
11
9
5
5
4
2
1
0
4
0
1
2
2
3
2
1
0
3
1
1
0
2
2
0
0
1
17
15
8
4
2
1
1
0
0
Abbreviations : MVU - maternal vascular underperfusion; AIUI - ascending intrauterine
infection; FTV - foetal thrombotic vasculopathy; NRBCs - nucleated red blood cells.
The distribution of placental lesions specified by gestational age (<28 weeks and ≥28 weeks) and
by birth weight (<750 grams, between 750 and 1000 grams and >1 kilo). The numbers exeed 100%,
Meconium associated
vascular necrosis
Umbilical cord
abnormalities
Chorioamniotic hemosiderosis
Placental lesions
Perivillous fibrinoid
Chorangiosis
FTV
NRBC
Chronic villitis
Chronic deciduitis
AIUI
MVU
Count
because a single placenta can have more than one lesions.
Figure 1. The distribution of placental lesions in our study group.
A single placenta can have more than one lesion.
Abbreviations: MVU, maternal vascular underperfusion; AIUI, ascending intrauterine infection; FTV,
foetal thrombotic vasculopathy; NRBCs, nucleated red blood cells.
66
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
Placental pathology and SNAPPE
SNAPPE ranged from 1 to 53 (median 10). The number of placental lesions did not correlate
with SNAPPE (Figure 2). Regarding specific pathologies, SNAPPE was significantly higher
in the presence of FTV, elevated NRBCs, and if maternal vascular underperfusion coexisted with elevated NRBCs. In the presence of these three pathological categories, the
respective median SNAPPE was 20, 20, and 25 points higher (Mann-Whitney U, P<.05)
(Figure 3).
Furthermore, a higher SNAPPE correlated with the coiling index of the umbilical cord
(median 0.29, range 0.06 – 0.57) with Spearman’s rho =.359 (P =.029).
Regarding placental pathology consistent with MVU in the absence of elevated
NRBCs, no association with SNAPPE was found. Infants with this type of pathology (n=24)
had a median SNAPPE of 10, while those without (n=16) had a median SNAPPE of 10.5.
Placental signs of AIUI did not affect SNAPPE either, not even when we subdivided the
infants whose placentas showed AIUI into a maternal and a foetal response. The same held
true for chronic, predominantly low-graded villitis, chronic deciduitis, perivillous fibrinoid,
chorioamniotic haemosiderosis, cord length, and placental weight.
SNAPPE
3
Number of placental lesions per infant
Figure 2. The number of placental lesions in relation to SNAPPE.
Three placentas showed no lesions. The maximum number of lesions in our group was six. There
was no significant correlation between number of placental lesions and SNAPPE.
Abbreviations: SNAPPE – Score of Neonatal Acute Physiology Perinatal Extension.
67
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
MVU
AIUI
3
Chronic
deciduitis
Elevated
NRBCs
FTV
Chronic
villitis
0
10
20
SNAPPE
30
40
50
60
24
16
*
17
23
10
30
6
*
34
6
*
34
*=p<.05
6
34
0
10
20
30
40
SNAPPE
50
60
Figure 3. Single placental pathological entities and distributon of SNAPPE.
The data in the graphs are presented as box-and-whisker plots. Boxes represent the individual
values between the 25th and 75th centiles (interquartile range, IQR); whiskers represent the range
of the values, with the exception of outliers. Outliers are the circles, defined as values between 1.5
IQRs and 3 IQRs from the end of a box. The numbers on the Y-axis signify numbers of infants
with the particular placental pathology (grey bars) and without the particular placental pathology
(white bars).
Abbreviations: FTV - foetal thrombotic vasculopathy; NRBCs - nucleated red blood cells; MVU
- maternal vascular underperfusion; AIUI - ascending intrauterine infection; SNAPPE – Score of
Neonatal Acute Physiology Perinatal Extention.
Because the associations of the various individual placental pathologies with SNAPPE
may be interdependent, we used multivariate linear regression, applying the transformed
logarithm of SNAPPE. In the multivariate model we entered pathological placental entities,
including combinations, that occurred five times or more in our cohort. These were MVU,
AIUI, chronic deciduitis, FTV, elevated NBRCs, VUE, MVU plus elevated NRBCs, and finally
MVU plus AIUI. Together they explained 25.0 percent of the variance of illness severity.
Following backward multivariate linear regression, only elevated NRBCs remained in the
model explaining 14.9 percent of the variance of SNAPPE (Table 3).
68
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
Table 3. Backward, multivariate linear regression: SNAPPE*.
Constant
Elevated NRBCs
B
2.130
1.098
95% CI
1.786 – 2.474
0.210 – 1.987
t
12.540
2.504
p
0.000
0.017
Abbreviations: NRBCs - nucleated red blood cells; CI - confidence interval; SNAPPE - score of
3
neonatal acute physiology perinatal extension.
Multivariate analysis using backward linear regression of placental pathology for SNAPPE.
N = 40, r2 = 0.149.
*
transformation SNAPPE into: log(SNAPPE)
Discussion
This study indicated that several placental lesions were associated with higher illness
severity of preterm infants during the first 24 hours after birth. These lesions included
elevated nucleated red blood cells, foetal thrombotic vasculopathy, placental pathology
consistent with maternal vascular underperfusion plus elevated nucleated red blood cells,
and a high coiling index of the umbilical cord. Other lesions, such as ascending intrauterine
infection, were not related to illness severity during the first 24 hours after birth. Our
hypothesis was therefore confirmed for some, but not all, lesions.
The strongest association existed with elevated NRBCs in the placenta. Elevated
NRBCs are a marker for foetal hypoxia. Elevated NRBCs are different in kind from the
other placental lesions. They are all potential causes of foetal physiologic disruption,
while elevated NRBC are the result of or indicators for this disruption.2 Placental lesions,
especially chronic and subacute lesions, may even be antecendents of elevated NRBCs.19
Redline found that elevated NRBCs in term infants were significantly more common in the
placentas of infants who later developed cerebral palsy.19 This signifies that foetal distress,
whether or not recognised, may lead to a high illness severity of the infant immediately
following birth. The placental lesions potentially leading to foetal hypoxia may be several.
Placental pathology consistent with MVU could be responsible, since elevated NRBCs
frequently co-existed with MVU. This combination could be considered a more severe
form of MVU, because of the presence of foetal hypoxia. Following multivariate regression,
our data suggested that particularly elevated NRBCs, and not MVU, contribute to higher
illness severity. Previous findings are in conflict on this point. A recent study reported that
placental pathology consistent with maternal vascular underperfusion was often present,
and possibly causative, in intrauterine foetal deaths, especially between 24 and 32 weeks
of gestation.4 Another study, in term infants, reported that maternal vascular underperfusion
is not associated with neurological impairment.2 Our findings in live-born preterm infants
were consistent with the latter study.
FTV was also associated with higher illness severity. FTV is characterized by
devascularised distal villi and is often accompanied by identifiable organising thrombi in
upstream feeding vessels in the chorionic plate or large stem villi.20 In term infants FTV is
highly associated with neurologic impairment and cerebral palsy.3 Another recent study
69
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
reported that FTV was also associated with a higher incidence of obstetric and perinatal
complications and an increase in foetal cardiac abnormalities.21 This is in line with our
findings in preterm infants that illness severity is higher during the first 24 hours after birth
in the presence of FTV. In the present study, however, the association with SNAPPE was
not as strong as the elevated NRBCs. After performing multivariate regression, FTV was no
longer an independent factor related to illness severity.
The present study indicated that the coiling index of the umbilical cord was also
associated with illness severity. It has been suggested that both a low and a high coiling
index are related with adverse perinatal outcome.22,23 A normal coiling index is between
0.1 and 0.3.22 The median in our group was 0.29. This means that almost half of the
umbilical cords of our infants had a high coiling index. In our study the higher coiling
index was indeed associated with higher illness severity. Previously, a high coiling index
was associated with asphyxia and intrauterine growth restriction.23 Both items are part
of the SNAPPE score. Furthermore, it has been demonstrated that a high coiling index
is associated with foetal thrombosis.24 This may lead to a higher illness severity, which
we found in our study. However, in our study the foetal thrombotic vasculopathy was not
associated with the coiling index.
To our surprise, placental signs of AIUI were not associated with higher illness severity
during the first 24 hours after birth. A previous study found that AIUIs are associated with
neurological impairment in later life,2 possibly due to elevated cytokines and cardiovascular
instability. Exposure of the foetal lung to chorioamnionitis may, however, induce lung
maturation leading to a lower illness severity immediately after birth.25 We think this might
be the reason why we could not find an association of ascending intrauterine infection with
illness severity.
We did not evaluate illness severity with some placental lesions that occurred rarely in
our study group; these included high grade foetal chorionic vasculitis, diffuse villous oedema
and recent nonocclusive chorionic vessel thrombi in association with chorioamnionitis.
Previously, these lesions were associated with adverse neurological outcomes.26
The present study demonstrated that placental pathology frequently accompanies birth
before 32 weeks of gestation. Only three placentas did not show any placental pathology,
while the others showed a wide range of various pathologies, alone or in combination.
This may reflect that conditions associated with preterm birth are frequently caused by
a diversity of pathological placental lesions. This does not necessarily imply that these
pathological lesions all lead to higher illness severity. The number of placental lesions was
not associated with illness severity.
We recognise several limitations of our study. Firstly, we only included singletons so
as to be certain the right placenta was linked to the right infant. It might be that placental
pathology in twins is different, e.g. in the case of twin-to-twin transfusion. Secondly, our
study had a low sample size. Thirdly, we did not check complete neonatal blood counts for
presence of NRBCs. Previously it was reported that the diagnosis of elevated NRBCs by
placental examination alone is significantly associated with elevated NRBCs in complete
3
70
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
neonatal blood count.19 Finally, we limited our outcome to neonatal illness severity during
the first 24 hours following preterm birth. It might well be that an adverse clinical course
due to placental pathology only becomes apparent later on.
Our findings may have implications for clinical practice. Placental pathology is very
common following preterm birth. An understanding of those pathological lesions that are
most frequently associated with illness severity may reveal the relevant pathophysiological
mechanisms that lead to neonatal morbidity. Our findings suggested that prenatal hypoxia
and activation of foetal coagulation might act as mediators in causing higher illness severity
in preterm infants. Due to hypoxia, there also may occur an increase in hematocrit with a
higher chance of thrombosis. Strategies should be aimed at detecting these conditions
before birth and finding preventive measures to improve the outcomes of these infants.
In conclusion, this study indicated that placental pathologies including elevated
nucleated red blood cells and foetal thrombotic vasculopathy were associated with higher
illness severity during the first 24 hours after birth in preterm infants. Ascending intrauterine
infection was not associated with a high illness severity.
3
Acknowledgements
We greatly acknowledge the help of Dr Titia van Wulfften Palthe in Utrecht for correcting the
English manuscript. This study was part of the research programme of the postgraduate
school for Behavioral and Cognitive Neurosciences, (BCN), University of Groningen.
Annemiek Roescher, Marrit Hitzert, and Elise Verhagen received financial support from the
Junior Scientific Master Class of the University of Groningen.
71
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
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Cioni M, Patusid P, Mazonne D, Romeo
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3. Redline RW. Severe fetal placental
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4. Korteweg FJ, Erwich JJHM, Holm JP,
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7. Langston C, Kaplan C, Macpherson T,
Manci E, Peevy K, Clark B, Murtagh
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8. Redline RW, Boyd T, Campbell V, Hyde
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Nosology Committee. Maternal
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9. Redline RW, Faye-Petersen O, Heller
D, Qureshi F, Savell V, Vogler C,
the Society for Pediatric Pathology,
Perinatal Section, Amniotic Fluid
Infection Nosology Committee.
Amniotic infection syndrome: nosology
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reaction patterns. Pediatr Dev Pathol
2003;6;435-48
10. Redline RW. Villitis of unknown
etiology: noninfectious chronic
villitis in the placenta. Hum Pathol
2007;38;1439-46
11. Yee Khong T, Bendon RW, Qureshi
F, Redline RW, Gould S, Stallmach T,
Lipsett J, Staples A. Chronic deciduitis
in the placental basal plate: definition
and interobserver reliability. Hum
Pathol 2000;31;292-5
12. Katzman PJ, Genest DR. Maternal
floor infarction and massive perivillous
fibrin deposition: histological
definitions, association with
intrauterine fetal growth restriction, and
risk of recurrence. Pediatr Dev Pathol
2002;159-64.
13. Redline RW, Ariel I, Baergen RN, Desa
DJ, Kraus FT, Roberts DJ, Sander M,
the Society for Pediatric Pathology,
Placental pathology is associated with illness severity in
preterm infants in the first twenty-four after birth
Perinatal Section, Fetal Vascular
Obstruction Nosology Committee.
Fetal vascular obstructive lesions:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2004;7;443–52.
14. Altshuler G, Arizawa M, MolnarNadasdy G. Meconium-induced
umbilical cord vascular necrosis and
ulceration: A potential link between
the placenta and poor pregnancy
outcome. Obstet Gynecol 1992;
79;760-66.
15. Ohyama M, Itani Y, Yamanaka M, Goto
A, Kato K, Ijiri R, Tanaka Y. Maternal,
neonatal, and placental features
associated with diffuse chorioamniotic
hemosiderosis, with special reference
to neonatal morbidity and mortality.
Pediatrics 2004;113;800-5
16. Ogino S, Redline RW. Villous
capillairy lesions of the placenta:
distinctions between chorangioma,
chorangiomatosis, and chorangiosis.
Hum Pathol 2000;8;945-54.
17. Baergen RN. Cord abnormalities,
structural lesions, and cord
“accidents”. Semin Diagn Pathol
2007;24;23-32.
18. Richardson DK, Gray JE, McCormick
MC, Workman K, Goldmann DA. Score
for Neonatal Acute Physiology: a
physiologic severity index for neonatal
intensive care.
Pediatrics. 1993;91:617-23
19. Redline RW. Elevated circulating fetal
nucleated red blood cells and placental
pathology in term infants who
develop cerebral palsy. Hum Pathol
2008;39:1378-84
20. Redline RW; Pappin A. Fetal
thrombotic vasculopathy: the clinical
significance of extensive avascular villi.
Hum Pathol 1995;26:80-5
21. Saleemuddin A, Tantbirojn P, Sirois
K, Crum CP, Boyd TK, Tworoger S,
Parast M. Obstetric and perinatal
complications in placentas with fetal
thrombotic vasculopathy. Pediatr Dev
Pathol. 2010 May [Epub ahead of print]
22. Kashanian M, Akbarian A,
Kouhpayehzadeh J. The umbilical
coiling index and adverse perinatal
outcome. Int J Gynecol Obstetr
2006;95:8-13
23. de Laat MWM, Franx A, Bots
ML, Visser GHA, Nikkels PGJ.
Umbilical coiling index in normal and
complicated pregnancies. Obstet
Gynecol 2006;107(5):1049-55
24. de Laat MWM, van Alderen ED, Franx
A, Visser GHA, Bots ML, Nikkels
PGJ. The umbilical coiling index in
complicated pregnancy. Eur J Obstet
Gynecol Reprod Biol 2007;103(1):6672
25. Kramer BW, Kallapur S, Newnham
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and lung development. Semin Fetal
Neonatal Med 2009;14:2-7
26. Redline RW, Minich N, Taylor HG, Hack
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3
73
General introduction and outline of the thesis
1
74
4
General introduction and outline of the thesis
Chapter 4
1
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Annemiek M Roescher
Albert Timmer
Marrit M Hitzert
Nathalie KS de Vries
Elise A Verhagen
Jan Jaap HM Erwich
Arend F Bos
Early Human Development 2014;90:21-25
75
Abstract:
Background: The placenta plays a crucial role during pregnancy and dysfunction causes
long-term neurological problems. Indentifying placenta-related risks for neurological
problems shortly after birth may provide clues for early interventions aiming to improve
neurological outcome.
Objective: To determine the association between placental pathology and neurological
morbidity in preterm infants during the first two weeks after birth.
Study design: Placentas of 52 singleton, preterm infants (GA 25-31 weeks, BW 560-2250
grams) were examined for histopathology. Infants’ neurological condition shortly after
birth was determined by assessing the quality of their general movements (GMs): normal,
abnormal, or hypokinetic, on days 5, 8, and 15. A motor optimality score (MOS) was also
assigned.
Results: Examination of the placentas revealed maternal vascular underperfusion (n=29),
ascending intrauterine infection (AIUI) (n=19), villitis of unknown aetiology (n=6), chronic
deciduitis (n=11), foetal thrombotic vasculopathy (FTV) (n=9), and elevated nucleated red
blood cells (NRBCs) as a marker for foetal hypoxia (n=7). None of the placental lesions
were significantly associated with the quality of GMs or MOS.
Conclusions: This study indicated that placental lesions were not associated with infants’
neurological condition as measured by the quality of their general movements during the
first two weeks after birth.
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Introduction
Preterm birth is one of the main causes of long-term neurodevelopmental problems in
preterm infants.1 Placental pathology may act as a causative factor of preterm birth,
with major implications for the child if placental function is impaired. A previous study
suggested that several placental lesions are associated with early neonatal morbidity in
preterm infants.2 We also know that several placental lesions are associated with long-term
neurological morbidity.3,4 These lesions include ascending intrauterine infection, chronic
villitis of unknown aetiology, meconium associated vascular necrosis, and foetal thrombotic
vasculopathy. The appearance of elevated nucleated red blood cells, which is a marker for
foetal hypoxia rather than a placental lesion, is also associated with long-term neurological
morbidity.3,4 What we do not know, however, is whether these same placental lesions are
associated with neurological morbidity in preterm infants shortly after birth. Placental
dysfunction possibly has its greatest impact shortly after birth. A detailed understanding
of the relation between placental lesions and an infant’s neurological condition shortly after
birth is necessary to indentify placenta-related risks for neurological problems and could
provide clues for early interventions aiming to improve neurological outcome.
The most reliable method to evaluate the neurological condition of preterm infants
shortly after birth is Prechtl’s method of assessing the quality of their general movements
(GMs).5,6 In addition to the qualitative assessment of GMs, a semi-quantitative analysis
of several qualitative aspects of GMs is expressed by a motor optimality score (MOS).7
The assessment of GMs is a sensitive and non-invasive method with high interobserver
agreement (Kappa-value 0.88).6 GMs are predictive of neurological outcome.6
Our objective was to determine whether placental pathology was associated with
neurological morbidity in preterm infants during the first two weeks after birth as expressed
by GM quality. We hypothesized that in the presence of placental pathology the quality of
GMs of preterm infants is poorer and their MOS lower.
4
Methods
Patient population
Our cohort consisted of 57 preterm, singleton infants. All infants had been admitted to
the Neonatal Intensive Care Unit of the Beatrix Children’s Hospital in Groningen, the
Netherlands. The inclusion criteria were singleton infants with a gestational age (GA) of less
than 32 weeks. Exclusion criteria were major chromosomal and congenital abnormalities.
We also excluded infants whose placentas were not available for pathological examination
(n=4) or if the video recordings to assess GMs on days 5, 8, and 15, were lacking (n=1).
Our final study group consisted of 52 preterm singleton infants.
We recorded several clinical characteristics of the infants, including illness severity,
based on the Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE).2
77
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Placental pathology
The placentas were examined by a perinatal pathologist (AT) in accordance with the
guidelines published by the Royal College of Obstetricians and Gynaecologists and the
Royal College of Pathologists in Britain, and the College of American Pathologists.8,9 With
the exception of GA, the pathologist was blinded as to clinical outcome. We included all the
placental lesions for which an association with neurological impairment was suggested.3,4
The lesions were: placental pathology consistent with maternal vascular underperfusion
(MVU),10 ascending intrauterine infection (AIUI),11 chronic villitis of unknown origin (VUE),12
chronic deciduitis,13 perivillous fibrinoid,14 foetal thrombotic vasculopathy (FTV),15 meconium
associated vascular necrosis,16 chorioamniotic haemosiderosis,17 elevated nucleated red
blood cells (NRBCs),18 chorangiosis,19 and umbilical cord abnormalities.20 Definitions and
scoring criteria are presented in Table 1.
4
78
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Table 1: Diagnostic terminology and definition of the placental lesions
Diagnostic terminology
Definition and scoring criteria
Maternal vascular underperfusion
(MVU)
Decidual vasculopathy, eg. incomplete or absent spiral artery remodelling, acute
atherosis, fibrinoid necrosis or thrombosis; parenchymal pathology such as placental
hypoplasia, increased syncytial knotting, villous agglutination, increased perivillous
fibrin, distal villous hypoplasia, infarction, retroplacental hematoma.10
Ascending intrauterine infection
(AIUI)
Acute inflammation of the extraplacental membranes and chorionic plate. Acute
chorioamnionitis and chorionitis represent the maternal response; chorionic or umbilical
vasculitis represents the foetal response.11
Villitis of unknown aetiology (VUE)
Chronic lymphohistiocytic inflammation of the stem- and chorionic villi, with or without
obliterative vasculopathy of stem villus vessels.12
Chronic deciduitis
Chronic lymphohistiocytic inflammation of the decidua.13
4
Maternal floor infarction (MFI) / massive perivillous Excessive perivillous fibrin deposition, either basally at a thickness of ≥3 mm on at least
fibrinoid deposition (MPVFD)
one slide (MFI) or transmural encasing ≥50% of villi on at least one slide (MPVFD).14
Fetal thrombotic vasculopathy
(FTV)
Fetal vascular thrombosis, intimal fibrin cushions, fibromuscular sclerosis, hemorrhagic
endovasculitis and groups of at least 5 avascular fibrotic villi without inflammation or
mineralization and/or adherent thrombi in stem vessels.15
Meconium associated vascular necrosis
Meconium associated necrosis of smooth muscle cells in the wall of chorionic plate
vessels.16
Chorioamniotic haemosiderosis
Presence of hemosiderophages in the amnion and chorion.17
Elevated nucleated red blood cells
(NRBCs)
Only rare NRBCs are normal after the first trimester. More than an occasionally NRBC
was considered as abnormal.18
Chorangiosis
Diffuse increase in the number of villous capillaries.19
Umbilical cord abnormalities
Obstruction or disruption of the umbilical cord blood flow (e.g. umbilical cord prolapse,
entanglement, knots, disrupted velamentous vessels, hyper/hypo-coiling).20
Video recording of general movements
We video recorded each infant’s general movements on days 5, 8, and 15. Each recording
lasted 50 minutes. The infant lay supine in the incubator wearing only a nappy. We placed
the video camera high above the infant at the foot of the incubator so as to obtain an
unobstructed view of the infant’s entire body and face. The infant could move limbs and
trunk freely. GMs during crying, hiccupping, or while the infant was sucking on a dummy
were excluded from the analysis.5,21
79
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Analysis of general movements
AMR, MMH, and AFB assessed the quality of GMs according to Prechtl’s method.5 This
method assesses the GMs on the basis of visual Gestalt perception. Normal GMs involve
the infant’s entire body, can last a few seconds to several minutes, and are characterized
by a complex and variable sequence of arms, legs, neck, and trunk. GMs are scored as
abnormal if they lack complexity, variability, and fluency. There are three types of abnormal
GMs that apply to the preterm period: poor repertoire, chaotic, and cramped-synchronized
GMs.22,23 If GMs are absent or very short (<3 seconds), the infant was assessed as being
hypokinetic.7
A more detailed analysis of GMs is obtained by the motor optimality score (MOS)
based on Prechtl’s optimality concept. For this purpose, we used a score sheet developed
by Ferrari et al.22 and modified by De Vries et al.7 The highest, most optimal score is 18 and
the lowest score is 8.7 A hypokinetic infant is assigned an 8. The assessors were blinded
as to placental lesions.
4
Statistical analysis
MOS was taken as our primary outcome measure for calculating sample size. In a previous
study the standard deviation of MOS was 3.7 With MOS ranging from 8 to 18, we considered
a difference of 4.5 as relevant. We expected to find five large categories of placental lesions:
MVU, AIUI, chronic deciduitis, FTV, and elevated NRBCs. On average 1 in 4 placentas are
affected.2 We set the level of significance at α=0.01, applying the Bonferroni correction
with regard to the five categories of placental lesions. With a power of 0.8 and a ratio of
1 to 4 with regard to the presence of placental lesions, we calculated that we needed to
include at least 34 infants for the purpose of our study.
We used SPSS 20.0 software for Windows (SPSS Inc., Chicago, Illinois, USA) for the
statistical analyses.
To analyze the course of infants’ GM quality and MOS during the study period, we used
the chi-square test for trend and Spearman’s rho. We used the Wilcoxon signed rank test
to analyze the course of the MOS for a specific placental lesion. For these tests P<.05 was
considered statistically significant.
To test the association between pathological placental lesions and the quality of the GMs
we used the chi-square test for trend. For the association with the MOS we used the
Mann-Whitney test. In both cases we considered P<.01 statistically significant.
To analyze the association between placental weight and umbilical cord length and GM
quality we used the students T-test and Mann-Whitney test, respectively. For the association
with the MOS we used Pearson’s correlation and Spearman’s rank correlation coefficient,
respectively.
80
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Results
Patient characteristics
The patient characteristics are presented in Table 2. Two infants died between 9 and 12
days after birth of respiratory and circulatory failure due to sepsis.
Table 2. Patient characteristics. Data are given as median (range) or numbers.
Study population
N=52
Gestational age in weeks
29.1 (25.1 – 31.7)
Birth weight in grams
1180 (560-2250)
Male/female
22/30
Apgar score 1 minute
6 (1-9)
Apgar score 5 minutes
8 (3-10)
Intracranial haemorrhage, grade 1-2
7
Intracranial haemorrhage, grade 3-4
4
Small for gestational age
6
4
Delivery characteristics
Spontaneous preterm birth
28
Induced
- foetal distress
15
- maternal reasons
4
- foetal and maternal reasons
5
Preterm pre-labour rupture of the membranes (PPROM)
9
Caesarean section (elective and emergency)
29
Placental weight in grams
250 (99 – 470)
Cord length in centimetres
27 (15 – 59)
81
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Placental pathology
In Table 3 we present the occurrence of placental pathologies, categorized by GA and birth
weight (BW). Four out of the 52 placentas showed no pathology. Twenty-nine placentas
showed pathology consistent with MVU (infarction, villous hypoplasia, retroplacental
hematoma), 19 placentas had signs of AIUI (maternal response, foetal response or both).
Thirty placentas showed more than one placental lesion. However, a combination of the
two largest groups of lesions (MVU and AIUI) was only present in four placentas. Other
combinations that were present in five placentas or more included MVU and elevated
NRBCs (6 placentas), MVU and FTV (6 placentas), and MVU and chronic deciduitis (5
placentas). We found no placental lesions consistent with perivillous fibrinoid, meconium
associated vascular necrosis, or complications of the umbilical cord.
4
Table 3. Presence of placental pathology specified by gestational age and birth weight.
Placental lesions
<28 wk
≥28 wk
<1 kg
≥1 kg
n=18
n=34
n=20
n=32
MVU (n=29)
6
23
12
17
AIUI (n=19)
8
11
5
14
Chronic deciduitis (n=11)
3
8
2
9
Chronic villitis (n=6)
2
4
2
4
FTV (n=9)
4
5
6
3
Elevated NRBCs (n=7)
3
4
5
2
Chorangiosis (n=2)
1
1
1
1
Chorioamniotic haemosiderosis (n=2)
2
-
2
-
Abbreviations: MVU - maternal vascular underperfusion; AIUI - ascending intrauterine
infection; FTV - foetal thrombotic vasculopathy; NRBCs - nucleated red blood cells.
The distribution of placental lesions specified by gestational age (<28 weeks and ≥28 weeks) and
by birth weight (<1 kilo and ≥1 kilo). The numbers exceed totals, because a single placenta can
have more than one lesion.
82
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
General movements
On day 5 we obtained videos of 46 infants, on day 8 of 43 infants, and on day 15 of
43 infants. We observed normal, poor repertoire and chaotic GMs, and hypokinesia. The
number of infants with normal GMs increased significantly during the study period (chisquare test for trend, P=.04). The MOS score tended to increase with increasing age
(Spearman’s rho, 0.16, P=.07).
4
Placental pathology and general movements
The number of placental lesions did not correlate with GM quality. We present the
presence or absence of specific placental lesions in relation to the quality of GMs on
days 5, 8, and 15 in Table 4. On day 5, more infants had abnormal GMs in the presence of
elevated NRBCs and FTV but it just failed to reach significance (chi-square test for trend,
P=.06 and P=.06, respectively). On day 5, none of the placental lesions were associated
with the MOS. On day 8 and 15, none of the placental lesions were associated with the
quality of GMs or with the MOS. On days 5, 8 and 15 placental weight was associated
with MOS (r=0.35 P=0.02, r=0.37 P=0.02 and r= 0.38 P=0.01, respectively) and with the
quality of GMs (P=0.03, P=0.01, and P=0.01, respectively). Lower placental weight was
associated with lower MOS and more abnormal GMs. Umbilical cord length was only on
day 8 associated with GM quality (P=0.02). Shorter umbilical cord length was associated
with more abnormal GMs.
83
84
1
0
Present
Absent
Present
Absent
Present
Absent
Present
Absent
Present
Absent
Present
Absent
MVU
AIUI
Chronic
deciduitis
VUE
FTV
↑NRBCs
4
23
4
23
2
25
6
21
7
20
16
11
PR
2
16
2
16
3
15
5
13
9
9
8
10
N
0.06
0.06
0.22
0.49
0.10
0.18
P
0
4
0
4
1
3
0
4
1
3
2
2
H
Day 8
0
1
0
1
0
1
0
1
0
1
1
0
CH
4
14
6
12
1
17
3
15
5
13
10
8
n=43
PR
2
18
2
18
3
17
4
16
10
10
10
10
N
0.67
0.77
0.78
0.29
0.21
0.76
P
1
0
0
1
0
1
0
1
0
1
1
0
CH
Day 15
CS
0
1
0
1
0
1
0
1
1
0
0
1
7
8
4
11
1
14
1
14
4
11
7
8
PR
n=43
15
11
3
23
3
23
7
19
9
17
15
11
N
0.75
0.65
0.50
0.11
0.80
0.75
P
red blood cells.
vascular underperfusion; AIUI - ascending intrauterine infection; VUE - villitis of unknown aetiology; FTV - foetal thrombotic vasculopathy; NRBCs - nucleated
Abbreviations: GMs - general movements; H - hypokinetic; CH - chaotic; CS - cramped synchronized; PR - poor repertoire; N - normal; MVU - maternal
1
0
1
0
1
0
0
1
0
1
H
Placental lesions
n=46
4
Day 5
Table 4: Relation between placental lesions and the quality of GMs on days 5, 8 and 15.
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
Potential confounders or mediators of GM quality
We performed unifactorial analyses to determine whether GM quality was affected by
other clinical characteristics. Lower gestational age and birth weight were both associated
with more abnormal GMs and lower optimality scores on day 5, 8 and 15 (Mann-Whitney
test and Spearmans rho P<0.01). A higher illness severity during the first 24 hours after
birth as determined using the SNAPPE score was associated with lower optimality scores
on all days (Spearmans Rho P<0.01). Intubation after one week was also associated with
more abnormal GMs (chi-square test for trend, P<0.01). Being small or appropriate for
gestational age and intracranial haemorrhages (mostly grade 1-2) were not associated
with the quality of GMs.
Next, we checked whether these potential confounders were also related to placental
lesions. A lower birth weight was associated with a higher occurrence of FTV and elevated
NRBCs (Mann-Whitney test P<0.05). A higher illness severity during the first 24 hours after
birth was associated with both FTV and elevated NRBCs (Mann-Whitney test P<0.05).
We did not find an association between any placental lesion and respiratory conditions
requiring intubation or additive oxygen after one week, or between placental lesions and
intracranial haemorrhages.
4
Discussion
This study indicated that placental lesions were not associated with infants’ neurological
condition as measured by the quality of their general movements during the first two weeks
after birth. We hypothesized that placental dysfunction had its greatest impact shortly after
birth. This was not confirmed in our study. Only placental weight was associated with the
quality of GMs on all days.
We assessed GMs during the first two weeks after birth. It might well be that during
this period the quality of GMs is not fully reflected by the placental lesions, because other
clinical and biochemical factors influence the quality of GMs more during this period. This
might especially be true for the preterm period. Many physiological changes take place
during the first weeks after birth that influence brain function and, as a consequence, the
quality of GMs.7 In addition, very preterm infants often have complicating illnesses that
may affect brain function in the acute phases. In our study we found lower gestational
age, lower birth weight, higher illness severity and ventilatory support to be associated
with poorer GM quality. It might be, however, that lower gestational age confounded the
relations of illness severity and ventilatory support to GM quality. The relation between
clinical factors and GM quality suggests that other factors had more influence on GM
quality than placental pathology shortly after birth. It might be that effects of placental
lesions on neurological functioning in preterm infants become apparent only later in life.
Placental pathology consistent with FTV and elevated NRBCs (a marker for foetal
hypoxia) nearly reached significance with abnormal GM quality. These lesions were
associated with high illness severity, which confirms findings in a previous study.2 In
the present study, high illness severity was also associated with abnormal GM quality.
85
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
This higher illness severity might, in turn, have affected GM quality explaining the near
significant associations between these lesions and GM quality. This is, however, highly
speculative.
In term infants, FTV and elevated NRBCs are highly associated with neurological
impairment and cerebral palsy.3,4 FTV is also associated with a higher incidence of obstetric
and perinatal complications and an increase in foetal cardiac abnormalities.24 In addition to
the explanation stated above, another reason that the association between elevated NRBCs
and the quality of GMs in our preterm cohort just failed to reach significance might be due
to the small number of placentas with this lesion in our group (7 out of 52). We considered
a difference of 4.5 points on the motor optimality score relevant, with these numbers the
power for elevated NRBCs was 64%. However, the power of FTV was sufficient (82%).
Despite the marginal power of elevated NRBCs, the borderline significance of FTV and
elevated NRBCs might be relevant and important. Our results suggest that these particular
lesions are associated with neurological impairment, not only in term infants3,4 but also in
preterm infants.
MVU was reported to occur more often in intrauterine foetal deaths, especially
between 24 and 32 weeks of gestation.25 In infants >35 weeks GA, it was suggested that
macroscopic placental infarcts are associated with an increased risk of cerebral palsy.26
A study in term infants, however, showed no association between MVU and neurological
impairment.3 Our present findings in live-born preterm infants were consistent with this
study. MVU was present in 29 out of the 52 placentas, with this number we should have
been able to find a difference if it was present (power 99.6%).
Previous studies showed that AIUI, especially in the presence of a high grade foetal
response, is associated with neurological impairment at the age of two.3,27 Others associate
it with cerebral palsy and abnormal neurocognitive function at school age,28 possibly due to
elevated cytokines and cardiovascular instability. In our study we did not grade the foetal
response, which might possibly explain why we did not find an association between AIUI
and neurological impairment. AIUI is also suggested to be associated with lower Apgar
scores at 1 and 5 minutes after birth.29,30 In a previous study we found no association
between AIUI and illness severity in the first 24 hours after birth.2 This is consistent with
this study were we also found no association between AIUI and the quality of GMs. Again
the power would have been sufficient to demonstrate differences if present (99%).
In this study we did find an association between placental weight and quality of GMs.
On days 5, 8 and 15 lower placental weight was associated with more abnormal GMs
and lower MOS. Again, it might be that lower gestational age confounded this relation
between placental weight and GM quality. In literature, findings relating placental weight
and adverse neurological outcomes are inconclusive. Both light and heavy placental weight
is suggested to be associated with adverse neurological outcome.31 Low placental weight
is also suggested to be associated with stillbirth.32 Our findings indicate that low placental
weight is also associated with early neurological morbidity.
We acknowledge several limitations of our study. Firstly, we only included singletons
4
86
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
so as to be certain that each infant was linked to its own placenta. In twins placental
pathology is probably different, e.g. twin-to-twin transfusion. Secondly, we did not
determine the quality of GMs in our study group with such rare placental lesions as diffuse
villous oedema and/or recent non-occlusive chorionic vessel thrombi in association with
chorioamnionitis. In an earlier study, such lesions were found to be associated with adverse
neurological outcomes.28 Thirdly, several lesions we focused on, i.e. chronic villitis, foetal
thrombotic vasculopathy, elevated NRBCs, chorangiosis, and mecoinium associated
vascular necrosis, are lesions found in term placentas. This might be a reason why these
lesions were present in only a few preterm placentas. Finally, only four children in our
group had no placental lesions. Almost all children had one or more placental lesion. When
determining associations between placental lesions and GM quality, the comparison group
partly consisted of infants with other placental lesions than the one studied.
In conclusion, FTV and elevated NRBCs showed a borderline association with the
quality of GMs. Other placental lesions were not associated with the quality of GMs. We
demonstrated that it is difficult to identify a placenta-related risk group for neurological
problems as measured by the quality of GMs shortly after birth. This might be because
other conditions related to preterm birth might confound a possible association between
placental lesions and the quality of GMs.
4
Acknowledgements
We greatly acknowledge the help of Dr Titia van Wulfften Palthe in Utrecht for correcting the
English manuscript. This study was part of the research programme of the postgraduate
school for Behavioral and Cognitive Neurosciences, (BCN), University of Groningen.
Annemiek Roescher, Marrit Hitzert, and Elise Verhagen received financial support from the
Junior Scientific Master Class of the University of Groningen.
87
Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
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16. Altshuler G, Arizawa M, MolnarNadasdy G. Meconium-induced
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17. Ohyama M, Itani Y, Yamanaka M, et
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Placental pathology and neurological morbidity in preterm infants
during the fist two weeks after birth
4
91
92
Part III
Placental Lesions and Long-Term Outcome
Chapter 5: Placental lesions and neurodevelopmental outcome at toddler age
Chapter 6: The relation between placental lesions and functional outcomes
at early school age of children born between 32 and 36 weeks’ gestational age
93
General introduction and outline of the thesis
1
94
5
General introduction and outline of the thesis
Chapter 5
1
Placental lesions and neurodevelopmental
outcome at toddler age
Annemiek M Roescher
Albert Timmer
Elise A Verhagen
Koenraad NJA Van Braeckel
Peter H Dijk
Jan Jaap HM Erwich
Arend F Bos
Submitted
95
Abstract
Objectives: To determine whether placental pathology in preterm infants is associated
with neurodevelopmental outcome at toddler age.
Study design: In this prospective cohort study we included 73 children (GA <32wk). The
placentas of all children were assessed for pathology. Cognitive and motor outcomes
were assessed at two to three years of age using the Bayley Scales of Infant and Toddler
Development, third edition. Behavior was assessed using the Child Behavior Checklist.
Results: Ninety-five percent of the placentas showed pathology. Ascending intrauterine
infection was associated with abnormal cognitive, fine motor, and total motor outcomes
(P=.018, P=.032, and P=.056, respectively) but not with behavior. After excluding children
with cerebral palsy, we found no association between placental lesions and outcomes.
Conclusion: Placental lesions indicating ascending intrauterine infections are associated
with adverse cognitive and motor outcomes. No other placental lesions were associated
with neurodevelopmental outcome at toddler age.
Keywords: ascending intrauterine infection, follow up, placental pathology, preterm
infants
Placental lesions and neurodevelopmental outcome at toddler age
Introduction
The placenta is the link between mother and fetus during pregnancy. It plays a crucial
role in fetal growth and development by enabling the exchange of nutrients and oxygen
from the mother to the fetus and by removing fetal waste products. In recent years,
findings based on placental lesions have contributed to a better understanding of how
the placenta functions. Less than optimal placental performance may result in morbidity
or even mortality of both mother and fetus. There are indications that placental lesions
are the main cause of fetal death.1 It is also known that several placental lesions are
associated with neonatal morbidity such as a higher illness severity shortly after birth,2-4
higher incidence of bronchopulmonary dysplasia,4-7 necrotizing enterocolitis (NEC),8,9
retinopathy of prematurity,10-13 and cardiac abnormalities.12,14 The relationship between
placental lesions and neurodevelopmental outcome is less clear. Even though there
are indications that placental lesions are associated with adverse neurodevelopmental
outcomes, the results are inconsistent. Most of these studies are retrospective, performed
in a selected study population with neurological impairment.15-19 Prospective cohort studies
concerning placental lesions and neurodevelopmental outcome are scarce.20,21 A detailed
understanding of the relation between placental lesions and neurodevelopmental outcome
later in life is necessary to identify placental-related risks for developmental problems, and
such understanding could provide clues for early interventions to improve outcome.
The objective of this prospective cohort study was to determine whether placental
lesions were associated with neurodevelopmental outcomes at two to three years of age.
We hypothesized that in the presence of placental lesions neurodevelopmental outcome
would be poorer.
5
Methods
Patient population
We selected all singleton infants born in 2008 with a gestational age (GA) of less than 32
weeks and who were admitted to University Medical Center Groningen. From this cohort
we excluded infants who died, infants whose placentas were not available for pathological
examination, and infants with major chromosomal and congenital abnormalities. Written,
informed parental consent was obtained in all cases.
Placental lesions
The placentas were examined by a perinatal pathologist (AT) in accordance with the
guidelines published by the Royal College of Obstetricians and Gynaecologists and the
Royal College of Pathologists in Britain, and the College of American Pathologists.22,23 With
the exception of GA, the pathologist was blinded as to clinical outcome. We assessed
all the placentas for lesions of which an association with neurological impairment was
suggested.15,18 The lesions were: placental pathology consistent with maternal vascular
underperfusion (MVU),24 ascending intrauterine infection (AIUI),25 chronic villitis of unknown
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Placental lesions and neurodevelopmental outcome at toddler age
etiology (VUE),26 chronic deciduitis,27 perivillous fibrinoid,28 fetal thrombotic vasculopathy,29
meconium associated vascular necrosis,30 chorioamniotic hemosiderosis,31 increased
nucleated red blood cells (NRBCs),32 chorangiosis,33 and umbilical cord abnormalities.34
Table 1 contains the definition and scoring criteria of these placental lesions. In addition,
placental weights and umbilical cord lengths were noted.
Table 1. Diagnostic terminology and definition of the placental lesions
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Diagnostic terminology
Definition and scoring criteria
Maternal vascular underperfusion
Decidual vasculopathy, e.g. incomplete or absent spiral artery remodeling, acute atherosis,
fibrinoid necrosis, or thrombosis; parenchymal pathology such as placental hypoplasia,
increased syncytial knotting, villous agglutination, increased perivillous fibrin, distal villous
hypoplasia, infarction, retroplacental hematoma.24
Ascending intrauterine infection
Acute inflammation of the extraplacental membranes and chorionic plate. Acute
chorioamnionitis and chorionitis represent the maternal response; chorionic or umbilical
vasculitis represents the fetal response.25
Villitis of unknown etiology
Chronic lymphohistiocytic inflammation of the stem and chorionic villi, with or without
obliterative vasculopathy of stem villus vessels.26
Chronic deciduitis
Chronic lymphohistiocytic or plasmacytic inflammation of the decidua basalis.27
Maternal floor infarction or massive
perivillous fibrinoid deposition
Excessive perivillous fibrin deposition, either basally at a thickness of ≥3 mm on at least one
slide (maternal floor infarction) or transmural encasing ≥50% of villi on at least one slide
(massive perivillous fibrinoid deposition).28
Fetal thrombotic vasculopathy
Fetal vascular thrombosis, intimal fibrin cushions, fibromuscular sclerosis, hemorrhagic
endovasculitis and groups of at least five avascular fibrotic villi without inflammation or
mineralization and/or adherent thrombi in stem vessels.29
Meconium associated vascular necrosis
Meconium associated necrosis of smooth muscle cells in the wall of chorionic plate vessels.30
Chorioamniotic hemosiderosis
Presence of hemosiderophages in the amnion and chorion.31
Elevated nucleated red blood cells
Only rare NRBCs are normal after the first trimester. More than two NRBCs in a randomly
selected field of 4.5 mm2, corresponding to 18 consecutive fields at 40x magnification, or one
field at 10x magnification, was considered abnormal.32
Chorangiosis
Diffuse increase in the number of villous capillaries.33
Umbilical cord abnormalities
Obstruction or disruption of the umbilical cord blood flow (e.g. umbilical cord prolapse,
entanglement, knots, disrupted velamentous vessels, hypercoiling or hypocoiling).34
Placental lesions and neurodevelopmental outcome at toddler age
Neurodevelopmental outcome
Neurodevelopmental outcome was determined at 2 to 3 years of age (corrected age for
prematurity 23-45 months). Cognitive, fine motor, and gross motor outcomes were assessed
by using the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III).35
The starting point of the test was determined by the corrected age for prematurity. Cognitive
and total motor scores are composite scores with a mean of 100 and standard deviation
of 15. Fine and gross motor scores are scaled scores with a mean of 10 and standard
deviation of 3. These scores can be classified as normal, mildly abnormal, and abnormal.
Children with a cognitive composite score and total motor composite score ≥ 85 were
classified as normal, scores < 85 were classified as mildly abnormal, and < 70 as abnormal.
Children with a fine and gross motor scaled score ≥ 7 were classified as normal, < 7 were
classified as mildly abnormal, ≤ 3 as abnormal. Language scores of the Bayley-III were
not determined. Behavioral outcome was assessed using the Child Behavior Checklist.
It evaluates behavior and emotions and is filled out by parents. For the purpose of this
study we reported the total score. Children were classified as displaying normal, mildly
abnormal, or abnormal behavior in accordance with the manual.36 All children were tested
in the presence of their parents at University Medical Center Groningen. The examiners
were blinded as to placental lesions. Children diagnosed with cerebral palsy (CP) with a
gross motor functioning classification system (GMFCS) level ≥3 or higher were not invited
for follow-up testing. Based on information contained in the medical records on their motor
and cognitive skills, we classified these children as abnormal. Because we were unable to
determine the behavioral problems of these children reliably, we excluded them from the
analyses regarding behavioral outcome.
5
Clinical variables
We collected several clinical variables during the perinatal and neonatal periods. These
variables were mode of delivery, the presence of preeclampsia, GA, birth weight, gender,
small-for-GA, Apgar scores, sepsis, respiratory support, cerebral lesions, intestinal
pathologies, and socioeconomic status.
Statistical analysis
We used SPSS 20.0 software for Windows (SPSS Inc Chicago, Illinois, USA) for the
statistical analyses. Bayley-III data were tested for normality by using the KolmogorovSmirnov test. Cognitive and motor outcomes showed non-normal distributions. To test
the correlations between the number of placental lesions and the cognitive composite
and scaled motor scores we used Spearman’s rho. To test the associations between
specific placental lesions and the cognitive composite scores as well as scaled motor
scores we used the Mann-Whitney test. For the associations of placental lesions with
categorized cognitive, motor, and behavior outcomes, we used the chi-square for trend
test, exact method. In addition to categorized scores, we also tested the association of
placental lesions with dichotomous outcome scores with Fisher’s exact test. To test the
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Placental lesions and neurodevelopmental outcome at toddler age
relationship between placental weight or umbilical cord length and cognitive composite
or scaled motor scores, we used Spearman’s rho. We used the Kruskal-Wallis test for the
relationship between placental weight as well as umbilical cord length and categorized
cognitive, motor, or behavior outcomes. We used logistic regression to analyze the effects
of possible confounders of normal or abnormal functional outcomes.
Results
Patient characteristics
Out off the 99 singleton infants born <32 weeks’ GA in 2008, six died during the neonatal
period. One child died at two years due to respiratory problems. One child was diagnosed
with Down syndrome, the placentas of six infants were not available for pathological
examination. Three children had CP with a GMFCS level ≥3 (not invited for follow-up
testing). We invited the remaining 82 children for follow-up testing. The parents of 70
children gave their consent for follow-up testing. Including the three children with CP
(GMFCS ≥3), our final study group consisted of 73 children. Patient characteristics are
presented in Table 2.
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Placental lesions and neurodevelopmental outcome at toddler age
Table 2. Patient characteristics. Data are given as median (range) or numbers (percentage)
Study population
N=73
Male/female
41/32 (56% / 44%)
Gestational age in weeks
29.1 (25.2 – 31.6)
Birth weight in grams
1298 (680 - 2045)
Small for gestational age (P<10)
4 (6%)
Apgar score at 5 minutes
7.5 (4 – 10)
Cerebral lesions
- Periventricular leukomalacia
17 (23%) (all grade 1)
- Intracranial hemorrhage, grades 1-2
10 (14%)
- Intracranial hemorrhage, grades 3-4
2 (3%)
Cerebral palsy GMFCS I-II
1 (1%)
Cerebral palsy GMFCS III-V
3 (4%)
Sepsis
10 (14%)
Necrotizing enterocolitis
5 (7%)
Preterm prelabor rupture of the membranes
15 (21%)
Cesarean section (elective and emergency)
35 (48%)
Placental weight in grams
277.1 (140 – 456)
Cord length in centimeters
30.3 (15 – 59)
Placental lesions
69 (95%)
Maternal vascular underperfusion
42 (58%)
Ascending intrauterine infection
24 (32%)
Fetal thrombotic vasculopathy
12 (16%)
Villitis of unknown etiology
8 (11%)
Chronic deciduitis
10 (14%)
Perivillous fibrinoid
4 (6%)
Chorioamniotic hemosiderosis
3 (4%)
Meconium
9 (12%)
5
Markers
Elevated nucleated red blood cells
30 (41%)
Chorangiosis
2 (3%)
Placental lesions
We present the distribution of placental lesions in Table 2. Four (5.5%) out of 73 placentas
showed no lesions. Forty-two placentas showed pathology consistent with MVU and 24
placentas had signs of AIUI. Out of these 24 placentas a maternal response was present
in 22 placentas and a fetal response in 18 placentas. Thirty placentas showed elevated
NRBCs, a marker for fetal hypoxia. Thirty-six placentas (49%) showed more than one
lesion. A combination of the two most common lesions, MVU and AIUI, was present in
only five placentas. Other combinations that occurred in five placentas or more included
MVU and fetal thrombotic vasculopathy (11 placentas), MVU and VUE (6 placentas), and
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Placental lesions and neurodevelopmental outcome at toddler age
VUE and chronic deciduitis (5 placentas). Elevated NRBCs were most frequently seen in
combination with MVU (19 placentas). We found no complications of the umbilical cords.
The median placental weight was 277 gram (range 140 - 456 gram) and the median cord
length was 30 cm (range 15 – 59 cm).
Neurodevelopmental outcome
At follow-up the children’s median age was 28 months corrected for prematurity (range
23 - 45 months). The median cognitive composite score was 95 (interquartile range, IQR,
25th – 75th: 90-100). Two children were classified as mildly abnormal and three children
as abnormal. The scaled fine motor score was median 11 (IQR 10-12). One child was
classified as mildly abnormal and three children as abnormal. The median scaled gross
motor score was 9 (IQR 8 - 10). Five children were classified as mildly abnormal and four
as abnormal. The median total motor composite score was 100 (IQR 94- 107). Two children
were classified as mildly abnormal and three children as abnormal. The behavioral outcome
of one child was classified as mildly abnormal and as abnormal in three children.
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Placental lesions and neurodevelopmental outcome
Initially, the number of placental lesions per placenta did not correlate with cognitive, fine
motor, and gross motor outcomes, or behavior. Nor were any of the specific placental
lesions associated with composite cognitive scores, scaled motor scores, or behavior
(Figure 1). Subsequently, we categorized the data into normal, mildly abnormal, and
abnormal outcomes.
In the presence of AIUI we found more abnormal cognitive scores (chi-square for trend,
exact method, P=.018), and abnormal fine motor outcomes (chi-square for trend, exact
method, P=.032). The relation between AIUI and abnormal gross and total motor scores
just failed to reach statistical significance (chi-square for trend, exact method, P=.082 and
P=.056, respectively). The behavioral outcomes were comparable. Other placental lesions
were not associated with categorized cognitive, fine motor, and gross motor outcomes, or
behavior.
When we categorized the motor scores into normal, mildly abnormal (scaled scores
>3), and abnormal (scaled scores ≤3), we found more abnormal cognitive, fine motor,
and total motor scores in the presence of AIUI (Fisher’s exact test, P=.034, P=.032, and
P=.034, respectively). For gross motor outcome we found more abnormal outcomes in the
presence of AIUI (Fisher’s exact test, P=.097), although not reaching statistical significance
(Table 3).
When we divided AIUI into a maternal and a fetal response, the association of AIUI
with a maternal response and cognitive, fine motor, and total motor outcomes remained
statistically significant (Fisher’s exact test P=.026, P=.024, and P=.025, respectively). For
AIUI with a fetal response the relation with cognitive, fine motor, and total motor outcomes
did not reach statistical significance anymore (Fisher’s exact test P=.152, P=.144, and
P=.148, respectively).
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Placental lesions and neurodevelopmental outcome at toddler age
In addition to categorizing the data into normal and abnormal outcomes, we also
studied the 25 percent lowest scores on cognitive and motor outcomes and found that
none of the placental lesions were associated with the lowest scores on these outcomes.
Placental weights and cord lengths were also not associated with neurodevelopmental
outcome at two years of age.
When we excluded the three children with CP with a GMFCS ≥3, AIUI was no longer
significantly associated with cognitive or motor outcomes. After excluding these children,
other placental lesions were also not associated with neurodevelopmental outcome.
5
Table 3. Raw and categorized outcome scores in the presence and absence of AIUI
Raw outcome scores#
median scores, range)
Categorized outcome scores# #
(numbers)
Normal + mildly abnormal (≥3)
Abnormal
(<3)
AIUI present
Cognition
Fine motor
100 (75 - 115)†
11 (8 - 16)††
21
21
3
3
Gross motor
9 (4 - 13)††
21
3
†
21
3
Cognition
Fine motor
95 (75 - 110)†
10.5 (6 - 19)††
49
49
0
0
Gross motor
9 (1 - 19)††
48
1
Total motor
100 (76 - 145)†
49
0
Total motor
103 (85 - 118)
AIUI absent
Abbreviations: AIUI - ascending intrauterine infection
† composite scores
†† scaled scores
# Children with CP with a GMFCS ≥ 3 (n=3) were not invited for follow-up testing. No raw scores
are known for these children and are therefore not reported.
# # Children with CP with a GMFCS ≥3 (n=3) were categorized as abnormal (based on medical
files), and are therefore reported in the categorized outcome scores column in the table.
Clinical variables
Gestational age, Apgar scores at 5 minutes, and the presence of NEC were associated with
poorer cognitive, fine motor, and total motor outcomes categorized as normal and mildly
abnormal versus abnormal (P<.05). We performed a logistic regression to disentangle the
effects of AIUI, Apgar scores, and NEC on cognitive, fine motor, and total motor outcomes.
None of these predictors remained significant in the model (P>.1). Lower GA was also
associated with abnormal cognitive and motor outcomes. We did not adjust our analyses
for GA because a lower GA can be the result of AIUI. The other collected variables (i.e.
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Placental lesions and neurodevelopmental outcome at toddler age
mode of delivery, the presence of preeclampsia, birth weight, gender, small-for-GA, sepsis,
respiratory support, cerebral lesions, and socioeconomic status) were not associated with
outcome in our group.
Total motor scores
Cognitive scores
Composite scores
5
MVU
AIUI
*
FTV
NRBCs
MVU
AIUI
FTV
NRBCs
Placental lesion absent
Placental lesion present
Figure 1: Composite scores of cognitive and total motor outcomes in the presence or absence of
placental lesions
Data are shown in box and whisker plots. Dots and asterisks represent outliers.
Only placental lesions that are more than ten times present are included in the figure.
Abbreviations: MVU – maternal vascular underperfusion; AIUI – ascending intrauterine infection;
FTV – fetal thrombotic vasculopathy; NRBCs – nucleated red blood cells.
Discussion
This prospective cohort study suggested that of all placental lesions only AIUI was
associated with abnormal outcome measures at two years of age. Ascending intrauterine
infection was associated with abnormal cognitive, fine motor, and total motor outcomes.
This was an unexpected finding because 94.5% of the placentas in our study group
showed one or more lesions. As a result, our hypothesis that placental lesions would lead
to impaired neurodevelopmental outcome was only partly confirmed.
We draw attention to the fact that in our study group only three children had abnormal
fine motor skills. They were the only children in our cohort diagnosed with cerebral
palsy with a GMFCS ≥3. After we had excluded them, AIUI was no longer associated
with cognitive or motor outcome, which suggested an association between AIUI and CP.
After their exclusion no other placental lesions were associated with neurodevelopmental
outcome either.
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Placental lesions and neurodevelopmental outcome at toddler age
Ascending intrauterine infection occurs more frequently in preterm than in fullterm
infants and is an important cause of preterm birth.37,38 It can be divided into a maternal
response (acute chorioamnionitis and/or subchorionitis) and a fetal response (acute
umbilical and/or chorionic vasculitis). Previous studies showed AIUI (both maternal and
fetal response) to be associated with white matter brain injury39 and intraventricular
hemorrhage.4,12 Other studies, however, failed to find such a relationship between.16,40 The
reason for this inconsistency may be ascribed to differences in adjusting for potential
confounders, such as GA. In the case of correcting for GA it should be acknowledged
that a lower GA could be the result of AIUI. Studies on preterm infants38,41 and fullterm
infants15,20,39,42 found an association between AIUI and NI and/or CP. It has also been
associated with the poorer neurodevelopmental outcomes of preterm-born children at
toddler age: in the presence of AIUI with a fetal response, a higher incidence of moderate
to severe disability was found.43 In our study we also found an association between AIUI
and poorer neurodevelopmental outcome at toddler age. More specifically, in accordance
with previous findings, the presence of AIUI was associated with abnormal cognitive scores
and motor skills (scaled score ≤3), predominantly fine motor skills. It is important to note
that the three children in our cohort who were diagnosed with CP with a GMFCS ≥3, were
categorized in the abnormal motor outcome group. No other children had abnormal scores
on motor skills. The placentas of these three children all showed AIUI. This suggested
that the children with CP were responsible for the association between AIUI and impaired
motor outcomes.
It is hypothesized that elevated cytokine levels in the presence of AIUI play a role
in the etiology of CP.38,39,41,44,45 The elevated blood and brain cytokine levels resulting
from maternal infection might lead to central nervous system damage in the fetus. The
inflammatory cytokines can be neurotoxic and inhibit oligodendrocytes in the developing
white matter. As a consequence, the oligodendrocytes can lose their myelin production.
This results in damage of astrocytes, microglia, and white matter, which can in turn lead to
cerebral palsy.39,41,45,46 Another explanation is the association between AIUI and premature
delivery. Low GA is associated with a host of intrinsic vulnerabilities within the brain that
have been implicated in the pathogenesis of cystic periventricular leukomalacia and CP.39
Maternal vascular underperfusion (MVU) is a group of placental lesions caused by
malfunctioning of the spiral arteries and is commonly seen in pregnancies complicated
by hypertensive disorder. It is the largest group of placental lesions and is known to
be associated with fetal death, especially between 24 and 32 weeks’ gestation.1 An
increased risk of cerebral palsy is seen in the presence of macroscopic placental
infarcts.21 Nevertheless, a study in fullterm infants showed no association between MVU
and neurological impairment.15 Our findings in preterm infants were in line with this latter
study.
Another important finding of this study is that after we had excluded the children with CP
with a GMFCS ≥3, none of the placental lesions were associated with neurodevelopmental
outcome. An explanation for this fact might be that this was a prospective study. Most
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Placental lesions and neurodevelopmental outcome at toddler age
studies concerning placental lesions and neurological impairment are retrospective, with
a selected study population, often comprising children with CP, encephalopathy, or white
matter injury.15-19 We studied a year cohort in which many children had no developmental
problems. In a subanalysis we also excluded the children with a GMFCS score ≥3.
Therefore this study also focused on milder developmental problems. Possibly, the
influence of placental lesions is higher in severe neurological disabilities such as cerebral
palsy and neurological impairment compared to milder developmental problems. This is an
important finding. Only a minority of the preterm-born children develops severe neurological
disabilities like CP, which underlines the relevance of investigating the effect of placental
lesions on children without severe neurological disabilities. It appeared to be limited.
We assessed the neurodevelopmental outcome in our study group by using the
Bayley-III. It is suggested that the Bayley-III might overestimate development compared
to the Bayley Scales of Infant Development, second edition, thus leading to lower rates of
abnormal development.47 We therefore used a cut-off point of 70 instead of 55 for abnormal
composite cognitive and total motor scores. In addition, we studied the 25% lowest scores
on cognitive and motor outcomes to identify those children who scored worst. This was
not associated with the presence of placental lesions.
We also demonstrated that placental lesions are common in preterm infants. In our
group 94.5% of the placentas had one or more lesions. In fullterm placentas this is more
or less the opposite. Approximately 70% percent of the placentas of a normal, fullterm
population show normal histology. The largest group of placental lesions in a fullterm
population is AIUI (11%) followed by MVU (7%).37 In this study we found that the largest
group of placental lesions in preterm placentas was MVU (58%), followed by AIUI (33%).
The strength of this study was its prospective character. Most studies concerning
placental lesions and neurological impairment are retrospective, with a selected study
population. We studied a year cohort in which many children had no neurodevelopmental
problems. After excluding children with CP, we focused on milder neurodevelopmental
problems.
There are, however, several limitations to our study that we need to point out. Firstly,
we only included singletons so as to be certain that each infant was linked to its own
placenta. Placental lesions might also differ between twins, e.g. twin-to-twin transfusion.
Secondly, only eight children in our group had no placental lesions; the remainder had at
least one placental lesion. When determining the associations between placental lesions
and neurodevelopment, the comparison group consisted partly of infants with placental
lesions other than the one under study. Thirdly, we studied multiple placental findings
against multiple neurodevelopmental outcomes through several statistical tests. The risk
of a type I error should therefore be considered. Finally, we tested the children at toddler
age. More reliable neurodevelopmental outcomes are obtained at school age.
In conclusion, our study indicated that AIUI was associated with impaired cognitive
and motor skills at toddler age. In addition, after we had excluded the children with CP
with a GMFCS ≥3, none of the placental lesions were associated with neurodevelopmental
outcome at toddler age. For clinicians this finding might be the most relevant one to come
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Placental lesions and neurodevelopmental outcome at toddler age
out of this study because the majority of preterm-born children develop without severe
neurological disabilities.
Acknowledgements
This study was part of the research program of the postgraduate school for Behavioral
and Cognitive Neurosciences, (BCN), University of Groningen. Annemiek Roescher and
Elise Verhagen received financial support from the Junior Scientific Master Class of the
University of Groningen. We greatly acknowledge the help of Dr Titia van Wulfften Palthe
in Utrecht for correcting the English manuscript.
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Placental lesions and neurodevelopmental outcome at toddler age
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Dev Pathol 2003;6:435-48.
26. Redline RW. Villitis of unknown
etiology: noninfectious chronic
villitis in the placenta. Hum Pathol
2007;38:1439-46.
27. Khong TY, Bendon RW, Qureshi
F, et al. Chronic deciduitis in the
placental basal plate: definition and
interobserver reliability. Hum Pathol
2000;31:292-5.
28. Katzman PJ, Genest DR. Maternal
floor infarction and massive perivillous
fibrin deposition: histological
definitions, association with
intrauterine fetal growth restriction, and
risk of recurrence. Pediatr Dev Pathol
2002;5:159-64.
29. Redline RW, Ariel I, Baergen RN, et
al. Fetal vascular obstructive lesions:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2004;7:443-52.
30. Altshuler G, Arizawa M, MolnarNadasdy G. Meconium-induced
umbilical cord vascular necrosis
and ulceration: a potential link
between the placenta and poor
pregnancy outcome. Obstet Gynecol
1992;79:760-6.
31. Ohyama M, Itani Y, Yamanaka M, et
al. Maternal, neonatal, and placental
features associated with diffuse
5
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Placental lesions and neurodevelopmental outcome at toddler age
chorioamniotic hemosiderosis,
with special reference to neonatal
morbidity and mortality. Pediatrics
2004;113:800-5.
32. Lewis S, Perrin E. Pathology of the
Placenta. Churchill Livingstone, 1999.
33. Ogino S, Redline RW. Villous
capillary lesions of the placenta:
distinctions between chorangioma,
chorangiomatosis, and chorangiosis.
Hum Pathol 2000;31:945-54.
34. Baergen RN. Cord abnormalities,
structural lesions, and cord
“accidents”. Semin Diagn Pathol
2007;24:23-32.
35. Bayley N. Bayley Scales of Infant and
Toddler Development. San Antonio, TX,
USA: The Psychological Corporation: ,
2005.
36. Achenbach TM RL. Manual for the
ASEBA Preschool Forms and Profiles.
Burlington, VT, USA: University of
Vermont, Research Center for Children,
Youth and Families; 2000.
37. Pathak S, Lees CC, Hackett G, Jessop
F, Sebire NJ. Frequency and clinical
significance of placental histological
lesions in an unselected population
at or near term. Virchows Arch
2011;459:565-72.
38. Soraisham AS, Trevenen C,
Wood S, Singhal N, Sauve R.
Histological chorioamnionitis and
neurodevelopmental outcome
in preterm infants. J Perinatol
2013;33:70-5.
39. Wu YW, Colford JM,Jr.
Chorioamnionitis as a risk factor for
cerebral palsy: A meta-analysis. JAMA
2000;284:1417-24.
40. Chau V, Poskitt KJ, McFadden DE, et
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al. Effect of chorioamnionitis on brain
development and injury in premature
newborns. Ann Neurol 2009;66:155-64.
41. Horvath B, Grasselly M, Bodecs
T, Boncz I, Bodis J. Histological
chorioamnionitis is associated with
cerebral palsy in preterm neonates.
Eur J Obstet Gynecol Reprod Biol
2012;163:160-4.
42. Redline RW, Minich N, Taylor HG, Hack
M. Placental lesions as predictors
of cerebral palsy and abnormal
neurocognitive function at school
age in extremely low birth weight
infants (<1 kg). Pediatr Dev Pathol
2007;10:282-92.
43. Rovira N, Alarcon A, Iriondo M, et al.
Impact of histological chorioamnionitis,
funisitis and clinical chorioamnionitis
on neurodevelopmental outcome
of preterm infants. Early Hum Dev
2011;87:253-7.
44. Dammann O, Leviton A. Maternal
intrauterine infection, cytokines, and
brain damage in the preterm newborn.
Pediatr Res 1997;42:1-8.
45. Dammann O, Leviton A. Infection
remote from the brain, neonatal white
matter damage, and cerebral palsy
in the preterm infant. Semin Pediatr
Neurol 1998;5:190-201.
46. Thomas W, Speer CP.
Chorioamnionitis: important risk factor
or innocent bystander for neonatal
outcome? Neonatology 2011;99:17787.
47. Bos AF. Bayley-II or Bayley-III: what
do the scores tell us? Dev Med Child
Neurol 2013;55:978-9.
Placental lesions and neurodevelopmental outcome at toddler age
5
111
General introduction and outline of the thesis
1
112
6
General introduction and outline of the thesis
Chapter 6
1
Placental lesions and functional outcomes at early school age of
children born between 32 and 35 weeks’ gestational age
Annemiek M Roescher
Albertus Timmer
Koenraad NJA Van Braeckel
Elise A Verhagen
Jorien M Kerstjens
Sijmen A Reijneveld
Jan Jaap HM Erwich
Arend F Bos
Submitted
113
Abstract
Objective: To determine whether the presence of placental lesions were associated with
functional outcome at 7 years of age in children born between 32 and 35 weeks GA.
Method: This study was part of a larger community based cohort study. We included
44 moderately and late preterm born, singleton children from whom the placenta was
available for examination. The placentas were assessed for pathology. Cognitive and
motor outcomes were assessed at a median age of 6.9 years.
Results: Almost 80 percent of the placentas showed one or more lesions. In the presence
of maternal vascular underperfusion (MVU) we found lower total IQ scores (mean [SD]
97.8 [7.2] vs 105.0 [8.3]) and verbal IQ scores (mean 100.4 [8.9] vs 109.1 [9.1]) (P=.017
and, P=.003 respectively). In the presence of ascending intrauterine infection (AIUI) we
found lower total motor outcome percentile scores (median 32.1 vs 53.5, P=.028). Other
placental lesions were not associated with cognitive or motor outcome.
Conclusion: Placental lesions consistent with MVU are associated with lower IQ scores,
whereas placental lesions indicating AIUI are associated with impaired motor skills at early
schoolage. These findings suggest that placental lesions might be an early indicator for
impaired outcome later in life.
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Introduction
Preterm birth is a major contributor to long-term neurodevelopmental problems.1 This not
only holds true for early preterm birth, i.e. infants born at < 32 weeks’ gestational age
(GA), but also for moderately preterm-born (GA 32-34 weeks) and late preterm-born (GA
34-36 weeks) children.2-4 The outcomes of moderately preterm-born and late pretermborn children as a group are less well studied than those of preterm-born children of
< 32 weeks GA and fullterm-born children. It is known that compared to their fulltermborn counterparts, moderately preterm-born and late preterm-born children are at risk of
developmental delays at preschool age2 and at early school age they obtain lower scores
on intelligence tests and their neuropsychological functioning is poorer.3
Placental lesions may cause preterm birth and may have major implications for the
child if placental function is impaired. Placental lesions are known to be associated with
adverse functional outcomes in very preterm and fullterm infants.5-8 Whether this also
holds for moderate and late preterm infants is unknown, but would seem likely. Available
evidence suggests that several placental lesions are associated with neonatal morbidities
in preterm infants.9 This association may be even more apparent in moderate and late
preterm infants because rates of neonatal complications, which frequently confound
findings on the association between placental lesions and functional outcomes, are much
lower in these two groups. Moderate and late preterm birth offers an excellent opportunity
to bypass this confounding effect of non-placenta-related neonatal complications.
A better understanding of the association between placental lesions and cognitive and
motor outcomes in later life is necessary to identify placenta-related risks for developmental
problems. Such an understanding could provide clues for early interventions to improve
functional outcomes. The objective of this study was, therefore, to determine whether the
presence of placental lesions in general, and specific placental lesions in particular, were
associated with functional outcomes at the age of seven in children born between 32 and
35 weeks’ GA. We hypothesized that in case of placental lesions functional outcomes
would be poorer.
6
Methods
In this community-based cohort study we related placental lesions to functional outcomes
at seven years of age.
Study population
Our cohort consisted of forty-four moderate and late preterm-born, singleton children,
who participated in the Longitudinal Preterm Outcome Project (LOLLIPOP). LOLLIPOP is
a large prospective, community-based cohort study designed to investigate the growth,
development, and general health of preterm-born children. Within LOLLIPOP we focused
moderately preterm-born and late preterm-born children. From the northern part of the
Netherlands, were our hospital is situated, we invited 248 moderate and late preterm-born
children, born without major chromosomal and congenital abnormalities, to participate in
115
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
follow-up testing at seven years of age .3
For the study reported on here, we selected the singleton, moderately preterm-born
and late preterm-born children who had participated in the above mentioned followup study (181). Of this group the placentas of 44 children, i.e. 24%, were available for
pathological examination. We determined whether this group, who were included in this
study, differed in terms of gender, GA, birth weight, small-for-gestational age (SGA), Apgar
scores, age, length, and weight at follow-up from the children whose placentas were not
available (excluded from this study). We found statistically significant lower mean GAs,
BWs, and a higher incidence of SGA among children whose placentas were available
(Table 1).
6
Table 1. Patient demographics, patient characteristics, and placental characteristics. Data are given
as median (range) or numbers (percentage)
Study populationa / exluded infantsb
Boys / girls
Gestational age, weeks
Birth weight, grams
Small for gestational age (P<10)
Apgar score at 5 min <6
Parental education levelc
Low
Middle
High
Placental weight, grams
Cord length, centimeters
Placenal lesions†
Maternal vascular underperfusion
Ascending intrauterine infection
Fetal thrombotic vasculopathy
Villitis of unknown etiology
Chronic deciduitis
Perivillous fibrinoid
Chorioamniotic hemosiderosis
Meconium
Placental markers
Elevated nucleated red blood cells
Chorangiosis
Follow up
Age at follow up, years
Length at follow up, centimeters
Weigth af follow up, kilogram
N = 44a
24/20 (55% / 45%)
34 (32-35)
2000 (1190-3710)
10 (22.7%)
2 (4.5%)
N = 137b
71/66 (52% / 48%)
34 (32-35) *
2400 (975-3900)*
12 (8.8%)*
3 (2.2%)
6 (13.6%)
16 (36.4%)
20 (45.5%)
373 (170-680)
33.5 (10-70)
35 (79.5%)
17 (38.6%)
8 (18.2%)
6 (13.6%)
5 (11.4%)
2 (4.5%)
0
0
4 (9.1%)
11 (25%)
3 (6.8%)
6.9 (6.8-7.0)
124 (111-135)
23 (17-35)
* P<.05
†
The summed number exceeds the total numbers, because a single placenta can have more than
one lesion.
Parental education level is defined as the mean of the highest education completed by mother and
c
father (low, elementary school; middle, high school or technical school; high, college or university),
n=2 are missing.
116
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Procedure and variables
Placental lesions
Placental lesions were assessed by using the histopathologic coupes of placentas that
had been obtained from the hospitals where the infants were born. These coupes were
reexamined by a perinatal pathologist (AT) in accordance with the guidelines published by
the British Royal College of Obstetricians and Gynaecologists and the Royal College of
Pathologists, and by the College of American Pathologists.9,10 The pathologist was blinded
as to clinical outcomes. We assessed all the placentas for lesions found in preterm and/
or fullterm infants and that may possibly be associated with neurodevelopment.5-7 Each
lesion was scored as either resent or absent.
The lesions were classified as placental pathology consistent with maternal vascular
underperfusion (MVU),11 ascending intrauterine infection (AIUI) with a maternal and/
or a fetal response,12 chronic villitis of unknown etiology (VUE),13 chronic deciduitis,14
perivillous fibrinoid,15 fetal thrombotic vasculopathy,16 meconium associated vascular
necrosis,17 chorioamniotic hemosiderosis,18 increased nucleated red blood cells (NRBCs),19
chorangiosis,20 and umbilical cord abnormalities.21 Table 2 presents the definition and
scoring criteria of these placental lesions. In addition, data on placental weights and
umbilical cord lengths were obtained.
6
117
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Table 2: Diagnostic terminology and definitions of the placental lesions
6
118
Diagnostic terminology
Definition and scoring criteria
Maternal vascular underperfusion
Decidual vasculopathy, e.g. incomplete or absent spiral artery remodeling, acute
atherosis, fibrinoid necrosis, or thrombosis; parenchymal pathology such as placental
hypoplasia, increased syncytial knotting, villous agglutination, increased perivillous
fibrin, distal villous hypoplasia, infarction, retroplacental hematoma.11
Ascending intrauterine infection
Acute inflammation of the extraplacental membranes and chorionic plate. Acute
chorioamnionitis and chorionitis represent the maternal response; chorionic or umbilical
vasculitis represents the fetal response.12
Villitis of unknown aetiology
Chronic lymphohistiocytic inflammation of the stem and chorionic villi, with or without
obliterative vasculopathy of stem villus vessels.13
Chronic deciduitis
Chronic lymphohistiocytic or plasmacytic inflammation of placental decidua.14
Maternal floor infarction / massive perivillous
fibrinoid deposition
Excessive perivillous fibrin deposition, either basally at a thickness of ≥3 mm on at least
one slide (maternal floor infarction) or transmural encasing ≥50% of villi on at least one
slide (massive perivillous fibrinoid deposition).15
Fetal thrombotic vasculopathy
Fetal vascular thrombosis, intimal fibrin cushions, fibromuscular sclerosis, hemorrhagic
endovasculitis and groups of at least five avascular fibrotic villi without inflammation or
mineralization and/or adherent thrombi in stem vessels.16
Meconium associated vascular necrosis
Meconium associated necrosis of smooth muscle cells in the wall of chorionic plate
vessels.17
Chorioamniotic hemosiderosis
Presence of hemosiderophages in the amnion and chorion.18
Elevated nucleated red blood cells
Only rare NRBCs are normal after the first trimester. More than two NRBC in a randomly
selected field of 4.5 mm2, corresponding to 18 consecutive fields at 40x magnification, or
one field at 10x magnification was considered as abnormal.19
Chorangiosis
Diffuse increase in the number of villous capillaries.20
Umbilical cord abnormalities
Obstruction or disruption of the umbilical cord blood flow (e.g. umbilical cord prolapse,
entanglement, knots, disrupted velamentous vessels, hyper/hypo-coiling).21
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Assessment of functional outcomes at seven years of age
The children and their parents were invited to visit University Medical Center Groningen
or a well-infant clinic in their neighborhood for a three-hour assessment consisting of
standardized neuropsychological tests. While their parents waited in the waiting room, each
child was tested individually by a trained psychologist, who was blind as to gestational age
and placental pathology . We assessed cognitive and motor outcomes.
With regards to cognitive outcomes we assessed total, verbal, and performance
intelligence with a shortened version of the Wechsler Intelligence Scale, third edition, Dutch
version (WISC-III-NL).22 We assessed visuomotor integration with the Design Copying Test,
a subtest of the Developmental Neuropsychological Assessment Battery, second edition,
Dutch version (NEPSY-2-NL).23 Verbal memory, including learning capacity, long-term
memory, and recognition, we assessed with the Dutch version of the Rey Auditory Verbal
Learning Test (AVLT).24 We assessed the attention skills required for effective functioning
at school with the following subtests of the Test of Everyday Attention for Children,
Dutch version (TEA-Ch-NL): Map Mission (selective attention), Score! (sustained auditory
attention), Same World (attention control), and Opposite World (inhibition).25
With regards to motor outcomes we used the Dutch version of the Movement Assessment
Battery for Children (Movement-ABC).26 We determined total motor performance, which is
based on subscale scores for manual dexterity (fine motor skills), ball skills, and static and
dynamic balance.
Additionally, we collected data on several neonatal and obstetrical characteristics
such as mode of delivery, GA, birth weight, gender, SGA, Apgar scores, and parental
education.
6
Statistical analysis
We used SPSS 20.0 software for Windows (SPSS Inc Chicago, Illinois, USA) for the
statistical analyses. For demographic characteristics, placental lesions, and outcome
scores at follow-up we used descriptive statistics . We present the outcome scores
as raw scores and percentiles, where appropriate. On the basis of the test scores and
following the tests’ manuals, we assigned the children to one of three categories: normal,
borderline, or abnormal. Subsequently, we assessed the association of outcome scores
with placental lesions. We did this in two ways. First, we assessed outcome measures
for no, one, or more than one placental lesion using regression analyses. Because GA
and parental education are known to be associated with outcome measures, we adjusted
for these variables. Finally, we assessed the association between outcome measures
and each specific placental lesion. We used linear regression models (‘enter’ method) for
all placental lesions occurring more than four times in the study group. We once again
adjusted for GA and parental education and entered these variables into a second model.
A predetermined P value of < .05 was considered statistically significant.
119
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Results
Study population characteristics
We present the perinatal and follow-up characteristics of the study population in Table 1
and the follow-up outcomes of the entire group, irrespective of placental lesions, in Table 3.
Table 3: Outcome data at follow-up. We present raw test scores and percentiles of several tests (left
part) and number of children categorized as normal, borderline or abnormal (right part)
Variables
Test scores
Mean (SD)
Percentile scores
Median (P25-75)
Number of children categorized
Normal
Borderline
Abnormal
Total
WISCa
6
IQ-total
102.2 (8.6)
-
44
0
0
44
IQ-verbal
105.7 (9.9)
-
44
0
0
44
IQ-performance
98.5 (11.1)
-
41
3
0
44
7.6 (2.3)
-
29
14
1
44
Selective attention
11.8 (3.8)
37 (16-50)
34
7
3
44
Sustained attention
6.2 (2.7)
50 (18-75)
36
5
3
44
Attention control
37.3 (8.3)
50 (25-82)
41
3
0
44
Inhibition
48.6 (15.0)
50 (18-84)
37
4
3
44
Recall
36.2 (7.8)
55 (34-91)
41
2
0
43
Delayed recall
7.8 (2.2)
59 (25-75)
36
6
1
43
Recognition
28.1 (1.9)
-
-
-
-
43
Total motor skills
4.7 (4.6)
44 (26-78)
38
3
3
44
Manual dexterity
1.4 (2.2)
-
41
0
3
44
Ball skills
1.7 (1.7)
-
31
8
5
44
Balance
1.2 (2.1)
-
36
4
4
44
NEPSY
b
Visuomotor
TEACh
c
AVLTc
Movement ABC
c
Abbreviations: WISC – Wechsler Intelligence scale; NEPSY – Developmental Neuropsychological
Assessment battery; TEACh – Test of Everyday Attention for Children; AVLT – Auditory Verbal
Learning Test; Movement ABC – Movement Assessment Battery for Children.
a: Test score: Intelligence quotient. Categorized: normal ≥85; borderline 70-84; abnormal <70.
b: Test score: Scaled score. Categorized: normal ≥7; borderline 3-6; abnormal <3.
c: Test score: raw scores. Categorized: normal p ≥15; borderline p5-14; abnormal p<5.
120
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Placental lesions
See Table 1 for the distribution of placental lesions. We found no lesions in nine out of fortyfour placentas (20.5%). Eighteen placentas showed one lesion and seventeen showed
more than one lesion. The maximum number of lesions was three. The largest group of
placental lesions consisted of MVU, in seventeen placentas, followed by AIUI in eight.
All eight placentas with AIUI showed a maternal response, while six placentas showed a
fetal response in addition to the maternal response. Chronic deciduitis occurred twice and
chronic chorioamnionitis once. Both lesions were, therefore, not included in the analyses
with outcome measures. Perivillous fibrinoid deposition, chorioamniotic hemosiderosis,
and meconium-associated vascular necrosis did not occur in our study population.
6
Association between placental lesions and cognitive outcomes
The number of placental lesions in general was not associated with cognitive outcomes
(Table 4). After adjustment for gestational age and parental education, scores on selective
attention became marginally better with more placental lesions (P = .048, Table 4).
Regarding specific placental lesions, only MVU was associated with IQ (Table 5). In the
presence of MVU we found lower total IQ scores (mean 97.8, SD 7.2 versus mean 105.0,
SD 8.3) and verbal IQ scores (mean 100.4, SD 8.9 versus mean 109.1, SD 9.1) (P = .017
and P = .003, respectively). In the presence of MVU the unstandardized coefficient (B) was
-7.1 for total IQ, which explains a decline of 7.1 IQ points in the presence of MVU. For
verbal IQ we found a B of -8.7. MVU was not associated with performance IQ (P = .340)
When we assigned the children to either one of the three categories normal, borderline,
or abnormal in accordance with their outcomes scores, none of the placental lesions were
associated with outcome.
121
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Table 4 Relation of cognitive and motor outcomes and the presence of placental lesions
Outcome scores
No placental lesions
1 placental lesion
≥2 placental lesions#
N= 9 (SD)
N=18 (SD)
N=17 (SD)
IQ-total
106.1 (9.0)
99.6 (5.1)
IQ-verbal
110.6 (8.3)
IQ-performance
101.4 (12.9)
7.7
F
P
F†
P†
102.9 (9.3)
1.934
.158
0.527
.595
104.4 (8.2)
104.6 (11.8)
1.379
.263
0.856
.434
94.6 (9.7)
101.1 (10.9)
1.998
.149
0.503
.609
7.7
7.4
(2.1)
0.085
.919
0.115
.892
Intelligence (IQ)
Visuomotor
a
(1.7)
(2.7)
Verbal memory
Recallb
Delayed recall
6
b
Recognitionc
46.9 (29.3)
63.2 (27.0)
60.9 (32.5)
0.964
.390
0.638
.535
59.1 (30.6)
57.0 (26.6)
48.5 (29.5)
0.539
.587
1.087
.349
27.6 (2.7)
27.9 (1.8)
28.6 (1.4)
1.066
.354
0.363
.698
23.8 (17.0)
34.0 (25.2)
41.7 (19.9)
1.992
.149
3.331
.048*
Attention
Selectiveb
Sustained
43.4 (25.4)
43.3 (35.7)
53.4 (33.4)
0.486
.618
1.008
.376
Attention controlb
46.6 (33.7)
53.7 (23.2)
55.1 (31.3)
0.276
.761
0.540
.588
Inhibitionb
45.7 (35.4)
50.6 (36.3)
53.4 (30.7)
0.152
.859
0.375
.690
54.1 (30.3)
48.0 (32.0)
48.9 (26.0)
0.137
.872
0.299
.744
Manual dexterity
1.7
(2.2)
1.9
(2.8)
0.8
(1.2)
1.308
.281
0.079
.191
Ball skillsd
1.9
(2.1)
1.6
(1.6)
1.7
(1.6)
0.104
.902
0.106
.900
Balance
0.7
(1.0)
1.1
(2.7)
1.6
(1.9)
0.681
.512
0.620
.544
b
Motor skills
Totalb
d
d
Data are mean (SD). P values of the F tests in ANOVA. Higher scores represent better performance
on the subtests, except for Attention control, inhibition, and all motor skills.
#: with a maximum of 3 placental lesions.
†: adjusted for parental education and gestational age in ANOVA.
*: P <.05
a: scaled score, higher score represent better performance
b: percentile scores
c: raw scores, higher score represent better performance
d: raw scores, higher scores represent worse performance
Association between placental lesions and motor outcomes
The number of placental lesions in general was not associated with motor outcomes (Table 4).
With regards to specific placental lesions only AIUI was associated with motor outcomes
(Table 5). In the presence of AIUI we found lower total motor outcome percentile scores
(mean 32.1, SD 19.8 versus mean 53.5, SD 29.3, P = .048). AIUI with a fetal response was
associated with lower total motor outcome scores (median 26.2, SD16.2 versus median
53.3 SD 28.8, P = .031) (Figure 1).
After assigning the children to one of the three categories normal, borderline, or
abnormal, only AIUI and AIUI with a fetal response, were associated with poorer static and
dynamic balance (P = .035 and P = .085, respectively), but not with total motor skills.
122
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Table 5 Relation of cognitive and motor outcome scores and placental lesions, using multivariable
linear regression models
Variable
B†
95% CI for B†
Beta†
R2†
P-value†
Beta††
P-value††
MVU
-7.10
-12.86 to -1.34
-.41
17.8
.017*
-.35
.033*
AIUI
0.74
-6.23 to 7.70
.03
17.8
.832
.15
.288
FTV
0.88
-7.11 to 8.87
.04
17.8
.825
-.04
.787
VUE
0.16
-8.15 to 8.46
.01
17.8
.969
.23
.119
↑NRBCs
1.39
-4.52 to 7.29
.07
17.8
.637
.01
.935
MVU
-0.69
-2.30 to 0.93
-.15
7.7
.396
-.31
.114
AIUI
1.08
-0.88 to 3.03
.19
7.7
.217
.19
.280
FTV
1.01
-1.23 to 3.25
.16
7.7
.366
.27
.176
VUE
0.12
-2.21 to 2.45
.02
7.7
.918
.01
.937
NRBCs
-0.60
-2.26 to 1.06
-.12
7.7
.469
-.06
.743
MVU
-4.93
-26.73 to 16.72
-.08
3.6
.647
-.17
.394
AIUI
-7.53
-33.68 to 18.62
-.10
3.6
.563
-.08
.674
FTV
5.37
-26.52 to 37.27
.06
3.6
.735
-.01
.976
VUE
10.60
-20.57 to 41.77
.12
3.6
.495
.20
.304
↑NRBCs
2.10
-20.10 to 24.29
.03
3.6
.849
.03
.860
MVU
-2.66
-18.66 to 13.35
-.06
7.6
.739
-.13
.507
AIUI
-0.63
-19.99 to 18.73
-.01
7.6
.948
.04
.818
FTV
12.57
-9.64 to 34.78
.20
7.6
.259
.28
.169
VUE
0.89
-22.19 to 23.97
.01
7.6
.938
.06
.729
↑NRBCs
10.85
-5.56 to 27.27
.21
7.6
.189
.28
.116
MVU
-11.01
-30.93 to 8.91
-.19
13.5
.270
-.27
.159
AIUI
-27.22
-51.31 to -3.12
-.37
13.5
.028*
-.36
.041*
IQ-total
a
Visuomotor integrationb
6
Verbal memoryc
Selective attentiond
Total motor skills
d
FTV
-4.93
-32.57 to 22.71
-.06
13.5
.720
-.06
.772
VUE
-11.02
-39.74 to 17.71
-.12
13.5
.442
-.07
.671
↑NRBCs
3.34
-17.09 to 23.76
.05
13.5
.743
.05
.767
Abbreviations: MVU – maternal vascular underperfusion; AIUI – ascending intrauterine infection;
FTV – fetal thrombotic vasculopathy; VUE – villitis of unknown etiology; NRBCs – nucleated red
blood cells.† Model 1: all placental lesions for outcome measures, method enter.
††
Model 2: all placental lesions, gestational age, and parental education for outcome measures,
method enter.
*: P <.05
a: Intelligence quotient
b: scaled score, higher score represent better performance
c: Verbal memory: recall, percentile score
d: percentile scores
123
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Movement-ABC percentile score
100
6
*
*
80
60
40
20
0
absent
present
AIUI
absent
present
* P <.05
AIUI with fetal
response
Figure 1: Total Movement-ABC scores in the presence or absence of AIUI with and without a fetal
response.
Data are shown in box and whisker plots.
Abbreviations: AIUI – ascending intrauterine infection; Movement-ABC – Movement Assessment
Battery for Children.
124
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
Discussion
Our study showed that placental lesions in general hardly associated with functional
outcomes in moderately preterm-born and late preterm-born children at early school age.
Only the presence of one or more placental lesions was marginally associated with better
selective attention. On considering specific placental lesions, however, we found a strong
association between the presence of MVU and lower total IQ scores and between the
presence of AIUI and poorer motor skills. Other placental lesions were not associated with
cognitive or motor functioning. Our hypothesis that functional outcomes would be poorer
in the presence of placental lesions was thus confirmed for MVU and AIUI, but not for other
placental lesions.
The presence of placental lesions in general was not associated with outcome scores.
We only found that the presence of one or more placental lesions in general were marginally
associated with better selective attention. This is not supported by the literature and may be
a chance finding due to multiple testing. The presence of any placental lesion, unspecified,
might also be too broad an operationalization to find any associations. We draw attention
to the fact that almost 80% of the moderately preterm-born and late preterm-born children
in our study had one or more placental lesions.
We did find associations between specific placental lesions and functional outcomes,
in particular for placental lesions with signs of MVU and AIUI. MVU was associated with
lower IQ scores. We found a decline of 7.1 IQ points on total IQ in the presence of MVU.
This is almost one SD lower compared to the group without MVU (SD = 8.3), which
constitutes a relevant IQ difference. Only a few other studies addressed the association
between MVU and cognition, albeit in early preterm infants.6,33 Van Vliet et al. found poorer
mental development in the presence of MVU compared to AIUI at the age of two. At
seven years they found better, although not significant, mental and motor development
in the presence of AIUI compared to MVU, suggesting lower scores in the presence of
MVU.33 These findings suggest a similar association between MVU and IQ in moderately
preterm-born and late preterm-born children. Conversely, Redline et al. did not find an
association at school age between MVU and cognitive measures, including executive
functions and memory, in early preterm-born children.6 They did not, however, investigate
IQ. We also did not find an association between MVU and memory tests, but we did find an
association between MVU and IQ. IQ scores are a global indication for cognition, whereas
visuomotor integration, memory, and attention tests are more specific. This may explain
why we only found differences concerning MVU and cognition on IQ scores and not on
specific subtests.
An explanation for lower IQ scores in the presence of MVU may be due to the chronic
nature of MVU. The onset of MVU occurs more than one week prior to delivery,36 and is
caused by inadequate spiral artery remodeling leading to decidual vasculopathy.11 Decidual
vasculopathy may result in placental underperfusion leading to a lasting non-optimal
intrauterine environment. This in turn may lead to some degree of cerebral underperfusion
resulting in lower cognition scores at school age. Another possibility is that due to the
6
125
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
lasting non-optimal intrauterine environment the infant is more susceptible to the inherent
stress of delivery leading to intrapartum complications.5 Finally, it might also be a chance
finding since we assessed multiple associations.
The second placental lesion that we found to be associated with outcome measures
was AIUI. AIUI was associated with poorer motor skills, particular in the case of AIUI with
a fetal response. These findings are consistent with the literature. AIUI is known to be
associated with poorer motor outcomes in early preterm and in fullterm infants.5,7,8,37,38 We
now add that this association is also potentially present in moderately preterm-born and
late preterm-born children. Notably, we found a stronger association between AIUI and
motor outcomes in the presence of a fetal response. Other studies also reported that the
association between AIUI and motor outcomes is predominantly seen in the presence of
AIUI with a fetal response in the placenta.5,7,8
Several hypotheses have been proposed to explain the association between AIUI
and motor outcomes. The first hypothesis concerns the presence of cytokines in fetal
circulation and postulates that the elevated blood and brain cytokine levels resulting
from AIUI might lead to central nervous system damage in the fetus. The inflammatory
cytokines can be neurotoxic and inhibit oligodendrocytes from developing white matter.3841
Another possible explanation is the multiple hit hypothesis.42 This hypothesis addresses
the etiology of retinopathy of prematurity. Dammann et al. explained that multiple hits of
exposure to inflammation might contribute to the risk of retinopathy of prematurity.42 This
might also be the case for motor outcome. Postnatal inflammatory exposure in addition to
AIUI might be an additional risk factor for developing poorer motor skills in later life.
The strength of this study is that to the best of our knowledge we are the first to study
the association between placental lesions and functional outcomes in moderate and late
preterm infants. We do, however, point out a few limitations too. to. First, the placentas of
only 24% of the children initially tested in LOLLIPOP and who met our inclusion criteria
were available for pathological examination. This 24% may constitute a biased group
because the placentas had probably not been submitted for examination without reason.
In comparison to the children whose placentas had not been sent to the pathologist,
we found that the children whose placentas were available had lower GAs, lower birth
weights, and a higher percentage were SGA. This suggests that the children included in
our study were more at risk of adverse outcomes than the children whose placentas were
not available.
Secondly, almost 80% of the children in our study group were born with one or more
placental lesions. When determining the associations between a specific placental lesions
and outcomes, the comparison group consisted partly of children with placental lesions
other than the one under study, which may have led to a degree of underestimation of the
real differences.
In conclusion, our study indicated that in moderately preterm-born and late pretermborn children MVU was associated with lower IQ scores and AIUI with impaired motor
skills at early school age. These findings suggest that placental lesions might be early
6
126
Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
indicators of impaired outcome later in life. Placental lesions should, therefore, be taken
into account when evaluating the functional outcomes of all preterm-born children.
Acknowledgements
This study was part of the research program of the postgraduate school for Behavioral and
Cognitive Neurosciences, University of Groningen. Annemiek Roescher received financial
support from the Junior Scientific Master Class of the University of Groningen. We greatly
acknowledge the help of Dr Titia van Wulfften Palthe in Utrecht for correcting the English
manuscript.
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of children born between 32 and 35 weeks’ gestational age
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41. Horvath B, Grasselly M, Bodecs
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43. Pathak S, Lees CC, Hackett G, Jessop
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Placental lesions and functional outcomes at early school age
of children born between 32 and 35 weeks’ gestational age
6
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132
Part IV
Disease Mechanisms of Placental Lesions Leading
to Neurological Morbidity
Chapter 7
In preterm infants ascending intrauterine infection is associated
with lower cerebral tissue oxygen saturation and higher oxygen
extraction
Chapter 8
Cytokine Response in Preterm Infants with Placental Lesions
133
General introduction and outline of the thesis
1
134
7
General introduction and outline of the thesis
Chapter 7
1
In preterm infants ascending intrauterine infection is
associated with lower cerebral tissue oxygen saturation
and higher oxygen extraction
Annemiek M Roescher
Albertus Timmer
Michelle E van der Laan
Jan Jaap HM Erwich
Arend F Bos
Elisabeth MW Kooi
Elise A Verhagen
Provisionally accepted, Pediatric Research
135
Abstract
Background Placental lesions are associated with neurological morbidity but the
mechanism leading to morbidity is unclear. To provide insight into such a possible
mechanism we determined whether placental lesions were associated with regional
cerebral tissue oxygen saturation (rcSO2) and fractional tissue oxygen extraction (FTOE)
in preterm infants during their first five days after birth. We hypothesized that as a result
of cerebral hypoperfusion, regional cerebral tissue oxygen saturation would be lower and
fractional tissue oxygen extraction would be higher.
Method A prospective, observational study of 42 preterm infants (GA <32wk). The infants’
placentas were examined for histopathology. We measured rcSO2 and transcutaneous arterial
oxygen saturation on days one to five. FTOE was calculated as FTOE = (transcutaneous
arterial oxygen saturation – rcSO2)/transcutaneous arterial oxygen saturation.
Results Only three placentas showed no pathology. Ascending intrauterine infection was
associated with lower rcSO2 and higher FTOE values on days two, three, and four (P≤.05).
Other placental lesions were not associated with rcSO2 and FTOE.
Conclusion Ascending intrauterine infection is associated with lower rcSO2, and higher
FTOE shortly after birth. The effect it has on cerebral oxygenation might be the mechanism
leading to neurodevelopmental problems.
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Introduction
The placenta is the link between mother and fetus during pregnancy and as such it is
an essential organ for the development of the fetus. It is the only organ that enables the
exchange of nutrients and oxygen from mother to fetus and that removes fetal waste
products.1 Placental lesions carry the risk of fetal hypoxia, neonatal morbidity, and even
perinatal death.2-6 Moreover, such lesions are associated with several neurological problems
including intraventricular hemorrhage, white matter injury, cerebral palsy, and long-term
neurodevelopmental problems.7-13
To date the mechanism whereby placental lesions lead to cerebral damage is
unclear. One study hypothesized that chronic placental insufficiency could induce fetal
hypoxia which in turn could result in cerebral hypoperfusion which leads to cerebral
damage.14 Longstanding placental hypoperfusion can result in a non-optimal intrauterine
environment. The placental underperfusion can lead to a reduction of perfusion surface
and, as a consequence, non-optimal oxygen delivery to the fetal circulation. This might
result in some degree of intrauterine cerebral underperfusion, and as a consequence
to a (transitional) effect on postnatal cerebral blood flow. On the other hand, cerebral
hyperperfusion could also lead to cerebral damage.15 Understanding the mechanism of
placental lesions leading to neurodevelopmental problems is necessary to provide possible
clues for early interventions aiming to improve neurological outcome. To determine
whether disturbances in hemodynamics shortly after birth could be a possible mechanism
underlying cerebral damage caused by placental lesions, it would be useful if we could
measure cerebral tissue oxygen saturation and extraction. A non-invasive method of
doing so is near-infrared spectroscopy (NIRS). It measures regional cerebral tissue oxygen
saturation (rcSO2). From this value fractional cerebral tissue oxygen extraction (FTOE) can
be calculated which reflects the balance between cerebral oxygen supply and cerebral
oxygen consumption.16
Our objective was to determine whether placental lesions were associated with
cerebral tissue oxygen saturation and extraction shortly after birth. We hypothesized that
in the presence of placental lesions cerebral tissue oxygen saturation would be lower due
to cerebral hypoperfusion.
7
137
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Methods
Patient population
Our cohort consisted of 42 preterm, singleton infants that had been admitted to the
neonatal intensive care unit of Beatrix Children’s Hospital in Groningen, the Netherlands,
between May 2006 and February 2008. The inclusion criteria were singleton birth and a
gestational age (GA) of less than 32 weeks. Infants with major chromosomal and congenital
abnormalities were not included. The review board of University Medical Center Groningen
approved the study. Written, informed parental consent was obtained in all cases.
The majority of the infants included in this study were also part of another study
concerning placental lesions and outcome.17 In that study we determined the relation
between placental lesions and early neurological outcome based on the quality of general
movements.
7
Placental lesions
A perinatal pathologist (AT) examined the placentas in accordance with the guidelines of the
Royal College of Obstetricians and Gynaecologists and the Royal College of Pathologists
in Britain, and of the College of American Pathologists.18-19 Apart from knowing the
infants’ GAs, the pathologist was blinded as to their clinical outcomes. We examined all
placentas for lesions suspected of having an association with neurological impairment.13-20
Such lesions are: placental pathology consistent with maternal vascular underperfusion
(MVU),21 ascending intrauterine infection (AIUI),22 chronic villitis of unknown origin,23 chronic
deciduitis,24 perivillous fibrinoid,25 fetal thrombotic vasculopathy,26 meconium-associated
vascular necrosis,27 chorioamniotic hemosiderosis,28 elevated nucleated red blood cells
(NRBCs),29 chorangiosis,30 and umbilical cord abnormalities.31 A single placenta can have
more than one lesion. All lesions presented in a single placenta were scored separately. In
Table 1 we present the diagnostic terminology and definitions of these placental lesions. In
addition to the placental lesions, we also collected data on placental weights and umbilical
cord lengths.
138
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Table 1: Diagnostic terminology and definition of the placental lesions
Diagnostic terminology
Definition and scoring criteria
Maternal vascular underperfusion
Decidual vasculopathy, e.g. incomplete or absent spiral artery remodelling, acute
atherosis, fibrinoid necrosis, or thrombosis; parenchymal pathology such as placental
hypoplasia, increased syncytial knotting, villous agglutination, increased perivillous
fibrin, distal villous hypoplasia, infarction, retroplacental hematoma.21
Ascending intrauterine infection
Acute inflammation of the extraplacental membranes and chorionic plate. Acute
chorioamnionitis and chorionitis represent the maternal response; chorionic or umbilical
vasculitis represents the fetal response.22
Villitis of unknown etiology
Chronic lymphohistiocytic inflammation of the stem and chorionic villi, with or without
obliterative vasculopathy of stem villus vessels.23
Chronic deciduitis
Chronic lymphohistiocytic or plasmacytic inflammation of placental decidua.24
Maternal floor infarction / massive perivillous
fibrinoid deposition
Excessive perivillous fibrin deposition, either basally at a thickness of ≥3 mm on at least
one slide (maternal floor infarction) or transmural encasing ≥50% of villi on at least one
slide (massive perivillous fibrinoid deposition).25
Fetal thrombotic vasculopathy
Fetal vascular thrombosis, intimal fibrin cushions, fibromuscular sclerosis, hemorrhagic
endovasculitis and groups of at least five avascular fibrotic villi without inflammation or
mineralization and/or adherent thrombi in stem vessels.26
Meconium associated vascular necrosis
Meconium associated necrosis of smooth muscle cells in the wall of chorionic plate
vessels.27
Chorioamniotic hemosiderosis
Presence of hemosiderophages in the amnion and chorion .28
Elevated nucleated red blood cells
Only rare NRBCs are normal after the first trimester. More than two NRBC in a randomly
selected field of 4.5 mm2, corresponding to 18 consecutive fields at 40x magnification, or
one field at 10x magnification was considered as abnormal.29
Chorangiosis
Diffuse increase in the number of villous capillaries.30
Umbilical cord abnormalities
Obstruction or disruption of the umbilical cord blood flow (e.g. umbilical cord prolapse,
entanglement, knots, disrupted velamentous vessels, hyper/hypo-coiling).31
7
139
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Near-infrared spectroscopy
We used an INVOS 4100 near-infrared spectrometer (Somanetics Corporation, Troy,
Michigan) in combination with the pediatric SomaSensor to obtain rcSO2 values. We
placed the Somasensor on the left frontoparietal side of the infant’s head and it was held
in place by elastic bandaging. A more detailed description of the method was published
previously.32
We measured rcSO2 within the first 24 hours after birth and subsequently on the
second, third, fourth, and fifth days. On these days rcSO2 was measured over a clinically
stable two-hour period. Fifteen minutes were allowed for stabilization of the measurement.
Simultaneously, we measured arterial oxygen saturation (SpO2) by pulse oximetry. We
calculated FTOE with the equation FTOE = (SpO2 – rcSO2) / SpO2 .16
Clinical variables
Prospectively, we collected details on perinatal and neonatal characteristics that might
influence hemodynamics. These included GA, birth weight, small-for-gestational age
(SGA), Apgar score, umbilical cord pH, birth asphyxia, early- and late-onset sepsis (culture
proven), clinical infection, C-reactive protein (CRP), intraventricular hemorrhage, signs of
circulatory failure, ventilatory status, patency of the ductus arteriosus, and medication.
Clinical infection was defined as maternal fever during labor and/or fetal tachycardia and/
or a CRP value ≥10 during the first 72 hours after birth, and/or positive blood cultures
during the first 48 hours after birth. Maternal and pregnancy variables included antihypertensive medication (labetalol, MgSO4, nifedipine), fetal growth restriction, preterm
pre-labor rupture of the membranes (PPROM), pre-eclampsia, and mode of delivery.
The infants’ heart rates, respiratory rates and mean arterial blood pressures were
recorded simultaneously with the rcSO2 and SpO2 measurements. Blood gas values,
blood glucose, and hemoglobin concentrations were recorded on the day of NIRS
measurements.
7
Statistical analysis
We used SPSS 20.0 software for Windows (SPSS Inc, Chicago, Illinois, USA) for the
statistical analyses. The rcSO2 and SpO2 values were collected every five seconds. The
mean values for rcSO2, SpO2, and FTOE were calculated for the 2-hour recording periods.
We used the Kolmogorov-Smirnov test to determine the normality of the rcSO2 and FTOE
values. Both showed a normal distribution. For the analyses of the relationships between
placental lesions and NIRS parameters we used univariate linear regression. We included
those placental lesions in our analyses which were 5 or more times present in our study
group.
When determining associations between a specific placental lesion and cerebral
oxygenation, the control group consisted of infants with no placental lesions and infants
with other placental lesions than the one under study. We used backward multiple linear
regression analyses to determine which variables were independently associated with
140
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
rcSO2 and FTOE throughout the analyses. For placental lesions we chose a univariate level
of significance of P≤.05 to be included into the multivariate analyses. Variables that were
potential confounders and differed between the group with and without a placental lesion
were included in the regression analyses at P<.1. A predetermined P value of <.05 was
considered statistically significant.
Results
We present the patient characteristics in Table 2. No infants died during the first five
days after birth. Four infants died between six and nineteen days after birth: three died of
respiratory and circulatory insufficiency due to sepsis and one infant died of gastrointestinal
perforation.
Placental lesions
Out of the 42 placentas we examined only three showed no lesions (Table 2). The largest
group of placental lesions consisted of MVU (25 placentas). Sixteen placentas, representing
the second largest group, showed signs of AIUI. A maternal response was present in 15
placentas, a fetal response in 13 placentas, a maternal and fetal response was present in
12 placentas. In 25 placentas we found more than one placental lesion.
7
141
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Table 2. Patient characteristics. Data are given as median (range) or numbers (percentage).
Study population
Male/female
Gestational age in weeks
Birth weight in grams
Small for gestational age (P<10)
Apgar score at 5 minutes
Umbilical cord pH
Cerebral lesions
Periventricular leukomalacia
Intracranial haemorrhage, grade 1-2
Intracranial haemorrhage, grade 3-4
Early-onset sepsis (culture proven)
Late-onset sepsis (culture proven)
Clinical infectiona
C-reactive protein (mg/L)b
Circulatory failure
Fluid resuscitation
Inotropes
Artificial respiration needed
Preterm pre-labour rupture of the membranes
Caesarean section (elective and emergency)
Placental weight in grams
Cord length in centimeters
Placental lesionsc
Maternal vascular underperfusion
Ascending intrauterine infection
Fetal thrombotic vasculopathy
Villitis of unknown etiology
Chronic deciduitis
Chorioamniotic hemosiderosis
Perivillous fibrinoid
Placental markers
Elevated nucleated red blood cells
Chorangiosis
7
a
N=42
20/22 (48% / 52%)
29.4 (25-32)
1230 (560-2250)
7 (17%)
8 (3-10)
7.22 (7.01-7.40)
17 (40%) (all grade 1)
8 (19%)
2 (5%)
2 (5%)
13 (31%)
8 (19%)
1 (1-112)
18 (43%)
2 (5%)
25 (60%)
13 (31%)
23 (55%)
260 (142-470)
28 (15-59)
39 (93%)
25 (60%)
16 (38%)
6 (14%)
6 (14%)
11 (26%)
1 (2%)
1 (2%)
20 (48%)
3 (7%)
Clinical infection was defined as maternal fever during labor and/or fetal tachycardia and/or a
CRP value ≥10 during the first 72 hours after birth, and/or positive blood cultures during the first 48
hours after birth
b
Highest CRP value during the first 72 hours after birth for each infant. From 20 infants no CRP
values were determined during the first 72 hours after birth.
c
The numbers exceed totals, because a single placenta can have more than one lesion.
Relationship between placental lesions and rcSO2 and FTOE
On the first day after birth none of the placental lesions were associated with rcSO2 or
FTOE.
142
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
On the second day the presence of AIUI was associated with lower rcSO2 and higher
FTOE (P=.05 and P=.04, respectively). AIUI with a fetal response was associated with
lower rcSO2 (P=.05) and higher FTOE (P=.06) although neither were statistically significant.
AIUI with a maternal response was also associated with lower rcSO2 (P=.11) and higher
FTOE (P=.07), but not significant. There was a trend towards an association between MVU
and higher rcSO2 (P=.08) and lower FTOE (P=.06).
On the third and fourth days AIUI was still associated with lower rcSO2 (day 3 P=.008,
day 4 P=.007) and higher FTOE (day 3 P=.01, day 4 P=.01). AIUI with a fetal response was
also associated with lower rcSO2 (day 3 P=.009, day 4 P=.002) and higher FTOE (day 3
P=.02 day 4 P=.002). AIUI with a maternal response was associated with lower rcSO2 values
(day 3 P=.05, day 4 P=.06) and higher FTOE values (day 3 P=.05 day 4 P=.09) although not
statistically significant. On the fourth day a tendency was seen for an association between
elevated NRBCs and lower rcSO2 (P=.09) and higher FTOE (P=.06).
On the fifth day after birth we found no association between AIUI and cerebral
oxygenation. Figure 1 shows the relation between AIUI and rcSO2 (A) and FTOE (B) during
the first five days after birth. SpO2 did not differ in the presence or absence of AIUI. No
other placental lesions were associated with rcSO2 or FTOE (Table 3) during the first five
days after birth.
A
7
B
*
100
**
Ascending
intrauterine
infection
**
*
0,50
Absent
Present
90
*
*
3
4
Ascending
intrauterine
infection
Absent
Present
0,40
rcSO2 (%)
80
FTOE
0,30
70
0,20
60
0,10
50
40
1
2
3
Days
4
5
0,00
1
2
Days
5
Figure 1: The course of rcSO2 (A) and FTOE (B) during the first five days after birth in the presence
and absence of ascending intrauterine infection
Data are shown in box and whisker plots. Dots represent outliers.
Significant differences between the two groups are marked with asterisks (* P<.05 and ** P<.01).
Abbreviations: rcSO2 – regional cerebral tissue oxygen saturation; FTOE – fractional tissue oxygen
extraction.
143
144
-9.48 to 6.85
-1.31
0.48
Chronic
deciduitis
FTV
↑ NRBCs
-12.35 to 5.92
-3.22
0.01
FTV
↑ NRBCs
-8.96 to 4.33
-11.87 to 4.71
-2.31
-3.58
-6.36
Chronic
deciduitis
FTV
↑ NRBCs
-12.44 to -2.11
-.31
-.16
-.13
.00
-.46
.15
.00
-.13
-.03
-.01
-.45
.21
-.02
-.05
-.06
-.07
-.32
.29
Beta
-1.78
-0.88
-0.71
0.02
-2.87
0.86
0.00
-0.72
-0.18
-0.05
-2.84
1.22
0.13
-0.33
-0.37
-0.40
-2.03
1.82
t
9.3
2.4
1.6
0.00
21.0
2.30
0.00
1.6
0.10
0.00
20.1
4.4
0.00
0.30
0.40
0.40
10
8.2
R
.09
.39
.48
.98
.007*
.40
.99
.48
.86
.96
.008*
.23
.90
.75
.71
.70
.05*
.08
P value
0.07
0.01
-0.00
-0.02
0.07
-0.03
-0.02
0.00
0.01
-0.00
0.08
-0.05
0.00
0.00
0.01
0.05
0.06
-0.05
B
FTOE
-0.00 to 0.14
-0.07 to 0.09
-0.07 to 0.06
-0.13 to 0.09
0.02 to 0.12
-0.08 to 0.03
-0.11 to 0.06
-0.09 to 0.10
-0.06 to 0.09
-0.11 to 0.10
0.02 to 0.13
-1.10 to 0.01
-0.08 to 0.08
-0.09 to 0.09
-0.05 to 0.07
-0.04 to 0.14
0.00 to 0.11
-0.11 to 0.00
95% CI for B
.33
.04
-.01
-.06
.43
-.17
-.09
.00
.07
-.02
.43
-.26
.00
.01
.07
.20
.33
-.31
Beta
1.93
0.24
-0.06
-0.32
2.62
-0.94
-0.54
0.00
0.37
-0.09
2.71
-1.58
0.02
0.06
0.42
1.22
2.15
-2.00
t
10.7
0.20
0.00
0.30
18.1
2.8
0.90
0.00
0.40
0.00
18.1
7.0
0.00
0.00
0.50
3.9
11.1
9.8
R2
.06
.81
.93
.75
.01*
.35
.59
.99
.71
.93
.01*
.13
.99
.95
.68
.23
.04*
.06
P value
* Indicates P≤.05. B indicates un-standardized coefficient, Beta indicates standardized coefficient.
ascending intrauterine infection; VUE - villitis of unknown etiology; FTV - fetal thrombotic vasculopathy; NRBCs - nucleated red blood cells.
Abbreviations: rc SO2 – regional cerebral tissue oxygen saturation; FTOE – fractional tissue oxygen extraction; MVU- maternal vascular underperfusion; AIUI -
-13.63 to 0.92
-11.37 to 11.60
-7.27
0.11
AIUI
-3.18 to 7.78
-8.36 to 8.39
VUE
2.30
MVU
Day 4
-7.60 to 6.39
-0.61
Chronic
deciduitis
-13.28 to -2.19
-10.74 to 10.18
-7.74
-0.28
AIUI
-2.34 to 9.28
-6.94 to 7.90
-9.75 to 6.57
VUE
3.47
MVU
Day 3
-6.51 to 4.50
-1.59
-1.01
VUE
-9.68 to -0.00
4.33
-4.84
MVU
-0.50 to 9.17
95% CI for B
AIUI
Day 2
B
2
7
Variable
rcSO2
Table 3: Univariate regression model for placental lesions and rcSO2 and for placental lesions and FTOE
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Clinical variables
To test whether the clinical variables we collected had confounded our findings regarding
AIUI and rcSO2 and FTOE, we performed multiple linear regressions. We first tested whether
these variables differed between the groups of infants with and without AIUI (P<.1).
Gestational age, birth weight, Apgar scores, umbilical cord pH, birth asphyxia, early- and
late onset sepsis, CRP, intraventricular hemorrhage, signs of circulatory failure, ventilatory
status, patency of the ductus arteriosus, medication (including antibiotic therapy for at
least 48 hours after birth), and maternal anti-hypertensive medication were not significantly
associated with AIUI in our group. The variables that differed were SGA, whether the mother
had preeclampsia, PPROM, and whether the child was delivered by Caesarean section.
On days three and four after birth, in the presence of AIUI, the infants’ heart rates were
higher: mean 155 versus 145.7 and 155.5 versus 148, i.e. P=.007 and P=.08, respectively.
We entered these variables into the regression model; separately for each day.
On day two the parameters applied in our final model for rcSO2 and FTOE consisted
of AIUI, whether the mother had preeclampsia, whether the infant was SGA, whether the
mother had PPROM, and whether the child was delivered by Caesarean section. The final
models for days three and four consisted of AIUI, whether the mother had preeclampsia,
whether the infant was SGA, whether the mother had PPROM, whether the child was
delivered by Caesarean section, and the infant’s heart rate.
On day two only preeclampsia remained significant in the regression model with rcSO2
and FTOE. On day three AIUI remained significant in the model for rcSO2. For FTOE only
SGA remained significant in the model. On day four only AIUI remained significant in the
regression model for rcSO2 (Table 4). AIUI, PPROM, and the infant’s heart rate remained
significant in the model for FTOE (Table 5).
The presence of a clinical infection was also associated with placentas showing signs
of AIUI. We did not adjust for this because the relation between AIUI and clinical infection
is interdependent and can therefore falsely affect our results. In a univariate analysis,
clinical infection was not associated with NIRS values during the first five days after birth
(independent t-test, P>.1)
7
145
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Table 4. Univariate and multiple linear regression model for AIUI and rcSO2.
Variable
B
95% CI for B
beta
t
R2
P value
-4.84
-9.68 to -0.00
-.32
-2.03
10
.05*
Day 2
Univariate
AIUI
Multivariatea
AIUI
-3.67
-8.67 to -2.47
-.24
-1.49
15.6
.15
Pre-eclampsia
4.38
-1.39 to 10.15
.25
1.54
15.6
.13
-7.74
-13.28 to -2.19
-.45
-2.84
20.1
.008*
AIUI
-5.98
-11.6 to -0.28
-.35
-2.14
28
.04*
SGA
6.44
-0.71 to 13.59
.30
1.84
28
.08
-7.27
-12.44 to -2.11
-.46
-2.87
21
.007*
-7.27
-12.44 to -2.11
-.46
-2.87
21
.007*
Day 3
Univariate
AIUI
Multivariate
7
b
Day 4
Univariate
AIUI
Multivariateb
AIUI
Abbreviations: rcSO2 – regional cerebral tissue oxygen saturation; AIUI - ascending intrauterine
infection; SGA - small-for-gestational age.
* Indicates P ≤.05. B indicates un-standardized coefficient, Beta indicates standardized coefficient.
a
corrected for potential confounders: whether the mother had pre-eclampsia, whether the child
was small-for-gestational age, whether there was preterm pre-labor rupture of the membranes,
whether the infant was delivered by Caesarean section.
b
corrected for potential confounders: whether the mother had pre-eclampsia, whether the child was
small-for-gestational age, whether there was preterm pre-labor rupture of the membranes, whether
the infant was delivered by Caesarean section, and the infant’s heart rate.
146
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Table 5. Univariate and multiple linear regression model for AIUI and FTOE.
Variable
B
95% CI for B
beta
t
R2
P value
0.06
0.00 to 0.11
.33
2.15
11.1
.04*
Day 2
Univariate
AIUI
Multivariatea
AIUI
0.04
-0.01 to 0.09
.23
1.48
21.3
.15
Pre-eclampsia
-0.07
-0.13 to -0.00
-.34
-2.16
21.3
.04*
0.08
0.02 to 0.13
.43
2.71
18.1
.01*
0.04
-0.02 to 0.10
.22
1.36
36.8
.19
Day 3
Univariate
AIUI
Multivariate
b
AIUI
Pre-eclampsia
-0.05
-0.11 to 0.02
-.24
-1.48
36.8
.15
SGA
-0.08
-0.15 to -0.01
-.36
-2.30
36.8
.03*
0.07
0.02 to 0.12
.43
2.62
18.1
.014*
0.11
0.06 to 0.17
.72
4.02
37.9
<.001*
7
Day 4
Univariate
AIUI
Multivariate
AIUI
b
PPROM
-0.06
-0.12 to -0.00
-.37
-2.15
37.9
.04*
Heart rate
-0.00
-0.01 to -0.00
-.44
-2.73
37.9
.01*
Abbreviations: FTOE – fractional tissue oxygen extraction; AIUI - ascending intrauterine infection;
SGA - small-for-gestational age; PPROM – preterm pre-labor rupture of the membranes.
* Indicates P≤.05. B indicates un-standardized coefficient, Beta indicates standardized coefficient.
a
corrected for potential confounders: whether the mother had pre-eclampsia, whether the child
was small-for-gestational age, whether there was preterm pre-labor rupture of the membranes,
whether the infant was delivered by Caesarean section.
b
corrected for potential confounders: whether the mother had pre-eclampsia, whether the child
was small-for-gestational age, whether there was preterm pre-labor rupture of the membranes,
whether the child was delivered by Caesarean section and the infant’s heart rate.
147
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
Subanalysis of the ascending intrauterine infection group
Of the 16 infants with AIUI, one had a culture proven early onset sepsis and three infants
had signs of a clinical infection. In the group of 16 infants with AIUI no difference was found
in cerebral tissue oxygen saturation and oxygen extraction in the presence or absence of
clinical / culture proven infection (P>.10).
Discussion
Our study indicated that AIUI was associated with lower rcSO2 and higher FTOE on the
second, third, and fourth days after birth. SpO2 did not differ in the presence or absence of
AIUI. During the first five days after birth we found no other placental lesions that associated
with rcSO2 and FTOE. Therefore, in the case of AIUI, our hypothesis that cerebral oxygen
saturation is lower in the presence of placental lesions was confirmed, albeit not for other
placental lesions.
The lower rcSO2 and higher FTOE in the presence of AIUI may be due either to reduced
cerebral oxygen supply or to higher cerebral oxygen consumption.33 Firstly, the reduced
cerebral oxygen supply might be the result of lower cerebral blood flow. Due to the presence
of AIUI, several immune-derived cytokines may be induced: interleukin (IL) -1, IL -6, and
tumor necrosis factor (TNF)–α.34 These cytokines are major initiators of the acute-phase
liver response that leads to an increase in chemokines, cytokines, and prostaglandins. In
turn, prostaglandin activation leads to vasodilatation.35 Such systemic vasodilatation may
lead to lower cerebral blood flow. We would expect to find lower blood pressures in the
presence of vasodilatation. Systemic blood pressure, however, did not differ between the
group with and without AIUI. We did find higher heart rates in the presence of AIUI. It is
possible that blood pressure is maintained through a higher heart rate. Conversely, it is
known that blood pressure in preterm infants is not a reliable measure of cardiac output
and, therefore, low cerebral blood flow.36 This means that in the presence of adequate
blood pressure microcirculation might be disturbed and end-organ perfusion is reduced.
As a consequence, it might be that in the presence of AIUI blood pressure is adequate, but
that the microcirculation is reduced. This could result in lower end-organ perfusion and,
therefore, lower cerebral oxygen supply, which explains higher FTOE. This is, however,
highly speculative. It is, for example, not supported by clinical findings as clear signs of
circulatory failure were absent in the infants with AIUI.
A second possible explanation for lower rcSO2 and higher FTOE was higher cerebral
oxygen consumption. Higher cerebral oxygen consumption may reflect increased cerebral
metabolic activity.33 We surmise that increased metabolic activity might be due to cytokine
activation in the presence of AIUI.
Our results could also be explained by higher rcSO2 and lower FTOE in the group
without AIUI compared to the group with AIUI. Even though our cohort consisted of
preterm infants, the etiology of their preterm births differed. Some infants were born
preterm after PPROM, while others were born following maternal or fetal indications such
as preeclampsia or fetal growth restriction. Indeed, we found a higher rate of preeclampsia
7
148
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
and SGA in the group without AIUI compared to the group with AIUI. It was suggested that
maternal anti-hypertensive drugs, often prescribed in cases of preeclampsia, are associated
with a decrease in cerebral oxygen consumption (↓FTOE).37 Nevertheless, we did not find
a difference in anti-hypertensive drug use between the group with and the group without
AIUI. Other factors that are presumed to be associated with a decrease in cerebral oxygen
consumption, e.g. medication for the infant like morphine and midazolam, did not differ on
the research days between the group with and without AIUI.37-38 Although we were unable
to find a difference in clinical variables that could affect cerebral oxygenation between the
group with and without AIUI, we could not completely exclude this option.
Another possibility is that the effect of AIUI on rcSO2 and FTOE is secondary to a
systemic inflammatory response in early onset sepsis. We did not find a relation between
the presence of AIUI and culture proven early onset sepsis (EOS). This can be due to the
small number of infants with EOS (n=2). We did find a relation between AIUI and clinical
infection. Clinical infection, however, was not associated with rcSO2 and FTOE.
Ascending intrauterine infection is known to be associated with neonatal morbidity, like
low Apgar scores shortly after birth, a higher incidence of neonatal infections, necrotizing
enterocolitis, and bronchopulmonary dysplasia.39-42 In addition, AIUI is also associated with
neurological problems such as intraventricular hemorrhages, periventricular leukomalacia,
cerebral palsy, and poorer neurodevelopmental outcomes at toddler and school ages.7,13,42,43
We now add the association between lower cerebral oxygen saturation, higher cerebral
oxygen extraction, and the presence of AIUI. To the best of our knowledge only one other
study investigated the relation between AIUI with a fetal response (fetal vasculitis) and
cerebral tissue oxygen saturation and extraction shortly after birth.44 These authors found
no difference in cerebral oxygenation in the presence or absence of AIUI with a fetal
response. In their study, however, cerebral oxygenation was only measured during the first
24 hours after birth. Likewise, in our study we also found no relation between AIUI and
cerebral oxygenation on the first day. During this transitional day, other factors might exert
more influence on cerebral oxygenation than AIUI. We did, however, find an association on
days two, three, and four.
It was suggested that during the first two weeks after birth cerebral oxygenation is
associated with neurodevelopmental outcome. Lower rcSO2 and higher FTOE are associated
with poorer neurodevelopmental outcome at two to three years of age.45 Ascending
intrauterine infection is also known to be associated with poorer neurodevelopmental
outcome.43 The status of cerebral oxygenation shortly after birth might be the mediating
factor for AIUI to lead to neurodevelopmental problems.
The strength of this study was that we investigated the relation between a broad
spectrum of placental lesions and cerebral oxygenation. This might contribute towards
gaining insight into the pathogenesis of placental lesions leading to neurological problems.
Nevertheless, we need to point out several limitations of our study. Firstly, only three children
in our group had no placental lesions. The others all had one or more placental lesions.
When determining associations between placental lesions and cerebral oxygenation, the
7
149
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
control group consisted partly of infants with other placental lesions than the one studied.
Because of the high incidence of placental lesions in a premature group, it is difficult to
include a large control group with no placental lesions. Secondly, we performed multiple
testing in the univariate analyses. We chose not to adjust our significance level, as this
was an explorative study. Thirdly, we only included singletons so as to be certain that each
infant was linked to its own placenta. Placental lesions might also differ between twins,
e.g. twin-to-twin transfusion. Finally, we studied rcSO2 and FTOE values during a 2-hour
stable period each day. These values, however, might be different during other moments
of the day. Mean arterial blood pressures were also studied during a 2-hour stable period,
and might therefore not be sufficient for the interpretation of hemodynamics.
Conclusion
Our study indicated that ascending intrauterine infection was associated with lower regional
cerebral tissue oxygen saturation and higher cerebral oxygen extraction on the second,
third, and fourth days after birth. Both ascending intrauterine infection and lower cerebral
oxygen saturation and a higher oxygen extraction shortly after birth are associated with
neurodevelopmental problems. The effect ascending intrauterine infection has on cerebral
oxygenation might be the mechanism that causes it to lead to neurodevelopmental
problems.
7
Acknowledgements
We greatly acknowledge the help of Dr. Titia Brantsma-van Wulfften Palthe in Utrecht
for correcting the English manuscript. This study was part of the research program of
the postgraduate school for Behavioural and Cognitive Neurosciences (BCN), University
of Groningen. Annemiek Roescher received financial support from the Junior Scientific
Master Class of the University of Groningen.
150
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
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32 weeks’ gestation. Am J Perinatol
1995;12:429-36.
10. Polam S, Koons A, Anwar M,
Shen-Schwarz S, Hegyi T.
Effect of chorioamnionitis on
neurodevelopmental outcome in
preterm infants. Arch Pediatr Adolesc
Med 2005;159:1032-5.
11. Leviton A, Allred EN, Kuban KC,
et al. Microbiologic and histologic
characteristics of the extremely
preterm infant’s placenta predict white
matter damage and later cerebral
palsy. the ELGAN study. Pediatr Res
2010;67:95-101.
12. Redline RW, Minich N, Taylor HG, Hack
M. Placental lesions as predictors
of cerebral palsy and abnormal
neurocognitive function at school
age in extremely low birth weight
infants (<1 kg). Pediatr Dev Pathol
2007;10:282-92.
13. Redline RW, O’Riordan MA. Placental
lesions associated with cerebral palsy
and neurologic impairment following
term birth. Arch Pathol Lab Med
2000;124:1785-91.
14. Blair E, de Groot J, Nelson KB.
Placental infarction identified by
macroscopic examination and risk of
cerebral palsy in infants at 35 weeks of
gestational age and over. Am J Obstet
Gynecol 2011;205:124.e1,124.e7.
15. Alderliesten T, Lemmers PM, Smarius
JJ, van de Vosse RE, Baerts W,
7
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In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
van Bel F. Cerebral oxygenation,
extraction, and autoregulation in very
preterm infants who develop periintraventricular hemorrhage. J Pediatr
2013;162:698,704.e2.
16. Naulaers G, Meyns B, Miserez M, et al.
Use of tissue oxygenation index and
fractional tissue oxygen extraction as
non-invasive parameters for cerebral
oxygenation. A validation study in
piglets. Neonatology 2007;92:120-6.
17. Roescher AM, Timmer A, Hitzert
MM, et al. Placental pathology and
neurological morbidity in preterm
infants during the first two weeks after
birth. Early Hum Dev 2014;90:21-5.
18. Royal College of Obstetricians and
Gynaecologists. Fetal and perinatal
pathology. Report of a joint working
party. London, UK: RCOG-press, 2001.
19. Langston C, Kaplan C, Macpherson
T, et al. Practice guideline for
examination of the placenta:
developed by the Placental Pathology
Practice Guideline Development Task
Force of the College of American
Pathologists. Arch Pathol Lab Med
1997;121:449-76.
20. Redline RW. Severe fetal placental
vascular lesions in term infants with
neurologic impairment. Am J Obstet
Gynecol 2005;192:452-7.
21. Redline RW, Boyd T, Campbell V, et
al. Maternal vascular underperfusion:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2004;7:237-49.
22. Redline RW, Faye-Petersen O, Heller
D, et al. Amniotic infection syndrome:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2003;6:435-48.
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23. Redline RW. Villitis of unknown
etiology: noninfectious chronic
villitis in the placenta. Hum Pathol
2007;38:1439-46.
24. Khong TY, Bendon RW, Qureshi
F, et al. Chronic deciduitis in the
placental basal plate: definition and
interobserver reliability. Hum Pathol
2000;31:292-5.
25. Katzman PJ, Genest DR. Maternal
floor infarction and massive perivillous
fibrin deposition: histological
definitions, association with
intrauterine fetal growth restriction, and
risk of recurrence. Pediatr Dev Pathol
2002;5:159-64.
26. Redline RW, Ariel I, Baergen RN, et
al. Fetal vascular obstructive lesions:
nosology and reproducibility of
placental reaction patterns. Pediatr
Dev Pathol 2004;7:443-52.
27. Altshuler G, Arizawa M, MolnarNadasdy G. Meconium-induced
umbilical cord vascular necrosis
and ulceration: a potential link
between the placenta and poor
pregnancy outcome. Obstet Gynecol
1992;79:760-6.
28. Ohyama M, Itani Y, Yamanaka M, et
al. Maternal, neonatal, and placental
features associated with diffuse
chorioamniotic hemosiderosis,
with special reference to neonatal
morbidity and mortality. Pediatrics
2004;113:800-5.
29. Lewis S, Perrin E. Pathology of the
Placenta. Churchill Livingstone, 1999.
30. Ogino S, Redline RW. Villous
capillary lesions of the placenta:
distinctions between chorangioma,
chorangiomatosis, and chorangiosis.
Hum Pathol 2000;31:945-54.
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction
31. Baergen RN. Cord abnormalities,
structural lesions, and cord
“accidents”. Semin Diagn Pathol
2007;24:23-32.
32. Verhagen EA, Keating P, ter Horst HJ,
Martijn A, Bos AF. Cerebral oxygen
saturation and extraction in preterm
infants with transient periventricular
echodensities. Pediatrics
2009;124:294-301.
33. Kissack CM, Garr R, Wardle SP,
Weindling AM. Cerebral fractional
oxygen extraction is inversely
correlated with oxygen delivery in the
sick, newborn, preterm infant. J Cereb
Blood Flow Metab 2005;25:545-53.
34. Hecht JL, Fichorova RN, Tang VF, et al.
Relationship Between Neonatal Blood
Protein Concentrations and Placenta
Histologic Characteristics in Extremely
Low GA Newborns. Pediatr Res
2011;69:68-73.
35. Hagberg H, Mallard C. Effect of
inflammation on central nervous
system development and vulnerability.
Curr Opin Neurol 2005;18:117-23.
36. Kluckow M, Evans N. Relationship
between blood pressure and cardiac
output in preterm infants requiring
mechanical ventilation. J Pediatr
1996;129:506-12.
37. Verhagen EA, Kooi EM, van den Berg
PP, Bos AF. Maternal antihypertensive
drugs may influence cerebral oxygen
extraction in preterm infants during the
first days after birth. J Matern Fetal
Neonatal Med 2013;26:871-6.
38. van Alfen-van der Velden AA, Hopman
JC, Klaessens JH, Feuth T, Sengers
RC, Liem KD. Effects of midazolam
and morphine on cerebral oxygenation
and hemodynamics in ventilated
premature infants. Biol Neonate
2006;90:197-202.
39. Beebe LA, Cowan LD, Altshuler G. The
epidemiology of placental features:
associations with gestational age and
neonatal outcome. Obstet Gynecol
1996;87:771-8.
40. Been JV, Zimmermann LJ. Histological
chorioamnionitis and respiratory
outcome in preterm infants. Arch Dis
Child Fetal Neonatal Ed 2009;94:F21825.
41. Kramer BW, Kallapur S, Newnham
J, Jobe AH. Prenatal inflammation
and lung development. Semin Fetal
Neonatal Med 2009;14:2-7.
42. Beaudet L, Karuri S, Lau J, Magee F,
Lee SK, von Dadelszen P. Placental
pathology and clinical outcomes
in a cohort of infants admitted to a
neonatal intensive care unit. J Obstet
Gynaecol Can 2007;29:315-23.
43. Rovira N, Alarcon A, Iriondo M, et al.
Impact of histological chorioamnionitis,
funisitis and clinical chorioamnionitis
on neurodevelopmental outcome
of preterm infants. Early Hum Dev
2011;87:253-7.
44. Sorensen LC, Maroun LL, Borch K,
Lou HC, Greisen G. Neonatal cerebral
oxygenation is not linked to foetal
vasculitis and predicts intraventricular
haemorrhage in preterm infants. Acta
Paediatr 2008;97:1529-34.
45. Verhagen EA, Van Braeckel KN,
van der Veere CN, et al. Neonatal
Cerebral Oxygenation is Associated
with Neurodevelopmental Outcome
of Preterm Infants at 2 to 3 Years of
Age. Archives of disease in childhood
2012;97:A30-1.
7
153
General introduction and outline of the thesis
1
154
8
General introduction and outline of the thesis
Chapter 8
1
Cytokine Response in Preterm Infants
with Placental Lesions
Annemiek M Roescher
Albertus Timmer
Johan Bijzet
Christian V Hulzebos
Jan Jaap HM Erwich
Arend F Bos
Submitted
155
Abstract
Background: The presence of specific cytokines in infants’ blood shortly after birth is
associated with cerebral palsy and other neurological problems. Several placental lesions
are also associated with neurological problems in later life. The pathogenesis of these
placental-related neurological problems is unclear.
Aim: To determine whether infectious and non-infectious placental pathologic lesions are
associated with cytokine levels in preterm infants.
Methods: Placentas of 31 singleton, preterm infants (gestational age 26-31wk, birth weight
850-2005g), were examined for histopathology. Blood samples were collected at (cord
blood) or immediately after birth, in which cytokine levels (MIP-1α, MIP-1β, IL-4 IL-6, IL-8,
IL-10, TNF-α, IL1-RA, L-2R, IL-1β, and IL-17) were determined by Luminex assay.
Results: The presence of inflammation consistent with ascending intrauterine infection
(AIUI) was associated with higher levels of MIP-1 β, IL-6, IL-8 and IL-2R at or immediately
after birth. Fetal thrombotic vasculopathy was associated with higher levels of IL-8, and
elevated nucleated red blood cells (NRBCs) with higher levels of IL-6. After backward
multiple regression analyses, only AIUI remained in the models, explaining the elevated
cytokine responses.
Conclusion: Our data suggest that placental inflammation consistent with AIUI is in
particular associated with cytokine responses at or immediately after birth. The presence
of these cytokine responses might be part of the mechanism how infectious placental
lesions lead to neurological morbidity. If so, the etiology of neurological problems related
to non-infectious lacental lesions is different compard to infectious placental lesions.
Cytokine Response in Preterm Infants with Placental Lesions
Introduction
The placenta is an essential organ for the development of the fetus and it is the link
between mother and fetus during pregnancy. The placenta is the organ that enables the
transport of nutrients and oxygen from the mother to the fetus and remove fetal waste
products.1 Placental lesions can interfere with placental function and may lead to fetal
hypoxia, neonatal morbidity and even perinatal death.2-6 Several placental lesions are
known to be associated with adverse neurological outcome in preterm and term born
infants. These problems include intraventricular hemorrhage, white matter injury, cerebral
palsy, and long-term neurodevelopmental problems.7-11
The mechanism by which placental lesions lead to cerebral damage is unclear. It
is hypothesized that elevated cytokine levels take a part in this mechanism. There are
indications that some cytokine levels are elevated in cord blood of infants born with
ascending intrauterine infection.12-15 It is known that infants born with placental signs of
AIUI are at risk to develop cerebral palsy 3,7,9,16 This increased risk for cerebral palsy may
be mediated by elevated cytokine levels. Apart from AIUI, other (non-infectious) placental
lesions are also associated with neurological impairment later in life.9-11,17,18 It might be that
cytokines are also produced in the presence of other (non-infectious) placental lesions.
The role of cytokines in the pathogenesis of these so-called placental-related neurological
problems has to be defined as yet.
Cytokine levels in the infant can be assessed in cord blood as well as in blood of the
infant sampled immediately after birth. The aim of this study was to determine whether
cytokine levels collected this way were elevated in the presence of infectious and noninfectious placental lesions. We hypothesized that cytokines are produced in the presence
of infectious as well as non-infectious placental lesions.
8
Methods
Patient population
Our cohort consisted of 31 preterm, singleton infants. All infants had been admitted to
the Neonatal Intensive Care Unit of the Beatrix Children’s Hospital in Groningen, the
Netherlands. The inclusion criteria for this study were singleton infants with a gestational
age (GA) of less than 32 weeks. Exclusion criteria were infants with major chromosomal
and congenital abnormalities. The review board of University Medical Center Groningen
approved the study. Written, informed parental consent was obtained in all cases.
Placental pathology
The placentas were examined by a perinatal pathologist (AT) in accordance with the
guidelines published by the Royal College of Obstetricians and Gynaecologists and the
Royal College of Pathologists in Britain, and the College of American Pathologists.19,20
The pathologist was blinded as to clinical outcome; he was only aware of gestational age
(GA). We assessed all the placentas for lesions of which an association with neurological
impairment was suggested.9,18 The lesions were: placental pathology consistent with
157
Cytokine Response in Preterm Infants with Placental Lesions
maternal vascular underperfusion (MVU)21, AIUI,22 chronic villitis of unknown origin (VUE)23,
chronic deciduitis24, perivillous fibrinoid25, fetal thrombotic vasculopathy (FTV)26, meconium
associated vascular necrosis27, chorioamniotic haemosiderosis28, elevated nucleated red
blood cells (NRBCs)29, chorangiosis30, and umbilical cord abnormalities31. An explanation
and description of these placental lesions are presented in Table 1. In addition to these
placental lesions, placental weight and umbilical cord length were also recorded.
Table 1: Diagnostic terminology and definition of the placental lesions
8
158
Diagnostic terminology
Definition and scoring criteria
Maternal vascular underperfusion
Decidual vasculopathy, e.g. incomplete or absent spiral artery remodelling, acute atherosis,
fibrinoid necrosis, or thrombosis; parenchymal pathology such as placental hypoplasia,
increased syncytial knotting, villous agglutination, increased perivillous fibrin, distal villous
hypoplasia, infarction, retroplacental hematoma.21
Ascending intrauterine infection
Acute inflammation of the extraplacental membranes and chorionic plate. Acute
chorioamnionitis and chorionitis represent the maternal response; chorionic or umbilical
vasculitis represents the foetal response.22
Villitis of unknown aetiology
Chronic lymphohistiocytic inflammation of the stem and chorionic villi, with or without
obliterative vasculopathy of stem villus vessels.23
Chronic deciduitis
Chronic lymphohistiocytic or plasmacytic inflammation of the decidua basalis.24
Maternal floor infarction / massive
perivillous fibrinoid deposition
Excessive perivillous fibrin deposition, either basally at a thickness of ≥3 mm on at least one
slide (maternal floor infarction) or transmural encasing ≥50% of villi on at least one slide
(massive perivillous fibrinoid deposition).25
Foetal thrombotic vasculopathy
Foetal vascular thrombosis, intimal fibrin cushions, fibromuscular sclerosis, hemorrhagic
endovasculitis and groups of at least five avascular fibrotic villi without inflammation or
mineralization and/or adherent thrombi in stem vessels.26
Meconium associated vascular necrosis
Meconium associated necrosis of smooth muscle cells in the wall of chorionic plate vessels.27
Chorioamniotic hemosiderosis
Presence of hemosiderophages in the amnion and chorion.28
Elevated nucleated red blood cells
Only rare NRBCs are normal after the first trimester. More than two NRBC in a randomly
selected field of 4.5 mm2, corresponding to 18 consecutive fields at 40x magnification, or one
field at 10x magnification was considered as abnormal.29
Chorangiosis
Diffuse increase in the number of villous capillaries.30
Umbilical cord abnormalities
Obstruction or disruption of the umbilical cord blood flow (e.g. umbilical cord prolapse,
entanglement, knots, disrupted velamentous vessels, hyper/hypo-coiling).31
Cytokine Response in Preterm Infants with Placental Lesions
Cytokine measurements
We collected blood samples from cord blood (CB) and from the infant immediately after birth
(T1). These blood samples were collected in anticoagulant-free tubes, centrifuged (at 1200
g for 10 min), and serum was stored at -80°C. Following thawing, serum samples were used
to quantify levels of cytokines, cytokine receptors and chemokines with Human Cytokine
25-plex Panel (Life Technologies, Carlsbad, CA, USA) according to the manufacturer’s
instructions. We measured samples using Luminex 100 System (Luminex, Austin, Tx, USA)
and analyzed data with StarStation software, version 2.3 (AppliedCytometry, Birmingham,
UK).
Several studies determined the relation between AIUI and cytokine levels in cord blood
or during the first days after birth. The choice which cytokines to measure was based on
these studies.12-15 In addition, we included cytokines which are known to be associated
with the fetal inflammatory response syndrome (FIRS).16,32-35,12-15 We included both proinflammatory as well as anti-inflammatory cytokines, and cytokines involved in acute and
chronic inflammation. Thus, the following cytokines, cytokine receptors and chemokines
were assessed: IL-1β, IL-4, IL-6, IL-10, IL-17, TNF-α, IL-1 receptor antagonist (IL-1RA),
IL-2R, (CCL11), IL-8, MIP-1α (CCL3), and MIP-1β (CCL4).
Cytokine measurements from cord blood and immediately after birth, from the infant,
were clustered as one group. In the cases that both cord blood and infant-blood sampled
after birth were available from the same patient, we took the samples taken from the infant
for further analysis.
8
Statistical analysis
We used SPSS 20.0 software for Windows (SPSS Inc, Chicago Illinois, USA) for the
statistical analyses. When cytokine levels were below detection level, we gave them the
lowest possible value (0.10) instead of missing values, to enable us to perform statistical
tests. The cytokine levels were tested for normality by the Kolmogorov-Smirnov test. All
cytokines showed a non-normal distribution. Because the associations of the various
placental lesions with cytokine levels may be interdependent, we used multiple linear
regression analyses, enter method. Because of the non-normal distribution of the cytokines,
we applied the logarithm of the cytokine levels for all cytokines except IL-2R, to meet the
criteria for the multiple linear regression analysis. For IL-2R we used root extraction. Next,
to determine which placental lesions were most explaining the cytokine response, we used
multiple linear regression analyses, backward method.
We did not adjust for clinical factors, because several clinical factors are known to be
associated with placental lesions (e.g. low gestational age can be the result of AIUI).
We only included those placental lesions in our analyses which were 5 or more
times present in our study group. A predetermined P value of .05 tested two-sided was
considered statistical significant.
159
Cytokine Response in Preterm Infants with Placental Lesions
Results
We present the patient characteristics and the distribution of placental lesions of the 31
infants in Table 2.
Table 2. Patient characteristics. Data are given as median (range) or numbers (percentage).
Study population
N=31
Male/female
19/12 (61% / 39%)
Gestational age in weeks
28+6 (26+0 – 31+5)
Birth weight in grams
1260 (850-2005)
Apgar score at 5 minutes
7 (5-10)
Cerebral lesions
8
Periventricular leukomalacia
13 (33%) (all grade 1)
Intracranial haemorrhage, grade 1-2
5 (16%)
Intracranial haemorrhage, grade 3-4
- (0%)
Necrotizing enterocolitis
1 (3%)
Preterm pre-labour rupture of the membranes
8 (26%)
Caesarean section (elective and emergency)
8 (26%)
Placental weight in grams
294 (153-453)
Cord length in centimeters
30 (15-56)
Placental lesionsc
28 (90%)
AIUI
16 (52%)
Maternal vascular underperfusion
11 (36%)
Foetal thrombotic vasculopathy
6 (19%)
Villitis of unknown etiology
5 (16%)
Chronic deciduitis
2 (7%)
Chorioamniotic hemosiderosis
4 (13%)
Perivillous fibrinoid
- (0%)
Placental markers
Elevated nucleated red blood cells
6 (19%)
Chorangiosis
- (0%)
Placental lesions
Out of the 31 placentas we examined only 3 were normal (10%). The largest group of
placental lesions showed signs of AIUI (16 placentas). Eleven placenta’s showed a maternal
as well as a fetal response, in four placentas only a maternal response was present, and in
one placenta only a fetal response was present. The second largest group, consisting of
11 placentas, showed signs of MVU. Six placentas had elevated NRBCs, which is a marker
for fetal hypoxia. The distribution of placental lesions is presented in Table 2. The median
placental weight was 294 grams (153- 453 grams) and the median cord length was 30 cm
(15-56 cm).
160
Cytokine Response in Preterm Infants with Placental Lesions
Cytokine measurements
From the 31 infants in our study group, cord blood samples were available for 14 infants,
blood samples immediately after birth were available for 17 infants. The median levels of
the cytokines are presented in Table 3. The levels of MIP-1α, TNF-α, IL-4, IL-10, and IL1β were all not detectable and were therefore not included in the analyses.
Table 3: Cytokine levels immediately after birth
Cytokine
Description
Median (range)
Mip-1α
Chemokine, local inflammatory response
-
Mip-1β
Chemokine, local inflammatory response
8.4
IL-4
Anti-inflammatory cytokine
-
IL-6
Pro-inflammatory cytokine
0.1
(0.10 - 264.70)
IL-8
Pro-inflammatory chemokine
0.1
(0.10 - 323.40)
TNF-α
Pro-inflammatory cytokine, acute phase
-
IL1-RA
Anti-inflammatory cytokine
0.1
(0.10 - 8703.40)
IL-2R
Pro-inflammatory cytokine
31.7
(0.10 - 435.50
IL-10
Anti-inflammatory cytokine
-
IL-1β
Pro-inflammatory cytokine
-
IL-17
Pro-inflammatory cytokine
1.9
(2.15 - 33.34)
8
(0.90 - 7.50)
Abbreviations: Mip – macrophage inflammatory protein; IL – interleukin; TNF – tumor necrosis
factor; RA – receptor antagonist; R - receptor
-: not detectable in our samples
Placental pathology and cytokine levels
The presence of inflammatory pathology consistent with AIUI was associated with higher
levels of MIP-1β, IL-6, IL-8, and IL-2 receptor (IL-2R). We also found higher levels of
IL-1 receptor antagonist (IL-1RA) in the presence of AIUI, but this just failed to reach
significance.
FTV was associated with higher levels of IL-8, whereas the presence of elevated NRBCs
was associated with higher levels of IL-6 (Table 4).
161
Cytokine Response in Preterm Infants with Placental Lesions
Table 4: Multiple regression analyses of placental lesions explaining cytokine levels immediately
after birth
Cytokine
IL-6
Placental lesion
AIUI
MVU
beta
.400
-.323
FTV
.178
.381
VUE
-.173
.422
↑NRBCs
.390
AIUI
MVU
-.293
-.250
FTV
-.263
.211
VUE
-.117
.594
↑NRBCs
-.304
AIUI
MVU
.410
.052
FTV
.254
.272
VUE
-.216
.378
↑NRBCs
.285
.186
AIUI
MVU
.555
.005
FTV
-.082
.692
VUE
.104
.636
↑NRBCs
.098
.608
AIUI
MVU
.439
-.356
FTV
.580
.006*
VUE
-.377
.078
↑NRBCs
.153
MIP-1β
AIUI
.511
MVU
.214
.289
FTV
.197
.362
VUE
.077
.735
↑NRBCs
.130
.512
IL-17
IL-1RA
8
IL-2R
IL-8
R2
36.8
P
.033*
.095
.045*
33.4
.119
.203
.121
18.7
33.7
40.9
.052
.809
.005*
.979
.017*
.059
.399
28.8
.012*
Abbreviations: IL – interleukin; RA – receptor antagonist; R – receptor; AIUI – ascending intrauterine
infection; MVU – maternal vascular underperfusion; FTV – fetal thrombotic vasculopathy; VUE –
villitis of unknown etiology; NRBCs – nucleated red blood cells
Multiple regression, method enter. All placental lesions which were present 5 or more times in our
study group were entered in the model.
Beta represents the standardized coefficients.
* P<.05
162
Cytokine Response in Preterm Infants with Placental Lesions
In the presence of MVU we found slightly lower levels of IL-6 and IL-8, but the difference
failed to reach significance. In the presence of VUE we also found slightly lower levels of
IL-8, again not reaching statistical significance (Table 4).
To determine which placental lesions were most explaining the cytokine increase or
decrease, we performed multiple linear regression, backward method, entering all placental
lesions that occurred more than 5 times in our sample. After backward multiple regression,
AIUI and elevated NRBCs remained significant in the model for IL-6, explaining 28.8% of
the variance. For IL-2R, only AIUI remained significant in the model, explaining 31.1% of
the variance. For MIP-1β and IL-8 both AIUI and FTV remained in the model, AIUI with
P-values below .05, but FTV failing to reach statistical significance. Together, AIUI and FTV
explained 23.7% of the variance of MIP-1β and 27.1% of the variance of IL-8. For IL-17,
only FTV remained significant in the model explaining 15.7% of the variance. None of the
placental lesions remained significant in the model for IL-1RA (Table 5).
Finally, we determined whether cytokine responses in the AIUI cases differed between
presence of maternal response (15 cases), or fetal response (12 cases).We repeated the
multiple regression analyses, method backward, in 2 new models, now entering either
AIUI maternal response or AIUI fetal response, instead of AIUI. For IL-6, beta was higher
in case of a fetal response compared to a maternal response (beta = 0.568 and 0.500
respectively). For IL-2R, IL-8, and MIP-1β, beta was higher in case of a maternal response
(beta = 0.563 and 0.514, 0.313 and 0.296, 0.296 and 0.244 respectively).
8
Table 5: Multiple regression analyses of placental lesions explaining cytokine levels immediately
after birth
Cytokine
Placental lesion
beta
R2
P
IL-6
AIUI
.467
28.8
.008**
↑NRBCs
.362
.034*
IL-17
FTV
-.396
15.7
.028*
IL-1RA
AIUI
.279
7.8
.129
IL-2R
AIUI
.558
31.1
.001**
IL-8
AIUI
.468
27.1
.008**
FTV
.328
MIP-1β
AIUI
.436
FTV
.309
.055
23.7
.015*
.076
Abbreviations: IL – interleukin; RA – receptor antagonist; R – receptor; AIUI – ascending intrauterine
infection; FTV – fetal thrombotic vasculopathy; NRBCs – nucleated red blood cells
Multiple regression, method backward: AIUI, MVU, FTV, VUE, and elevated NRBCs were all
included in the model. We only reported the final step of the regression analyses.
Beta represents the standardized coefficients.
* P<.05
**P<.01
163
Cytokine Response in Preterm Infants with Placental Lesions
Discussion
Our study indicated that, in very preterm infants, placental pathology consistent with
ascending intrauterine infection is primarily associated with higher cytokine levels around
birth. Non-infectious placental lesions were not conclusively associated with cytokine
responses. Our primary hypothesis that cytokine levels are both higher in the presence of
infectious as well as non-infectious placental lesions was therefore not confirmed.
The most prominent relation existed between AIUI and cytokine responses. We found
AIUI to be associated with higher levels of the pro-inflammatory cytokines IL-6, IL-8, IL-2R,
and MIP-1β at or immediately after birth. This finding is in accordance with the detection
of elevated cytokines (IL-1β, IL-6, IL-10, IL-2R, TNF-α, IL-8, MIP-1β and RANTES) in the
amniotic fluid and cord blood in the presence of an ascending infection 12-15. In contrast
to these studies in our study IL-1β, IL-10, and TNF-α were not detectable (too low to
measure).
AIUI is an acute inflammation of the extraplacental membranes and chorionic plate.22
It can be divided into a maternal response (acute chorioamnionitis and chorionitis) and a
fetal response (umbilical or chorionic vasculitis). The fetal response is thought to be the
histological manifestation of the fetal inflammatory response syndrome (FIRS). FIRS is a
condition characterized by systemic activation of the fetal immune system.33 It is defined
by an elevated plasma IL-6 concentration in a fetus with preterm labor or preterm prelabor
rupture of the membranes.36 In our study we found IL-6 increase most related to AIUI with
a fetal response supporting the theory that AIUI with a fetal response is the histological
counterpart of FIRS.37
Placental lesions with signs of AIUI as well as FIRS are known to be associated with
neurological impairment and cerebral palsy.3,7,9,16,32,33. Mechanisms of early brain injury
leading to neurodevelopmental problems later in life can grossly be divided into three
groups: cerebral hypoperfusion, coagulopathy leading to thrombosis, and cytokine
mediated cerebral damage.32 Our study gives support that placental lesions with signs of
AIUI increase cytokine levels around birth in preterm infants and thus may be the mediating
factor leading to neurodevelopmental problems later in life. The inflammatory cytokines
can be neurotoxic and inhibit oligodendrocytes in their myelin production. This results in
damage of white matter, which can in turn lead to cerebral palsy. 16,38-40
We could not confirm the second part of our hypothesis, i.e. that non-infectious
placental lesions are also associated with cytokine levels, and therefore being a possible
mediating factor in non-infectious placental related neurological problems. We found several
associations, but they disappeared after multiple regression analyses. In the presence of
fetal thrombotic vasculopathy (FTV) levels of IL-8 were increased, and in the presence of
elevated nucleated red blood cells (NRBCs) levels of IL-6 were increased. But following
multiple regression, we found that AIUI explained the increase. Both FTV and elevated
NRBCs did not remain in the model. It could well be that AIUI led to activation of clotting
in some cases, resulting in FTV, and to more susceptibility of hypoxia in the fetus, resulting
in elevated NRBCs. FTV in itself may lead to neurological problems due to the presence
8
164
Cytokine Response in Preterm Infants with Placental Lesions
of thrombi in the fetal circulation of the placenta. Such thrombi may travel into the fetal
circulation via the umbilical vein and into large cerebral blood vessels across the foramen
ovale or ductus arteriosus, causing embolic cerebral arterial infarction.41 Elevated NRBCs
is a marker for fetal hypoxia. Elevated NRBCs are also suggested to be associated with
cerebral palsy. This might be explained by a direct effect of hypoxia to the (developing)
brain.9 Other non-infectious placental related neurological problems are probably also
mediated by a different mechanism than via elevated cytokine responses.
In the presence of FTV we also found lower levels of the pro-inflammatory cytokine
IL-17, compared to infants without FTV. The relation between FTV and IL-17 has not been
studied before. Due to the number of cytokines we tested, this might be due to chance
finding. In addition, the range of IL-17 in our study group was minimal, and therefore
probably not clinically significant.
The strength of this study is the broad spectrum of placental lesions we studied.
In most studies concerning placental lesions and cytokine responses, only placental
pathology consistent with AIUI is studied. In this study we also included non-infectious
placental lesions. There are, however, several limitations we have to point out. Firstly,
almost all children in our study group had one or more placental lesions. When focusing
on one specific placental lesion, the comparison group consists of infants with other
placental lesions. We therefore did not use univariate testing, but deliberately chose to
use regression models. Secondly, we categorized cord blood samples and blood samples
immediately post partum as one group. Thirdly, on forehand we made a selection which
cytokines would be analyzed. We did not use all cytokines measured with the Luminex
technique to avoid multiple testing.
In conclusion, this study indicated that placental lesions with signs of AIUI generate a
cytokine response at or immediately after birth in preterm infants. AIUI is suggested to be
associated with neurological impairment. This cytokine response in the presence of AIUI
might play a role in the etiology of these placental related neurological problems. Noninfectious placental lesions are not conclusively associated with cytokine responses. The
etiology of non-infectious placental related neurological problems is therefore different
compared to neurological problems related to infectious placental lesions.
8
Acknowledgements
We greatly acknowledge the help of Dr. Titia Brantsma-van Wulfften Palthe in Utrecht for
correcting the English manuscript. This study was part of the research program of the
postgraduate school for Behavioural and Cognitive Neurosciences, University of Groningen.
Annemiek Roescher received financial support from the Junior Scientific Master Class of
the University of Groningen.
165
Cytokine Response in Preterm Infants with Placental Lesions
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Cytokine Response in Preterm Infants with Placental Lesions
8
169
General introduction and outline of the thesis
1
170
9
General introduction and outline of the thesis
Chapter 9
1
General discussion and future perspectives
Annemiek Roescher
171
General discussion and future perspectives
The primary aim of this thesis was to determine whether placental lesions are associated
with neonatal morbidity and neurological development. The secondary aim was to
establish possible mechanisms through which placental lesions might lead to neonatal
and neurological morbidity. To study these aims we formulated the following research
questions:
1. What do we know about the relationship between placental lesions and perinatal
death, neonatal morbidity, and neurological outcome? (Chapter 2)
2. What is the relationship between placental lesions and short-term neonatal
outcome (Chapter 3) and neurological outcome (Chapter 4) in preterm-born
children?
3. What is the relationship between placental lesions and long-term neurological
outcome at toddler age (Chapter 5) and early school age (Chapter 6) in pretermborn children?
4. What is the relationship between placental lesions and cerebral tissue oxygen
saturation and extraction in preterm infants? (Chapter 7)
5. Are placental lesions associated with cytokine responses directly after birth in
preterm infants? (Chapter 8)
By addressing these questions we hope to create more awareness among health
professionals of the possible benefit of findings on placental lesions for neonatal care. If
placental lesions are associated with neonatal morbidity and neurological development,
placental examination immediately after birth may create the opportunity for early
interventions with a view to reducing later sequelae.
In this discussion we set out by answering our research questions and summarizing
our main findings. Subsequently, we consider the main findings in more detail. These
findings include the prevalence of placental lesions, placental lesions that were related
to outcome measures, placental lesions not related to outcome measures, and the
difficulties encountered in classifying placental lesions. Then, we describe possible disease
mechanisms underlying placental lesions that lead to morbidity and the consequences for
clinical practice. Finally, we describe future perspectives concerning placental examination
and outcome.
9
Main findings
1. What is known in the literature about the relationship between placental lesions
and perinatal death, neonatal morbidity, and neurological outcome?
The placenta plays a key role in fetal and neonatal mortality, morbidity, and outcome
(Chapter 2). Placental lesions are among the main contributors to fetal death and we found
that placental lesions consistent with maternal vascular underperfusion contributed most.
Several neonatal problems are also associated with placental lesions, whereby ascending
intrauterine infection, with a fetal inflammatory response, and fetal thrombotic vasculopathy
constitute the greatest problem.
173
General discussion and future perspectives
2. What is the relationship between placental lesions and short-term neonatal
outcome and neurological outcome in preterm-born children?
Both elevated nucleated red blood cells, a placental marker for fetal hypoxia, and fetal
thrombotic vasculopathy are associated with short-term outcome measures in pretermborn children. These outcome measures included illness severity and neurological
functioning.
We assessed the short-term neonatal outcome during the first 24 hours after birth with
the Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE) (Chapter3). This
score provides insight into the illness severity of infants during their first 24 hours after
birth. We found that elevated nucleated red blood cells and fetal thrombotic vasculopathy
were associated with higher illness severity in preterm infants during the first 24 hours after
birth.
We assessed short-term neurological outcome during the first two weeks after birth
by determining the quality of general movements (Chapter 4). These movements reflect
the infant’s neurological condition shortly after birth and are a predictor of neurological
outcome later in life. In this study we once again found that placental lesions consistent
with fetal thrombotic vasculopathy and elevated nucleated red blood cells were associated
with an abnormal quality of general movement, albeit not statistically significant.
9
3. What is the relationship between placental lesions and long-term neurological
outcome at toddler age and early school age in preterm-born children?
Of all placental lesions we studied only ascending intrauterine infection was associated
with abnormal outcome measures at two years of age (Chapter 5). Ascending intrauterine
infection was associated with abnormal cognitive, fine motor, and total motor outcomes
in preterm-born children. In moderately preterm-born and late preterm-born children
we found maternal vascular underperfusion and ascending intrauterine infection to be
associated with functional outcomes at early school age (Chapter 6). Maternal vascular
underperfusion was associated with lower IQ scores, and ascending intrauterine infection
was associated with more abnormal motor outcome scores.
4. What is the relationship between placental lesions and cerebral tissue oxygen
saturation and extraction in preterm infants?
Ascending intrauterine infection was associated with lower cerebral tissue oxygen
saturation, and higher fractional tissue oxygen extraction on the second, third, and fourth
days after birth (Chapter 7). No other placental lesions were associated with cerebral tissue
oxygen saturation and extraction shortly after birth. Both ascending intrauterine infection
and lower cerebral oxygen saturation, and higher oxygen extraction shortly after birth,
were associated with neurodevelopmental problems. The impact of ascending intrauterine
infection on cerebral oxygenation might be the mechanism leading to neurodevelopmental
problems.
174
General discussion and future perspectives
5. Are placental lesions associated with cytokine responses immediately after birth
in preterm infants?
Placental inflammation consistent with AIUI was associated with cytokine responses at
or immediately after birth in preterm infants (Chapter 8). The presence of these cytokine
responses might be part of the mechanism through which infectious placental lesions lead
to neurological morbidity.
General discussion
Placental lesions
During pregnancy the placenta is the link between the mother and her fetus and it plays
a crucial role in fetal growth and development. Non-optimal placental performance as
a result of placental lesions may lead to maternal or fetal problems or both. One could
envisage the placenta as the mirror of pregnancy in the sense that placental examination
may provide useful information regarding the intrauterine conditions experienced by the
fetus. The types of placental lesion and the frequencies of placental lesions found during
examination are diverse and differ according to the neonates’ gestational ages (GA) at
birth. Placental lesions are common in preterm infants. In the studies presented in this
thesis the incidence of one or more placental lesions in preterm infants of < 32 weeks’
GA ranged from 89 to 93%. This is three times higher compared to fullterm infants in an
unselected, random population in which approximately 30% have placental lesions.1 In
Chapter 6 we studied placental lesions in a selected group of moderate preterm and late
preterm infants. Here we found that 80% of the infants had one or more placental lesions.
Thus the prevalence of lesions in moderate and late preterm infants is more than two-fold
higher than in fullterm infants. We point out that the prevalence in our group of moderate
and late preterm infants may be overestimated, because only approximately one quarter
of the placentas were sent in to the pathologist for histological examination. It might well
be that these pregnancies had more complications, resulting in a selected population of
children examined.
Placental lesions with signs of maternal vascular underperfusion and ascending
intrauterine infection were most frequently seen in the preterm period. The highest prevalence
of ascending intrauterine infection is seen in extreme preterm birth, < 28 weeks’ GA, and
the highest prevalence of maternal vascular underperfusion in births between 28 and 33
weeks’ GA.2 The frequency of fetal thrombotic vasculopathy, villitis of unknown etiology,
and chronic chorioamnionitis all increase with gestational age. The highest prevalence
of fetal thrombotic vasculopathy and villitis of unknown etiology is seen at fullterm birth,
whereas chronic chorioamnionitis is most frequently seen in births between 34 and 36
weeks’ GA.2
The high prevalence of placental lesions, particularly in the preterm-born group,
suggests that placental lesions are a sign of complications that lead to preterm birth or
9
175
General discussion and future perspectives
that even cause preterm birth. The association between ascending intrauterine infection
and preterm birth is well known. Especially in spontaneous preterm births it is thought
to be the cause of preterm delivery.3 In the presence of ascending intrauterine infection
several cytokines are found to be elevated in the amniotic fluid and cord blood. Tumor
necrosis factor (TNF) is thought to activate the cytokines and initiates labor by stimulating
prostaglandin production from the decidua.3 Maternal vascular underperfusion, regularly
seen in the presence of hypertensive disorders such as preeclampsia, may also lead to
preterm birth. This is, however, an induced preterm birth which must be accomplished
prematurely due to maternal or fetal indications.3
Despite the high rate of placental lesions in preterm infants, the majority develop
without major neurologic problems. This raises the question of the role of placental lesions
in general on neonatal morbidity and neurological outcome in the individual infant. Before
addressing this question we first discuss whether specific placental lesions relate to
outcome measures.
Placental lesions related to outcome measures
In our studies we found that fetal thrombotic vasculopathy, ascending intrauterine infection,
maternal vascular underperfusion, and elevated nucleated red blood cells most frequently
associated with poorer outcome measures (Table 1).
9
176
-
-
Higher illness severity
-
-
-
-
MVU
AIUI
FTV
Chronic deciduitis
VUE
Chorioamniotic
hemosiderosis
Perivillous fibrinoid
-
Chorangiosis
-
Abnormal GMs Day 5
-
-
-
-
Abnormal GMs Day 5
-
-
General movements
Chapter 4
-
-
-
-
-
-
-
Abnormal cognition and
motor scores*
-
Neurodevelopment 2-3years
Chapter 5
Chapter 7
Near infrared spectroscopy
Lower cerebral tissue oxygen
saturation
-
Chapter 6
Neurodevelopment
6-7years**
Lower IQ scores
Lower motor scores
-
-
-
-
-
-
-
-
Higher levels of IL-6, IL-8,
IL-2R and MIP-1β.
-
Cytokine response
Chapter 8
** moderately preterm-born infants (GA 32-36weeks)
* After exclusion of the children with cerebral palsy no placental lesions were associated with neurodevelopmental outcome at 2 to 3 years of age.
unknown etiology; NRBCs – elevated nucleated red blood cells
Abbreviations: MVU – maternal vascular underperfusion; AIUI – ascending intrauterine infection; FTV – fetal thrombotic vasculopathy; VUE – villitis of
Higher illness severity
Elevated NRBCs
Markers
Illness severity (SNAPPE)
Placental lesions
Chapter 3
Table 1: Thesis outcome table
General discussion and future perspectives
9
177
General discussion and future perspectives
Both fetal thrombotic vasculopathy and elevated nucleated red blood cells, as a marker
of fetal hypoxia, only have their impact shortly after birth, whereas ascending intrauterine
infection and maternal vascular underperfusion have their impact later in life. Our findings
on early and long-term outcomes were consistent throughout this thesis. In both early
outcome studies the same placental lesions were associated with adverse outcomes. In
both long-term outcome studies ascending intrauterine infection were associated with
adverse outcomes. Maternal vascular underperfusion was only associated with adverse
outcome in the study on moderate and late preterm infants, not in the early preterm study
(Table 2). In the presence of ascending intrauterine infection we also found changes in the
status of cerebral tissue oxygenation during the first days after birth (Chapter 7) and higher
cytokine levels immediately after birth
Table 2: The association between placental lesions and outcome in early preterm-born and
moderately preterm-born children
9
Preterm group
FTV
↑ NRBCs
MVU
AIUI
early preterm
+ short-term only
+ short-term only
-
+ ↓ motor outcome (CP)
Moderately preterm
-
-
+ ↓cognition scores 7y
+ ↓ motor outcome
Abbreviations: FTV – fetal thrombotic vasculopathy; NRBCs – nucleated red blood cells; MVU –
maternal vascular underperfusion; AIUI – ascending intrauterine infection; CP – cerebral palsy;
y - years
Early preterm: <32 weeks gestational age
Moderately preterm: 32-36 weeks gestational age
Elevated nucleated red blood cells
Elevated nucleated red blood cells (NRBCs) in the placenta are a marker of fetal hypoxia.
Significant hypoxia leads to erythropoietin release and subsequent release of red blood
cell precursors in an attempt to maximize tissue oxygen delivery.4-6 Several hypotheses
were proposed concerning the timing of hypoxia in the presence of elevated NRBCs - from
48 hours before delivery to an acute event shortly before delivery. Animal studies showed
an increase in NRBCs between 6 to 12 hours after the onset of hypoxia.5,7 A more recent
study suggested that NRBCs emerge into the circulation at least 28 to 29 hours before
birth,8 suggesting a prolonged duration of the long-term hypoxia. There may be several
reasons for fetal hypoxia. Whereas other placental lesions are all potential causes of fetal
hypoxia, elevated NRBCs are not the cause but an indicator of this disruption.4 In addition
to our findings, elevated NRBCs were also suggested to be associated with early-onset
neonatal seizures, cerebral white matter injury, and cerebral palsy.4,9,10 Our conclusion is
that the presence of elevated NRBCs indicate some level of fetal distress. This suggests
that fetal distress may be the hallmark in this cascade, leading to higher illness severity
and impaired quality of general movements.
178
General discussion and future perspectives
Fetal thrombotic vasculopathy
Fetal thrombotic vasculopathy (FTV) is defined as the presence of a thrombus in the
fetal circulation of the placenta, which may lead to avascular villi.11 FTV is known to be
associated with neonatal problems and neurological impairment later in life.4,12 Perinatal
asphyxia was described as being associated with placental lesions affecting fetal vascular
supply. These lesions include umbilical cord complications (disrupted velamentous
vessels, cord tear, hypercoiled cord, cord hematoma), ascending intrauterine infection with
fetal vasculitis, and fetal thrombotic vasculopathy.13,14 Our findings that the presence of
FTV was associated with higher illness severity shortly after birth were in line with these
findings. FTV was also suggested as being associated with ventriculomegaly, neonatal
stroke, cerebral ultrasound abnormalities as intraventricular hemorrhages, periventricular
leukomalacia and infarction, and neurological impairment later in life.4,12,15-17 Several
hypotheses were proposed explaining the relation between FTV and neurological problems.
The etiology of several neurological problems is thought to have an antenatal as well as an
intrapartum component.13 FTV was described as a chronic event with an onset more than
one week before delivery,18 leading to a non-optimal intrauterine environment. This might
result in increased susceptibility to brain injury by decreasing the ability of normal infants
to withstand the inherent stresses of routine labor and delivery.4,12 Another explanation of
FTV leading to neurological problems is the presence of thrombi in the fetal circulation of
the placenta. Such thrombi may travel into the fetal circulation via the umbilical vein and
into large cerebral blood vessels across the foramen ovale or ductus arteriosus, causing
embolic cerebral arterial infarction.17
It is thought that the pathogenesis of neurological impairment has both an antenatal
and an intra-partum component. An event weeks before delivery can result in a nonoptimal fetal environment. This might result in lowering the threshold required for more
recent events to cause brain injury. This is in line with our findings, and FTV could be
such an antenatal event.4,19,20 Our findings also suggested that these placental related
neurological problems were already present during the first weeks after birth. Examining
the placenta for the presence of this lesion may create the opportunity for intervention to
improve outcome early in life.
9
Ascending intrauterine infection
Ascending intrauterine infection (AIUI) is an acute inflammation of the extraplacental
membranes (chorion and amnion) or chorionic plate.21 In our systematic review (Chapter
2) we found AIUI most frequently associated with neurological problems. We confirmed
this in Chapters 5 and 6. In Chapter 5 we reported that AIUI was associated with abnormal
cognitive and motor outcomes at toddler age in very preterm infants. Please note that
these abnormal outcomes were only seen in children diagnosed with cerebral palsy (CP) in
our study group. When we excluded the children with CP, AIUI was no longer associated
with outcome, suggesting an association between AIUI and CP. In Chapter 6 we also found
AIUI to be associated with lower motor scores, but now in moderately preterm-born and
179
General discussion and future perspectives
late preterm-born children. Several other investigators also found a relationship between
AIUI and motor outcome and/or CP.4,12,22-26
It is hypothesized that elevated cytokine levels in the presence of AIUI play a role in the
etiology of CP.24,27-30 The elevated blood and brain cytokine levels resulting from maternal
infection might lead to central nervous system damage in the fetus. The inflammatory
cytokines can be neurotoxic and inhibit oligodendrocytes in the developing white matter.
As a consequence, the oligodendrocytes can lose their myelin production. This results
in damage of astrocytes, microglia, and white matter, which can in turn lead to cerebral
palsy.27,28,30-32
Maternal vascular underperfusion
Maternal vascular underperfusion (MVU) is a chronic placental lesion with its onset more
than one week before delivery.18 It is caused by inadequate spiral artery remodeling
leading to decidual vasculopathy.33 Decidual vasculopathy may in turn lead to placental
underperfusion which leads to a lasting non-optimal intrauterine environment. In our
systematic review we found that MVU associated with fetal death (Chapter 2). It is even
suggested as being the main cause of fetal death.34 In our study of moderate and late
preterm infants, we found that MVU associated with lower IQ scores (Chapter 6). In our
studies of early preterm infants, we did not find a relationship between MVU and outcome
(Chapter 5). The literature is also unclear about the relationship between MVU and outcome
in surviving infants. One investigator found MVU to be associated with neonatal morbidities
such as low Apgar scores and the presence of necrotizing enterocolitis in preterm infants,35
while others did not find this relation.36,37 A few studies addressed the relation between
MVU and long-term outcome, with a main focus on neurological impairment.4,19,38,38-40 Only
one study on preterm infants addressed the issue of IQ scores in relation to the presence
of MVU and found lower IQ scores in its presence.39
The presence of enduring placental hypoperfusion results in a non-optimal intrauterine
environment. As in the presence of other chronic placental lesions, this may result
in increased susceptibility to brain injury by decreasing the threshold to withstand the
inherent stresses of routine labor and delivery.4,12 Placental underperfusion in the presence
of MVU can lead to a reduction of the perfusion surface and, as a consequence, nonoptimal oxygen delivery to the fetal circulation. This may result in some degree of cerebral
underperfusion which may be harmful to the developing brain, perhaps even leading to
lower cognitive scores at school age.
9
Placental lesions not related to outcome measures
Most of the placental lesions we studied were associated with short-term neonatal and
long-term outcomes. For a few placental lesions we could not find an association with
outcome measures.
180
General discussion and future perspectives
Villitis of unknown etiology and chronic deciduitis
Villitis of unknown etiology (VUE) and chronic deciduitis are both lymphohistiocytic
inflammations of the stem and chorionic villi, and the decidua, respectively VUE was
suggested to be associated with neonatal infection, neonatal encephalopathy, and
neurological impairment.4,12,19,36 No associations were found regarding chronic deciduitis
and outcome. Both lesions are predominantly present toward fullterm age. This might be
the reason for the low frequency of these placental lesions in our study groups and the
absence of an association with outcome.
Chorangiosis
Chorangiosis, similar to elevated nucleated red blood cells, is a placental marker rather
than a placental lesion. Chronic hypoperfusion is thought to increase in the number of
villous capillaries leading to chorangiosis.41 The highest incidence of chorangiosis is seen
between 34 and 39 weeks’ GA,42 which explains the sporadic occurrence of chorangiosis in
our study groups. The association between chorangiosis and neonatal outcome is unclear.
Only a few studies focused on the relation between this placental marker and outcome.
Congenital malformations and low Apgar scores were suggested to be associated with
chorangioisis.43,44 The low number of placentas with chorangiosis might be the reason why
we did not find a relationship with outcome. More studies focusing on chorangiosis are
needed to determine its relationship with outcome.
9
Difficulties in classifying placental lesions
For fullterm infants the definitions of placental lesions are clear as proposed by several
committees and textbooks.3,11,21,33,45-47 These definitions focus predominantly on the fullterm
placenta. Some lesions considered abnormal in the case of fullterm placentas may be
normal for preterm placentas. An example is the presence of NRBCs. In fullterm placentas
only sporadic NRBCs may be present in the fetal circulation. But during the preterm period
the presence of more NRBCs is normal.46 The absence of definitions specific for preterm
placentas makes it difficult to compare studies that focus on this lesion.
Placental lesions can be classified in several ways: by categories (developmental
disorders, infectious disorders, and circulatory disorders), by diagnosis (MVU, AIUI, FTV,
VUE, chronic deciduitis, placental markers), or by specific characteristics per placental
lesion (for example, infarcts in the presence of MVU, avascular villi in the presence of
FTV). During recent years most studies focused on placental diagnosis rather than specific
characteristics of placental lesions. This placental diagnosis approach seems most
relevant because it is based on a common pathophysiological mechanism per diagnosis.
The studies included in this thesis were also based on this classification. The use of
placental diagnosis groups enhances comparability between studies focusing on placental
lesions and outcome. Classifying by specific characteristics is probably too specific and
not relevant for clinical practice.
During our search of the literature we noticed that studies on placental pathology
181
General discussion and future perspectives
and perinatal death one the one hand, and studies on neonatal outcome on the other,
classify placental lesions differently. The majority of studies on placental pathology and
stillbirth focus on the presence or absence of placental lesions without specifying the
diagnosis of placental lesions. This is probably due to the stillbirth classification systems
used. Most of these systems only report the presence or absence of placental pathology.
Studies concerning placental lesions and neonatal or neurological outcome do specify the
lesions and find several relations between placental diagnoses and outcome. Classifying
placental lesions in placental diagnosis groups in stillbirth studies may provide additional
information on the cause of death.
Possible disease mechanisms and consequences for clinical practice
We found several associations between placental lesions and outcome. These associations
do not necessarily reflect a causal relationship. It is more plausible that placental lesions
are part of a multiple interaction model leading to morbidity. Multiple interactions of
maternal, placental, and fetal origin are likely to play a role in the etiology of neonatal and
neurological morbidity. This is supported by the fact that almost all preterm infants have one
or more placental lesion, or more, while only a few of these children develop neurological
morbidities. The presence of placental lesions alone is, therefore, not conducive of an
adverse outcome. We need additional measures or characteristics to provide a risk profile
for placental lesions that lead to morbidity.
We endeavored to gain insight into possible mechanisms which possibly play a role in the
development of placenta-related neurological problems. We studied the relation between
placental lesions and cerebral oxygenation and the presence of cytokine responses shortly
after birth. In the presence of ascending intrauterine infection we found lower cerebral
tissue oxygen saturation and higher oxygen extraction on Days 2, 3, and 4 after birth.
We found elevated cytokine levels immediately after birth in the presence of ascending
intrauterine infection. These findings suggest that several mechanisms may play a role in
the development of placenta-related morbidities. In the presence of ascending intrauterine
infection the cerebral circulation might be disturbed by higher metabolic activity resulting in
higher oxygen extraction. Higher metabolic activity may be the result of elevated cytokines
in the presence of ascending intrauterine infection. We did indeed find elevated cytokines
at or directly after birth in the presence of ascending intrauterine infection, suggesting an
important role of cytokines in the development of placenta-related adverse outcomes.
Other placental lesions, however, were not associated with cerebral oxygenation
or the presence of elevated cytokine levels. The other placental lesions we found to be
associated with adverse outcome were all chronic lesions, whereas ascending intrauterine
infection is a more acute event. The chronic placental lesions probably create a nonoptimal intrauterine environment, leading to adverse outcomes.
9
Strengths and limitations of this thesis
A major strength of this thesis is the consistent classification of placental lesions throughout.
182
General discussion and future perspectives
All placentas were examined by the same pathologist using a single case record file. In
addition, we studied a broad spectrum of placental diagnostic lesions with respect to
several outcome measures.
The studies presented here had several potential limitations. Firstly, our results were
based on relatively small study populations. Nevertheless, we did find associations between
placental lesions and outcome. Secondly, due to the high incidence of placental lesions
in the preterm population we only had a few placentas without placental lesions. When
determining associations between placental lesions and outcome, the control groups
consisted partly of infants with other placental lesions than the one under study.
Implications and consequences for clinical practice
This thesis focused on placental lesions and outcome and is, therefore, embedded in
three disciplines: pediatrics, pathology, and obstetrics. We are of the opinion that the
findings presented here have consequences for the specialists involved in each of these
disciplines.
Pediatricians: Our recommendation to pediatricians is that they make an effort to
obtain placental examination results, particularly in the case of unexpected preterm
births or unexpected neonatal morbidities. In the current situation the placenta results are
only reported back to the obstetrician and not to the pediatrician as well. It may benefit
childcare if reporting placental examination to the pediatrician were to become standard
practice. These findings can provide clues towards understanding neonatal morbidities
and should, therefore, be taken into consideration. Understanding neonatal morbidities
may also provide opportunities for early interventions.
Obstetricians: The question is in which cases placentas should be sent to the
pathologist for examination. In this thesis we focused on preterm infants born at less than
32 weeks’ GA and infants born between 32 and 36 weeks’ GA. In both groups we found
associations between placental lesions and outcome. We also showed, however, that
placental examination alone is not a specific screening method for the individual patient.
It does increase the understanding of the reason of preterm birth, and it can give insight
into adverse outcome for children as a group. For this reason we recommend that all
placentas of all preterm infants be sent to the pathologist. Further research is needed to
determine in which cases placental examination can be used as a screening method for
adverse outcome, creating a risk profile in combination with additional risk factors. Cost
effectiveness should be taken into account in answering this question.
Pathologists: Placental examination categorized as placental diagnostic groups seems
most relevant for understanding outcome, as these diagnostic groups are based on
pathophysiological mechanisms. Definitions of these diagnostic categories are presented
by the committees of the perinatal section of the Society for Pediatric Pathology, and in
various textbooks on the pathology of the placenta. The results of the placental examination
should be reported not only to the obstetrician, but to the pediatrician as well.
9
183
General discussion and future perspectives
Future perspectives
We demonstrated that several placental lesions are associated with short-term and longterm neonatal and neurological morbidities. As stated before, this association does not
imply a causal relationship. Approximately 90% of preterm infants are born with one or
more placental lesions, but only a small group will develop neurological problems. Placental
lesions are, therefore, not suitable as screening method. More information is needed to
discover which children are at risk of adverse outcomes, and for establishing a risk profile.
Placental lesions should be part of this profile, but additional measurements are needed
as placental lesions alone are not specific enough to predict neonatal or neurological
morbidity in the individual patient. This risk profile should exist of both ante partum factors
and post partum measurements.
Part of the risk profile may consist of epigenetic factors. Placental lesions might already
have their onset early in pregnancy due to epigenetic alterations leading to changes in
gene expression. Causes for these placental epigenetic changes may include intrauterine
stress due to a maternal disease or adverse insults to the intrauterine environment.48 This
may in turn cause placental dysfunction and hence adverse neonatal outcome. Further
research into these epigenetic changes might give more clues as to which children are at
risk of adverse outcome.
Placental examination can be used to answer specific clinical questions. For example,
placental examination might provide additional information on the question whether to
start administering antibiotics to a preterm infant. When there are no signs of infection
in the placenta and no signs of clinical infection, it might strengthen the choice not to
start antibiotics. Antibiotic exposure in preterm infants is known to be associated with
an increased risk of necrotizing enterocolitis and other adverse outcomes. The role of
placental examination in such specific situations should be further investigated. 49,50
In this thesis we addressed questions relating to placental lesions and morbidity in a
selected population of preterm-born children. Additional research is needed to address
the relevance and implications of placental examination in an unselected group.
We know now that placental lesions play a role in developing adverse short-term and
long-term outcomes. The findings of placental examination can be made available in a
relatively short time period. This gives an opportunity for early interventions in order to
lower the risk of adverse outcomes. These possible early interventions should be studied
to improve neonatal and neurological outcome.
9
184
General discussion and future perspectives
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9
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1
188
10
General introduction and outline of the thesis
Chapter 10
1
Summary in English
Samenvatting in het Nederlands
Abbreviations
Dankwoord
Curriculum Vitae
List of publications
189
Summary in English
The placenta is the link between mother and fetus during pregnancy and plays a crucial
role in fetal growth and development. A non-optimal placental performance, as a result
of placental lesions, can lead to maternal and or fetal problems. The placenta can be
seen as the mirror of pregnancy and placental examination can therefore provide useful
information regarding the intrauterine condition the fetus was in. In the studies presented
in this thesis the incidence of one or more placental lesions in preterm infants (<32wk GA)
ranged from 89 to 93%.
The primary aim of this thesis was to determine whether placental lesions are
associated with neonatal morbidity and neurological development. The secondary aim
was to establish a possible mechanism of placental lesions leading to neonatal and
neurological morbidity. We started this thesis with a review of the literature to provide an
overview of what is known concerning the relation between placental lesions and perinatal
death, neonatal outcome, and neurological development (Chapter 2). During this literature
search placental lesions emerged as one of the leading causes of perinatal death. The
associations between placental lesions and outcome in live born infants were less clear.
In this thesis we determined associations between placental lesions and several short
term and long term outcome measures, and possible mechanisms of placental lesions
leading to morbidity. In all studies we focused on preterm infants born below 32 weeks of
gestational age (GA), except for Chapter 6. In Chapter 6 we assessed the relation between
placental lesions and outcome in a group of moderately and late preterm born infants with
a GA between 32 and 36 weeks.
10
Placental lesions and short term outcome
We assessed the short term neonatal outcome during the first 24 hours after birth and
during the first two weeks after birth. We assessed neonatal morbidity during the first 24
hours after birth by using the Score of Neonatal Acute Physiology Perinatal Extension
(SNAPPE) (Chapter3). This score provides the illness severity of infants during the first
day after birth. In this study we found placental lesions consistent with fetal thrombotic
vasculopathy and elevated nucleated red blood cells, placental marker for fetal hypoxia,
to be associated with a higher illness severity during the first 24 hours after birth. No other
placental lesions were associated with illness severity shortly after birth.
Another outcome measurement shortly after birth we used was the quality of general
movements (GMs). We assessed the relation between placental lesions and the quality
of GMs during the first two weeks after birth (Chapter 4). The quality of the GMs reflects
the neurological condition shortly after birth and can predict neurological outcome later
in life. In this study fetal thrombotic vasculopathy and elevated nucleated red blood cells
showed a borderline association with a lower quality of GMs. Again, no other placental
lesions were associated with the quality of GMs. We demonstrated that it is difficult to
identify a placenta-related risk group for neurological problems as measured by the quality
191
of GMs shortly after birth. This might be because other conditions related to preterm birth
confound a possible association between placental lesions and the quality of GMs.
10
Placental lesions and long term outcome
In addition to short term outcomes we also assessed the relation between placental
lesions and long term outcomes. We determined the relation between placental lesions
and neurodevelopmental outcome at 2 to 3 years (Chapter 5) and in group of late preterm
born infants at the age of 6 to 7 (Chapter 6). Placental lesions with signs of ascending
intrauterine infection were predominantly associated with long term outcome. We found
ascending intrauterine infection to be associated with impaired cognitive and motor skills at
2 to 3 years of age. After we had excluded the children with severe cerebral palsy, however,
none of the placental lesions were associated with neurodevelopmental outcome at toddler
age, suggesting a relation between ascending intrauterine infection and cerebral palsy. For
clinicians this finding might be the most relevant one to come out of this study because
the majority of preterm-born children develop without severe neurological disabilities. In
our study with late preterm infants, we found placental lesions consistent with maternal
vascular underperfusion associated with lower IQ scores, whereas ascending intrauterine
infection is associated with impaired motor skills at early school age. These findings
suggest that placental lesions might be an early indicator for impaired outcome later in
life.
Possible disease mechanisms
In addition to the associations between placental lesions and outcome measures, we
investigated possible mechanisms of placental lesions leading to neurological problems.
The first mechanism we studied in relation to placental related neurological problems was
the cerebral blood flow. We assessed the relation between placental lesions and cerebral
tissue oxygen saturation and extraction by using near infrared spectroscopy (NIRS)
(Chapter 7). In this study we found ascending intrauterine infection to be associated with
lower regional cerebral tissue oxygen saturation and higher cerebral oxygen extraction on
the second, third, and fourth days after birth. Both ascending intrauterine infection and
lower cerebral oxygen saturation and a higher oxygen extraction shortly after birth are
associated with neurodevelopmental problems. The effect ascending intrauterine infection
has on cerebral oxygenation might be one of the mechanisms that causes it to lead to
neurodevelopmental problems.
The second possible mechanism we studied was cytokine responses in the presence
of placental lesions (Chapter 8). Placental inflammation consistent with AIUI was associated
with cytokine responses at or immediately after birth in preterm born children. The presence
of these cytokine responses might be part of the mechanism how infectious placental
lesions lead to neurological morbidity.
We found several associations between placental lesions and outcome. These
associations between placental lesions and outcome do not necessarily reflect a causal
192
relation. It is more plausible that placental lesions are part of a multiple interaction model
leading to morbidity. Multiple interactions from maternal, placental, and fetal origin are
likely to play a role in the etiology of neonatal and neurological morbidity. This is supported
by the fact that almost all preterm born infants have one or more placental lesions, but
only few of these children will develop neurological morbidities. The presence of placental
lesions alone is therefore not specific for adverse outcome. We need additional measures
or characteristics to provide a risk profile for placental lesions leading to morbidity.
10
193
General introduction and outline of the thesis
1
194
10
General introduction and outline of the thesis
Chapter 10
1
Summary in English
Samenvatting in het Nederlands
Abbreviations
Dankwoord
Curriculum Vitae
List of publications
195
Nederlandse samenvatting
De placenta is de link tussen moeder en foetus tijdens de zwangerschap en speelt
hierdoor een cruciale rol bij de groei en ontwikkeling van de foetus. Een niet optimale
placenta functie, als gevolg van placenta afwijkingen, kan leiden tot maternale en/of
foetale problemen. De placenta kan worden gezien als de spiegel van de zwangerschap
en placenta onderzoek kan dan ook bijdragen aan nuttige informatie over de intra uteriene
toestand van het pasgeborne kind. In de studies gepresenteerd in dit proefschrift laten
we zien dat placenta afwijkingen veel voorkomen bij prematuur geboren kinderen. De
incidentie van één of meer placenta afwijkingen bij prematuur geboren kinderen onder de
32 weken ligt tussen de 89 en 93%.
Het primaire doel van dit proefschrift was het onderzoeken van mogelijke associaties
tussen placenta afwijkingen en neonatale morbiditeit en neurologische ontwikkeling. Het
tweede doel was het onderzoeken van mogelijke mechanismen welke een rol kunnen
spelen bij placenta afwijkingen die leiden tot neonatale en neurologische morbiditeit. Dit
proefschrift begint met een overzicht van de literatuur die verschenen is over de relatie
tussen placenta afwijkingen en perinatale sterfte, neonatale morbiditeit en neurologische
ontwikkeling (hoofdstuk 2). Tijdens dit literatuur onderzoek kwam naar voren dat placenta
afwijkingen een van de belangrijkste oorzaken zijn van perinatale sterfte. De associaties
tussen placenta afwijkingen en morbiditeit bij levend geboren kinderen is minder
eenduidig. In dit proefschrift hebben we onderzoek gedaan naar mogelijke associaties
tussen placenta afwijkingen en zowel korte als lange termijn uitkomsten en mogelijke
mechanismen welke een rol spelen bij placenta afwijkingen die leiden tot morbiditeit. In
bijna alle studies in dit proefschrift hebben we ons gericht op prematuur geboren kinderen
met een zwangerschapsduur onder de 32 weken, met uitzondering van hoofdstuk 6. In
hoofdstuk 6 hebben we de associatie onderzocht tussen placenta afwijkingen en uitkomst
van een groep kinderen geboren met een zwangerschapsduur tussen de 32 en 36 weken.
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Placenta afwijkingen en korte termijn uitkomst
De neonatale uitkomst hebben we op twee momenten kort na de geboorte onderzocht:
tijdens de eerste 24 uur na de geboorte en gedurende de eerste twee weken na geboorte.
De neonatale morbiditeit tijdens de eerste 24 uur na de geboorte hebben we bepaald
met behulp van de Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE)
(hoofdstuk 3). Deze score geeft de mate van ziek zijn weer tijdens de eerste 24 uur na
geboorte. In deze studie vonden we dat placenta afwijkingen bestaande uit foetale
thrombotische vasculopathie en een verhoogd aantal kernhoudende erytrocyten (marker
voor foetale hypoxie) geassocieerd zijn met een hogere mate van ziek zijn in de eerste 24
uur na geboorte. Andere placenta afwijkingen waren niet geassocieerd met de mate van
ziek zijn kort na geboorte.
Een andere uitkomstmaat die we gebruikt hebben kort na de geboorte is de kwaliteit
van de spontane, gegeneraliseerde bewegingen (general movements). We hebben
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de relatie onderzocht tussen placenta afwijkingen en de kwaliteit van de spontane
bewegingen tijdens de eerste twee weken na geboorte (hoofdstuk 4). De kwaliteit van
de spontane bewegingen geeft de neurologische conditie van het kind weer kort na de
geboorte en is voorspellend voor de neurologische uitkomst op latere leeftijd. In deze
studie vonden we een borderline associatie tussen placenta afwijkingen geassocieerd met
foetale thrombotische vasculopathie en een verhoogd aantal kernhoudende erytrocyten
en een verminderde kwaliteit van de spontane bewegingen. Ook in deze studie waren
geen andere placenta afwijkingen geassocieerd met de spontane bewegingen. Het blijkt
moeilijk te zijn om een placenta gerelateerde risico groep voor neurologische problemen
te identificeren kort na de geboorte, met behulp van de spontane bewegingen. Dit kan
komen doordat andere problemen, die gerelateerd zijn aan de prematuriteit, een mogelijke
associatie tussen placenta afwijkingen en de kwaliteit van de spontane bewegingen kan
beïnvloeden.
Placenta afwijkingen en lange termijn uitkomst
Naast korte termijn morbiditeit hebben we ook gekeken naar de ontwikkeling op latere
leeftijd in relatie tot placenta afwijkingen. We hebben de relatie tussen placenta afwijkingen
en de ontwikkeling op 2 tot 3 jarige leeftijd onderzocht (hoofdstuk 5) en in een groep
laat preterm geboren kinderen op 6 tot 7 jarige leeftijd (hoofdstuk 6). Hieruit bleek dat
voornamelijk placenta afwijkingen ten gevolge van een opstijgende intra uteriene infectie
geassocieerd zijn met lange termijn uitkomst. Opstijgende intra-uteriene infectie is
geassocieerd met verminderd cognitief en motorisch functioneren op een leeftijd van 2-3
jaar. Echter, wanneer we kinderen met een ernstige cerebrale parese excluderen vinden
we geen relatie meer tussen placenta afwijkingen en cognitie of motoriek. Dit suggereert
voornamelijk een verband tussen opstijgende intra-uteriene infectie en cerebrale parese.
Ook dit is een belangrijke bevinding, aangezien het grootste deel van preterm geboren
kinderen zich ontwikkelt zonder ernstige neurologische problemen. In de groep laat preterm
geboren kinderen vonden we een relatie tussen maternale vasculaire onderperfusie en
lagere IQ scores en in de aanwezigheid van opstijgende intra-uteriene infectie slechtere
motoriek op 6 tot 7 jarige leeftijd. Deze bevindingen suggereren dat placenta afwijkingen
een vroege indicator kunnen zijn voor ontwikkelingsproblemen op latere leeftijd.
Mogelijke ziekte mechanismen
Naast de associatie tussen placenta afwijkingen en de verschillende uitkomstmaten,
hebben we ook mogelijke mechanismen onderzocht die kunnen leiden tot placenta
geassocieerde neurologische problemen. Het eerste mogelijke mechanisme welke we
onderzocht hebben is de cerebrale zuurstofvoorziening. We hebben de relatie onderzocht
tussen placenta afwijkingen en cerebrale zuurstofsaturatie en cerebrale zuurstofextractie,
gemeten met behulp van nabij-infrarood licht spectroscopie (NIRS) (hoofdstuk 7).
Hierbij vonden we dat een opstijgende intra-uteriene infectie geassocieerd is met een
verminderde regionale cerebrale zuurstofsaturatie en een verhoogde zuurstofextractie op
de tweede, derde en vierde dag na geboorte. Zowel opstijgende intra-uteriene infectie als
een verlaagde cerebrale zuurstofsaturatie en verhoogde zuurstofextractie is geassocieerd
met neurologische ontwikkelingsproblemen. Het effect dat de opstijgende intra-uteriene
infectie heeft op de cerebrale zuurstofoxygenatie kan een onderdeel van een mechanisme
zijn leidend tot neurologische problemen.
Het tweede mogelijke mechanisme dat we bestudeerd hebben zijn cytokine reacties in
aanwezigheid van placenta afwijkingen (hoofdstuk 8). Wij vonden dat placenta inflammatie
ten gevolge van een opstijgende intra-uteriene infectie geassocieerd is met een verhoogde
cytokine respons tijdens of direct na de geboorte bij preterm geboren kinderen. De
aanwezigheid van deze cytokines kan ook een rol spelen in het mechanisme van hoe
infectieuze placenta afwijkingen leiden tot neurologische morbiditeit.
We hebben verschillende associaties gevonden tussen placenta afwijkingen en
morbiditeit. Deze associaties reflecteren geen direct causaal verband. Het is waarschijnlijker
dat placenta afwijkingen onderdeel zijn van een meervoudig interactie model, wat leidt tot
morbiditeit. Interactie van maternale, placentaire en foetale factoren spelen waarschijnlijk
een rol in de etiologie van neonatale en neurologische morbiditeit. Dit wordt onderstreept
doordat bijna alle preterm geboren kinderen één of meer placenta afwijkingen hebben,
terwijl maar een klein aantal van deze kinderen neurologische problemen ontwikkelt.
De aanwezigheid van placenta afwijkingen op zichzelf is dan ook niet specifiek genoeg
als een screening instrument voor neonatale en neurologische morbiditeit. Hiervoor zijn
aanvullende gegevens nodig, zodat een risico profiel opgesteld kan worden voor placenta
afwijkingen leidend tot morbiditeit.
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Abbreviations
AIUI:
ascending intrauterine infection
AVLT:
Auditory Verbal Learning Test
Bayley-III:
Bayley Scales of Infant and Toddler Development – third edition
BPD:
bronchopulmonary dysplasia
BW:
birth weight
CA:
chorioamnionitis
CBCL:Child Behavior Checklist
CI:
confidence interval
CP:
cerebral palsy
CRP:C-reactive protein
CS:
cramped synchronized
FTOE fractional tissue oxygen extraction
FTV:
fetal thrombotic vasculopathy
GA:
gestational age
GMFCS: gross motor functioning classification system
GMs:
general movements
IL:
interleukine
IQR:
interquartile range
IUGR:
intrauterine growth restriction
IVH:
intraventricular hemorrhage
Movement ABC:Movement Assessment Battery for Children
MOS:
motor optimality score
MVU:
maternal vascular underperfusion
NE:
neonatal encephalopathy
NEC:
necrotizing enterocolitis
NEPSY developmental Neuropsychological Assessment battery
NI:
neurological impairment
NICU:Neonatal Intensive Care Unit
NRBC:
nucleated red blood cells
OR:
odd’s ratio
PDA:
patent ductus arteriosus
PPROM:
preterm pre-labour rupture of the membranes
PR:
poor repertoire
PVL:
periventricular leukomalacia
RDS:
repiratory distress syndrome
regional cerebral tissue oxygen saturation
rcSO2:
ROP:
retinopathy of prematurity
RR:
relative risk
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SNAPPE:Score of Neonatal Acute Physiology Perinatal Extension
TEACh:
Test of Everyday Attention for Children
UMCG: University Medical Center Groningen
VUE:
villitis placenta of unknown etiology
WISC:
Wechsler Intelligence scale
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Dankwoord
Het is een cliché, maar promoveren doe je zeker niet alleen. Graag wil ik iedereen
bedanken die op welke manier dan ook betrokken is geweest bij de totstandkoming van
dit proefschrift. Enkele mensen wil ik in het bijzonder bedanken.
Allereerst wil ik graag mijn Promotor, Prof. dr. A.F. Bos bedanken. Beste Arie, dank je wel
dat je mij de mogelijkheid hebt gegeven om onder jouw leiding dit promotietraject tot een
goed einde te brengen. Jij bracht mij op de hoogte over de mogelijkheid van een MD/PhD
traject, promotie onderzoek tijdens mijn studie. Mijn eerste reactie was: kan ik dat wel?
Jouw reactie was: waarom niet? En inderdaad, waarom niet. Zie hier het resultaat. Dank je
wel voor je vertrouwen hierin. Met veel rust kon jij datgene helder duidelijk maken, wat als
een warboel in mijn hoofd zat. Ik bewonder de rust die je uitstraalt ook al ben je heel druk.
Altijd kon ik even aankloppen voor een korte vraag. Je nam me niet alleen mee in de voor
mij nog nieuwe wereld van onderzoek, maar je nam me zelfs een aantal keer mee naar je
eigen huis. Samen met Marrit heb ik een aantal keer bij jou en je familie mogen genieten
van heerlijke pizza’s. Dank je wel Arie, voor de mogelijkheid die je me gegeven hebt om op
mijn eigen manier dit project vorm te kunnen geven en het goed te kunnen doorlopen.
Dr. A. Timmer, beste Bert, dank je wel dat je mijn co-promotor hebt willen zijn. Jij hebt mij
wegwijs gemaakt in de wondere wereld van de placenta pathologie. Meerdere uren hebben
we samen naar placenta’s gekeken, waarbij jij me vol enthousiasme de verschillende
afwijkingen liet zien. Je deur stond altijd open, waardoor we altijd laagdrempelig even
konden overleggen.
10
Prof. dr. J.J.H.M. Erwich, beste Jan Jaap, hartelijk dank voor je kritische blik op onze
manuscripten. Als gynaecoloog kwam je vaak met andere invalshoeken en nuttige tips,
wat mij weer nieuwe inzichten gaf. Hartelijk dank voor je waardevolle bijdrage aan de
ontwikkeling van onze onderzoeken en het uiteindelijke resultaat van dit proefschrift.
Graag wil ik ook de leden van de leescommissie bedanken, prof. dr. R. de Krijger, prof. dr.
S. A. Scherjon en prof. dr. L. Zimmermann. Hartelijk dank voor de beoordeling van mijn
proefschrift.
Marrit en Lenneke, ik ben er trots op dat jullie mijn paranimfen willen zijn.
Lieve Marrit, wat hebben we veel aan elkaar gehad tijdens de afgelopen jaren. Niet
alleen onze onderzoeksjaren doorliepen we samen, maar ook vele leuke activiteiten
daaromheen.
Tijdens het onderzoek, welke we precies gelijk hebben doorlopen, zaten we bij elkaar op
de kamer. Het was altijd heerlijk om samen positieve momenten te vieren, maar ook om
209
even lekker te zeuren wanneer alles tegen zat. Vaak konden we elkaar dan weer nieuwe
positieve energie geven. Dank ook dat ik zo nu en dan op jouw goede planningscapaciteiten
mee mocht liften! We hebben samen genoten van heerlijke vakanties in Italië, wijntjes
gedronken en regelmatig uit eten wanneer wij vonden dat we dat weer eens verdiend
hadden. Mijn promotieperiode is mede dankzij jou een erg leuke periode geweest. Ik vind
het erg speciaal dat we onze proefschriften op dezelfde dag mogen verdedigen. Jij als
paranimf aan mijn zijde, ik als paranimf aan jouw zijde. Mooier kan het in mijn ogen niet.
Naast goede vriendinnen en onderzoekscollega’s worden we nu ook ‘echt’ collega’s in het
Martini ziekenhuis. Ik ben blij dat we nog lang niet van elkaar af zijn!
10
Lieve Lenneke, vroeger was je mijn grote zus, nu ben je daarnaast ook een hele goede
vriendin. Onder het genot van een heerlijke maaltijd en een wijntje hebben we leuke en
ook diepgaande gesprekken, welke ik zeer waardeer. Jij was mijn voorbeeld om te gaan
studeren. Jij hebt me gestimuleerd en geïnspireerd om mijn eigen weg te bewandelen.
Daarnaast heb je me een fantastisch cadeau gegeven: een nichtje! Wat was ik blij dat ik in
de periode dat jij zwanger was voor mijn coschappen ook in Zwolle woonde, waardoor ik
het van dichtbij mee kon maken. Samen met Bastiaan en kleine Catoo vormen jullie een
geweldig gezinnetje, waar ik me altijd welkom voel. Dank jullie wel hiervoor. Na alle knuffels
van Catootje ga ik altijd met een grote glimlach weer richting Groningen, met hernieuwde
energie om mijn proefschrift af te ronden.
Lieve Karen, samen met jou en Marrit hebben we het grootste gedeelte van onze
promotietijd een kamer in de kelder mogen delen: KZ0023. Wat hebben we ons vermaakt,
hard werken maar ook gezelligheid. Plannen maken voor een etentje, lekker borrelen in de
stad en natuurlijk onze wijncursus niet te vergeten. Dank voor de gezelligheid.
Karen, Jozien, Michelle, Janyte, Mirthe, Sara, Chris Peter, Elise, Elise, Nynke, Willemijn, Markjan, Menno, Martijn, Djoeke, Danique, Rianne, Esther, Nicole. Beste (oud)-ganggenoten,
ik vond het altijd erg gezellig met zijn allen in de kelder. Zo af en toe opstijgen naar
de bewoonde wereld voor een kopje koffie in de zon, maar ook lekker borrelen om een
acceptatie te vieren. Dit maakt onderzoek doen nog leuker! Ook naast het werk hebben we
zo nu en dan samen wat ondernomen. Met zijn allen meedoen aan een pubquiz, waar we
er weer achter kwamen dat we toch vaker die kelder uit moeten komen om onze algemene
kennis op te schroeven… Dank jullie wel voor de gezellige tijd!
Dit proefschrift was er niet gekomen zonder de ouders die toestemming hebben gegeven
om hun kinderen deel te laten nemen aan het onderzoek. Ik wil hen hier hartelijk voor
danken. Ook wil ik alle medewerkers van de afdeling neonatologie bedanken voor de rol
die zij gespeeld hebben in de totstandkoming van dit proefschrift. De neonatologen voor
het meedenken en hun suggesties tijdens de onderzoeksbesprekingen. En natuurlijk ook
voor de gezellige tijd tijdens de verschillende congressen. De verpleegkundigen van de
210
afdeling bij het filmen van de kinderen. Janette, Heidi, Joke, Renee, Jannie, Els en Aad,
hartelijk dank voor jullie ondersteunende rol bij allerlei zaken. Koen van Braeckel, dankjewel
voor het aanleren van de Bayley Scales of infant and Toddler Development en voor je mails
vol Belgische humor.
De (oud) onderzoekers van de neonatologie, Jozien, Michelle, Janyte, Mirthe, Sara, Tjitske,
Sietske, Nynke, Rachel, Elise en Elise, voor de prettige samenwerking en gezellige tijd.
Jozien, ik kan de kamer niet meer binnen komen zonder achter de deur te moeten kijken
of jij er toevallig niet staat. Michelle, de avonden in het Triade waren een stuk gezelliger als
we er weer samen waren. Hierbij moet ik toch eigenlijk ook de beveiliging bedanken, voor
de hilariteit die zei ons tijdens deze avonden bezorgd hebben!
Graag wil ik alle mede auteurs van de artikelen in dit proefschrift bedanken voor hun input
en kritische blik.
De Junior Scientific Masterclass wil ik graag bedanken voor de mogelijkheid die ze hebben
geboden om het MD/PhD traject te doorlopen.
Beste Titia Brantsma – van Wulfften Palthe, dank u wel voor de correctie van het Engels
van de artikelen in dit proefschrift.
Peter Ijdel, dank je wel voor het ontwerpen van de cover en lay-out van dit proefschrift. Ik
ben erg blij met het resultaat!
Lieve vrienden en familie, dank jullie wel voor de interesse die jullie toonden, ook al was het
niet altijd even duidelijk wat ik daar in Groningen aan het doen was.
Lieve Nicolien, sinds het eerste jaar van onze geneeskunde studie zijn we vriendinnen.
Samen hebben we de eerste jaren doorlopen, daarna ben jij doorgegaan met je coschappen en ben ik met het onderzoek begonnen. De woensdag avond was onze avond,
samen eten en lachen. Even kort bespraken we mijn onderzoeksperikelen, daarna over
op allerlei andere dingen. Eigenlijk altijd spraken we bij jou en Boudewijn af, jullie hebben
nu eenmaal een vaatwasser. Dank je wel voor deze gezellige avonden en je vriendschap.
Dat je net een paar weken voor mijn promotie naar Nieuw-Zeeland moet emigreren, daar
hebben we het nog wel eens over.. Ik ga je wel missen!
Lieve Hanneli en Peter, samen met Marrit komen we regelmatig een weekendje naar Joure.
Lekker ontspannen en heerlijk eten en wijntjes drinken. Dank jullie wel voor deze gezellige
weekenden, hierna kon ik altijd met hernieuwde energie verder met mijn onderzoek.
10
Lieve Papa en Mama, dank jullie wel dat jullie Lenneke en mij de kans hebben gegeven
om te gaan studeren. Daar is het allemaal mee begonnen. Een wereld welke nieuw voor
jullie was. Jullie hebben ons altijd gestimuleerd om het beste in ons naar boven te halen.
Volgens mij is dat hiermee aardig gelukt. Dank jullie wel hiervoor. Ik vind het heerlijk om
af en toe een paar dagen bij jullie in Luttenberg te zijn en te genieten van de rust en jullie
gezelschap. Hopelijk heb ik nu weer wat meer tijd om vaker langs te komen!
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Curriculum Vitae
Annemiek (Maria) Roescher is geboren op 4 augustus 1985 in Luttenberg. Hier is ze,
als jongste in een gezin van twee kinderen, opgegroeid en blijven wonen totdat ze naar
Groningen verhuisde voor haar studie Geneeskunde. Nadat ze in 2001 haar MAVO diploma
heeft behaald aan het Carmel College Salland in Raalte, is ze begonnen met de opleiding
tot doktersassistente. Na drie jaar behaalde ze in 2004 hiervoor haar diploma. Na deze
periode kwam ze tot het besef dat werken als doktersassistente niet de juiste carrière
voor haar was. Ze is toen in 2004 begonnen met de havo-sprint aan het Deltion College
in Zwolle, waar ze het 4e en 5e jaar van de havo combineerde, resulterend in een diploma
in 2005. Datzelfde jaar is ze doorgegaan naar het VWO-sprint, waarvan ze een jaar later
in 2006 haar diploma in ontvangst mocht nemen. Met (eindelijk) de juiste papieren op
zak werd ze in 2006 ingeloot voor de opleiding Geneeskunde aan de Rijksuniversiteit
Groningen.
Tijdens het tweede jaar van deze studie is Annemiek begonnen met het doen van
onderzoek op de afdeling Neonatologie van het Universitair Medisch Centrum
Groningen, onder leiding van Professor dr Arie Bos. Dit onderzoek heeft uiteindelijk
geresulteerd in het aanvragen van het uitdagende MD/PhD traject, waarvoor ze in 2010
werd aangenomen. Haar promotietraject heeft ze gecombineerd met haar coschappen.
Haar junior en senior coschappen heeft ze respectievelijk in het Universitair Medisch
Centrum Groningen en de Isala klinieken in Zwolle doorlopen. Haar keuze coschap heeft
ze in het Martini ziekenhuis op de afdeling Kindergeneeskunde doorlopen, waarna ze
haar verdieping op de afdeling neonatologie in het UMCG heeft afgerond. In augustus
2014 heeft ze haar studie geneeskunde afgerond waarna ze vandaag, tijdens deze
speciale dag, haar artsen bul in ontvangst mag nemen. In september 2014 is Annemiek
begonnen aan haar eerste baan in het Martini ziekenhuis als ANIOS op de kinderafdeling.
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List of Publications
AM Roescher, A Timmer, J Bijzet, CV Hulzebos, JJHM Erwich, AF Bos. Cytokine response
in preterm infants with placental lesions. Submitted
AM Roescher, A Timmer, KNJA Van Braeckel, JM Kerstjens, SA Reijneveld, JJHM Erwich,
AF Bos.Placental lesions and functional outcomes at early school age of children born
between 32 and 35 weeks’ gestational age. Submitted
AM Roescher, A Timmer, EA Verhagen, KNJA van Braeckel, PH Dijk, JJHM Erwich, AF
Bos. Placental lesions and neurodevelopmental outcome at toddler age. Submitted
AM Roescher, A Timmer, ME van der Laan, JJHM Erwich, AF Bos, EM Kooi, EA Verhagen.
In preterm infants ascending intrauterine infection is associated with lower cerebral
tissue oxygen saturation and higher oxygen extraction. Provisionally accepted Pediatric
Research
MM Hitzert, AM Roescher, AF Bos. The quality of general movements after treatment
with low-dose Dexamethasone in preterm infants at risk of bronchopulmonary dysplasia.
Neonatology,2014:106(3);222-228
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AM Roescher, A Timmer, MM Hitzert, EA Verhagen, JJHM Erwich, AF Bos. Placental
pathology and neurological morbidity in preterm infants during the first two weeks after
birth. Early Hum Dev, 2014:90;21-25
AM Roescher, A Timmer, JJHM Erwich, AF Bos. Placental pathology, perinatal death,
neonatal outcome, and neurological development: a systematic review. Plos One,
2014:25;9(2):e89419
MM Hitzert, MJNL Benders, AM Roescher, F van Bel, LS de Vries, AF Bos. Hydrocortisone
vs. Dexamethasone treatment for bronchopulmonary dysplasia and their effects on general
movements in preterm infants. Pediatr Res, 2012;71(1):100-6
AM Roescher, MM Hitzert, A Timmer, EA Verhagen, JJHM Erwich, AF Bos. Placental
pathology is associated with illness severity in preterm infants in the first twenty-four hours
after birth. Early Hum Dev, 2011:87;315-319
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