University of Groningen
Placental lesions and outcome in preterm born children
Roescher, Annemiek
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2014
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Roescher, A. (2014). Placental lesions and outcome in preterm born children: the relation between
placental lesions, neonatal morbidity and neurological development [S.l.]: [S.n.]
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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.
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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.
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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.
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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.
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Part I
Literature overview of placental lesions and outcome
Chapter 2: Placental Pathology, Perinatal Death, Neonatal Outcome
and Neurological Development: A Systematic Review
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General introduction and outline of the thesis
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