Ultrasound Obstet Gynecol 2014; 44: 293–298
Published online 21 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13310
Uterine artery Doppler, birth weight and timing of onset
of pre-eclampsia: providing insights into the dual etiology
of late-onset pre-eclampsia
S. VERLOHREN*†, K. MELCHIORRE†, A. KHALIL† and B. THILAGANATHAN†
*Department of Obstetrics, Charité University Medicine Berlin, Berlin, Germany; †Fetal Medicine Unit, St George’s Hospital NHS
Healthcare Trust, London, UK
K E Y W O R D S: large-for-gestational-age; pre-eclampsia; resistance index; small-for-gestational age; uterine artery Doppler
ABSTRACT
INTRODUCTION
Objective To investigate the relationship between uterine
artery Doppler ultrasound indices and birth weight
in women with early-, intermediate- and late-onset
pre-eclampsia as compared with women with uneventful
pregnancy outcome.
Pre-eclampsia, occurring in 2–5% of all pregnant women,
is a leading cause of maternal and fetal morbidity and
mortality in pregnancy1 . The pathophysiology of the
syndrome is largely unknown and clinicians have to
rely on arbitrary measures of common features such
as blood pressure and proteinuria to make the diagnosis of pre-eclampsia2 . It is well known that these parameters do not correlate well with pre-eclampsia-related
adverse outcomes nor do they reflect the pathophysiological basis of the disease3 – 5 . In clinical practice a
distinction is made between early and late pre-eclampsia,
defined as the onset of the disease before or after 34 weeks’
gestation, respectively6 . This distinction is mainly based
on the different impact on neonatal morbidity, being
more striking in early-onset disease necessitating delivery
before 34 weeks. The overall incidence of pre-eclampsia is
3–5% in western industrialized countries, 25% of which
is early-onset and 75% late-onset6,7 . While early-onset
pre-eclampsia is often associated with intrauterine growth
restriction (IUGR), the majority of neonates in late-onset
pre-eclampsia are of normal size8 . Concurrently, the
placentae of early-onset pre-eclamptic patients show significantly more histological signs of underperfusion than
do those of patients with late-onset disease9 . Based on
these findings, two distinct disease entities are postulated, i.e. early- and late-onset pre-eclampsia10 . However,
even though the accepted paradigm is that poor trophoblast development predisposes to the development of
pre-eclampsia, it remains unclear if this is true of both
these presentations11 – 13 .
Doppler sonography of the uterine arteries in the
second trimester has an established association with both
pre-eclampsia and fetal growth restriction14 – 16 . Pathologically high values of uterine artery resistance indices are
related to failure of a number of trophoblast cell processes
Methods In a retrospective, observational cohort study,
uterine artery Doppler assessment was carried out at
18 + 0 to 23 + 6 weeks’ gestation in 26 893 women
attending for routine antenatal care in a tertiary care
center. The mean resistance index (RI) and its relationship
to the outcome of pregnancy and birth-weight centiles
were evaluated.
Results Uterine artery RI showed a significant, negative
correlation with birth weight (r = −0.20, P < 0.0001).
Patients with early-onset pre-eclampsia had an increased
prevalence of high uterine artery mean RI, above the
90th centile, corresponding to an increased proportion
of small-for-gestational age (SGA) neonates with a birth
weight below the 10th centile. In late-onset pre-eclampsia,
however, there was an unexpectedly higher proportion
of large-for-gestational-age (LGA) neonates with a birth
weight above the 90th centile without a concurrent
increase in the prevalence of low uterine artery mean
RI below the 10th centile.
Conclusions The finding of a bimodal skewed distribution of birth weight, with neonates exhibiting a higher
prevalence of both LGA and SGA with late-onset
pre-eclampsia, indicates that there are two types of
late-onset pre-eclampsia. These findings explain the poor
performance of mid-trimester uterine artery Doppler in
predicting pre-eclampsia at term and provide insights
into the placental origins of the early and late forms of
pre-eclampsia. Copyright © 2014 ISUOG. Published by
John Wiley & Sons Ltd.
Correspondence to: Dr S. Verlohren, Department of Obstetrics, Charité University Medicine Berlin, D-13353 Berlin, Germany
(e-mail: [email protected])
Accepted: 6 January 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Verlohren et al.
294
including motility, survival, endometrial invasion, natural
killer cell and smooth muscle cell interactions, which
have been noted from as early as the first trimester of
pregnancy17 – 19 . The latter all predispose to incomplete
spiral artery remodeling and subsequent placental
underperfusion, which are recognized as prerequisites
for the later development of both pre-eclampsia and
IUGR20 – 22 . However, these associations do not explain
why the sensitivity of an increased uterine artery
resistance to blood flow as a predictor of early-onset
pre-eclampsia or IUGR is high, but the test is less accurate
when it comes to detecting late-onset pre-eclampsia or
IUGR.
The aim of this study was to investigate the relationship
between mid-trimester uterine artery Doppler resistance
indices and birth weight and the subsequent development
of pre-eclampsia in a large pregnancy cohort in an attempt
to provide insights into the placental origins of the early
and late forms of pre-eclampsia.
METHODS
This was a retrospective cohort study at St George’s
Hospital, London, UK, for which institutional review
board approval was granted. All women with singleton
pregnancies attending for routine prenatal care in the fetal
medicine unit were included in the analysis. Gestational
age was calculated from the last menstrual period and
confirmed by crown–rump length measurement.
Ultrasound examinations were performed at 18 + 0 to
22 + 6 weeks’ gestation, using standard obstetric ultrasound machines (Philips iu22 (Philips Medical Systems,
Solingen, Germany), GE E8 (GE Healthcare, Kretztechnik, Zipf, Austria) and Toshiba Aplio (Tokyo, Japan))
equipped with a 5-MHz transabdominal transducer. Uterine artery resistance index and other parameters were
recorded on a ViewPoint database (GE Healthcare, Solingen, Germany). Uterine artery Doppler indices were
measured using a well-established technique23,24 . Briefly,
the right and left uterine arteries are identified by color
flow at the apparent crossover with the external iliac
arteries and pulsed-wave Doppler is used to obtain waveforms. When three similar, consecutive waveforms have
been obtained, the resistance index is measured and the
mean of both sides is calculated (UtA-mRI). Women with
UtA-mRI > 95th centile were warned about the increased
risk of pre-eclampsia, asked to report immediately any
pre-eclampsia-related symptoms and scheduled a growth
scan at 36 weeks’ gestation. Multiple pregnancies and
pregnancies that ended before 24 weeks because of fetal
chromosomal abnormality, structural abnormality, miscarriage and social or maternal conditions were excluded.
Routine prophylaxis with aspirin was not used during this
period of the study.
Pregnancy demographic data and outcomes were
obtained from the obstetric ultrasound and delivery
suite database. All cases with hypertensive pregnancy
complications (pre-eclampsia and gestational hypertension) were identified and verified by a chart review.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
Pre-eclampsia and gestational hypertension were defined
according to the guidelines of the International Society for the Study of Hypertension in Pregnancy6 .
Pre-eclampsia cases were subdivided into early-onset
pre-eclampsia (delivering at or before 33 + 6 weeks),
intermediate-onset pre-eclampsia (delivering at 34 + 0 to
36 + 6 weeks) and late-onset pre-eclampsia (delivering
at or after 37 + 0 weeks). It is important to note that
we chose the endpoint ‘delivery’ for classification into
early-, intermediate- and late-onset disease. Birth weight
Z-scores were calculated using the Yudkin formula25 .
Data were analyzed using SPSS software version 20 (SPSS
Inc., Chicago, IL, USA). Variables were compared using
ANOVA, the Kruskal–Wallis test, Mann–Whitney U-test
or χ2 -test, as appropriate. Paired-group comparisons
were only undertaken if ANOVA indicated significant
differences.
RESULTS
A total of 27 669 patients underwent uterine artery
Doppler ultrasound examination at 18 + 0 to 22 + 6
weeks’ gestation. Outcome data for 26 893 women
seen during December 1999 to November 2011 were
available for analysis. Of these, 154 (0.6%) patients
had to be delivered for pre-eclampsia before or at 33+6
weeks, 251 (0.9%) between 34+0 and 36+6 weeks and
1551 (5.8%) at or after 37+0 weeks; 1785 patients
with non-pre-eclamptic pregnancy outcome delivered
before 37 weeks for other reasons and 23 152 patients
with uneventful pregnancy outcome delivered after 37
weeks. Complete data on maternal characteristics were
available for 21 677 patients (Table 1). Women with
pre-eclampsia were more likely to deliver early and to
have lower birth-weight neonates (P < 0.05). Intergroup
comparison showed a significant difference in height,
weight and body mass index (BMI) between those
patients with pre-eclampsia delivering after 37 weeks and
the control group (P < 0.05). Single-group comparison
showed significant differences for BMI when comparing
women with pre-eclampsia requiring delivery at or after
37 weeks with those requiring delivery before 34 weeks
and controls (Mann–Whitney U-test, P < 0.05) and for
controls vs those requiring delivery before 34 weeks
(Mann–Whitney U-test, P < 0.05). Gestational age at
delivery and birth weight were significantly different
when comparing women with pre-eclampsia requiring
delivery before 34 weeks and those requiring delivery
at 34–37 weeks with all other groups. No significant
differences were discerned when comparing women with
pre-eclampsia requiring delivery at or after 37 weeks and
controls (Mann–Whitney U-test, P < 0.05).
There was a significant, negative correlation between
UtA-mRI and birth weight. A higher UtA-mRI was
associated with a lower birth weight (Figure 1; r = −0.20,
P < 0.0001). The prevalence of UtA-mRI > 90th centile
with early pre-eclampsia, intermediate pre-eclampsia,
late pre-eclampsia and normal pregnancy was 63.6%,
38.2%, 15.5% and 8.8%, respectively (Figure 2a).
Ultrasound Obstet Gynecol 2014; 44: 293–298.
UtA Doppler, birth weight and pre-eclampsia
295
Table 1 Baseline characteristics of 21 677 women who delivered between December 1999 and November 2011 at St George’s Hospital
London
Pre-eclampsia at delivery:
Parameter
Maternal height (cm)
Maternal weight (kg)
Maternal BMI (kg/m2 )
GA at delivery (weeks)
Birth weight (g)
< 34 weeks (n = 28)
34–37 weeks (n = 67)
≥ 37 weeks (n = 1167)
Controls (n = 20 415)
163.51 ± 6.41
68.76 ± 13.46
25.69 ± 6.62*
31+5 ± 2*
1565.32 ± 541.1*
163.47 ± 6.9
64.36 ± 12.0
24.07 ± 4.17
36+0 ± 1*
2437.09 ± 510.68*
164.18 ± 7.17*
64.53 ± 13.04*
23.94 ± 4.6*
40+0 ± 1
3366.48 ± 491.86
164.25 ± 7.33*
65.29 ± 13.14*
24.20 ± 4.65*
39+5 ± 2
3254.71 ± 610.59
Data are given as mean ± SD. *Statistically significant difference on intergroup comparison (Kruskal–Wallis test, P < 0.05) for maternal
height, weight and body mass index (BMI) in pre-eclamptic patients (PE) requiring delivery ≥ 37 weeks and controls; and statistically
significant difference on single group comparisons (Mann–Whitney, P < 0.05) for: BMI in PE group requiring delivery ≥ 37 weeks vs
< 34 weeks as well as vs controls and in controls vs PE < 34 weeks; GA at delivery and birth weight were significantly different between all
groups except for PE requiring delivery ≥ 37 weeks vs controls.
1.2
(a)
80
∗
∗
1.0
Prevalence (%)
60
UtA-mRI
0.8
0.6
0.4
40
∗
20
0.2
0
0
2000
4000
∗
∗
UtA-mRI > 90th centile
∗
SGA
6000
Birth weight (g)
Figure 1 Correlation between mean uterine artery resistance index
(UtA-mRI) and birth weight in 26 893 women who gave birth at St
George’s Hospital, London, UK between December 1999 and
November 2011. Pearson correlation coefficient, r = −0.20;
P < 0.0001.
Intergroup comparison showed significant differences for
all outcome groups (P < 0.001), which were confirmed
by single-group comparison (P < 0.05 for all groups).
Similarly, the later the onset of pre-eclampsia, the less
frequent was birth weight below the 10th centile, with
small-for-gestational-age (SGA) neonates being present in
66.2%, 46.2%, 16.7% and 10.8% in the early, intermediate and late pre-eclampsia and control groups, respectively. Intergroup and single-group comparison showed
significant differences for all outcome groups (P < 0.05).
The prevalence of UtA-mRI < 10th centile with
early pre-eclampsia, intermediate pre-eclampsia, late
pre-eclampsia and normal pregnancy was 3.9%, 7.2%,
8.1% and 8.9%, respectively (Figure 2b). Intergroup
comparison showed only significant differences for
comparison of the early-onset pre-eclampsia (before
34 weeks) group as compared with all other groups
(P < 0.001). No significant differences were found when
comparing the other outcome groups (P > 0.05). The
distribution of large-for-gestational-age (LGA) fetuses
did not follow a similar trend, prevalence being
significantly higher in the late-onset pre-eclampsia group
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
(b) 10
∗
∗
8
Prevalence (%)
0
∗
∗
6
4
∗
∗
2
0
∗
UtA-mRI < 10th centile
LGA
Figure 2 Prevalence of: (a) mean uterine artery Doppler resistance
index (UtA-mRI) > 90th centile and small-for-gestational-age (SGA)
neonates and (b) UtA-mRI < 10th centile and large-for-gestationalage (LGA) neonates, in pre-eclamptic women who delivered before
34 ( ), at 34–37 ( ) and after 37 ( ) weeks’ gestation and
matched controls ( ). *Statistical significance (P < 0.05) for
comparison of women with pre-eclampsia before 34 weeks with all
other groups.
(8.6%) than in those with early- and intermediate-onset
pre-eclampsia and the control group (0.6%, 2.0%
and 7.2%, respectively). Intergroup comparison showed
significant differences for all outcome groups (P < 0.001),
and single-group comparison confirmed a significant
difference between late-onset pre-eclampsia and control
groups (P < 0.001).
Ultrasound Obstet Gynecol 2014; 44: 293–298.
296
DISCUSSION
The study findings demonstrate that there is a significant
correlation between mid-trimester uterine artery blood
flow, a key index of placentation, and subsequent birth
weight, as well as the timing of onset of pre-eclampsia.
In early-onset pre-eclampsia, as shown previously, there
was a very high prevalence of UtA-mRI > 90th centile,
which was associated with more SGA and fewer LGA
births. However, an interesting finding in this study is
that not only is late pre-eclampsia associated with a
higher prevalence of SGA births, but there is also an
unexpectedly higher prevalence of LGA births without
a concomitant increase in the prevalence of UtA-mRI
below the 10th centile. These findings therefore clearly
demonstrate a bimodal skewed distribution of birth
weight in late pre-eclampsia, with neonates exhibiting a
higher prevalence of both LGA and SGA compared with
normal pregnancy.
Uterine artery resistance to blood flow in pregnancy
is one of the best available screening tools for
pre-eclampsia. A low resistance to uterine blood flow
reflects successful trophoblast invasion with adequate
spiral artery remodeling, and thus normal placental
function. Birth weight is correlated with resistance to
blood flow in the uterine artery. Campbell et al.26 showed
that women with normal uterine artery blood flow at 20
weeks’ gestation give birth to babies with significantly
higher mean birth weight than those who had a later
normalization of the uterine artery resistance, i.e. between
20 and 24–26 weeks.
However, insufficient trophoblast invasion and
impaired spiral artery remodeling, the pathognomonic
lesion of placental dysfunction, mostly occurs in
early-onset pre-eclampsia. Placental underperfusion
lesions on histology and their assumed functional correlate, placental hypoxemia, have been implicated as the
main pathophysiologic entity in pre-eclampsia. Numerous studies have shown that women with pre-eclampsia
exhibit significantly higher numbers of placental lesions
(consistent with maternal underperfusion) than do
women with normal pregnancy. However, in late-onset
pre-eclampsia only a small proportion of placentae show
signs of incomplete spiral artery remodeling. Ogge et al.27
showed that the prevalence of placental underperfusion
lesions was higher in early-onset pre-eclampsia (58%)
than in late-onset pre-eclampsia (33%), with term
controls having the lowest prevalence (16%). Patients
destined to develop hypertensive pregnancy disorders also
demonstrate altered placental expression and circulating
serum concentrations of pro and anti-angiogenic factors
several weeks before the clinical onset of disease.
Soto et al.28 found that the prevalence of histological
placental underperfusion lesions was significantly higher
in women with pre-eclampsia, and an abnormal ratio of
placental growth factor/soluble fms-like tyrosine kinase-1
(PlGF/sFlt-1). As such, both uterine artery Doppler and
PlGF/sFlt-1 ratio have a high sensitivity and specificity for
the prediction of early-onset pre-eclampsia, commonly
presenting with SGA births29 .
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
Verlohren et al.
It is well known that uterine artery Doppler and
sFlt-1/PlGF ratio perform much worse in the prediction
of late-onset pre-eclampsia30 . The weakness of the
relationships between the onset of pre-eclampsia and
uterine artery Doppler indices and the sFlt-1/PlGF ratio, as
well as the relative lack of placental lesions in late-onset
pre-eclampsia, have been interpreted as a consequence
of a different disease etiology, one that is unrelated to
placental hypoxemia.
The finding of a bimodal birth-weight distribution with
late-onset pre-eclampsia in this study, at least initially,
appears to support the assertion that pre-eclampsia may
have two different etiologies: early-onset pre-eclampsia
with an increased prevalence of high UtA-mRI, poor trophoblast development and SGA births, and late-onset
pre-eclampsia with normal mid-gestational UtA-mRI
related to good trophoblast development and more LGA
births. However, the bimodal birth-weight distribution
in late-onset pre-eclampsia, with increased prevalence of
both SGA and LGA infants, deserves further explanation.
This finding implies that late-onset pre-eclampsia may
have two different etiologies: one shared with early-onset
pre-eclampsia resulting in SGA births and another associated with LGA births. The LGA form of late-onset
pre-eclampsia is also clinically seen with placentomegaly
in association with fetal macrosomia, multiple pregnancies and fetal hydrops with mirror syndrome. The
dual etiology of late-onset disease might also explain the
weaker relationship with UtA-mRI and sFlt-1/PlGF ratio
compared with early-onset pre-eclampsia. This explanation implies that the placental biochemical ‘cascade’ that
triggers the signs and symptoms of pre-eclampsia is related
to placental hypoxemia in the early-onset disease and
SGA form of late-onset pre-eclampsia, but has a different pathophysiology in the LGA form of the late-onset
disease, unrelated to placental hypoxemia31 .
It is, however, worth considering the possibility that
both the early and late varieties of pre-eclampsia have
placental hypoxemia in common; this is of placental
origin in early-onset pre-eclampsia and the SGA form
of late-onset disease32 . In the LGA form of late-onset
pre-eclampsia, maternal cardiac dysfunction and the
inability to meet the metabolic demands of an enlarged
placenta may result in placental hypoxemia. This
hypothesis is supported by the finding that maternal
cardiac dysfunction precedes the clinical presentation of
both early and late pre-eclampsia33 – 35 . Recent work
on maternal cardiovascular function in pre-eclampsia
shows that women destined to develop pre-eclampsia
exhibit altered left ventricular geometry, impaired
myocardial activity and left ventricular dysfunction33 – 35 .
Importantly, morphological, structural and hemodynamic
cardiovascular changes are equally prevalent, but more
severe, in women destined to develop early-onset
pre-eclampsia than in those who develop late-onset
disease. The role of maternal cardiovascular function in
the etiology of pre-eclampsia also reconciles the finding
that both pre-eclampsia and adult cardiovascular disease
share the same predisposing factors such as age, obesity,
Ultrasound Obstet Gynecol 2014; 44: 293–298.
UtA Doppler, birth weight and pre-eclampsia
hypertension and certain ethnic origins36,37 . Furthermore,
the combined placental and maternal cardiovascular
origin of pre-eclampsia is compatible with the findings of
increased long-term cardiovascular morbidity in mothers
with pre-eclampsia and that cardiovascular disease and
pre-eclampsia have similar candidate gene profiles38 .
Despite the major strength of a very high caseload
enabling us to find subtle differences in associations
between uterine blood flow, birth weight and prevalence
of pre-eclampsia in a cohort of over 26 000 patients, our
study has some limitations. We made inferences about the
potential pathophysiological explanations of our findings
without having analyzed histological and/or biochemical
samples. However, we believe that the latter weakness is
mitigated to some extent by the myriad of published data
available that provide circumstantial support to the new
insights provided in this study.
While early-onset pre-eclampsia is thought to be
caused primarily by inadequate spiral artery remodeling
and placental dysfunction, the mechanisms leading to
the late-onset disease are unclear. We show here that
late-onset pre-eclampsia is associated with both SGA
and an unexpectedly higher proportion of LGA fetuses
compared with controls. These findings support the
hypothesis that late-onset pre-eclampsia has a mixed
etiology, partly analogous to early-onset pre-eclampsia
with SGA and partly distinct, the LGA form of late-onset
pre-eclampsia. We propose that placental hypoxemia
leading to the pre-eclamptic cascade may develop
from placental dysfunction either as a consequence
of poor trophoblast development, as with early-onset
pre-eclampsia, or, in the case of late pre-eclampsia, from
the inability of the maternal heart to meet the increased
metabolic demands of an overgrown fetoplacental unit.
This hypothesis favors a disease continuum and explains
many of the clinical paradoxes seen with pre-eclampsia.
Further studies are needed to verify the proposed concept.
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