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Received: 26 February 2020    Accepted: 15 April 2020

DOI: 10.1002/ijgo.13173

REVIEW ARTICLE
Obstetrics

Preterm parturition and pre-­eclampsia: The confluence of two

great gestational syndromes

Aswathi Jayaram* | Charlene H. Collier | James N. Martin

Department of Obstetrics and

Gynecology, Division of Maternal Fetal
Medicine, University of Mississippi Medical
Center, Jackson, MS, USA
*Correspondence
Aswathi Jayaram, Department of Obstetrics
and Gynecology, Division of Maternal Fetal
Medicine, University of Mississippi Medical
Center, Jackson, MS, USA.
Email: aswathi.j@gmail.com
Abstract
Background: Preterm birth (PTB) and pre-­eclampsia independently, and frequently con-
currently, adversely affect the pregnancy outcomes of millions of mothers and infants
worldwide each year.
Objectives: To fill the gap between PTB and pre-­eclampsia, which continue to consti-
tute the two most important current global challenges to maternal and perinatal health.
Methods: Pubmed, Embase, and Cochrane databases were searched from inception
until December 2019 using the terms spontaneous PTB (SPTB), indicated preterm deliv-
ery (IPTD), early-­onset pre-­eclampsia, and pre-­eclampsia.
Results: History of PTB and pre-­eclampsia were the strongest risk factors contributing
to the occurrence of SPTB or IPTB. The risk of PTB and pre-­eclampsia among non-­
Hispanic African American women was higher than the rate among all other racial/eth-
nic groups in the United States. Low-­dose aspirin (LDA) has been reported to reduce
the risk of pre-­eclampsia by at least 10% and PTB by at least 14%. Lastly, women and
their fetuses who develop early-­onset pre-­eclampsia are at higher risk for developing
hypertension and cardiovascular disease later in life.
Conclusions: While better clarity is needed, efforts to coordinate prevention of both
PTB and pre-­eclampsia, even though imperfect, are critically important as part of any
program to make motherhood as safe as possible.

KEYWORDS
Aspirin; Eclampsia; Indicated preterm birth; Pre-eclampsia; Preterm birth

1 | INTRODUCTION
Preterm birth (PTB) and pre-­eclampsia can both kill or injure perma-
nently those mothers who suffer either condition. PTB, defined as
delivery before 37 weeks of gestation, is the world's most common sin-
gle cause of perinatal and infant mortality.1–4 PTB is the leading cause
of neonatal mortality in the United States, with approximately one-­
third of all infant deaths related to prematurity.5 Globally, every year
approximately 15 million babies are born preterm, of which one-­third
to one-­half die by the age of 5 years, secondary to complications of
prematurity.6,7 A significant number of survivors experience long-­term
cognitive, visual, and learning impairments. The costs to patients, fam-
ilies, providers, healthcare systems, and society in general are substan-
tial although difficult to objectively and accurately measure.8,9
Preterm birth numbers include spontaneous PTB (SPTB),
associated with intact or prematurely ruptured amnion, and non-­
spontaneous indicated preterm delivery (IPTD), undertaken by the
provider for maternal and/or fetal indications. It is important to con-
sider these two entities separately in order to determine the rates of
SPTB versus the IPTD rates. WHO subdivides PTB into chronologic
categories denoting extremely PTB (<28  weeks of gestation), very
PTB (between >28 and <32 weeks of gestation), and moderate to late

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© 2020 International Federation of Int J Gynecol Obstet 2020; 150: 10–16
Gynecology and Obstetrics
Jayaram ET AL.
PTB (>32–36  weeks  +  6  days of gestation).10 In the United States,
these definitions can vary to define early PTB as the gestational period
between 24 and 31 weeks, moderate PTB as 32–34 weeks, and late
PTB inclusive of 34–36 weeks of gestation.11
2 | TRENDS IN PRETERM BIRTH
During the years 2013–2016, the International Federation of
Gynecology and Obstetrics’ (FIGO's) Working Group on PTB, with
generous support from the March of Dimes Foundation and expert
input from the Boston Consulting Group, undertook a robust cross-­
country analysis of individual patient-­level pregnancy and birth data
from 4.1 million singleton pregnancies in four very high human devel-
opment index countries (Sweden, Slovenia, New Zealand, and Czech
Republic) and the state of California, where one-­eighth of deliveries
in the United States occur annually. These countries were chosen
for investigation because each had an excellent high-­quality, long-­
standing perinatal data system in place from which extensive and
highly reliable data could be readily retrieved. Using the results of a
systematic review which identified 21 factors attributable to PTB, the
Working Group utilized advanced analytics to interrogate this large
number of individual patient datasets in order evaluate the poten-
tial for prediction of SPTB or IPTD. It was disappointing to find that
approximately two-­thirds of patients had no apparent risk factors
or identifiable reasons for PTB to occur. Importantly, however, in all
country datasets, prior PTB and pre-­eclampsia were the strongest risk
factors contributing to the occurrence of spontaneous or indicated
PTB, respectively.12,13 By population group, the patients at the high-
13
est risk for PTB were nulliparous and patients carrying a male fetus.
Other groups of investigators have struggled similarly to define risk
factors and a phenotype to the patient most at risk for SPTB.14
3 |  RACIAL/ETHNICITY CONSIDERATIONS
There are notable racial differences in both the incidence and sever-
ity of both PTB and pre-­eclampsia. In the United States, the risk of
PTB among non-­Hispanic black women is 49% higher than the rate
among all other racial/ethnic groups in the United States, with 13.3%
delivering preterm compared to 8.5% for Asian women and 8.9% for
white women.15 These differences are not well understood although
socioeconomic, environmental, behavioral, and psychosocial factors
along with potential genetic variations have been implicated.16–18 An
analysis of 56 617 nulliparous singleton women from the Consortium
on Safe Labor was conducted by the Eunice Kennedy Shriver National
Institute of Child Health and Human Development, the National
Institutes of Health, involving 19 US hospitals between 2002 and
2008. Data from this study revealed that non-­Hispanic black women
are at higher risk for every form of pre-­eclampsia-­related conditions
during pregnancy.19 Furthermore, in comparison to non-­Hispanic
white women, non-­Hispanic black women were more likely to enter
pregnancy with chronic hypertension (adjusted odds ratio [AOR]
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1.43, 95% confidence interval [CI] 1.11–1.84) and had a higher risk
of developing mild (AOR 1.26, 95% CI 1.10–1.45), severe (AOR 1.31,
95% CI 1.10–1.57), and superimposed pre-­eclampsia (AOR 1.98, 95%
CI 1.40–2.80).20 An analysis of 902 460 singleton births in New York
City during 1995–2003 found women of Mexican descent to be at
highest risk of developing pre-­eclampsia (AOR 2.9, 95% CI 2.7–3.1),
followed by African-­American women (AOR 2.3, 95% CI 2.2–2.3).
There are notable variations in risk within groups by ethnicity and
nativity for both PTB and pre-­eclampsia.21,22
4 | PRETERM GESTATION AND PRE-­
ECLAMPSIA
The development of pre-­eclampsia in the preterm period is well
known to result in IPTD inasmuch as the only way to initiate recovery
from pre-­eclampsia is to deliver the fetus and remove the supporting
placental tissues/membranes, at or shortly after the time of diagno-
sis.23 Definitions for pre-­eclampsia generally concur internationally
although countries differ in specifics—no one specific country or inter-
national definition is considered in the present work because it varies
among authors. In general, between one-­quarter to one-­third of all
PTB is associated with pre-­eclampsia.24 Auger et al.25 demonstrated
that approximately 38% of IPTDs between 28 and 31 weeks of ges-
tation are undertaken due to worsening pre-­eclampsia, a number
which decreases to 22% later in gestation for pregnancies between
32 and 36 weeks of gestation. Fetal growth restriction (FGR) result-
ing in small-­for-­gestational age (SGA) neonates and increased perina-
tal morbidity and mortality occurs in proportion to the prematurity
of the pregnancy and the severity of the pre-­eclampsia.26,27 There
is a great variation among patient groups in relation to their coun-
try of birth and the occurrence of indicated PTB for what has been
termed “early-­onset” pre-­eclampsia (EOPE). Compared to Canadian-­
born mothers with a 2.7 per 1000 rate of pre-­eclampsia-­indicated
PTB at 24–36 weeks of gestation, this is 50%–100% more common in
women from the Philippines, Colombia, Nigeria, Jamaica, and Ghana
who now reside in Canada and deliver there.28
5 | EPIDEMIOLOGY
Similar to PTB, pre-­eclampsia and pre-­eclampsia-­spectrum disorders
are also a major threat to maternal and fetal well-­being, especially in
low-­ and middle-­income countries (LMICs). Several epidemiological
studies have determined the ranges of prevalence for a combination
of all hypertensive disorders of pregnancy in general (5.2%–8.2%)
as well as gestational hypertension (1.8%–4.4%) and pre-­eclampsia
(0.2%–9.2%) as specific categories.29 In LMICs, pre-­eclampsia and
pre-­eclampsia-­spectrum disorders such as HELLP syndrome (labora-
tory evidence of hemolysis, elevated liver enzymes, and low plate-
lets/thrombocytopenia), eclampsia, pre-­eclampsia superimposed on
chronic hypertension, and severe gestational hypertension are the
major cause of approximately 400 000 maternal deaths and six million
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12       Jayaram ET AL.

perinatal deaths each year worldwide. In addition to maternal and per-
inatal deaths, pre-­eclampsia/eclampsia in LMICs is a significant risk
factor for PTB and low birth weight infants.
6 |  EARLY VERSUS LATE ONSET
PRE-­E CLAMPSIA
Subtyping of PE into two main groups based on the time of onset
and first recognition of the disease during pregnancy has clinical impli-
cations and is reflective of variable underlying pathophysiology. By
definition, evidence of EOPE is detected before 34 weeks of gesta-
tion and comprises the minority (20%–30%) of cases of pre-­eclampsia;
on the other hand, this group is associated with the majority of PTBs
and increased maternal–perinatal morbidity and mortality.30–34
Patients with EOPE exhibit evidence of incomplete transformation of
the spiral arteries resulting in impaired placentation/hypoperfusion,
reduced fetal nutrient supply, and the potential to develop FGR. The
principal Doppler changes occur at the level of the umbilical artery
with progression from absent to reverse end-­diastolic flow.35 High
levels of the two antiangiogenic mediators soluble (sFlt-­1) and solu-
ble endoglin (sEng) are significantly correlated with increased uter-
ine artery Doppler evidence of vascular resistance.36 When sampled
around the time of indicated delivery, angiogenic imbalance is more
pronounced in patients with EOPE showing higher sFlt-­1/PlGF ratios
(PlGF=platelet growth factor) and sFlt-­1 serum values with lower
serum PlGF values.37,38 High levels of proteinuria are usually encoun-
tered in patients with EOPE.39
In contrast to EOPE, late-­onset pre-­eclampsia (LOPE) presents at or
after 34 weeks of gestation, usually without placental or fetal compro-
mise; it comprises the majority (>80%) of patients with pre-­eclampsia.
The rate of severe maternal morbidity is doubled (12.2% vs 5.5%) in the
EOPE group compared to LOPE; the adjusted hazard ratio and odds
ratios for risk factors and poor birth outcomes is eight times higher for
the EOPE versus LOPE pregnancies.40 In one large study, the incidence
of abnormal uterine artery Doppler waveforms, SGA fetuses, stillbirth,
the Apgar scores <7 at 5  minutes, and early neonatal death was sig-
nificantly higher in the EOPE versus LOPE pregnancies.41 The EOPE
and LOPE patient groups have different implications for pregnancy and
progeny: the EOPE group for immediate adverse perinatal outcomes
including IPTD with complications of prematurity/SGA, whereas the
LOPE group have a higher risk for late cardiovascular disease risk in
the offspring.31,42 Finally, EOPE recurs in 94% of patients versus only
a 56.5% rate of recurrence for patients with prior LOPE.43 The salient
features of EOPE and LOPE are summarized in Table 1.
7 | PRE-­E CLAMPSIA: SCREENING
Screening strategies to accurately detect patients at risk for pre-­
eclampsia are limited in predictive accuracy and applicability due
in part to the complex pathophysiology of this syndromic disorder.

T A B L E   1   Important features characterizing EOPE versus LOPE.

EOPE LOPE

Gestational age at diagnosis <34 >34

(weeks)
Placentation Abnormal Normal
Extent of spiral arteriole Abnormal (many/most) Mostly normal; placenta outgrows uterine
remodeling vasculature→overcrowding of microvilli, restricted villous
perfusion
sFlt-­1 Early increase Late increase
PlGF Early decrease Late decrease
Prediction Yes No
Prevention LDA started by 16 weeks Induction/delivery at 37 weeks or when diagnosis made
>37 weeks of gestation
Gestational age at delivery Preterm Early term/term
Estimated fetal weight actual Early onset fetal growth restriction→SGA Normal→AGA, LGA
delivery weight
Degree of hypoxia ++ Chronic + Acute
Adaptation to hypoxia Systemic/gradual over time Central nervous system focused/rapid
Tolerance to hypoxia High Low
Doppler abnormalities Early onset/rapid progression Late onset/slow progression
Neonatal outcome High morbidity and mortality Low morbidity and mortality
Immediate adverse outcomes Later cardiovascular disease
Severe maternal morbidity About 12% About 6%

Abbreviations: AGA, appropriate-­for-­gestational age; EOPE, early-­onset pre-­eclampsia; LDA, low-­dose aspirin; LGA, large-­for-­gestational age; LOPE, late-­
onset pre-­eclampsia; PIGF, platelet growth factor; SGA, small-­for-­gestational age.
Jayaram ET AL.
Most screening strategies, therefore, have focused upon a search
for risk factors early in gestation. The highest, most significant clini-
cal and obstetric risk factors are chronic hypertension, obesity, and
severe anemia as determined in a secondary analysis of the WHO
Global Survey on Maternal and Perinatal Health.44 Investigators
undertaking a recent systematic review of 29 studies determined
that a simple prediction model using parity, a prior pre-­eclamptic
pregnancy, race, chronic hypertension, and method of conception
constituted the best system to identify with few false positives and
three-­quarters of patients are destined to develop pre-­eclampsia.45
The ASPRE trial demonstrated that early screening for pre-­eclampsia
in the first trimester using an algorithm with maternal factors, mean
arterial pressure (MAP), uterine artery pulsatility index, and maternal
serum pregnancy‐associated plasma protein‐A (PAPP‐A) and placental
growth factor (PlGF), had a detection rate of 77% for the development
of pre-­eclampsia before 37  weeks of gestation.46 Another group of
investigators undertaking a systematic review of 15 studies involv-
ing 11 779 pregnancies observed that the first and second trimes-
ter serum assessment of the sFlt-­1 to PlGF ratio was inconsistently
elevated in women who later developed PE, thwarting hopes that an
objectively measured serum biomarker might replace the risk predic-
tion models based on obstetric parameters.47,48
8 | PRETERM BIRTH:
SCREENING AND PREDICTION
Efforts to predict and/or prevent either SPTB or pre-­eclampsia have
been hampered by the absence of a clear understanding of the patho-
genesis of either syndromic disorder such that effective prevention
strategies for PTB and pre-­eclampsia have struggled and taken dif-
ferent courses.49 Because a history of prior singleton SPTB is one of
the strongest risk factors for recurrent PTB, patients with this history
have had some success receiving progesterone supplementation and,
in some cases, cerclage placement when serial cervical surveillance
with transvaginal ultrasound identifies a patient for whom this inter-
vention might be beneficial.50,51 Although labor-­intensive and costly,
transvaginal cervical length screening of all pregnant women has been
advocated in order to determine the risk for preterm delivery so that,
if present, vaginal progesterone can be initiated.
9 | RISK OF RECURRENCE FOR PRE-­
ECLAMPSIA
Women with prior pre-­eclampsia have been shown to be at high risk
for SPTB, IPTB, and SGA newborns. In a recent systematic review
and meta-­analysis of 92 studies involving more than 25 million preg-
nancies, data revealed that patients with prior pre-­eclampsia had the
highest pooled relative risk of developing pre-­eclampsia again.52 This
was confirmed in another study involving 606 pregnancies with prior
pre-­eclampsia whose mothers had a subsequent PTB rate of 23%. The
outcome of PTB was almost evenly split between SPTB (47%) and
|
      13
IPTB (53%) pregnancies; slightly more than one-­third of patients (37%)
in this investigation developed EOPE.53 As expected, the frequency of
SGA infants was significantly higher in the IPTB group (21.3 vs 1.4%).
10 | PRE-­E CLAMPSIA AND
PRETERM BIRTH: REDUCTION OF
OCCURRENCE OR RECURRENCE
A reduction in the occurrence of EOPE should comparably reduce
the need for IPTB as well as SPTB. A high-­dose calcium supple-
mentation (>1 g/day) to women with low calcium diets (WHO rec-
ommends 1.5–2.0  g/day) has been associated with a significant
reduction in the overall risk of PE and PTB.54 A probiotic intake
during early pregnancy has been shown to significantly lower the
risk of SPTB and IPTB in a large Scandinavian cohort of 70 149
singleton pregnancies.55 Work activities and occupational expo-
sures (working hours, shift work, lifting, standing, and physical
workload) do not appear to impact either the risk for prematurity,
low birth weight, or pre-­eclampsia.56
11 | THE ROLE OF LDA IN
PREVENTION OF PRE-­E CLAMPSIA AND
PRETERM BIRTH
11.1 | LDA: Pre-­eclampsia
The majority of efforts to reduce pre-­eclampsia have been focused
on the use of LDA (75–150  mg daily). After transformation into
salicylic acid, aspirin inhibits cyclooxygenase production of throm-
boxane by platelets for the remainder of its lifespan of 7–10 days,
without impacting prostacyclin production. LDA thus works to
impede placental and platelet-­produced thromboxane A2, which
functions as a vasoconstrictor, and remodel vasculature in the set-
ting of increased platelet aggregation and adhesion. Prostacyclin
mediates vasodilation and decreases platelet aggregation, adhesion,
and vascular remodeling, functions that are not antagonized by use
of LDA. A further action of LDA is to decrease the production of
tissue factor thrombin, thus favoring fibrinolysis at the expense of
thrombin formation.
Since 1985, numerous studies have been undertaken to investi-
gate whether daily LDA initiated early in gestation (14–16 weeks of
gestation) reduces the risk of developing pre-­eclampsia, particularly
EOPE.57–60 Systematic reviews and large meta-­analyses including indi-
vidual patient data have provided evidence of the benefit of LDA in
reducing the risk of pre-­eclampsia by at least 10%, FGR by at least
20%, and PTB by at least 14% without posing a safety risk to fetuses
or mothers, although there is generally a poor reporting of childhood
outcomes.61–63 The rate of LOPE also appears to be lessened by early
initiation (<17 weeks of gestation) of daily LDA but not to the degree
that EOPE is impacted by this therapy.64,65 Relaxing the indications for
utilization of LDA to prevent pre-­eclampsia was suggested a decade
ago and has been advocated in order to increase utilization versus
 |
14       Jayaram ET AL.
use of a universal approach for all patients, which has been modeled
52,66,67
to show that it was cost-­effective in 99% of simulations.
would, of course, include the largest population groups at the high-
est risk for PTB: nulliparous patients and mothers with male gender
fetuses.12,13 Preconception LDA has not been shown to significantly
reduce the overall rate of PTB.68
11.2 | LDA: Preterm birth
Several studies have been performed that suggest the use of LDA
can also reduce the risk of spontaneous PTB during pregnancy, sug-
gesting that it should be considered as a therapeutic intervention
for the prevention of SPTB in the absence of risk factors for pre-­
eclampsia. Aspirin-­facilitated reduction of PTB has been demon-
strated in at least five trials before 2015.57,63,69,70 More recently,
among almost 1800 women prospectively randomized early in
pregnancy to receive either LDA or placebo, a trend was observed
favoring fewer SPTB and fewer preterm amnion ruptures.71 Similar
findings were reported by Andrikopoulou et al.72 at the 2018 Society
for Maternal-­Fetal Medicine meeting in the United States. A very
recent systematic review and meta-­analysis evaluating antiplatelet
agents for the prevention of SPTB showed a 7% lower risk of SPTB
at less than 37 weeks of gestation and a 14% lower risk at less than
34  weeks of gestation.73 The APRIL multicenter randomized pla-
cebo controlled trial to test the efficacy of LDA to prevent recurrent
SPTB is now underway in the Netherlands as well as the ASPIRIN
trial in seven LMICs.74,75 A critically important limiting factor for the
efficacy of LDA with regard to either prevention of pre-­eclampsia or
PTB is patient compliance.76
12 | CONCLUSION
Linkages between these two great gestational syndromes—PTB
and pre-­eclampsia—serve to underscore the importance of efforts
to investigate and understand the biologic mechanism(s) undergird-
ing the pathogenesis of both pregnancy disorders. With precision
science, we can hopefully move from the “shotgun” approach to
prevention and treatment for both syndromes in favor of a more
specific, targeted “rifle” approach using serum biomarkers and spe-
cific treatment modalities.77 While better clarity is awaited, efforts
to coordinate prevention efforts for both PTB and pre-­eclampsia,
even though imperfect, are critically important as part of any pro-
gram to make motherhood as safe as possible. The urgency is not
only for the prevention of future cardiovascular disease in the
mothers, but also from the perspective for an increased risk of the
affected fetus developing hypertension and cardiovascular disease
later in adult life.78–81
AUTHOR CONTRI B UTI O N S
All authors contributed to the design and implementation of the research,
the analysis of the results and the writing of the manuscript.
CO NFL I C TS O F I NT ER ES T
This
The authors have no conflicts of interest
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