®

Review
OPEN

First Trimester Screening for Preeclampsia: An

Asian Perspective
Sakita Moungmaithong, Xueqin Wang, Angela S.T. Tai, Qiaoli Feng, Daljit Sahota, Tak Yeung Leung,
Liona C. Poon∗

Abstract
Preeclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. This disorder has
profound short-term and long-term impacts on both the affected woman’s and her child’s health. Early-onset PE requiring preterm
delivery (preterm PE) is of particular importance because it is associated with a higher risk of adverse pregnancy outcomes than term
PE. First trimester screening model developed by the Fetal Medicine Foundation (FMF), which uses Bayes-theorem to combine
maternal characteristics and medical history together with measurements of mean arterial pressure, uterine artery pulsatility index,
and serum placental growth factor, has been proven to be effective and have superior screening performance to that of traditional risk
Downloaded from http://journals.lww.com/mfm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 11/23/2021

factor-based approach for the prediction of PE. Identification of high risk pregnant women for preterm PE and giving aspirin
prophylaxis before 16th week of gestation would reduce the incidence of preterm PE. In Asia, although the prevalence of PE is slightly
lower than the global estimation, early screening and prevention of this life-threatening condition is still crucial. The FMF Bayes-
theorem based screening method has been validated in a large-scale prospective Asia-wide study and revealed that the first trimester
triple test achieves the highest detection rate, compared with the traditional risk factor-based approaches, and that the screening
performance is comparable to the published data from the FMF in East Asian women. However, in order to achieve optimal screening
performance, the key is to establish standardized methods for biomarker measurements and regular biomarker quality assessment,
as each biomarker is susceptible to inaccurate measurement, thus affecting performance of screening. Furthermore, it is of great
importance to emphasize that the optimal preventive effect of aspirin on preterm PE is clearly associated with good compliance to
treatment. In conclusion, global implementation of an effective first trimester “screen and prevent” program for preterm PE would
provide the opportunity to reduce the risk of both short-term maternal and perinatal morbidity and mortality, with the possibility of
intergenerational prevention of future chronic diseases for both the mother and her offspring.
Keywords: Pre-eclampsia; Asian population; Aspirin prophylaxis; Fetal medicine foundation (FMF); Screening

Introduction PE cases, is one of the leading causes of indicated preterm

Preeclampsia (PE) is one of the most serious pregnancy-
specific multisystem disorder. This condition could be
subclassified according to the time of delivery as early-
onset (with delivery at <34 weeks’ gestation), preterm
(with delivery <37 weeks’ gestation), late-onset PE (with
delivery at ≥34 weeks’ gestation), and term PE (with
delivery ≥37 weeks’ gestation).1–4 This is because early-
onset/preterm PE is more likely to be associated with
placental insufficiency than late-onset/term PE, with
different clinical manifestations and impact on pregnancy
outcome.5 Preterm PE, which accounts for one-third of all
Department of Obstetrics and Gynaecology, The Chinese University of
Hong Kong, Shatin, Hong Kong 999077, China.
∗
Corresponding author: Liona C. Poon, Department of Obstetrics and
Gynaecology, The Chinese University of Hong Kong, Shatin, Hong
Kong 999077, China. E-mail: liona.poon@cuhk.edu.hk
Copyright © 2021 The Chinese Medical Association, published by
Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the
Creative Commons Attribution-Non Commercial-No Derivatives License
4.0 (CCBY-NC-ND), where it is permissible to download and share the
work provided it is properly cited. The work cannot be changed in any
way or used commercially without permission from the journal.
Maternal-Fetal Medicine (2021) 3:2
Received: 30 December 2020
http://dx.doi.org/10.1097/FM9.0000000000000101
delivery as well as maternal and perinatal mortality and
morbidity.6,7 On the contrary, term PE is more frequent,
but with reduced severity of maternal and neonatal
complications.7–9
The prevalence of PE is estimated to be around 2%–8%
worldwide but it varies significantly depending on racial
origin or ethnicity and geographical region.10–12 Previous
studies have demonstrated that there is a lower frequency
of PE among Asian women. Bilano et al. reported a
secondary analysis of the World Health Organization
Global Survey on Maternal and Perinatal Health across
three regions consisting of 24 low- and middle-income
countries (LMICs) and demonstrated that in Asia the
prevalence of PE is about 3.13% overall, ranging from
1.19% in Vietnam to 5.60% in the Philippines.13 India had
the highest perinatal mortality and preterm birth rates
associated with PE, while Sri Lanka had the highest rate of
low birth weight among all 24 countries.13 The prevalence
of PE in Chinese women has been reported to be relatively
low at 1.4%–1.9%, which may partly be explained by the
lower frequency of risk factors; for example, the age and
body mass index (BMI) are relatively lower among Asian
pregnant women, compared to Caucasian and Afro-
Caribbean women.14–17 Furthermore, race or ethnicity
may be a surrogate for several environmental factors
including lifestyle, healthcare system, as well as genetic

116
Moungmaithong et al., Maternal-Fetal Medicine (2021) 3:2
susceptibility to PE.13,16,18–20 Although in Asia the overall
prevalence of PE is not high, the prevalence of preterm PE,
which is believed to be a placental disorder rather than a
maternal disorder, is comparable to that of other countries
at 0.7%.14
PE poses to both pregnant women and their offspring an
increased risk for immediate and long-term health
problems.6,21,22 Maternal complications of PE include
hepatorenal impairment, pulmonary edema, coagulation
disorder, cerebral injury, and death23–25; while uteropla-
cental insufficiency associated with PE predisposes the
fetus to growth restriction, placental abruption, iatrogenic
preterm birth, and stillbirth.5,26 Long-term health con-
sequences of the woman affected by term or preterm PE
include a 2- to 5-fold increase in risk of developing
hypertension, cardiovascular and cerebrovascular disease
as well as metabolic syndromes in the future, compared to
those who are unaffected.27,28 The life expectancy of
women affected by preterm PE is reduced on average by
10 years.22 Furthermore, infants born to mothers
affected by preterm PE are at risk of prematurity-related
complications and neurodevelopmental impairment, later
in life they also have an increased risk for developing
diabetes, hypertension, cardiovascular disease, and meta-
bolic syndromes.29–31
Despite the sophisticated pathophysiology of PE, recent
advances have made it possible to predict and prevent
preterm PE. In order to effectively prevent this disorder
and its complications, identifying pregnant women who
are at high risk of developing preterm PE is of great
importance.32 First trimester PE screening allows initiation
of aspirin prophylaxis in high risk women early enough to
possibly improve placentation and reduce the incidence as
well as the severity of this disorder.33–35 Although there is
now increased awareness of the importance of early
screening for preterm PE and providing aspirin prophy-
laxis to high-risk pregnant women in Asia, there are some
variations in practice in terms of methods of screening and
recommended dosage of aspirin prophylaxis as well as
limited implementation as part of routine prenatal care.32
Global expansion of first trimester screening and preven-
tion for preterm PE would provide the opportunity to
reduce the risk of both short-term maternal and perinatal
morbidity and mortality, with the possibility of intergen-
erational prevention of future chronic diseases for both the
mother and her offspring.33
First trimester screening for PE
The traditional approach to screening for PE is based on
maternal risk factors, which has been recommended by
various professional organizations.36–38 Although the
recognition of maternal risk factors appears clinically
useful and has been widely adopted in identifying high risk
women in clinical practice because of its simplicity, it is not
sufficient for effective prediction of PE.33,35,39 Screening
based on the 2013 American College of Obstetricians and
Gynecologist (ACOG) recommendation achieves detec-
tion rates of only 5% (95% confidence interval (CI): 2%–
14%) and 2% (95% CI: 0.3%–5%) for preterm and term
PE, respectively, at a 0.2% false-positive rate (FPR).40 The
expanded list of clinical risk factors included in the United
States Preventive Services Task Force recommendation41
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has subsequently been endorsed by the ACOG and led to a
considerable improvement in the detection rates to 90%
(95% CI: 79%–96%) and 89% (95% CI: 84%–94%) for
preterm and term PE, respectively; however, the FPR has
also increased to as high as 64%.14,41 Whereas screening
based on the National Institute for Care and Health
Excellence (NICE) guideline achieves detection rates of
39% (95% CI: 27%–53%) and 34% (95% CI: 27%–
41%), at a 10% FPR, for preterm and term PE,
respectively.35,40 A recent Asia-wide cohort study has
revealed that for the screening of PE the ACOG
recommendation achieves a detection rate of 54.6% at
20.4% FPR, whilst the detection rate with the use of the
NICE guideline is 26.3% at 5.5% FPR.14,35,40 In addition
to the poor performance of screening with the maternal
risk factor approach, the uptake of aspirin prophylaxis by
high risk pregnant women, with risk status defined by the
maternal risk factor-based screening, is variable. In the
Screening Programme for Preeclampsia study, aspirin was
reported to be taken by 23.2% of women in the NICE
screen-positive group,42 whilst in Canada, a retrospective
study among 8176 pregnant women revealed that aspirin
was prescribed for only 7.6% of high risk pregnancies.43
These findings highlight the issue that risk factor-based
approach to screening is ineffective in ensuring high aspirin
uptake in high risk women. In Asia, our study demon-
strated that only 4% of women were taking aspirin, which
also underlined the fact that the use of aspirin for high risk
pregnant women in reducing the risk of PE had not been
widely adopted.14
An alternative approach to screening for PE is based on
the Fetal Medicine Foundation (FMF) multi-marker
prediction algorithm, namely the first trimester combined
test for PE, which has been endorsed by the International
Federation of Gynecology and Obstetrics (FIGO).44,45 This
approach aims to universally provide patient-specific risks
of PE requiring delivery before a specified gestational age for
pregnant women.46–48 The FMF first trimester combined
test uses Bayes theorem to combine maternal a priori risk
based on maternal characteristics, obstetrics and medical
history with “triple test”, which consists of mean arterial
pressure (MAP), uterine artery pulsatility index (UtA-PI)
and serum placental growth factor (PlGF) measured at
gestational age 11–13+6 weeks.17,44,47,49,50 This screening
should ideally be done at the time of first trimester screening
for fetal common trisomies.35 This approach provides
superior screening performance to the traditional ap-
proach35; it achieves detection rates of 90%, 75%, and
47% for early, preterm, and term PE, respectively, at a FPR
of 10%.17,35,51 The FMF first trimester prediction algorithm
has been extensively validated and comparable predictive
performance corresponding to the original study17 has been
reported in British,42 mixed-European,52–54 Australian,55
and Asian populations.14
Bayes-theorem based method screening for Asian
pregnant women
The FMF first trimester combined test uses Bayes-theorem,
which is a mathematical formula for determining
conditional probability that provides a way to revise
existing predictions incorporating new information. The
formula for Bayes-theorem is:56
Moungmaithong et al., Maternal-Fetal Medicine (2021) 3:2
PðAÞ⋅PðBjAÞ
PðAjBÞ ¼
PðBÞ
Where A and B are events and:
P(A) = The probability of event A occurring;
P(B) = The probability of event B occurring;
P(AjB) = The probability of event A occurring given that
B is true;
P(BjA) = The probability of event B occuring given that
A is true.
This approach allows estimation of patient-specific risks
of PE requiring delivery before a specified gestational age
by modifying prior distribution of gestational age at
delivery with PE, obtained from maternal characteristics,
obstetric, and medical history, with the results of various
combinations of biomarkers measurements.17 We have
recently completed a large prospective, nonintervention
multicenter study involving 10,935 singleton pregnancies
across seven regions in Asia (China, India, Japan, etc), with
224 women (2.05%) affected by PE, including 151 women
(1.38%) with term PE and 73 women (0.67%) with
preterm PE. In our study, we applied the Bayes-theorem
approach to combine the a priori risk from maternal
factors with multiples of the median (MoM) values of
MAP, UtA-PI, and PlGF. Based on this approach, a
competing risk model, which uses a survival time analysis,
assumes that all pregnant women would develop PE if the
pregnancy were to continue indefinitely, whether they do
so or not before a specified gestational age depends on the
competition between the timing of delivery and the onset
of PE. The competing risk model is visually expressed with
a Gaussian distribution having the mean gestational week
at delivery with PE. In a low risk woman, the distribution is
shifted to the right which implies that delivery occurs
before PE, whilst in a high risk woman, the distribution is
shifted to the left and implies that PE occurs before
delivery.35 Our validation study has demonstrated that the
FMF triple test achieves the best screening performance
compared to that derived from the ACOG and NICE
recommendations for both preterm and all PE and the
detection rates for preterm PE are 48.2%, 64.0%, 71.8%,
and 75.8% in the overall Asian study population at specific
thresholds of 5%, 10%, 15%, and 20% fixed FPRs,
respectively. The screening performance is comparable to
the published data from the FMF that has demonstrated
that the detection rate of the triple test for preterm PE in
East Asian women is 50.0% (95% CI: 6.8–93.2) at a fixed
FPR of 10%,14,17 which is lower to that of Caucasian and
Afro-Caribbean women. To understand these differences
in screening performance, we compared our biomarker
distribution with the data from previously published FMF
study.17 The regression line of MAP MoM is steeper than
that of FMF,17 however the regression line of UtA-PI
MoM is steeper than that of ours. For PlGF MoM, the
regression lines of the two studies were nearly the same,
suggesting that PlGF performs equally well in both
populations. The lower performance of screening for
preterm PE in East Asian women can be partly explained
by poor performance of UTA-PI, which is not compensat-
ed by better performance of MAP, which is not a specific
marker of impaired placentation.14
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Maternal-Fetal Medicine
Maternal characteristics and history
Factors from maternal characteristics, medical and
obstetrical history that are used to predict the risk of PE
include maternal age, weight, height, racial origin, parity,
method of conception, medical conditions, prior history,
and family history of PE.14,17 Advancing maternal age,
increasing weight, Afro-Caribbean and South Asian racial
origin, previous pregnancy with PE, conception by in vitro
fertilization, and a medical history of chronic hyperten-
sion, diabetes mellitus, and systemic lupus erythematosus
or antiphospholipid syndrome increase the risk of PE. In
comparison to East Asian women, women of South Asian
racial origin are associated with a 2.66-fold increase in risk
of PE.57,58 The risk of PE in women in their first pregnancy
is three times higher than in women with previous
pregnancies that have not been complicated by PE.
Women who have had PE in their first pregnancy are
up to 10 times more likely to develop PE in a second
pregnancy.58
In our Asia-wide validation study, we observed a lower
frequency of maternal risk factors, compared with the
European population from which the first trimester Bayes
theorem-based model was developed. Our study popula-
tion had lower median BMI (21.5 vs. 24.5 kg/m2), lower
frequency of chronic hypertension (0.5% vs. 1.6%),
diabetes mellitus (0.3% vs. 0.9%), family history of PE
(1.6% vs. 4.2%), and prior history of PE (0.7% vs. 3.6%).
In contrast, there was a higher frequency of systemic lupus
erythematosus or antiphospholipid syndrome in our study
population, compared with the European population
(0.4% vs. 0.15%).14,17 Apart from the differences in the
maternal risk factors and biomarker distributions that may
contribute to the lower screening performance of preterm
PE in Asian women, a slightly lower frequency of preterm
PE in Asian women compared with the European women
may also play a role. The lower prevalence could be
explained by differences in anthropometric measurements,
sociodemographic factors, living standard, education
level, accessibility to healthcare, and climate as well as
genetic susceptibility to PE.13,16,18–20,59
Biomarker measurement
There is a need to provide more effective screening for PE.
Considerable efforts have been made to identify biomark-
ers to predict PE in early pregnancy. There is evidence that
biomarker combinations are better predictors than single
biomarkers.49,60 To date, the FMF first trimester com-
bined models are the only models that have undergone
extensive internal and external validation.14,40,42
The key to maintaining optimal screening performance
is to establish standardized methods for biomarker
measurements and regular biomarker quality assessment
(QA). Regular biomarker QA plays an important role in
PE screening because each biomarker is susceptible to
inaccurate measurement that affect screening perfor-
mance.35,60 Tools commonly used to evaluate quality
control include cumulative sum (CUSUM) and target
plot.35 CUSUM is a rapid and powerful approach to assess
changes in means or slopes of trend of sequential data. The
reference value (mean or common reference point) is
selected and then subtracted from each data point in
Moungmaithong et al., Maternal-Fetal Medicine (2021) 3:2
succession. The successive deviations of the data from the
reference value are then added to the previous sum. A
change in the CUSUM represents a change in the mean or
trend of the data from the baseline (mean or reference
point), which allows the detection of small but persistent
changes that are obscured by conventional methods or
original data. The target plot is a tool to evaluate central
tendency (deviation from expected median MoM) and
dispersion (deviation from expected median standard
deviation (SD)). Acceptable performance is considered if
the central tendency and dispersion are within 10% of the
expected median MoM and SD. Additionally, the QA
process of the biomarker measurements can be used to
assess a potentially significant underlying difference in
population characteristics.37,41
According to our Asian-wide study, individual bio-
marker measurements were converted into their MoM
equivalent and adjusted for gestational age and cova-
riates affecting their levels using the models employed
in the previously reported Screening Programme for
Preeclampsia study, based on a largely Caucasian
population in Europe.31,61
The most frequently used biomarkers in the PE
prediction models are MAP and UtA-PI. These biophysical
markers are susceptible to considerable variability in their
measurements, mainly as a result of poor adherence to
well-defined protocols.31,62 A simplified protocol for MAP
measurement could be followed with the use of automated
blood pressure (BP) monitors, which allow standardized
measurements to be taken, but accurate measurements still
require correct cuff size and patient positioning.35 Patients
should be asked to rest for at least 5 minutes in the sitting
position. During BP measurement, their back should rest
against the seat, their arms supported at the level of the
heart, and legs uncrossed. The BP should be measured
twice from both arms simultaneously and the final MAP is
calculated from the average of the four measurements.35
We have observed that in the Asian population the MoM
values of MAP are 4% lower than those obtained from the
European population.31,35
Abnormal uteroplacental circulation can be observed as
abnormal uterine artery Doppler velocimetry as early as
during the first trimester of pregnancy. According to the
FMF, pragmatically transabdominal ultrasound is used to
obtain a sagittal section of the uterus and to locate the
internal cervical os. Then, the ultrasound transducer is
tilted slightly to the lateral sides of the cervix. Color
Doppler flow mapping is used to identify the uterine
arteries at the level of the internal cervical os. Pulsed wave
Doppler is then performed to measure the left and right
UtA-PI with the sampling gate set at 2 mm to cover the
vessel. The UtA-PI and peak systolic velocity are measured
automatically when 3 similar consecutive waveforms are
obtained. The peak systolic velocity must be at >60 cm/s
to ensure that PI measurement is of the uterine artery.63
We have observed that the UtA-PI MoM values are similar
between Asian and European pregnant women.31,35
Placental growth factor is a glycoprotein secreted by
trophoblastic cells and angiogenic vascular endothelial
growth factor. PlGF is synthesized in villous and
extravillous cytotrophoblasts and has both vasculogenic
and angiogenic functions. Changes in the PlGF levels have
been implicated in the development of PE.64–66 PlGF MoM
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values are overall 11% lower in Asian women than those
obtained from the European population.31,35 We have
demonstrated that the MAP MoM was significantly
higher, and the PlGF MoM was significantly lower in
women with preterm and term PE than in those without.
The mean UtA-PI MoM was significantly higher in women
with preterm PE, but not term PE, than in those without.14
Furthermore, differences in the biomarker distributions
described above highlight the need for adjustment or
regional-specific formulas for the normalization of the
biomarkers before their incorporation for the calculation
of patient-specific risks of PE.31,35
Prevention of PE with aspirin
Although the underlying pathophysiology of PE is not
entirely understood, a long-held belief of the underlying
pathophysiology of PE is that it is a 2-stage process. Stage I,
inadequate trophoblast invasion that leads to shallow
placentation which may be the result of genetic, maternal,
and immunologic factors. Reduced placental perfusion
leads to stage II, which is characterized by oxidative stress
that stimulates the release of inflammatory cytokines,
angiotensin 1 autoantibodies, antiangiogenic factors, and
microparticles, causing widespread endothelial dysfunc-
tion resulting in the clinical manifestations of PE.35
Screening for preterm PE and giving aspirin prophylaxis
to high risk women should be aimed for various reasons.
Such “screen and prevent” program has been proven to
reduce the rate of preterm PE as well as its associated
complications, such as preterm delivery67 and fetal growth
restriction,68 which often lead to lifelong consequences for
the child. In addition, mothers affected by PE are more
likely to develop hypertension, cardiovascular and
cerebrovascular disease in the future when compared
with mothers who do not have PE in their pregnancies,
prevention of PE may also help prevent the long-term
health consequences of both the women and their children.
According to the FMF prediction algorithm, women
with a predicted risk of ≥1 in 100 are deemed high risk for
preterm PE.34,35 Currently, the only proven effective
preventive strategy is administration of low-dose aspirin to
high risk women for preterm PE69–71 at <16 weeks of
gestation. Aspirin at doses below 300 mg selectively and
irreversibly inactivates the cyclooxygenase-1 enzyme,
suppressing the production and modifies the imbalance
between thromboxane A2 and prostacyclin, inhibiting
inflammation and platelet aggregation.72 Meta-analyses
of aggregate data have revealed a dose-response effect of
aspirin on PE rates, which is maximized when the
medication is initiated at <16 weeks of gestational age
before placentation completes.34,73 Aspirin has been
hypothesized to reduce the severity of PE, converting
preterm PE to term PE; this could explain the absence of
any reduction in the rate of term PE with aspirin
prophylaxis.70 The ACOG recommends that high risk
women, defined according to maternal risk factors, should
take low dose aspirin 81 mg/day and the NICE
recommends the aspirin dosage of 75–150 mg for early
prevention,38,41 while the Aspirin for Evidence-Based
Preeclampsia Prevention (ASPRE) trial revealed that
aspirin 150 mg/night started at 11–14 until 36 weeks
of gestation reduced the rate of delivery with PE before
Moungmaithong et al., Maternal-Fetal Medicine (2021) 3:2
37 weeks’ gestation in high risk women identified by the
FMF prediction algorithm by >60%.69 The benefit of
aspirin on neonatal outcomes was demonstrated in a
secondary analysis of data of 1620 participants with 1571
liveborn neonates from the ASPRE trial, showing that the
total (1696 vs. 531 days) and mean (31.4 vs. 11.1 days)
length of stay in neonatal intensive care unit was
significantly shorter in the aspirin group than the placebo
group.74 A recent meta-analysis including 16 trials, with a
combined total of 18,907 participants, has demonstrated
that daily minimum dosage of aspirin should be 100 mg
started at 16 weeks’ gestation in order to achieve a 65%
reduction in the rate of preterm PE. Neither initiation of
aspirin at >16 weeks nor the daily dose of <100 mg is
associated with a reduction in the rate of preterm or term
PE.70 On the other hand, a systematic review and meta-
analysis of randomized controlled trials with a combined
total of 1426 participants concluded that the administra-
tion of low-dose aspirin at <11 weeks’ gestation in women
with a history of recurrent pregnancy loss, women who
have undergone in vitro fertilization, or women with
thrombophilia or antiphospholipid syndrome did not
decrease the risk of PE.75 It is probable that these
subgroups of women have preexisting endothelial dys-
function before pregnancy. Thus far, the benefit of aspirin
in the prevention of PE in women with thrombophilia is
not established.
A secondary analysis of the ASPRE data revealed a
consistent effect size of aspirin prophylaxis within sub-
groups according to recognized risk factors of PE except in
the subgroup of women with chronic hypertension, where
no indication of beneficial effect was seen, possibly because
of preexisting endothelial dysfunction or preestablished
suboptimal cardiovascular function.76 The prevalence of
chronic hypertension in pregnancy is estimated to be 3%–
5% worldwide,77,78 however, there are significant differ-
ences between geographical regions. In Asian countries, the
prevalence is reported to be 6%, 1.5%, 1.2% in China,
Pakistan, and India, respectively,79,80 while the prevalence
in our Asia-wide study was approximately 0.5%.14 Suitable
agents for the prevention of preterm PE in this subgroup
require further investigation.
The beneficial effect of aspirin is clearly associated with
good compliance to treatment.34,81 At 90% compliance,
the effect size of aspirin is even higher at 76% and could
reach 90% when the high risk women do not have a
history of chronic hypertension.34,81 These findings
emphasize the importance of aspirin compliance in order
to have an optimal preventive effect on preterm PE. We
anticipate that good compliance with aspirin prophylaxis
is achievable in Asia because of the nature of Asian
pregnant women. In our center, the general compliance
with aspirin is >90% (unpublished data). On the other
hand, there are concerns with the daily aspirin dosage of
150 mg, especially in Asia, as maternal weight tends to be
lower than that in European countries. Masotti et al.
demonstrated that aspirin at 2.5–3.5 mg/kg is the
required dosage to produce a consistent inhibition of
platelet aggregation with slight inhibition of prostaglandin
production.82 The FIGO guidelines have pragmatically
recommended a daily dosage of 100 mg for women with
weight <40 kg, which is the minimum dosage of aspirin to
be prescribed to high risk women, whilst those at or over
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Maternal-Fetal Medicine
40 kg, the recommended daily required dosage is 150–
160 mg.44
Safety of aspirin during pregnancy
Previous large cohort and case-control studies have
reported that aspirin is not associated with an increased
risk of congenital heart defects or other structural or
developmental anomalies.50,83,84 A meta-analysis review
on behalf of the United States Preventive Services Task
Force in 2015 concluded that daily aspirin at dosages of up
to 160 mg was not associated with an increased risk of
maternal postpartum hemorrhage (relative risk (RR):
1.02; 95% CI: 0.96–1.09) and perinatal mortality (RR:
0.92; 95% CI: 0.76–1.11), but was associated with a risk
reduction in preterm birth (RR: 0.86; 95% CI: 0.76–0.98),
fetal growth restriction (RR: 0.80; 95% CI: 0.65–0.99),
and PE (RR: 0.76; 95% CI: 0.62–0.95).85 In the ASPRE
trial, the incidence of untoward medication effects was
similar between the intervention and the placebo groups.
There was no statistically significant difference in the rate
of vaginal bleeding (3.6% vs. 2.6%) and upper gastroin-
testinal symptoms (7.4% vs. 7.1%) between placebo and
aspirin groups.69 However, a recent systematic review and
meta-analysis regarding the use of low-dose aspirin for the
primary prevention of cardiovascular disease in older
adults without symptomatic cardiovascular disease has
demonstrated that low-dose aspirin is associated with an
overall increased risk of intracranial hemorrhage, and
heightened risk of intracerebral hemorrhage for those of
Asian race/ethnicity or people with a low BMI.86
Nonetheless, the beneficial effect of aspirin on PE in high
risk women is now evident and research has shown that low-
dose aspirin is safe during pregnancy, with no significant
increase in adverse events and serious adverse events.
Implementation
The key question of clinical implementation of a novel
screening program is whether the developed prediction
model is ready to be implemented in routine clinical
practice. Screening of PE using maternal factors and
biomarkers is considered challenging in LMICs because
nearly all risk assessment tools have been developed
exclusively in high-income countries. The risk factors of
high risk women in LMICs may be different from those in
high-income countries and it is important to determine
whether they have unique risk factors, such as malaria and
human immunodeficiency virus.87,88 There are also some
other factors (eg, diet, smoking status, and coital and
partner history) which may alter the risk, severity, and
pertinent pathophysiology of PE compared with that
observed in high-income countries. Therefore, the prior
risk models developed in high-income populations require
validation in LMICs.35 In Asia, tests such as UtA-PI and
PlGF may not be readily available in primary healthcare
settings. FIGO has pragmatically recommended that,
where resources are limited, “contingent screening” for
preterm PE can be considered. First-stage screening with a
model that combines maternal factors and MAP is
performed for all pregnancies and those who have positive
screening result could be referred for second-stage screening
with the addition of PlGF and UtA-PI measurements.44
Moungmaithong et al., Maternal-Fetal Medicine (2021) 3:2
In a prospective screening study including more than
120,000 singleton pregnancies, the performance of screen-
ing for preterm PE by this strategy was examined. At a fixed
screen-positive rate of 10%, a detection rate of 71% was
achieved by this two-stage screening.89 FIGO also encour-
ages all countries and its member associations to ensure
that risk assessment and resource-appropriate testing for
preterm PE become an integral part of routine first trimester
evaluation protocol offered at all maternal health services.44
Currently, an implementation study of the first trimester
“screen and prevent” program for preterm PE is being
conducted across 10 regions in Asia (China, Indonesia,
Japan, Malaysia, Singapore, etc), which aims to evaluate the
efficacy, acceptability, and safety of first trimester screening
and prevention for preterm PE using the Bayes-based
method (maternal factors, MAP, UtA-PI, and PlGF)
followed by commencement of low-dose aspirin (150–
160 mg/night or 100 mg/night when body weight <40
kg) from <15 weeks till 36 weeks or, in the event of
early delivery, at the onset of labor) in high risk women
(Trial identifier: NCT03941886).
Conclusions
In Asia, there is now increased awareness for early PE
screening and prevention, however, there is a need to
expand this program across the different Asian regions and
countries. Incorporation of screening for preterm PE using
the FMF prediction algorithm with first trimester screening
for fetal common trisomies in routine prenatal care and
offering prophylactic low-dose aspirin to high risk women
would be an effective approach in reducing the incidence
and severity of preterm PE and its lifetime consequences
for both mother and child.
Funding
None.
Conflicts of Interest
None.
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Edited By Dandan Shi
How to cite this article: Moungmaithong S, Wang X, Tai AS, Feng Q, Sahota
D, Leung TY, Poon LC. First Trimester Screening for Preeclampsia: An Asian
Perspective. Maternal Fetal Med 2021;3(2):116–123. doi: 10.1097/
FM9.0000000000000101.