doi:10.1111/jog.13599 J. Obstet. Gynaecol. Res.

2018

Prediction and prevention of pre-eclampsia in Asian

subpopulation

Tuangsit Wataganara , Jarunee Leetheeragul, Suchittra Pongprasobchai,

Anuwat Sutantawibul, Chayawat Phatihattakorn and Surasak Angsuwathana
Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand

Abstract
The benefit of the early administration of aspirin to reduce preterm pre-eclampsia among screened posi-
tive European women from multivariate algorithmic approach (ASPRE trial) has opened an intense
debate on the feasibility of universal screening. This review aims to assess the new perspectives in the
combined screening of pre-eclampsia in the first trimester of pregnancy and the chances for prevention
using low-dose aspirin with special emphasis on the particularities of the Asian population. PubMed,
CENTRAL and Embase databases were searched from inception until 15 November 2017 using combina-
tions of the search terms: preeclampsia, Asian, prenatal screening, early prediction, ultrasonography,
pregnancy, biomarker, mean arterial pressure, soluble fms-like tyrosine kinase-1, placental growth factor,
pregnancy-associated plasma protein-A and pulsatility index. This is not a systematic review or meta-
analysis, so the risk of bias of the selected published articles and heterogeneity among the studies need
to be considered. The prevalence of pre-eclampsia and serum levels of biochemical markers in Asian are
different from Caucasian women; hence, Asian ethnicity needs to be corrected for in the algorithmic
assessment of multiple variables to improve the screening performance. Aspirin prophylaxis may still be
viable in Asian women, but resource implication needs to be considered. Asian ethnicity should be taken
into account before implementing pre-eclampsia screening strategies in the region. The variables included
can be mixed and matched to achieve an optimal performance that is appropriate for economical restric-
tion in individual countries.
Key words: first trimester screening, placental volume, pre-eclampsia, serum biomarker, uterine artery.

Introduction for prediction of early pre-eclampsia are based on

Pre-eclampsia remains a major cause of maternal
and perinatal morbidities. The Combined Multimar-
ker Screening and Randomized Patient Treatment
with Aspirin for Evidence-Based Preeclampsia Pre-
vention (ASPRE) trial showed that 150 mg/day of
aspirin taken from 11–14 weeks until 36 weeks of
gestation reduces preterm pre-eclampsia among
high-risk women based on the Bayes theorem-based
predictive algorithm.1 Most of the modeling studies
the Caucasian population.2,3 While its implementa-
tion in Europe has more supporters, in America,
there is still great skepticism on the need for and fea-
sibility of universal screening, mainly because this
strategy is relatively complex and has a large num-
ber of false positives as well as a very low positive
predictive value, which makes its screening success
doubtful. In addition, the ASPRE study has been val-
idated in the European population, which should be
taken into account when extrapolating to other

Received: July 18 2017.

Accepted: December 31 2017.
Correspondence: Assoc. Professor Tuangsit Wataganara, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics and
Gynecology, Faculty of Medicine Siriraj Hospital, 2 Prannok Road, Bangkoknoi, Bangkok 10700, Thailand. Email: twataganara@yahoo.com

© 2018 Japan Society of Obstetrics and Gynecology 1

T. Wataganara et al.
populations such as Asian. Less than 2% of subjects
allocated for aspirin prophylaxis or the placebo in
ASPRE trials were of East Asian descent.1 The detec-
tion rate (DR) and false positive rate (FPR) of the
screenings are varied among studies.4 The reported
differences may be attributed to: (i) characteristics of
the populations studied, (ii) definition and preva-
lence of the disorder and (iii) techniques and meth-
odology used in performing these tests.5 Hence,
racial origin needs to be corrected for in all statistical
algorithms of prediction.6 The implications for Asian
populations in the prediction and prevention of pre-
eclampsia has not been closely examined because
there is a paucity of information, and the Asia-wide
assessment of this issue is currently underway. This
review aims to assess the new perspectives in the
combined screening of pre-eclampsia in the first tri-
mester of pregnancy and the chances for prevention
using low-dose aspirin from this early phase of ges-
tation, with special emphasis on the particularities of
the Asian population.
Methodology
PubMed, CENTRAL and Embase databases were
searched from inception until November 15, 2017
using combinations of the search terms: preeclampsia,
Asian, prenatal screening, early prediction, ultraso-
nography, pregnancy, biomarker, mean arterial pres-
sure, soluble fms-like tyrosine kinase-1, placental
growth factor, pregnancy-associated plasma protein-A
and pulsatility index. The filters used were abstract
available, human and English. Reference lists of rele-
vant studies, systematic reviews and meta-analyses
were also hand-searched. The title and abstracts of all
citations identified in the search were screened. Dupli-
cate citations were identified and discarded. Then, the
full texts of the remaining articles were obtained and
reviewed. Studies meeting the inclusion criteria, and
not the exclusion criteria, were included in the review.
Inclusion criteria were: (i) prospective, retrospec-
tive, case–controlled or cohort studies and (ii) system-
atic reviews or meta-analyses. Exclusion criteria were:
(i) letters, comments, editorials, case reports, proceed-
ings or personal communications that did not provide
quantitative outcome data and (ii) non-English arti-
cles. As this article is not a systematic review or meta-
analysis, the risk of bias of the selected published arti-
cles and heterogeneity among the studies need to be
considered.
2 © 2018 Japan Society of Obstetrics and Gynecology
Proposed Screening Strategies
in Relation to Pathophysiology
of Pre-eclampsia
Screening variables
Abnormal placental perfusion and trophoblastic stress
contribute to the pathogenesis of early- (< 34 weeks’
gestation) and late- (≥ 34 weeks’ gestation) onset pre-
eclampsia. The former has an extrinsic cause poor pla-
centation, whereas the latter has an intrinsic cause,
‘microvillous overcrowding’, as placental growth
reaches its functional limits. When placental growth
reaches its limits at term, terminal villi become over-
crowded with increasing intervillous hypoxic stress.7
This approach implies that: (i) the first-trimester pre-
diction is less effective for the late-onset than for the
early-onset syndrome; (ii) the fetuses in late-onset pre-
eclampsia are well-grown because trophoblastic stress
without antecedent pathology is a late event; (iii) all
pregnant women may be destined to get pre-eclamp-
sia, but spontaneous or induced delivery averts this
outcome in most instances; and (iv) lower effect of
preventive measures (such as low-dose aspirin) on
late pre-eclampsia started in the first trimester.
Incomplete spiral artery remodeling typically pre-
vails in the early-onset syndrome. This dysregulated
uteroplacental perfusion increases placental oxidative
stress. Oxidatively stressed trophoblasts oversecrete
proteins that perturb maternal angiogenic balance.
The up- and downregulations of these placental-
derived proteins, such as soluble fms-like tyrosine
kinase-1 (sFlt-1) and placental growth factor (PlGF),
may be clinically used as pre-eclampsia biomarkers.
Maternal factors
Several guidelines recommend different approaches for
using maternal factors to identify women at risk of
pre-eclampsia who might benefit from aspirin preven-
tion. There are also recent publications demonstrating
that simple models using routinely collected maternal
characteristics in the antenatal settings can be used as a
good tool to identify women at high risk.8 However,
most of these guideline approaches and published
tools have not yet been externally validated to verify
that they can be applied in the other antenatal settings.
The UK’s National Collaborating Centre for
Women’s and Children’s Health (NICE) recom-
mended a screening based on maternal characteris-
tics; any one high-risk factor or any two
moderate-risk factors should be considered to be
 Pre-eclampsia prediction in Asian women

indicators of a woman being at high risk of the
development of pre-eclampsia.9 This simple
approach would have resulted in DR of 89.2%,
93.0% and 85.0% for early, intermediate and late
pre-eclampsia (defined as pre-eclampsia mandated
delivery at <34, 34–37 and >37 weeks), respec-
tively. By fixing the FPR at 5%, the DR for early,
intermediate and late pre-eclampsia dropped to
only 33.0%, 27.8% and 24.5%, respectively.10
Maternal factors suggested by professional organi-
zations are summarized in Table 1.
At a fixed FPR of 10%, Wright and colleagues
(2015) showed that their survival time model (Bayes
theorem) predicted 40%, 48% and 54% of cases of
total pre-eclampsia and pre-eclampsia requiring
delivery at <37 and <34 weeks’ gestation, respec-
tively, which were significantly higher than the
respective values of 35%, 40% and 44% achieved by
application of NICE (2013) guidelines.11 Such an esti-
mation of the a priori risk of pre-eclampsia is an
essential first step in the use of Bayes theorem to com-
bine maternal factors with biomarkers for the continu-
ing development of more effective methods of
screening for the disease. Although South Asian racial
origin may predict late-onset pre-eclampsia and gesta-
tional hypertension, but not early-onset disease, to
date, there have been no studies that provide data for
the direct comparison of risk factor or risk model per-
formance for Asian versus non-Asian populations.12
Compensatory responses of the placenta to certain

Table 1 Maternal risk factors for pre-eclampsia as suggested by professional organizations

NICE WHO SOGC ACOG
High-risk (≥1) • History of pre-eclampsia High-risk (≥1)
• History of hypertensive in previous pregnancy • History of pre-eclampsia in • History of
disease in previous • Chronic hypertension previous pregnancy early-onset
pregnancy • Diabetes mellitus • Presence of antiphospholipid pre-
• Chronic hypertension • Autoimmune disease antibodies eclampsia or
• Type 1 or type 2 diabetes • Chronic kidney disease • Medical history of chronic preterm
mellitus • Multifetal gestation hypertension, diabetes mellitus delivery at
• Autoimmune diseases or chronic kidney disease <34 weeks’
(i.e. SLE or APS) • BMI ≥35kg/m2 on first visit gestation
• Chronic kidney disease • Familial history of pre- • History of
Moderate-risk(≥2) eclampsia pre-
• Age ≥40 years • Nulliparity eclampsia in
• Nulliparity • Pregnancy interval > 10 years ≥2 previous
• Pregnancy • SBP >130 mmHg or DBP pregnancies
interval > 10 years >80 mmHg on first visit
• BMI ≥35 kg/m2 on first • Multifetal gestation
visit Moderate-risk (≥2)
• Familial history of • Ethnicity (Nordic, Black, South
pre-eclampsia Asian or Pacific Island)
• Multifetal gestation • Lower socioeconomic status
• Nonsmoker
• Inherited thrombophilias
• Increased pre-pregnancy
serum triglycerides level
• Familial history of early-onset
cardiovascular disease
• Cocaine or methamphetamine
use during pregnancy
• Pregnancy interval < 2 years
• Use of assisted reproductive
technology
• New partner
• Gestational trophoblastic
disease
• Excessive weight in pregnancy
• Infection during pregnancy
APS, antiphospholipid syndrome; ACOG, American College of Obstetricians and Gynecologists; BMI, body mass index; DBP, diastolic
blood pressure; NICE, National Institute for Health and Care Excellence; SLE, systemic lupus erythematosus; SOGC, The Society of Obste-
tricians and Gynecologists of Canada; SBP, systolic blood pressure; WHO, World Health Organization.

© 2018 Japan Society of Obstetrics and Gynecology 3

T. Wataganara et al.
maternal characteristics suggest different underlying
mechanisms.13
Biophysical factors
Integration of body mass index (BMI) and mean arte-
rial pressure (MAP) into the algorithm improves the
prediction.14 Increased BMI is only associated with
late-onset pre-eclampsia.12 Thai women have lower
BMI than Caucasians.15–17 As increased MAP in the
first trimester is associated with pre-eclampsia, a sim-
ple protocol for MAP measurement has been estab-
lished.18 The US Preventive Services Task Force
recently endorsed screening for pre-eclampsia with
blood pressure monitoring throughout pregnancy.19
To date, there have been no studies that provide data
for the direct comparison of biophysical factors or bio-
physical model performance for Asian versus non-
Asian populations.
Uterine artery Doppler velocimetry
Prediastolic notching and elevated pulsatility index of
uterine artery (UtAPI) in the first trimester predict
early-onset pre-eclampsia better than all other types
of pre-eclampsia (DR 47.8% and 26.4%, respec-
tively).20,21 The UtAPI in low-risk populations yields
moderate sensitivity (34–76%) and specificity
(83–93%).22 It is not predictive until week 11 as recent
data indicate that trophoblast plugs block the spiral
arteries until 11 weeks of gestation.23 With standard-
ized techniques and quality control, screening with
UtAPI is effective across all racial origins.24–29 As a
component of a multivariate regression risk model,
the DR of early pre-eclampsia at 10% FPR increase
from 47% in screening by maternal factors alone to
81% in screening by maternal factors and UtAPI, and
the respective DR for late pre-eclampsia increased
from 41% to 45%. The use of UtAPI in isolation may
not be adequate to justify aspirin prophylaxis. To
date, there have been no studies that provide data for
the direct comparison of UtAPI or UtAPI model per-
formance for Asian versus non-Asian populations.
Biochemical profiles
Serum markers implicated in the pathogenesis of
impaired placentation and early pre-eclampsia
include, but are not exclusive to, pregnancy-
associated plasma protein A (PAPP-A), placental
growth factor (PlGF), soluble fms-like tyrosine kinase-
1 (sFlt-1), soluble endoglin (sEng.), placental protein
13 (PP13), free vascular endothelial growth factor (free
VEGF), growth factor angiopoietin-2 (Ang-2), matrix
4 © 2018 Japan Society of Obstetrics and Gynecology
metalloproteinase-9 (MMP-9), A disintegrin and
metalloprotesase (ADAM 12), tumor necrosis factor
soluble receptor-1 (TNF-R1), inhibin-A, activin-A,
interleukin-1β, interleukin-6 and cell-free fetal
DNA.30–40 Individually, these markers fail to achieve
adequate positive predictive value (PPV) because of:
(i) overlapping serum levels between cases and
controls,41 (ii) different isoforms measured by various
automated assays4 and (iii) effects of maternal fac-
tors.42,43 These placental-derived markers are for
placental-related complications and are not specific to
pre-eclampsia. The PPV for nonspecific adverse out-
comes can be increased to >65% after combining ≥2
markers with maternal variables.44,45
Low-serum PAPP-A concentrations in the first tri-
mester can predict early-onset pre-eclampsia.46–48
PAPP-A is a protease for insulin-like growth factor
(IGF) binding protein-4 produced by developing tro-
phoblastic cells.49 An insufficient level of PAPP-A
leaves IGF binding protein-4 uncleaved and remain-
ing in its bound (inactive) form. Fewer free IGF may
lead to diminished fetal and placental growth.50 The
PPV of PlGF is poor if used in isolation.14,51 Its level
in the first trimester is strongly influenced by mater-
nal characteristics, previous history of pre-eclampsia
and UtAPI.52 A combination of serum PAPP-A with
nulliparity, prior hypertension, diabetes, prior pre-
eclampsia and MAP can predict early pre-eclampsia
with 55% DR for a 10% FPR.53 Prediction of pre-
eclampsia in pregnant women carrying trisomic
fetuses should be avoided because of their readily
low serum PAPP-A concentrations.54–60
At 11–14 weeks’ of gestation, serum concentrations
of PlGF increase with gestational age and decrease
with maternal weight.61 An association between low-
serum PlGF concentrations in the first trimester and
subsequent development of pre-eclampsia is consistent
across all racial origins.62–67 Although PlGF is a power-
ful screening tool, its serum levels can be affected by
(i) quantitation assay, (ii) gestational age at assessment,
(iii) maternal age, (iv) parity (increased levels in parous
women), (v) maternal weight, (vi) racial origin
(increased levels in Afro-Caribbeans, South Asians and
East Asians compared with Caucasians), (vii) use of
cigarettes (increased levels in smokers), (viii) diabetes
mellitus (decreased levels in insulin-dependent dia-
betics) and (ix) history of preterm delivery.43,68 A con-
ventional PlGF test using manual enzyme-linked
immunosorbent assay (ELISA) was less sensitive and
inconsistent.64,69 Currently, automated PlGF assays are
offered by most major manufacturers.61,70,71

Elevated serum sFlt-1, especially with low PlGF
levels, in women with symptomatic pre-eclampsia are
found in all ethnicities.72,73 The sFlt-1 concentrations
in serum elevate even before pre-eclampsia become
symptomatic, but not in the first trimester.34,64,74,75
Therefore, sFlt-1 may be more useful for short-term
prediction of the disease.61,76 Hypoxia may initiate the
production and release of sFlt-1 from the placenta to
maternal circulation, where it binds and removes the
free PlGF molecules.77 A recent in-vivo study con-
ducted at the time of a cesarean section suggested pla-
cental release of sFlt-1, but not PlGF, contributed to
the development of early-onset pre-eclampsia.78
Although a combination of serum markers can
improve the screening performance, it should be
noted that less than one fourth of women with pre-
eclampsia have serum PAPP-A levels <5th centile
(<0.4 MoM). At serum PAPP-A concentrations <5th
centile, the reported odds ratios for pre-eclampsia are
only 1.5–4.6.79 Considerable improvement of predic-
tion can be achieved only when PAPP-A is combined
with UtAPI.58 Therefore, simply adding PAPP-A into
the algorithm based on maternal characteristics,
UtAPI and any combination of serum biomarkers that
readily included PlGF may not improve the DR.4 If
serum PAPP-A is to be used for the calculation of
patients specific risk for preeclampsia, its MoM
should be modified by UtAPI with the use of appro-
priate multiple regression equations. The contribu-
tions from maternal characteristics, MAP, UtAPI and
PlGF remain significant even after the removal of
PAPP-A from the competing risks model.4 With a low
prevalence of pre-eclampsia in Asian population, the-
oretical projection suggests that low-serum PAPP-A
level in an Asian woman without previous history of
pre-eclampsia would have the smallest increase in
risk compared to a White or Black woman.54–60 Nev-
ertheless, most of the studies on serum biomarkers for
pre-eclampsia screening were retrospective in nature,
and the data are still limited to what extent the levels
of these markers were adjusted or controlled for vari-
ous confounders in Asian population.80,81 To date,
there have been no studies that provide data for the
direct comparison of serum biomarkers or biomarker
model performance for Asian versus non-Asian
populations.
Screening strategies
Personalized risk assessment of pre-eclampsia uti-
lizes the same methodology of fetal aneuploidy
screening: prior risk from background prevalence
© 2018 Japan Society of Obstetrics and Gynecology
Pre-eclampsia prediction in Asian women
multiplied by likelihood ratios (LR) for maternal, bio-
physical and biochemical profiles.2,82 However, an
absence of the disease at the time of screening and
the complex interaction between placental angiogenic
activity and endothelial susceptibility to the circulat-
ing mediators make it more challenging than fetal
aneuploidy screening. The development of a screen-
ing strategy in Asian women should consider
(i) impacts on maternal and perinatal outcomes,
(ii) feasibility of universal screening, (iii) definitions
and implications of screened positive and negative
and (iv) efficacy and acceptability of prophylactic
interventions for screened positive women. There are
two proposed strategies.
First-trimester screening with multimarker
approach
Early screening aims to identify pre-eclampsia in its
latent stage when there is an opportunity for aspirin
prophylaxis. The variables should be high in PPV and
LR for the disease. An 11–14 weeks’ screening model
that combines maternal characteristics, elevation of
MAP and UtAPI and decrease of serum PAPP-A and
PlGF concentrations has been developed and tested.14
Early separation of MAP, UtAPI, serum PAPP-A and
PlGF MoM in cases suggested their higher DR for pre-
term pre-eclampsia, which has more severe fetal and
maternal consequences.29,83,84 Adding a secondary
screening step for cardiovascular and metabolic risk
profiles for screened positive women was able to
reduce FPR by 26%, and was able to alleviate those
risks in 91% of women who subsequently developed
pre-eclampsia.85 A different algorithm is needed for
twin pregnancies because of their readily elevated
serum PAPP-A levels,86 in addition to different values
of PlGF, UtAPI and the a priori risk of pre-eclampsia,
which is greater. Table 2 summarizes the DR for 5%
and 10% FPR achieved by the most extended/promis-
ing strategies.
Short-term prediction
The marked elevation of sFlt-1 and decrease of PlGF
concentrations in the serum precede the development
of pre-eclampsia in all ethnicities.64,87–93 The sFlt-1:
PlGF ratio cut-off value of ≤38 rules out adverse out-
comes within 1 week with high negative predictive
value (NPV) of 99.3%, which help clinical decisions
regarding the intensity of monitoring.45 High NPV is
crucial for this rule-in-rule-out approach as failure to
detect imminent disease could have devastating con-
sequences. The optimal cut-off points of sFlt-1:PlGF
5
T. Wataganara et al.

Table 2 Detection rate for the prediction of early and late pre-eclampsia from some of the most promising multivariate
algorithms
Study Parameters Early Late
pre-eclampsia pre-eclampsia
DR (%) for FPR of
5% 10% 5% 10%
Poon et al.184 Maternal factors, MAP, UtA, PAPP-A and PlGF 93 N/A 45 N/A
Poon et al.124 Maternal factors, MAP, UtA and PAPP-A 84 95 N/A N/A
Akolekar et al.10 Maternal factors, MAP, UtA, PAPP-A, PlGF, PP13, 91 95 61–97 71–88
sEng, inhibin A, activin A, PTX3 and P-selectin
Akolekar et al.14 Maternal factors, MAP, UtA, PAPP-A and PlGF 93 96 38–61 54–77
Scazzocchio et al.115 Maternal factors, MAP, UtA and PAPP-A 69 81 29 42
Parra-Cordero et al.185 Maternal factors, UtA and PlGF 33 47 20 29
Crovetto et al.186 Maternal factors, MAP, UtA, PlGF and sFlt-1 88 91 68 76
Rolnik et al.127 Maternal factors, MAP, UtA, PAPP-A and PlGF N/A 77 N/A 43
DR, detection rate; FPR, false positive rate; MAP, mean arterial pressure; PAPP-A, pregnancy-associated plasma protein A; PlGF, placental
growth factor; PP13, placental protein 13; PTX3, pentatrexin 3; sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase-1; UtA, uter-
ine artery Doppler; UtA, uterine artery Doppler.

ratio may differ among commercial assays.94 Possible
clinical impacts of the short-term prediction approach
obtained from observational studies will need to be
proven in randomized trials.45 Late measurements of
serum sFlt-1 and PlGF levels at 30–33 weeks were
tested in a multivariate competing risk model for pre-
diction of delivery within 4 weeks for pre-eclamp-
sia.95,96 Strengths and limitations of these two
strategies are summarized in Table 3. It is also impor-
tant to note that the sFlt-1/PlGF ratio is a CE
(Conformité Européene)-certified in vitro diagnostic
test manufactured by different pharmaceutical com-
panies. It is thus available in all countries accepting
the CE mark in Europe, Latin America, Middle East,
Africa and Asia. It is not available in the United States
as the Food and Drug Association (FDA) has not
approved it yet. Approval in Japan is also pending.97
It is important to note that “first trimester screening
of preeclampsia with multimarker approach” and
“short term prediction of preeclampsia” are not con-
fronting but rather complementary strategies. Regard-
less of the preventive effect of aspirin, screen-positive
women should be intensively followed, and the sFlt-
1/PlGF ratio could be eventually implemented in
those high-risk women.98 Unlike the first-trimester
pre-eclampsia screening, there are prestigious scien-
tific societies (such as the NICE) that have currently
incorporated the recommendation of using the sFlt-1
/ PlGF ratio as a cost-effective tool to rule out pre-
eclampsia for women presenting with suspected pre-
eclampsia between 20 and 34 weeks of gestation and
PlGF-based testing to help diagnose suspected
pre-eclampsia.99
Alterations of Serum Biomarkers
Concentrations in Asian Ethnicity and
Possible Impacts on Pre-eclampsia
Prediction
Importance of establishing median values
There is a significant ethnic variation in serum levels
of the placental-derived analytes. Therefore, the
development of multimarker screening requires an
establishment of population-specific MoM and regres-
sion algorithm.6,100–105 The racial-associated variations
may be from genetic, dietary or lifestyle differences.106
Asian women have higher median serum levels of
PAPP-A and PlGF in the first trimester than Cauca-
sian women after adjustment for weight and gesta-
tional age.67,100 Without adjustment for ethnicity,
lower DR and FPR of pre-eclampsia detection in lieu
of decreased serum PAPP-A and PlGF levels are
expected in Asian populations.37,93,107 The dropping
of serum PlGF levels in Chinese pre-eclamptic women
was 0.71, and whether such degree of changes is con-
sistent among Asian subethnic groups remains
unknown.107 Elevation of serum PlGF levels in the
first trimester also increases the risk of fetal Down
syndrome; therefore, algorithmic integration of PlGF
may additionally improve the DR of fetal Down syn-
drome screening in Asian populations.34,61,67,108
Albeit those theoretical projections, regional data
pertaining to clinical implications of the ethnic varia-
tions of serum biomarkers in predicting pre-eclampsia
are limited. It is important to determine localized bio-
chemical marker correction factors and modeling
rather than simply adopting published numbers

6 © 2018 Japan Society of Obstetrics and Gynecology

 Pre-eclampsia prediction in Asian women

Table 3 Strengths and limitations of strategies for prediction of pre-eclampsia

First-trimester screening with multimarker approach Short term prediction
Strengths High DR; the multifactorial algorithm potentially identify about Economical use of medical
90, 80 and 60% of pregnancies that subsequently develop early, resources.
intermediate and late preeclampsia, respectively, for 5% FPR.10 Limit the number of women being
High NPV; Negative (or low risk) result from the algorithm can tested.
give 97.5–99.8% certainty that pre-eclampsia will not Broader implementation.
develop.184 For investigational targeted
Applicable to the entire obstetric population; most pre- therapy.186
eclampsia patients cannot be detected by assessment
maternal factors alone.10
Improvement of the statistical and clinical validity of
intervention trials from the ability to evaluate the impact of
preventive therapies on the observed-to-expected pre-
eclampsia rate, 144
Better predictive performance for preterm pre-eclampsia; all
markers showed more separation at earlier, rather than later,
gestations. Aspirin prophylaxis is also more effective in the
prevention of preterm pre-eclampsia rather than term pre-
eclampsia.4,185
Limitations Low PPV (6–10%) and lack of reproducibility.187,188 Become positive only weeks before
Complex algorithm Not dressing all cascades of pre-eclampsia the disease develop.
etiologies. Prophylaxis in the second and third
Current algorithms are not valid for multiple pregnancies. trimesters is not available
Lack of cost-effectiveness studies in Asian population.
Lack of evidence of decreased maternal and perinatal adverse
effects.
Potential long-term side effects resulting from the high
proportion of false positives and aspirin intake.
Challenges in translation into low-income setting.
Efficacy of prophylactic measures remains low; 50% reduction
of preterm pre-eclampsia from ASPRE trial but not
reproducible from other trials.1,187,188
Lack of validity in external populations.116
Preferential prediction of preterm; term pre-eclampsia may also
have devastating maternal and fetal morbidities.1
Psychological issues after positive screening; the right-to-know
versus the right-not-to-know.
ASPRE, The Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Preven-
tion; DR, detection rate; FPR, false positive rate; NPV, negative predictive value; PPV, positive predictive value.

elsewhere for the development of a screening strategy
in the region.61,76 The possible effects of covariates
factors, such as smoking and mode of conception,
have to be excluded to ensure that ethnicity was the
only factor considered other than gestation and
weight. When assessing the effects of weight and ges-
tation, a multiple regression analysis approach, as
opposed to a sequential adjustment approach, should
be used.6,80,101
Lower incidence of pre-eclampsia in Asian
women
In populations with high disease prevalence, the risk
of being affected given a screen-positive result is con-
siderably higher, whereas the risk of being affected in
those screened negative is considerably reduced.4 It is
important to note that most modeling studies are
short of pre-eclampsia cases, and data from those tri-
als need to be cautiously interpreted. The prevalence
of pre-eclampsia in Southeast Asia is <2%, compared
to 8–9% in North America.109–111 This discrepancy
may be a genuine difference in the incidence of pre-
eclampsia or due to different diagnostic criteria
used.112 A prospective study of pre-eclampsia in pri-
migravidas in Burma, China, Thailand and Vietnam
showed that clinically recognized hypertension during
pregnancy varies by a factor of 25 between countries.
The variation was down to a factor of five after a
strict definition of proteinuric hypertension was
applied. Serial measurements of blood pressure in

© 2018 Japan Society of Obstetrics and Gynecology 7

T. Wataganara et al.
each country showed remarkably similar levels early
in the second trimester but a divergence thereafter;
therefore, the differences were not caused by underly-
ing differences in the baseline blood pressures but the
diagnostic criteria used in these populations.113 Even
in Europe, significantly different prevalences among
their populations may be explained by different rates
of aspirin prophylaxis.114–117
It is conceivable that the lower prevalence of pre-
eclampsia in Asian women may result in (i) lower
prevalence of previous and family history of pre-
eclampsia and (ii) lower PPV of the pre-eclampsia
screening test. There are some limitations to validate
this concept. Firstly, there would be fewer cases of
early-onset pre-eclampsia available for analysis. As
there were wide 95% confidence intervals and limited
analyses performed in some studies, assessment of
the serum biomarker MoM in pre-eclampsia cases
could not be stratified according to gestation to ascer-
tain if the mean and SD remain constant, increased or
decreased for risk calculation purposes.107 Secondly,
the expected MoM serum biomarker levels in normo-
tensive controls could only be corrected for fetal CRL,
gestational age and maternal weight, whereas the
effects from mode of conception, multiple pregnancies
and smoking, which are significantly associated with
serum levels of first-trimester markers in Chinese and
other ethnic groups, could not always been ascer-
tained.80,100,101 Lastly, if quantitation of biomarkers is
calculated from archived maternal samples rather
than fresh samples, the results need to be adjusted for
the freezer storage time.38,54 It has previously been
postulated that low levels of certain analytes quanti-
tated from archived sera may be due to longer storage
time of these cases in contrast to controls that can be
accumulated more quickly and thus usually have
shorter storage times.118
Statistical Point of View
Broad variations of serum marker concentrations can
be corrected by (i) analysis in log10 of MoM and
(ii) algorithmic statistics. Multivariate logistic regres-
sion was originally used to analyze the archived data
to develop the most fitted model.27,119 Conversely,
prospective prediction with a logistic regression
model is seriously affected by the disease prevalence
specific to population. Therefore, the “constant term”
derived from various models is very different among
studies. In other words, logistic regression models
8 © 2018 Japan Society of Obstetrics and Gynecology
work only for the exact population used to build up
the model. For example, if the maternal age of the
study population ranges between 18 and 35 years, a
hypothetical woman whose age is outside this bound
will not receive a correct risk. This is true for any vari-
able of the model and is a major reason for prediction
failure, mainly from overfitting because of an increase
in the parameter estimate. Integrating several quanti-
tative variables in logistic equation raises doubts
about their genuine prospective performance. Basi-
cally, the DR (at fixed FPR) of different algorithms are
reflected by areas under the receiver operating charac-
teristic (ROC) curves. Underemphasizing the statisti-
cal contribution of these factors while developing the
algorithm for Asian women could jeopardize predic-
tive accuracy.
The recently proposed competing risks model uti-
lizes a Bayes-based method to individually estimate
risks of pre-eclampsia requiring delivery before a
specified gestation by multimarker approach at differ-
ent gestational periods.120 This model assumes that, if
the pregnancy was to continue indefinitely, all
women would experience pre-eclampsia; whether
they do so before a specified gestational age depends
on competition between delivery (possibility A) and
the development of pre-eclampsia (possibility B).120 In
low-risk pregnancies, the gestational age distribution
is shifted to the right, implying that delivery will
occur before pre-eclampsia. In high-risk pregnancies,
the distribution is shifted to the left, implying that
preeclampsia will occur before delivery at particular
gestational age. This approach can detect 96% of
early-onset pre-eclampsia and 54% of any pre-
eclampsia at 10% FPR.4
Fundamentally, a multivariate Gaussian model of
marker profiles was used to predict the performance
in a standardized population with a fixed distribu-
tion of risk factors. Hence, it does not necessarily
yield comparable DR in different populations as
originally reported.14,117,121,122 The discrepancies of
performance metrics (DR, FPR and PPV) from vari-
ous studies in Europe and United States may partly
be due to (i) inhomogeneous prevalence rates (up to
twofold) among studied populations, (ii) shortage of
pre-eclampsia cases with respect to the numbers of
variables used, (iii) inconsistency of diagnostic cri-
teria, (iv) different combinations of markers in algo-
rithms and (v) the if risk factors included in
algorithms are neither predictive nor truly indepen-
dent.114,115,117,123,124 Although a better prediction is
expected for a higher population prevalence of pre-

eclampsia, this hypothesis was not proven.117 Varia-
tion in pretest probability of pre-eclampsia may in
fact play a minor role in the test accuracy. The great-
est concordance was observed for the prediction rule
developed in American population, suggesting a
potential impact of the population risk profile.125
The multimarker algorithm developed in the United
States is simpler, including only history of hyperten-
sion, history of pre-eclampsia, prior diabetes, MAP
and PAPP-A MoM.53 The UtAPI and serum PlGF
are not included. Although a multivariate algorithm
is particularly effective in identifying early- rather
than late-onset disease, late pre-eclampsia may
equally be devastating and shall not be ignored for
screen-negative women.126
Benefits and Limitations of Prophylactic
Measured for Pre-eclampsia
Prophylaxis in relation to pathophysiological
cascades of pre-eclampsia
Another important point is the choice of the cut-off
value to define a screen-positive woman. In the
ASPRE study, women with an estimated risk for pre-
term pre-eclampsia of >1 in 100 who took aspirin
(150 mg per day) from 11–14 weeks until 36 weeks’
gestation had a reduction of preterm pre-eclampsia
by 62%.1 This cut-off value was conveniently applica-
ble for the goal of pre-eclampsia screening on reduc-
tion of preterm pre-eclampsia. For different goals of
screening, that is, to prevent specific adverse maternal
or perinatal outcomes, the cut-off values will need to
be specific to the goal. According to the ASPRE trial,
the combined first-trimester screening for preterm
pre-eclampsia with a risk cut-off value of 1 in 100, the
DR was 76.7% for preterm pre-eclampsia and 43.1%
for term pre-eclampsia at a screen-positive rate of
10.5% and FPR of 9.2% (see Table 2).127 However, the
American College of Obstetricians and Gynecologists
(ACOG) recommends against screening for pre-
eclampsia combined in the first trimester as the effec-
tiveness of such a triage would be hindered by the
low PPV of early-onset pre-eclampsia reported in the
literature and lack of data demonstrating improved
clinical outcomes.128
If the primary objective of pre-eclampsia screening
is to reduce the incidence of preterm pre-eclampsia,
then it will be achievable only when Wilson’s criteria
is met by early prediction of the disease in the first tri-
mester of pregnancy so that aspirin can be
© 2018 Japan Society of Obstetrics and Gynecology
Pre-eclampsia prediction in Asian women
administered.129 Prophylactic measures for early pre-
eclampsia may need to tackle the following:
(i) ischemic placental disease, (ii) imbalance of circu-
lating angiogenic factors,130 (iii) systemic endothelial
damage by reactive oxygen species, (iv) imbalance
between prostacyclin (vasodilator) and thromboxane
A2 (vasoconstrictor) and (v) end-organ damage.131
Aspirin irreversibly inhibits cyclooxygenase (COX) in
platelets but reversibly in the endothelium, thus
swinging the balance in favor of prostacyclin, which
is a potent vasodilator and inhibitor of platelet aggre-
gation.1,3,112,132 Recent meta-analyses suggested that
low-dose aspirin commenced before 16 weeks’ gesta-
tion reduces the incidence of pre-eclampsia in high-
risk women.3,133 The benefit is dose-related and is
most notable for early-onset disease.134 The
12–16 weeks therapeutic window offers maximum
benefits with the lowest risk for complications
because it precedes the interstitial migration of pla-
cental trophoblasts.135 The ASPRE study proposed a
daily aspirin dosage of 150 mg/day based on previ-
ously reported 30%, 10% and 5% chances of resistance
for daily aspirin dosage of 81, 121 and 160 mg,
respectively.136 The 60 mg/day of aspirin is insuffi-
cient in most women, whereas 75–80 and 100 mg/
day of aspirin are sufficient in about two third and
90% of women, respectively.134
It is important to note that prophylactic benefits of
aspirin in screen-positive women from ASPRE study
(n = 1620) are not in agreement with the results from
at least seven randomized trials, including (i) the Pre-
diction and Prevention of Preeclampsia (PREDO) pro-
ject (n = 498);137 (ii) the Early Prediction and Aspirin
for Prevention of Preeclampsia (EPAPP) study
(n = 53);138 (iii) Estudo Colaborativo para Prevenção
da Pré-eclampsia com Aspirina (ECPPA) study
(n = 1009);139 (iv) Collaborative Low-dose Aspirin
Study in Pregnancy (CLASP) study (n = 9364);140
(v) Italian Study of Aspirin in Pregnancy
(n = 1106);141 (vi) the National Institute of Child
Health and Human Development (NICHD)-funded
study on prevention of pre-eclampsia with low-dose
aspirin in healthy, nulliparous pregnant women
(n = 2985);142 and (vii) Barbados Low Dose Aspirin
Study in Pregnancy (BLASP) (n = 3647).143 The dis-
crepancies may be attributable from (i) different
screening protocols and screen-positive criteria,
(ii) different aspirin dosages and commencing gesta-
tional ages, (iii) limited prophylactic efficacy of aspi-
rin at this low dose or (iv) alternative pathways
leading to the development of pre-eclampsia among
9
T. Wataganara et al.
different risk groups that may not be responsive to
early initiation of low-dose aspirin. Certain maternal
factors, including chronic hypertension, pre-
gestational diabetes mellitus and high BMI, can pre-
dict failure of aspirin prophylaxis.137,144 Due to a
shortage of Asian women enrolled in those trials, it is
still unclear whether aspirin prophylaxis is equally
effective in women of Asian descent.3
Although the U.S. Preventive Services Task Force
(USPSTF) recommends the use of low-dose aspirin
(81 mg/d) as preventive medication after 12 weeks of
gestation in women who are at high risk of pre-
eclampsia,145 aspirin commenced before the comple-
tion of the first trimester has been demonstrated to be
associated with a small increase in the incidence of
gastroschisis.146 In terms of maternal risks, long-term
aspirin use may be linked with internal bleeding;
thus, a specialized enteric-coated preparation is
recommended. Aspirin can induce hypersensitivity
reactions and is contraindicated in those women who
are aspirin-allergic or have aspirin-sensitive asthma.
Although low-dose aspirin is not associated with ele-
vated rates of placental abruption, major post-partum
hemorrhage or intracranial neonatal hemorrhage, it
may increase vaginal bleeding in pregnancy.147 The
optimal policy would be to dispense aspirin at the
lowest effective dose. One must weigh the potential
side effects and acceptability of universal aspirin for
pregnant women and the risks of potential pre-
eclampsia development against a screen-and-treat-all
policy.148
Alternative prophylactic measures
Benefits versus risks of low-molecular weight heparin
for prevention of pre-eclampsia are still controver-
sial.149,150 Calcium supplementation can reduce pre-
eclampsia in ≤64% of women with dietary calcium
deficit (<600 mg/day) and in 78% of women identi-
fied as high risk from maternal factors.151,152
Although antioxidants may reduce oxidative stress at
the endothelium, its benefit to prevent pre-eclampsia
has not been proven.153–156 In fact, routine supple-
mentation of vitamins C and E may have adverse
effects.157,158 Supplementations of antioxidant, L-
arginine and vitamins C and E may reduce only the
risks related to high BMI (>30 kg/m2) but not other
maternal factors (i.e. history of pre-eclampsia in previ-
ous pregnancy, chronic hypertension and diabetes
mellitus) or abnormal UtAPI.30,159–161 The prophylac-
tic benefit of routine dietary supplementation needs
to be evaluated in a low-risk population to determine
10
the generalizability of the protective effect. There is
insufficient evidence to neither support nor discard
the use of antioxidants for prevention of pre-
eclampsia.156
Preconceptional control of cardiovascular risks
(i.e. high blood pressure) found in ~60%of women
with prior pre-eclampsia may reduce the chance of
recurrent pre-eclampsia or failure of aspirin prophy-
laxis.144,162 Metabolic risks (i.e. obesity, pre-gestational
diabetes mellitus, ovulation induction) found in
10–20% of women with prior pre-eclampsia can be
managed with lifestyle modification or medications
such as metformin or pravastatin.79,85,162 Additional
treatments evaluated for pre-eclampsia prevention are
detailed in Table 4.
Resource Implications of Pre-eclampsia
Prediction and Prophylaxis for Countries
in Asia
Many countries in Asia are resource limited and
already struggling simply to achieve safe delivery
and newborn care.163 Maternity deaths in Asia, with
the exception of a few countries, are related to limited
access to emergency care in lieu of pregnancy compli-
cations. Maternal mortality ratio (per 100 000 live
births) in 2015 was 59 for East Asia and the Pacific,
compared to 8 in the European union (http://data.
worldbank.org/indicator/SH.STA.MMRT. Accessed
June 1, 2017). Pre-eclampsia-related healthcare costs
encompass those for the mothers and their neonates.
There are various levels of complexity, costs, implica-
tions and applicability of individual components of
the combined test, compared with simple screening,
by taking maternal history alone. The variates
included in screening algorithms can be mixed and
matched to achieve the optimal performance that is in
balance with economical restriction for each country.
The MAP can be conveniently taken by a healthcare
assistant after minimal training. Measurement of
UtAPI requires only a few minutes and can be inte-
grated in the routine 11–13 weeks’ scan. It requires
specific training, quality assurance and external
audit.27 Measurement of serum PlGF (sFlt-1) levels
can be performed on the same sample and by the
same machines as for quantitation of PAPP-A for fetal
Down syndrome screening, but at an additional cost.
Quality assurance and external audit for the quantita-
tion of PlGF, sFlt-1 and other angiogenic markers
© 2018 Japan Society of Obstetrics and Gynecology
 Pre-eclampsia prediction in Asian women

Table 4 Proposed measures for pre-eclampsia prophylaxis

Measures Rationale References
Pharmacological agent
Antiplatelets (aspirin) Reduce thromboxane and platelets activation. Bujold et al.3
Nitric oxide donor Enhance physiologic vascular adaptation Vadillo-Ortega et al.161
Low-molecular weight Association between thrombophilia and pre-eclampsia Steegers et al.187
heparin
Antihypertensives Association between antihypertensive discontinuation during Nakhai-Pour et al.188
the first trimester of pregnancy and the risk of pre-eclampsia
and eclampsia.
Progesterone Association between progesterone suppression and Uddin et al. 189
pre-eclampsia
Furosemide Improvement of urine output and subsequent renal function in Keiseb et al. 2002.190
pre-eclamptic patients with oliguria
Nutritional supplementation
Calcium Relax wall of blood vessels through moderation of parathyroid, Hofmeyr et al.151
calcium and magnesium channels
Antioxidant Limit endothelial damage from oxidative stress Vadillo-Ortega et al.161
Folic acid Hyperhomocysteinemia can be corrected by supplementation Hua et al.191
with folic acid.
Magnesium Reduction of extracellular calcium and magnesium in pre- Idogun et al.192
eclampsia
Fish oil Omega-3 fatty acid competes with arachidonic acid (precursor Saccone et al.193
of thromboxane A2) and reduces oxidative stress markers
Lifestyle intervention and
dietary modification
Rest Reduce stress hormones release Sibai et al.194
Exercise Modulation of renin-angiotensin-aldosterone system in a mouse Genest et al.195
model
Reduce dietary salt Increased salt sensitivity of ambulatory blood pressure in Martillotti et al.196
women with a history of severe pre-eclampsia
Energy and protein intake Higher total energy intake is linked to pre-eclampsia Schoenaker et al.197
Garlic Effects on plasma lipids and platelet aggregation Ziaei et al.198

need be developed before routine adoption. Clinical
use of the plasma sFlt1:PlGF ratio may improve risk
stratification and eventually reduces costs and
resource use.164
Although prediction of pre-eclampsia can be inte-
grated into the current combined screening for fetal
aneuploidies, its cost and stringent quality control
may make it unfit for many Asian countries with low
resources.1 Screening with maternal history based on
either (i) an ACOG recommendation that can predict
37% and 28.9% for early and late pre-eclampsia,
respectively, at 5% FPR or (ii) NICE and US Preventa-
tive Task force recommendations that can improve
DRs of early and late disease to 89.2% and 93.0%,
respectively (at a much higher FPR), is literally with-
out additional cost.12 From economical perspectives,
whether aspirin prophylaxis is for (i) only test-
positive individuals on a formalized screening test
algorithm, (ii) only those with major risk factors or
(iii) all women without assessment of prior risks
remains to be explored.165–167 It is advisable to offer
aspirin in women with a prior history of pre-
eclampsia because it reduces the recurrence by
30%.168
Aspirin is regarded as a cheap drug with good
safety profiles well into the third trimester of preg-
nancy.148 It is not associated with increased risks of
structural or developmental anomalies, major bleed-
ing, placental abruption or adverse regional anesthetic
outcome.3,140,142,143,169–181 Even so, the major counter-
point for aspirin-for-all policy is lack of evidence of its
prophylactic benefits in low-risk women. It would
likely require >5000 low-risk participants to prove a
significant reduction of pre-eclampsia.148 Approxi-
mately 5–65% of women, varying with the assay used
and the populations studied, may be nonresponsive
to aspirin.148 This may be due to (i) genetic polymor-
phisms, (ii) treatment adherence, (iii) spontaneous
regeneration of COX-2 and (iv) enteric coating of the
tablet. In addition, there is a release of more immature
platelets from the placenta and an increased tendency
for platelet aggregation during pregnancy.182 Treating

© 2018 Japan Society of Obstetrics and Gynecology 11

T. Wataganara et al.
all pregnant women with aspirin targets only the
responders, which may not be as prevalent as previ-
ously anticipated.
Conclusions
The perspectives from this review may (i) facilitate the
design of research study and (ii) customize the screen-
ing strategies that are optimal for various resource limi-
tations. Taking a detailed history remains a viable
option for prediction of early pre-eclampsia. The central
etiopathogenesis of pre-eclampsia seems to occur at the
placenta, which can be assessed by a multimarker algo-
rithm in the first trimester. Higher physiological serum
concentrations of PAPP-A and PlGF in Asians, than
Caucasians, call for a large-scale validation of model
prediction in Asian population so that the algorithm
can be accordingly adjusted. The variables included in
the prediction of pre-eclampsia can be mixed and
matched to achieve an optimal performance that is
appropriate for economical restriction in individual
country. For each combination of biomarkers, back-
ward elimination will be needed to determine the sub-
set of biomarkers that contributed to the screening
performance.4,183 In places where accesses to screening,
diagnosis and treatment of pre-eclampsia are even
scarcer, potential options are either (i) a screen-and-
treat-all policy with maternal history and characteris-
tics or (ii) universal provision of low-dose aspirin,
which may provide a cheaper alternative and could
potentially reduce mortality rates in such countries.
Although early prediction of pre-eclampsia poses
fewer ethical considerations compared to screening
for fetal Down syndrome, many issues remain to be
properly addressed. Importantly, one should be
aware of the increased risk of pre-eclampsia when
managing individual patients found coincidentally to
have a low PAPP-A level during first-trimester
screening for trisomies. The choice of test for screen-
ing ultimately will depend not only on the basis of
performance but also on the feasibility of implementa-
tion and health economic considerations among coun-
tries in Asia, with broad distributions of resources
and limitations.
Disclosure
Tuangsit Wataganara, Jarunee Leetheeragul and
Suchittra Pongprasobchai have participated in a
12
sponsored trial conducted by Roche Diagnostics.
Tuangsit Wataganara has received travel bursary
from Thermo Fisher to actively participate in their
sponsored lecture event. The other authors declare no
conflicts of interest.
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