2. After performing a systemic review of screening tests for pre-
eclampsia, WHO affirmed that there is no clinically useful screening
test for predicting the development of pre-eclampsia in low-risk
populations [8]. No individual markers have been found to be effective
as a screening test in predicting pre-eclampsia [9,10]. Owing to the
heterogeneous nature of pre-eclampsia, a combination of two or more
independent biomarkers, each reflecting different pathophysiologic
processes may increase the likelihood of producing accurate predictive
algorithms [11,12]. A combination of maternal, biochemical, and
Doppler parameters has been found to be effective [13] but larger
studies in a low-risk population are required.
The aim of the present study was to investigate the value of
pregnancy-associated plasma protein A (PAPP-A) and free β-human
chorionic gonadotropin (hCG), as well as uterine-artery Doppler and
patient characteristics (age, body mass index [BMI, calculated as weight
in kilograms divided by the square of height in meters], and mean
arterial pressure) in predicting hypertension during pregnancy in a
low-risk population.
2. Materials and methods
The present study was a prospective cohort study conducted be-
tween December 1, 2012 and November 30, 2014 at the Lady Hardinge
Medical College, New Delhi, India. The study institute’s Independent
Ethics Committee approved the study protocol. All patients with
pregnancies between 11 weeks and 13 weeks and 6 days of pregnancy
attending the prenatal outpatient department of the study site, which
is a tertiary care hospital, were enrolled in the study after being
counselled about the objectives and utility of the screening tests and
having given written informed consent.
The patient characteristics investigated were age, parity, BMI, mean
arterial pressure, free β-hCG, PAPP-A, and findings on ultrasonography
(to determine nuchal translucency and uterine-artery Doppler). Pa-
tients were measured and weighed to calculate BMIs. Mean arterial
pressure was calculated as the diastolic pressure plus one-third of the
pulse pressure (defined as the systolic pressure minus the diastolic
blood pressure). Ultrasonography was performed to determine the
number of fetuses, crown rump length, nuchal translucency, uterine-
artery Doppler resistance index, uterine-artery Doppler pulsatility
index, and the presence or absence of the early diastolic notch (either
unilateral or bilateral). Following ultrasonography, venous blood was
collected from patients; 3 mL of venous blood was drawn by venipunc-
ture into non-heparinized tubes. Blood samples were allowed to clot for
15–20 minutes before being centrifuged at 1500 rpm for 5 minutes. The
serum was removed and aliquots were stored at −80 °C until further
use. The serum concentrations of PAPP-A and free β-hCG were analyzed
using a Immulite-1000 (Seimens India, Mumbai, India) chemilumines-
cent ELISA-based analyzer.
Patient follow-up occurred every month throughout the second tri-
mester, once every 2 weeks during the third trimester, and weekly after
36 weeks of pregnancy. Prenatal follow-up included blood pressure
charting, the measurement of urinary proteins, and the measurement
of fundal height and girth. Investigations for diagnosing hypertension
during pregnancy included liver-function tests, kidney-function tests,
fundus examination, blood film, and complete blood count, and were
performed if a patient’s blood pressure was greater than 140/90 mm
Hg at a follow-up visit. The ultrasound and Doppler examinations
were also performed if patient blood pressure was greater than
140/90 mm Hg. Following a diagnosis of hypertension during pregnan-
cy, intrauterine growth restriction and any other adverse effect, such as
fetal loss, were recorded and appropriate management for complica-
tions was provided (e.g. drugs for hypertension); following this,
monitoring of fetal and patient health continued. If necessary, labor
was induced in patients, with proper intrapartum monitoring of fetal
Patients enrolled for
study (n = 2190)
Patients attending
follow-up (n = 2042)
Patients lost to
follow-up (n =
148)
Deliveries by
normotensive patients
(n = 1651 [80.9%])
Deliveries by
hypertensive patients (n
= 198 [9.7%])
Patients who were
excluded from the study
following induced
abortion or
spontaneous abortion
(n = 193 [9.5%])
Fig. 1. Flowchart of patient recruitment and follow-up.
160 M. Kumar et al. / International Journal of Gynecology and Obstetrics 132 (2016) 159–164
3. and patient health. After delivery, a neonate’s Apgar scores, weight, and
any adverse effects were recorded, and appropriate management
was provided. Maternal condition was similarly monitored during the
postpartum period.
All enrolled patients attended regular follow-up until delivery, re-
ceiving standard prenatal care. Patients who underwent induced abor-
tion or experienced spontaneous abortion were excluded from study.
Patients that developed hypertension were included in the case cohort
and those who remained normotensive included as the control cohort.
Study data were analyzed using SPSS version 13.0 (SPSS Inc, Chicago,
IL, USA). Quantitative variables were expressed as the mean ± SD and
comparisons were made between the two groups using an unpaired t
test. The qualitative variables were expressed in terms of the number
of participants and percentage, and were compared between the two
groups using a χ2
or Fisher exact test as appropriate. Receiver operating
characteristic (ROC) curves were plotted for the all the variables that
demonstrated a significant difference between the two study groups
and cutoff values were determined. The sensitivity, specificity, positive
predictive value, and negative predictive value were determined
for each cutoff value. A multivariate analysis employing a logistic
regression was performed to determine the best set of predictors for hy-
pertension during pregnancy. The "Forward: likelihood ratio" selection
criteria was used to obtain the best model. A P value of b0.05 was
considered significant.
3. Results
During the study period, 2190 patients between 11 weeks and
13 weeks plus 6 days of pregnancy were enrolled. Throughout the
study period, 148 patients were lost to follow-up, with 2042 patients at-
tending follow-up until delivery or exclusion. Hypertension during
pregnancy was recorded in 198 (9.7%) patients; in 75 (37.9%) patients,
hypertension occurred before 34 weeks pregnancy and in 123 (62.1%)
patients, it occurred at or after 34 weeks of pregnancy. The remaining
1651(80.9%) patients remained normotensive. Of the 2042 patients,
there were 193 (9.5%) incidences of either spontaneous abortion or
induced abortion of pregnancy owing to major congenital anomaly in
the fetus; these patients were excluded from further analyses (Fig. 1).
The clinical characteristics of the study participants are shown in
Table 1. The BMI and mean arterial pressure were significant higher in
the case cohort in comparison with the control group (P b 0.001 for
both); there were no significant difference in the remaining clinical
characteristics between the cohorts. The crown rump length of the
fetuses was 40–84 mm, and was dependent upon the duration of
the pregnancy. The birth weight of neonates was found to be signifi-
cantly lighter in the case cohort in comparison with the control
cohort (P = 0.001).
The biochemical and ultrasound findings of the case and control co-
horts are given in Table 2. In the uterine-artery Doppler analysis, the
mean Doppler pulsatility index (±SD) was found to be 1.70 ± 3.6 in
the control cohort and 2.0 ± 0.4 in the case cohort (P b 0.001). There
was no significant difference observed in the uterine-artery Doppler
resistance index and the uterine-artery systolic–diastolic ratio values
between the two study groups. Early diastolic notch, observed during
left uterine-artery Doppler, was present in a significantly greater
proportion of patients in the case cohort than in the control cohort
(P = 0.02). The serum PAPP-A concentration was 0.1–10.0 mIU/mL across
the entire study population. In the case cohort, the mean PAPP-A serum
concentration was 3.71 mIU/mL, in comparison with 6.0 mlU/mL in the
control cohort (P b 0.001). The free β-hCG serum concentration was
2–200 ng/mL across all study participants. There was no significant differ-
ence observed in the mean serum concentration of free β-hCG between
the case and control cohorts (49.2 ng/mL vs 53.73 ng/mL). For both
serum PAPP-A and free β-hCG, the multiple of median value (MoM)
was calculated using the median value from the control cohort and was
adjusted for the respective correlated variable (Table 2).
The variables with the strongest correlation with the diagnosis of
gestational hypertension were BMI, mean arterial pressure, uterine-
artery Doppler pulsatility index, early diastolic notch observed during
left uterine-artery Doppler, and serum PAPP-A level. The logistic regres-
sion analysis was applied to each of the significantly correlated variables
to provide the odds ratio, confidence interval, and P value of each of the
potential diagnostic markers, as shown in Table 3. Individually, the ROC
curve for each of these markers produced a very small area under the
curve; however, when all of these markers were combined into a single
ROC curve, the area under the curve obtained was 0.815 (Fig. 2) and was
Table 2
Biomarker and Doppler variables.a
Parameter Control cohort Case cohort P-value
Uterine-artery Doppler pulsatility index 1.7 ± 3.6 2.0 ± 0.4 b0.001
Uterine-artery Doppler resistance index 1.4 ± 3.4 0.7 ± 0.15 0.7
Presence of early diastolic notchb
0.5 ± 0.5 (0–1) 0.4 ± 0.5 (0–1) 0.02
Mean uterine-artery systolic–diastolic ratio 3.9 ± 1.7 3.9 ± 3.70 0.7
PAPP-A, multiples of median value 0.76 ± 0.3 0.48 ± 0.39 b0.001
Free β-hCG, multiples of median value 1.79 ± 1.41 1.8 ± 1.3 0.391
Abbreviations: PAPP-A, pregnancy-associated plasma protein A; hCG, human chorionic gonadotropin.
a
Values given as mean ± SD or mean ± SD (range), unless indicated otherwise.
b
0 = early diastolic notch absent; 1 = early diastolic notch present.
Table 1
Profile of case and control cohorts.a
Parameter Control cohort (n = 1651) Case cohort (n = 198) P value
Maternal age, y 24.3 ± 3.3 (18–35) 25.3 ± 3.9 (18–35) 0.055
Parity 0.6 ± 0.8 (0–4) 0.5 ± 1.1 (0–4) 0.135
Duration of pregnancy at time of study entry, wk 12 ± 0.7 (11–13) 11.6 ± 0.7 (11–13) 0.102
BMI 20.4 ± 4.0 23.9 ± 5.6 b0.001
Mean arterial pressure, mm Hg 79.1 ± 9.3 87.1 ± 13.2 b0.001
Crown rump length, mm 60.8 ± 12.0 (40–84) 68 ± 12.1 (40–83) 0.11
Birth weight, kg 2.8 ± 1.5 (2.5–3.5) 2.6 ± 1.6 (1.4–3.5) 0.001
Development of hypertension
b34 weeks pregnancy
0 75 (37.9)
Development of hypertension ≥34 weeks of pregnancy 0 123 (62.1)
Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters).
a
Values given as mean ± SD (range), mean ± SD, or number (percentage), unless indicated otherwise.
161M. Kumar et al. / International Journal of Gynecology and Obstetrics 132 (2016) 159–164
4. considered a good fit, with the sensitivity and specificity increasing to
76% and 80%, respectively. The positive predictive value and negative
predictive value of the combined test were 31% and 93%, respectively.
When only BMI and mean arterial pressure were combined, the
sensitivity and specificity were 52% and 80%, respectively. The cutoff,
sensitivity, specificity, positive predictive value, and negative predictive
values for each marker individually are given in Table 4.
The patient-specific risk for developing hypertension during preg-
nancy was formulated and was given as:
Risk ¼ Odds= 1 þ Oddsð Þ;
where
Odds ¼ eY
 Y:
The logistic regression analysis was used to derive the equation for
the value of Y; the equation is given as:
Y ¼ B1 þ B2 þ B3 þ B4 þ B5 þ −0:0:8044ð Þ;
where B denotes the following regression coefficients: B1 = 0.01
(regression coefficient for BMI), B2 = 0.51 (regression coefficient for
mean arterial pressure), B3 = 0.503 (regression coefficient for the
presence of the early diastolic uterine artery notch on the left side),
B4 = −1.664 (regression coefficient for PAPP-A MoM), and B5 =
0.145 (regression coefficient for free β-hCG MoM).
4. Discussion
The present study found that employing a combination of the BMI,
mean arterial pressure, uterine-artery Doppler pulsatility index, early di-
astolic notch observed during left uterine-artery Doppler, and serum
PAPP-A in predicting hypertension during pregnancy demonstrated a
sensitivity and specificity of 76% and 80%, respectively, and a positive pre-
dictive value and negative predictive value of 31% and 93%, respectively.
The present study is significant because it involves a large study pop-
ulation and, to our knowledge, is the first study to use integrated factors
for the early prediction of hypertension during pregnancy in an Indian
population. Additionally, a distinct cutoff value was ascertained for
each variable. In the present study, the incidence of hypertension during
pregnancy was 9.3%; other studies have previously reported similar in-
cidences when examining pre-eclampsia, ranging from 5% to 10% [1,14].
The age, parity, and socioeconomic status of patients had no influence
on the development of hypertension during pregnancy. There were no
smokers included in the study population; this is likely because
smoking is not a common practice among young Indian women [15].
Although definitive treatment of pre-eclampsia can be achieved
through the delivery of the fetus and placenta, successfully predicting
patients at a high-risk of gestational hypertension (and consequently
pre-eclampsia) at an early stage during pregnancy could enhance
patient care before disease manifestation, possibly helping to reduce
mortality and morbidity for the patient and fetus. Generally, previous
Area Under the Curve
Test result variable(s) Area
Standard
error
a
Asymptotic
significance
b
Asymptotic 95% confidence
interval
Lower Bound Upper Bound
Logistic regression
predicted probability
0.810 0.033 .000 0.746 0.875
Discriminant predicted
probability
0.815 0.032 .000 0.753 0.878
a
Under the nonparametric assumption
b
Null hypothesis: true area = 0.5
Fig. 2. Receiver operating characteristic curve of combined body mass index, mean arterial pressure, pregnancy-associated plasma protein A, and uterine-artery Doppler pulsatility index.
Green line: predicted probability; Blue line: probability of combined markers being present in the case cohort.
Table 3
Results of the logistic regression of potential markers correlated with hypertension during
pregnancy.
Variable Odds ratio 95% confidence interval P value
BMI 1.11 1.044–1.171 0.001
Mean arterial pressure 1.10 1.028–1.078 b0.001
Doppler pulsatility index 1.16 0.985–1.357 0.001
Presence of early diastolic notch 1.66 1.020–2.678 0.04
Multiples of median PAPP-A values 0.19 0.96–0.375 b0.001
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the
square of height in meters); PAPP-A, pregnancy-associated plasma protein A.
162 M. Kumar et al. / International Journal of Gynecology and Obstetrics 132 (2016) 159–164
5. screening strategies have demonstrated better accuracy when detecting
severe and/or early-onset pre-eclampsia compared with detecting
milder forms and late-onset cases such as gestational hypertension [16].
The results of this prospective cohort study confirm those of previ-
ous reports. These results support the notion that increased BMI or
mean arterial pressure in early pregnancy is correlated with an in-
creased likelihood of developing hypertension later in pregnancy [17].
In the United Kingdom, the National Institute for Health and Care Excel-
lence has published guidelines on prenatal care, recommending that a
patient’s level of risk for developing pre-eclampsia should be deter-
mined at their booking appointment (their first prenatal medical assess-
ment), on the basis of their medical and family history, with the
frequency and intensity of prenatal care that they receive being based
on this risk [18]. In the present study, the sensitivity and specificity of
combining BMI with mean arterial pressure were 52% and 80%, respec-
tively; therefore, in centers with limited resources, where Doppler and
biomarker testing facilities may not be available, combined BMI and
mean arterial pressure testing might be useful in predicting hyperten-
sion later in pregnancy. The results of a study by Poon et al., demonstrat-
ed that the recommendations issued by the National Institute for Health
and Care Excellence regarding using patients’ medical history and bio-
physical tests in predicting pre-eclampsia are potentially useful when
the various factors are incorporated into a combined algorithm. In this
study, Poon et al. found that, by adding factors such as mean arterial
pressure to biochemical markers and Doppler, the sensitivity of testing
increased to 83.8% [19]. In the present study, the combination of multi-
ple diagnostic markers increased the sensitivity and specificity of the
test in predicting hypertension to 76% and 80%, respectively.
Among all of the biomarkers analyzed in the present study, a low
PAPP-A level was found to be associated with the development of hyper-
tension during pregnancy, whereas free β-hCG was not a significant
marker. Many of the initial studies that examined the role of PAPP-A in
pre-eclampsia were retrospective, involved small sample sizes, and pro-
duced conflicting results [20,21]. More recent studies, involving larger
number of patients from the general low-risk population, have shown
more consistent findings. In a population consisting of more than
45 000 women who underwent first-trimester aneuploidy screening in
the United Kingdom, Spencer et al. reported an association between a
low PAPP-A level and an increased risk of a neonate being small for ges-
tational age at delivery, preterm delivery, fetal death, or pre-eclampsia
[2]. Some results have differed and, in a recent study by Skråstad et al.,
it was concluded that PAPP-A has limited diagnostic value [22]. Howev-
er, in the present study, PAPP-A emerged as a very important marker of
hypertension during pregnancy, with individual sensitivity and specific-
ity of 68.2% and 70.2%, respectively, with an odds ratio of 0.19.
Previous reports have asserted that uterine-artery Doppler is a use-
ful predictive tool for pre-eclampsia if it is applied during the second tri-
mester [23], but later reports have shown that changes detectable by
uterine-artery Doppler during the first trimester are also predictive of
pre-eclampsia [24,25]. It was suggested in a study by Aquilina et al.
that, in situations where access to Doppler ultrasonography is limited,
uterine-artery Doppler could be restricted to only being used in patients
that exhibit anomalous serum markers [26]. In the present study there
was positive association between a high uterine-artery Doppler
pulsatility index and future development of pre-eclampsia; the
optimum cutoff value for the Doppler pulsatility index was determined
as 1.5.
The combination of all the significantly correlated markers resulted
in a greater area under curve than was produced by any of the factors
individually, suggesting that all of the factors contributed to increasing
the sensitivity and specificity of the test. The positive predictive value
of the markers individually was 10%–21% but the negative predictive
value was 84%–92%. The importance of a high negative predictive
value in pre-eclampsia screening is that, when a test with high negative
predictive value produces a negative result, there is high chance of a
patient not developing pre-eclampsia; therefore, they do not require
intensive follow-up because they can be assured of not developing
pre-eclampsia later during pregnancy. Consequently, individuals with
a positive screening-test result can be subject to more intense follow-
up to allow early intervention if required. In the present study, a formula
was developed for calculating the risk of a patient within the general
population developing hypertension during pregnancy.
India is a low-income country with a vast population; low resources
result in limited access to health care for most of the population. The
doctor-to-patient ratio is low and women often cannot attend the
healthcare facilities repeatedly because each visit can mean a loss of
wages for their family. In the present study, it was possible to investi-
gate all of the parameters of a potential screening program for hyper-
tension in a single visit, despite increased patient load. Using only BMI
and mean arterial pressure, the risk of Down syndrome to the fetus
and hypertension to the mother could be assessed simultaneously with-
out extra cost. The present study also confirms that, in centers where
uterine-artery Doppler and biomarker facilities are not available,
combined BMI and mean arterial pressure testing has good sensitivity
and specificity, and could be used as a screening test.
Although the sensitivity of the test was modest, the very high nega-
tive predictive value of the test makes it a useful test in prenatal care
and facilitates possible early interventions for hypertension during
pregnancy until newer proven biomarkers are available [27]. The main
limitation of the present study was that newer markers were not
included in the testing protocol; however, adding more markers
would increase the cost of screening. In the present study, testing was
performed at no extra cost from that required for existing screening
for Down syndrome.
Using patient characteristics such as BMI and mean arterial pressure,
alone or in combination with PAPP-A and uterine-artery Doppler
pulsatility index, an integrated test for hypertension screening during
the first trimester of pregnancy was feasible in a low-resource country
like India. The test demonstrated high negative predictive value and,
therefore, has potential to be used in selecting patients for more intense
prenatal scrutiny and potential early intervention during pregnancy.
Acknowledgements
The present study was funded by the Indian Council of Medical
Research (Adhoc project no −5/7/509/10-RHN).
Conflict of interest
The authors have no conflicts of interest.
Table 4
Diagnostic properties of markers correlated with the presence of hypertension.a
Parameter Cut-off Sensitivity Specificity Positive predictive value Negative predictive value
Mean arterial pressure 82 mm Hg 67.0 33.4 19.0 89.7
BMI 25 38. 3 89.0 39 .6 88.2
PAPP-A 0.5 multiples of the median 68.2 70.2 21.0 89.0
Doppler pulsatility index 1.5 42.1 35.1 12.1 84.1
Presence of early diastolic notch Present 42.1 48.4 10.1 87.7
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters), PAPP-A, pregnancy-associated plasma protein A.
a
Values given as percentage unless indicated otherwise.
163M. Kumar et al. / International Journal of Gynecology and Obstetrics 132 (2016) 159–164
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