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CLINICAL ARTICLE
Early prediction of hypertension during pregnancy in a
low-resource setting
Manisha Kumar a,
⁎, Usha Gupta a
, Jayashree Bhattacharjee b
, Ritu Singh c
, Shalini Singh d
, Manish Goel e
,
Karuna Sharma c
, Mujeeb U. Rehman f
a
Department of Obstetrics and Gynecology, Lady Hardinge Medical College, New Delhi, India
b
Safdarjung Hospital and Vardhman Mahavir Medical College, New Delhi, India
c
Department of Biochemistry, Lady Hardinge Medical College, New Delhi, India
d
Indian Council of Medical Research, New Delhi, India
e
Department of Preventive Medicine, Lady Hardinge Medical College, New Delhi, India
f
Department of biochemistry, Vallabhbhai Patel Chest Institute, New Delhi, India
a b s t r a c ta r t i c l e i n f o
Article history:
Received 22 February 2015
Received in revised form 27 June 2015
Accepted 29 October 2015
Keywords:
Body mass index
PAPP-A
Pre-eclampsia screening
Uterine-artery Doppler
Objective: To evaluate the role of maternal factors, biomarkers, and uterine-artery Doppler in the prediction of hy-
pertension during pregnancy. Methods: A prospective cohort study was performed between December 2012 and
November 2014. All singleton pregnancies between 11 weeks and 13 weeks, 6 days of pregnancy were included.
Patients had their body mass index (BMI, calculated as weight in kilograms divided by the square of height in
meters), mean arterial pressure, uterine-artery Doppler pulsatility index, and pregnancy-associated plasma pro-
tein A (PAPP-A) and free β-human chorionic gonadotropin levels recorded. Any patients diagnosed with hyper-
tension during follow-up were assigned to the case cohort; all other patients were assigned to the control group.
Results: Hypertension during pregnancy was observed in 198 (9.7%) of 2042 patients that attended follow-up.
The mean BMI, mean arterial pressure, uterine-artery Doppler pulsatility index, and the PAPP-A level at study en-
rollment were all significantly correlated with the later development of hypertension (P b 0.001 for all variables).
The combined sensitivity, specificity, positive predictive value, and negative predictive value of using the inves-
tigated parameters to predict hypertension was 76%, 80%, 31%, and 93%, respectively. Conclusion: Patient BMI,
mean arterial pressure, PAPP-A, and pulsatility index were found to be effective predictors of hypertension
during pregnancy. Combining these predictors may be beneficial in selecting individuals for close monitoring
and early intervention during pregnancy.
© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Hypertensive disorders of pregnancy, including pre-eclampsia,
complicate up to 10% of pregnancies worldwide, constituting one
of the most significant causes of maternal and perinatal morbidity
and mortality [1].
The Task Force on Hypertension in Pregnancy of the American
College of Obstetricians and Gynecologists reviewed available data
and made evidence-based recommendations for the prevention,
diagnosis, and treatment of hypertension disorders that occur during
pregnancy. The report concluded that, in contrast to its classic defini-
tion, pre-eclampsia can be diagnosed in the absence of proteinuria [2].
Approximately 40% of patients diagnosed with preterm gestational
hypertension subsequently develop pre-eclampsia, or features of
it, leading to significant complications [3]. Consequently, gestational
hypertension can be thought of as representing a significant early
indicator of pre-eclampsia, and all hypertensive disorders of pregnancy,
if predicted or diagnosed early in pregnancy, can impact maternal
morbidity and mortality.
Although delivery is the only curative treatment for pre-eclampsia,
early prediction and subsequent intervention can improve perinatal
and maternal outcomes. Maternal-serum levels of first- and second-
trimester biomarkers for aneuploidy have been shown to be associated
with adverse obstetric outcomes [4,5]. Pre-eclampsia is characterized by
complex pathophysiology as well as heterogeneous clinical and labora-
tory findings. These can include impaired vascular remodeling of the
maternal–fetal interface, an excessive immune response to paternal an-
tigens, systemic inflammatory responses, and dysfunctional placental or
endothelial responses; these processes are all modulated by genetic and
environmental parameters [6,7]. Such heterogeneity in the processes
that potentially lead to, or result from, pre-eclampsia has contributed
to the lack of diagnostic means for identifying patients that may be sus-
ceptible to developing pre-eclampsia, resulting in delayed recognition
and severe complications for both the patient and fetus.
International Journal of Gynecology and Obstetrics 132 (2016) 159–164
⁎ Corresponding author at: Lady Hardinge Medical College, Shahid Bhagat Singh Marg,
New Delhi, India, Pin- 110001. Tel.: +91 98 180 14887; fax: +91 112 336 33728.
E-mail address: manishaonly@gmail.com (M. Kumar).
http://dx.doi.org/10.1016/j.ijgo.2015.07.021
0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics
journal homepage: www.elsevier.com/locate/ijgo
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
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
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
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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Kumar2016 2

  • 1. CLINICAL ARTICLE Early prediction of hypertension during pregnancy in a low-resource setting Manisha Kumar a, ⁎, Usha Gupta a , Jayashree Bhattacharjee b , Ritu Singh c , Shalini Singh d , Manish Goel e , Karuna Sharma c , Mujeeb U. Rehman f a Department of Obstetrics and Gynecology, Lady Hardinge Medical College, New Delhi, India b Safdarjung Hospital and Vardhman Mahavir Medical College, New Delhi, India c Department of Biochemistry, Lady Hardinge Medical College, New Delhi, India d Indian Council of Medical Research, New Delhi, India e Department of Preventive Medicine, Lady Hardinge Medical College, New Delhi, India f Department of biochemistry, Vallabhbhai Patel Chest Institute, New Delhi, India a b s t r a c ta r t i c l e i n f o Article history: Received 22 February 2015 Received in revised form 27 June 2015 Accepted 29 October 2015 Keywords: Body mass index PAPP-A Pre-eclampsia screening Uterine-artery Doppler Objective: To evaluate the role of maternal factors, biomarkers, and uterine-artery Doppler in the prediction of hy- pertension during pregnancy. Methods: A prospective cohort study was performed between December 2012 and November 2014. All singleton pregnancies between 11 weeks and 13 weeks, 6 days of pregnancy were included. Patients had their body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), mean arterial pressure, uterine-artery Doppler pulsatility index, and pregnancy-associated plasma pro- tein A (PAPP-A) and free β-human chorionic gonadotropin levels recorded. Any patients diagnosed with hyper- tension during follow-up were assigned to the case cohort; all other patients were assigned to the control group. Results: Hypertension during pregnancy was observed in 198 (9.7%) of 2042 patients that attended follow-up. The mean BMI, mean arterial pressure, uterine-artery Doppler pulsatility index, and the PAPP-A level at study en- rollment were all significantly correlated with the later development of hypertension (P b 0.001 for all variables). The combined sensitivity, specificity, positive predictive value, and negative predictive value of using the inves- tigated parameters to predict hypertension was 76%, 80%, 31%, and 93%, respectively. Conclusion: Patient BMI, mean arterial pressure, PAPP-A, and pulsatility index were found to be effective predictors of hypertension during pregnancy. Combining these predictors may be beneficial in selecting individuals for close monitoring and early intervention during pregnancy. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. 1. Introduction Hypertensive disorders of pregnancy, including pre-eclampsia, complicate up to 10% of pregnancies worldwide, constituting one of the most significant causes of maternal and perinatal morbidity and mortality [1]. The Task Force on Hypertension in Pregnancy of the American College of Obstetricians and Gynecologists reviewed available data and made evidence-based recommendations for the prevention, diagnosis, and treatment of hypertension disorders that occur during pregnancy. The report concluded that, in contrast to its classic defini- tion, pre-eclampsia can be diagnosed in the absence of proteinuria [2]. Approximately 40% of patients diagnosed with preterm gestational hypertension subsequently develop pre-eclampsia, or features of it, leading to significant complications [3]. Consequently, gestational hypertension can be thought of as representing a significant early indicator of pre-eclampsia, and all hypertensive disorders of pregnancy, if predicted or diagnosed early in pregnancy, can impact maternal morbidity and mortality. Although delivery is the only curative treatment for pre-eclampsia, early prediction and subsequent intervention can improve perinatal and maternal outcomes. Maternal-serum levels of first- and second- trimester biomarkers for aneuploidy have been shown to be associated with adverse obstetric outcomes [4,5]. Pre-eclampsia is characterized by complex pathophysiology as well as heterogeneous clinical and labora- tory findings. These can include impaired vascular remodeling of the maternal–fetal interface, an excessive immune response to paternal an- tigens, systemic inflammatory responses, and dysfunctional placental or endothelial responses; these processes are all modulated by genetic and environmental parameters [6,7]. Such heterogeneity in the processes that potentially lead to, or result from, pre-eclampsia has contributed to the lack of diagnostic means for identifying patients that may be sus- ceptible to developing pre-eclampsia, resulting in delayed recognition and severe complications for both the patient and fetus. International Journal of Gynecology and Obstetrics 132 (2016) 159–164 ⁎ Corresponding author at: Lady Hardinge Medical College, Shahid Bhagat Singh Marg, New Delhi, India, Pin- 110001. Tel.: +91 98 180 14887; fax: +91 112 336 33728. E-mail address: manishaonly@gmail.com (M. Kumar). http://dx.doi.org/10.1016/j.ijgo.2015.07.021 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
  • 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 Â 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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