IJG-08588; No of Pages 5

International Journal of Gynecology and Obstetrics xxx (2016) xxxxxx

Contents lists available at ScienceDirect

International Journal of Gynecology and Obstetrics

journal homepage: www.elsevier.com/locate/ijgo

CLINICAL ARTICLE

Correlation of rst-trimester serum levels of pregnancy-associated

plasma protein A with small-for-gestational-age neonates and
preterm births
Shridevi Gundu a, Mohan Kulkarni a, Sanjay Gupte b, Asmita Gupte b, Maitreyee Gambhir a,c, Prakash Gambhir c,
a
Division of Biochemistry, Department of Chemistry, Savitribai Phule Pune University, Pune, India
b
Gupte Hospital and Research Center, Pune, India
c
Birthright Genetic Clinic, Pune, India

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To analyze the relationship between rst-trimester levels of pregnancy-associated plasma protein A
Received 19 June 2015 (PAPP-A) and small-for-gestational-age (SGA) neonates and preterm births, and to assess predictive utility for
Received in revised form 2 September 2015 these events. Methods: A prospective study was conducted among women undergoing rst-trimester screening be-
Accepted 13 January 2016 tween January 1, 2012, and December 31, 2013, at two centers in Pune, India. Serum PAPP-A levels, pregnancy
course, and outcome were assessed. Results: Overall, 1474 women were included. An association was found between
Keywords:
the lowest quintile of PAPP-A levels (b0.4 multiples of median) for both SGA (b10th centile; 20.9% of cases in this
Pregnancy
Pregnancy-associated plasma protein A
PAPP-A quintile) and preterm birth (b37 weeks; 15.8%). Women in the lowest quintile of PAPP-A concentration
Preterm birth had a signicantly increased risk of SGA (b 10th centile) than did those with higher concentrations (adjusted
Small for gestational age odds ratio 2.92, 95% condence interval 2.004.27). Their risk of preterm birth (b37 weeks) was also increased
(adjusted odds ratio 1.84, 95% condence interval 1.252.72). The predictive sensitivities of the lowest quintile of
PAPP-A were 35.85% for SGA (b 10th centile) and 27.92% for preterm birth (b 37 weeks). Conclusion: Low levels of
PAPP-A were associated with SGA and preterm births; however, poor predictive sensitivity could restrict clinical
utility of this marker when used alone.
2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction At present, maternal serum markers and fetal ultrasonography are

Low birth weight (LBW) and preterm birth pose a huge public health
burden because these outcomes are important determinants of neona-
tal mortality and morbidity. Worldwide, 40% of all LBW neonates are
born in India [1]. This country also accounts for 23.6% of preterm births
globally [2]. Preterm and LBW neonates are at increased risk not only of
neurodevelopmental and visual disabilities, but also of chronic diseases
in adulthood, further contributing to social and economic costs [2,3].
New interventions have been sought to prevent LBW and preterm
births; however, the efcacy of such approaches is dependent on early
detection. Current methods of fetal growth monitoring enable diagnosis
of growth retardation and/or preterm birth only during the second and
third trimesters. Early detection of these outcomes would aid early in-
tervention, thus reducing their associated morbidity. This strategy
might benet every pregnancy, assuming that it is possible to introduce
such measures as part of prenatal screening in early pregnancy.
Corresponding author at: Birthright Genetic Clinic, Yashokamal, 23/14, Behind
Ayurved Ras Shala, Karve Road, Erandvane, Pune, Maharashtra State, India PIN-411004.
Tel.: +91 2025462215, +91 9422022526; fax: +91 2025467661.
E-mail address: drprakashgambhir@yahoo.com (P. Gambhir).
used to detect aneuploidies in the rst trimester of pregnancy [4].
Pregnancy-associated plasma protein A (PAPP-A) and free human cho-
rionic gonadotropin (-hCG) are used as biochemical markers [4]. Previ-
ous studies have reported their potential in predicting various obstetric
complications, other than chromosomal abnormalities. For example, an
association was found between adverse pregnancy outcomes and low
levels of PAPP-A and free -hCG in the rst trimester [5,6]. Low levels
of PAPP-A also correlated with neonates being small for gestational age
(SGA) [79] and preterm delivery [9,10]. Low levels of free -hCG were
associated with fetal loss at 24 weeks of gestation [5] and intrauterine
growth restriction [6]. The rate of fetal loss (spontaneous abortion at
b24 weeks and fetal death at 24 weeks) correlated with decreasing
levels of PAPP-A and free -hCG [11]. Nevertheless, some studies failed
to nd associations between the levels of PAPP-A/free -hCG and pre-
term delivery and fetal growth retardation [12]. According to recommen-
dations made by the Genetics Committee of the Society of Obstetricians
and Gynaecologists of Canada [13], an unexplained low PAPP-A level
(b0.4 multiples of median [MoM]) and/or a low free -hCG level
(b0.5 MoM) in the rst trimester is associated with an increased fre-
quency of adverse obstetric outcomes.
The aim of the present study was to assess the role of PAPP-A mea-
surement as part of rst-trimester screening for preterm birth and

http://dx.doi.org/10.1016/j.ijgo.2015.09.022
0020-7292/ 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Gundu S, et al, Correlation of rst-trimester serum levels of pregnancy-associated plasma protein A with small-for-
gestational-age neonates and p..., Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.022
2 S. Gundu et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxxxxx

Table 1
Demographic characteristics and adverse pregnancy outcomes.a

Characteristic Total population (n = 1474) Maternal age, y

b25 (n = 110) 2530 (n = 752) 3035 (n = 516) N35 (n = 96)

Maternal weight, kg 61.12 10.75b 55.75 10.04c 60.52 10.81 62.56 10.32 64.12 10.88
No. of pregnancies 1.87 1.09 1.48 0.93 1.58 0.83 2.22 1.15 2.66 1.62
Assisted conception 78 (5.3) 3 (2.7) 35 (4.7) 33 (6.4) 7 (7.3)
SGA (b10th centile) 159 (10.8) 21 (19.1) 73 (9.7) 56 (10.9) 9 (9.4)
Preterm birth (b37 wk) 154 (10.4) 13 (11.8) 75 (10.0) 55 (10.7) 11 (11.5)

Abbreviation: SGA, small for gestational age.

a
Values are given as mean SD or number (percentage).
b
n = 1472.
c
n = 108.

SGA among Indian women, given that India accounts for the major
global burden of these obstetric complications.
2. Materials and methods
A prospective study of women undergoing rst-trimester screening
was conducted at the Gupte Hospital and Research Center and the
Birthright Genetic Clinic, Pune, India, between January 1, 2012, and
December 31, 2013. The exclusion criteria were multiple pregnancies,
spontaneous abortion during the rst or second trimester, still births,
and conrmed congenital anomalies and/or aneuploidy. Women with
preexisting hypertension, diabetes mellitus, gestational diabetes mellitus,
or other systemic illnesses were also excluded. Approval for the present
study was granted by the ethics committee of the Regional Center of
Maharastra University of Health Sciences, Pune, India. Informed consent
was obtained from participants at enrollment.
Blood samples for rst-trimester PAPP-A screening were collected
between exactly 11 weeks (11+ 0 weeks) and 13 weeks and 6 days
(13+6 weeks) of pregnancy. Serum levels of PAPP-A were measured
using the dissociation-enhanced lanthanide uoroimmunoassay meth-
od and Dela PaPP-A kits (Wallac Oy, Turku, Finland). Demographic
data were collected at enrollment. Crownrump length (measured by
ultrasonography) was used to determine gestational age. Pregnancy
outcome data were collected from hospital records after delivery. All
women underwent ultrasonography between 11+ 0 and 13+6 weeks
and between 19+0 and 20+0 weeks. Pregnancy course was monitored
at monthly follow-up sessions. Every newborn was examined by a
qualied neonatologist.
A global reference was used for birth weight and SGA customization,
an approach recommended to avoid overestimation of fetal growth re-
tardation when evaluating the predictive performance of PAPP-A [14].
The data were analyzed using SPSS version 16 (SPSS Inc, Chicago, IL,
USA). The MoM values of PAPP-A were calculated. Analysis of variance
was used for parametric data (age, weight, gestational age, and gravidity)
to examine the trend in mean values by quintile groups of PAPP-A. The
lowest quintile group of PAPP-A (20th percentile) was considered the
study group and remaining quintiles were pooled as the reference
group. Local fetal weight percentiles were calculated from the fetal
weight equation of Hadlock et al. [15], which adapts the customization
proposed by Gardosi et al. [16]. Mean birth weight at term was 3288 g
and the standard deviation (expressed as a percentage) was 13.2%.
These values were used to calculate the SGA centiles at term and through-
out pregnancy [15,16]. The association between maternal serum PAPP-A
levels and adverse pregnancy outcome was assessed by the 2 test.
Multiple logistic regression was used to estimate the odds ratios (ORs)
and 95% condence intervals (CIs) for risk of adverse pregnancy out-
comes in the study group versus the reference group. The ORs were
adjusted for confounding variables (maternal weight and gestational
age). P b 0.05 was considered statistically signicant.
3. Results
A total of 1474 women with singleton pregnancies were included.
Both maternal weight and gravidity increased with age (P b 0.001 for
both) (Table 1). Use of assisted conception also increased with age
(Table 1), but the difference was not signicant. More cases of SGA
(b10th percentile) were observed among the lowest age quartile
(b25 years) than among the other age quartiles (P = 0.030)
(Table 1). No association was found between maternal age and
preterm birth (b37 weeks).
Maternal demographics and pregnancy outcomes by quintile of
PAPP-A are presented in Table 2. From the lowest to the highest quintile
of PAPP-A, a decreasing trend was observed for maternal age and mater-
nal weight (P b 0.001 for both). By contrast, gestational age at delivery
and birth weight exhibited an increasing trend (P b 0.001), with lower
values in the lower two quintiles of PAPP-A.
Overall, 159 (10.8%) of the pregnancies were characterized as SGA
(b 10th centile) and 154 (10.4%) were preterm deliveries at less than
37 weeks. The highest frequencies of SGA in all centiles were recorded
in the lowest quintile of PAPP-A, decreasing from the lowest to the

Table 2
Maternal and neonatal characteristics by PAPP-A levels.a

Characteristic Total population (n = 1474) Quintiles of PAPP-A concentration, MoM P value for trend

b0.40 (n = 273) 0.400.58 (n = 294) 0.580.78 (n = 297) 0.781.05 (n = 313) N1.05 (n = 297)

Maternal age, y 29.51 3.45 29.95 3.51 29.71 3.51 29.47 3.39 29.44 3.46 29.03 3.33 0.001
Maternal weight, kg 61.12 10.75b 64.27 10.67 61.10 11.39 60.47 9.95c 61.07 10.78 58.90 10.27 b0.001
No. of pregnancies 1.87 1.09 1.94 1.06 1.95 1.16 1.81 1.02 1.85 1.03 1.79 1.16 0.062
Gestational age, wk
At time of testing 12.63 0.54 12.67 0.54 12.62 0.54 12.66 0.51 12.65 0.56 12.57 0.58 0.106
At delivery 38.53 1.68 38.08 2.11 38.46 1.72 38.70 1.57 38.67 1.53 38.71 1.36 b0.001
Birth weight, kg 2.95 0.50d 2.76 0.60 2.93 0.47 3.02 0.47 3.00 0.46e 3.05 0.45 b0.001

Abbreviations: PAPP-A, pregnancy-associated plasma protein A; MoM, multiples of median.

a
Values are given as mean SD unless indicated otherwise.
b
n = 1470.
c
n = 293.
d
n = 1473.
e
n = 312.

Please cite this article as: Gundu S, et al, Correlation of rst-trimester serum levels of pregnancy-associated plasma protein A with small-for-
gestational-age neonates and p..., Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.022
 S. Gundu et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxxxxx 3

Fig. 1. Frequency of SGA according to quintiles of PAPP-A, by centile used to dene SGA. Fig. 3. Frequency of SGA according to centile used to dene SGA, by PAPP-A concentration.
Abbreviations: SGA, small for gestational age; PAPP-A, pregnancy-associated plasma Abbreviations: SGA, small for gestational age; PAPP-A, pregnancy-associated plasma
protein A; MoM, multiples of median. protein A; MoM, multiples of median.

highest quintiles (P b 0.001 in all centiles) (Fig. 1). A similar association
was detected for the three categories of preterm births (P = 0.015 for
b37 weeks; P = 0.001 for both b 34 weeks and b32 weeks) (Fig. 2). De-
spite the overall reduction, the frequencies of SGA and preterm birth
were fairly consistent in the three highest PAPP-A quintiles (Figs. 1 and
2). When the rst quintile for PAPP-A (study group) and the remaining
quintiles (reference group) were compared, a signicant between-
group difference was observed for SGA (P b 0.001 for all three centiles)
and preterm births (P = 0.003 for b37 weeks; P b 0.001 for both
b34 weeks and b32 weeks). An increased incidence of SGA and preterm
birth was seen in the low PAPP-A group (Figs. 3 and 4).
Logistic regression analysis of SGA risk among the low PAPP-A group
showed risk of SGA was increased, irrespective of the centile used to de-
ne SGA (Table 3). The OR for SGA was greatest when the rst centile
cutoff was considered. A similar result was observed for risk of preterm
birth (Table 3).
Table 4 outlines the utility of a low PPAP-A level (b 0.4 MoM) for de-
tection of SGA and preterm births. The detection rate (sensitivity) for
SGA of less than the 10th centile was 35.85%. This rate increased to
65.22% when the rst centile was used as the cutoff; however, the
positive predictive value decreased from 20.88% to 5.50%. The sensitivity
was 27.92% (positive predictive value, 15.75%) and 52.17% (positive
predictive value, 4.40%) for preterm births that occurred before 37 and
32 weeks, respectively.
4. Discussion
The present study found that the incidence of SGA and preterm birth
increased when a PAPP-A level of less than 0.4 MoM was used as the cut-
off for detection. This quintile of PAPP-A (equivalent to the 20th centile)
matched the fth centile cited in previously published studies [5,7,9,17,
18], indicating that more pregnancies in the present study population
had lower PAPP-A levels than did populations included in other studies.
The PAPP-A cut-off dened in the present study had previously been
associated with increased frequency of adverse obstetric outcomes [13].
The present study demonstrated a decreasing trend for SGA and pre-
term births with increasing quintiles of PAPP-A. Similar results were ob-
served in a study where decile values of PAPP-A illustrated a marked
trend for SGA and preterm births [19]. In the present study, sensitivity
of the PAPP-A test for detection of SGA increased with increasing

Fig. 2. Frequency of preterm birth according to quintiles of PAPP-A, by length of Fig. 4. Frequency of preterm birth according to length of pregnancy, by PAPP-A
pregnancy. Abbreviations: PAPP-A, pregnancy-associated plasma protein A; MoM, concentration. Abbreviations: PAPP-A, pregnancy-associated plasma protein A; MoM,
multiples of median. multiples of median.

Please cite this article as: Gundu S, et al, Correlation of rst-trimester serum levels of pregnancy-associated plasma protein A with small-for-
gestational-age neonates and p..., Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.022
4 S. Gundu et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxxxxx

Table 3 Methods for customizing reference ranges for indigenous populations

Outcomes among women with low levels of pregnancy-associated plasma protein A.a might avoid this bias and could improve performance in predicting ad-
Outcome OR (95% CI) Adjusted OR (95% CI) verse perinatal outcomes when compared with non-customized norms
Small for gestational age, centile
[14]. The socioeconomic status of the study population is a limitation of
b10th 2.84 (1.994.05) 2.92 (2.004.27)b the present study. Participants were from the middle and upper socioeco-
b5th 4.19 (2.636.68) 3.83 (2.336.28)b nomic strata in India and so might not be representative of the whole
b1st 8.66 (3.6420.65) 6.85 (2.7017.35)b country.
Preterm birth, wk
In conclusion, low levels of PAPP-A were associated with both SGA
b37 1.84 (1.262.68) 1.84 (1.252.72)c
b34 3.68 (1.887.19) 3.83 (1.927.66)c and preterm births. The large proportion of LBW and preterm births re-
b32 4.97 (2.1711.40) 5.11 (2.1512.14)c corded in India contributes to both a high infant mortality rate and a
Abbreviations: CI, condence interval; OR, odds ratio.
high incidence of chronic illnesses, such as type 2 diabetes mellitus
a
b0.40 multiples of median. and cardiovascular disease, in adulthood. Both new and conventional
b
Adjusted for gestational age at delivery and maternal weight. interventions have been proposed as part of the strategy to control the
c
Adjusted for maternal weight and gestational age at time of testing. incidences of LBW and preterm birth; however, early intervention re-
quires early detection of at-risk pregnancies. Measurement of maternal
severity of growth retardation. A comparable trend was observed for serum PAPP-A levels in the rst trimester might represent one such de-
preterm birth, particularly among deliveries that occurred before tection tool. The advantage of this strategy is that no extra cost or infra-
32 weeks. Similar results were observed in the FASTER trial [5]: test sen- structure would be required, assuming that rst trimester screening for
sitivity increased for preterm births (32 weeks versus b37 weeks) and aneuploidies was already in place. However, optimum predictive utility
LBW (fth centile versus b10th centile). might require the combination of PAPP-A with other markers, such as
In the present study, low PAPP-A levels were associated with both placental growth factor.
SGA and preterm birth, which is consistent with previously published
data [17,20]. However, some studies have reported a statistically signi-
cant association of low PAPP-A levels with SGA only [8,21,22]. A small Acknowledgments
study among Indian mothers demonstrated the association of low
PAPP-A levels with SGA and preterm births using 0.5 MoM as the cutoff S.G. was supported by the University Grants Commission
[18]. The present nding of an association between PAPP-A and birth Meritorious Fellowship.
weight supports the results of previous studies [7,8,23]. The proteolytic
activity of PAPP-A is specic for insulin-like growth factor-binding protein Conict of interest
4, a signaling protein that inhibits the activity of receptor-bound insulin-
like growth factor (IGF) [24]. Proteolysis of IGF binding proteins increases The authors have no conicts of interest.
the availability of free IGF, which is responsible for placental growth and
transfer of nutrients to the fetus. Low levels of PAPP-A cause low amounts References
of bioavailable IGF, potentially leading to impaired placental formation,
reduced fetal growth, and adverse pregnancy outcomes. [1] UNICEF, WHO. Low Birthweight: Country, Regional and Global Estimates. Geneva:
Unicef Publications; 2004.
Low levels of PAPP-A have been reported to be a good marker for [2] Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al. National,
prediction of poor pregnancy outcome [13]. In the present study, the regional, and worldwide estimates of preterm birth rates in the year 2010 with time
sensitivity of PAPP-A increased with increasing severity of growth retar- trends since 1990 for selected countries: a systematic analysis and implications.
Lancet 2012;379(9832):216272.
dation and prematurity; however, this increase decreased the positive [3] Muthayya S. Maternal nutrition & low birth weight- what is really important?
predictive value of the test. Therefore, poor sensitivity and low positive Indian J Med Res 2009;130:6008.
predictive value make PAPP-A a poor marker for SGA and preterm birth [4] ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: screening for
fetal chromosomal abnormalities. Obstet Gynecol 2007;109(1):21727.
when used in the absence of other parameters.
[5] Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. First-
Strengths of the present study included the fact that the cutoffs for trimester maternal serum PAPP-A and free-beta subunit human chorionic
SGA were customized for the study population. Because low- and gonadotropin concentrations and nuchal translucency are associated with obstetric
complications: A population-based screening study (The FASTER Trial). Am J Obstet
middle-income countries do not often have their own norms of birth
Gynecol 2004;191(4):144651.
weights for the indigenous population, use of the available reference [6] Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, et al. Association of
ranges could lead to overestimation of fetal growth retardation [1416]. extreme rst-trimester free human chorionic gonadotropin-, pregnancy-
associated plasma protein A and nuchal translucency with intrauterine growth re-
striction and other adverse pregnancy outcomes. Am J Obstet Gynecol 2004;
Table 4 191(4):14528.
Prediction of adverse outcomes among women with low levels of pregnancy-associated [7] Spencer K, Cowans NJ, Avgidou K, Molina F, Nicolaides KH. First-trimester biochem-
plasma protein A.a,b ical markers of aneuploidy and the prediction of small-for-gestational age fetuses.
Ultrasound Obstet Gynecol 2008;31(1):159.
Parameter Small for gestational Preterm birth, wk [8] Canini S, Prefumo F, Pastorino D, Crocetti L, Afitto CG, Venturini PL, et al. Association
age, centile between birth weight and rst-trimester free beta-human chorionic gonadotropin
and pregnancy-associated plasma protein A. Fertil Steril 2008;89(1):1748.
b10th b5th b1st b37 b34 b32 [9] DAntonio F, Rijo C, Thilaganathan B, Akolekar R, Khalil A, Papageourgiou A, et al.
c Association between rst trimester maternal serum pregnancy associated plasma
Sensitivity 35.85 46.15 65.22 27.92 44.44 52.17
protein-A and obstetric complications. Prenat Diagn 2013;33(9):83947.
Specicityd 83.56 83.01 82.21 82.58 82.13 82.01 [10] Spencer K, Cowans NJ, Molina F, Kagan KO, Nicolaides KH. First trimester ultrasound
Positive predictive valuee 20.88 13.19 5.50 15.75 5.86 4.40 and biochemical markers of aneuploidy and the prediction of preterm or early
Negative predictive valuef 91.5 96.5 99.33 90.76 98.34 99.08 preterm delivery. Ultrasound Obstet Gynecol 2008;31(2):14752.
Accuracyg 78.41 81.06 81.94 76.87 81.21 81.55 [11] Spencer K, Cowans NJ, Avgidou K, Nicolaides KH. First-trimester ultrasound and
biochemical markers of aneuploidy and the prediction of impending fetal death.
Abbreviations: TP, true positive; FN, false negative; TN, true negative; FP, false positive.
a Ultrasound Obstet Gynecol 2006;28(5):63743.
Values given as percentage.
b
[12] Morssink LP, Kornman L, Hallahan TW, Kloosterman MD, Beekhuis JR, de Wolf BT,
b0.40 multiples of median. et al. Maternal serum levels of free -hCG and PAPP-A in the rst trimester of
c
TP/(TP + FN). pregnancy are not associated with subsequent fetal growth retardation or preterm
d
TN/(TN + FP). delivery. Prenat Diagn 1998;18(2):14752.
e
TP/(TP + FP). [13] Gagnon A, Wilson RD, Audibert F, Allen VM, Blight C, Brock JA, et al. Obstetrical
f
TN/(TN + FN). complications associated with abnormal maternal serum markers analytes. J Obstet
g
(TP + TN)/(TP + TN + FP + FN). Gynaecol Can 2008;30(10):91849.

Please cite this article as: Gundu S, et al, Correlation of rst-trimester serum levels of pregnancy-associated plasma protein A with small-for-
gestational-age neonates and p..., Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.022
 S. Gundu et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxxxxx 5

[14] Mikolajczyk RT, Zhang J, Betran AP, Souza JP, Mori R, Gulmezoglu AM, et al. A global
reference for fetal-weight and birthweight percentiles. Lancet 2011;377(9780):
185561.
[15] Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a
sonographic weight standard. Radiology 1991;181(1):12933.
[16] Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM. Customised antenatal growth
charts. Lancet 1992;339(8788):2837.
[17] Lain SJ, Algert CS, Tasevski V, Morris JM, Roberts CL. Record linkage to obtain birth
outcomes for the evaluation of screening biomarkers in pregnancy: a feasibility
study. BMC Med Res Methodol 2009;9:48.
[18] Leung TY, Sahota DS, Chan LW, Law LW, Fung TY, Leung TN, et al. Prediction of birth
weight by fetal crown-rump length and maternal serum levels of pregnancy-
associated plasma protein-A in the rst trimester. Ultrasound Obstet Gynecol
2008;31(1):104.
[19] Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM. Early preg-
nancy levels of pregnancy-associated plasma protein A and the risk of intrauterine
growth restriction, premature birth, preeclampsia and stillbirth. J Clin Endocrinol
Metab 2002;87(4):17627.
[20] Barrett SL, Bower C, Hadlow NC. Use of the combined rst trimester screen result
and low PAPP-A to predict risk of adverse fetal outcomes. Prenat Diagn 2008;
28(1):2835.
[21] Ong CY, Liao AW, Spencer K, Munim S, Nicolaides KH. First trimester maternal serum
free beta human chorionic gonadotrophin and pregnancy associated plasma protein
A as predictors of pregnancy complications. BJOG 2000;107(10):126570.
[22] Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr-Urtreger A. Decreased rst trimester
PAPP-A is a predictor of adverse pregnancy outcome. Prenat Diagn 2002;22(9):
77882.
[23] Patil M, Panchanadikar T, Wagh G. Variation of papp-A level in the rst trimester of
pregnancy and its clinical outcome. J Obstet Gynaecol India 2014;64(2):1169.
[24] Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, et al. The
insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted
by human broblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci
U S A 1999;96(6):314953.

Please cite this article as: Gundu S, et al, Correlation of rst-trimester serum levels of pregnancy-associated plasma protein A with small-for-
gestational-age neonates and p..., Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2015.09.022