The Journal of Maternal-Fetal and Neonatal Medicine, 2011; Early Online, 1–5
Late pregnancy associated plasma protein A levels decrease in preterm labor ALEV ATIS1, TURKAN TANDOGAN1, YAVUZ AYDIN2, CIHAT SEN2, FATMA TURGAY3, NEZAKET EREN3, & NIMET GOKER1 Department of Obstetrics and Gynecology, Sisli Etfal Training and Research Hospital, Istanbul, Turkey, 2Department of Obstetrics and Gynecology, Cerrahpasa Medical Faculty of Istanbul University, Istanbul, Turkey, and 3Department of Biochemistry, Sisli Etfal Training and Research Hospital, Istanbul, Turkey 1
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(Received 12 July 2010; revised 30 July 2010; accepted 7 October 2010) Abstract Objective. The purpose of the present study is to evaluate late, ‘at admission’, Pregnancy-associated plasma protein-A (PAPP-A) levels as a predictor of preterm birth in women with complaints of preterm labor or preterm painful contractions. Methods. Prospective cohort study of singleton gestations, 23–37 weeks, and symptoms of preterm labor. Primary end point was delivery 5 37 weeks. Predictive PAPP-A values were calculated both for preterm delivery and threatened preterm delivery on receiver operator curve. Results. In all, 41 women (38.3%) delivered before 37 weeks (Group 1); 32 women (30.7%) had symptoms of preterm labor but did not deliver preterm (Group 2); 31 women (29.7%) delivered term (Group 3, control). Mean PAPP-A levels in preterm-labor and its matched control were 33.4 + 19.9 and 52.5 + 25.4 mIU/ml, respectively, and difference was statistically significant (p ¼ 0.003). Mean PAPP-A level in threatened preterm labor group was 47.6 + 25.3 mIU/ml and difference was significant compared to preterm-labor, but not significant compared to control group (p ¼ 0.028 and p ¼ 0.74, respectively). Conclusion. Late PAPP-A levels decreased in preterm labor, levels 5 29.8 mIU/ml was associated with increased risk for preterm birth, supporting active management whereas cutoff value of 33.6 mIU/ml is useful for discrimination of preterm birth from threatened preterm birth reaching to term. Keywords: PAPP-A, preterm birth, threatened preterm labor, late pregnancy
Introduction Preterm birth, defined as birth occurring before 37 gestational weeks, complicates 12.5% of all deliveries in the USA and accounts for approximately 75% of all neonatal deaths and 50% of childhood neurological morbidities [1,2]. Moreover, it is associated with high immediate and long-term costs after discharge from the hospital and remains the leading cause of perinatal mortality and morbidity [1–3]. The etiology of preterm delivery is unclear, but is likely to be complex and influenced by genetics and enviromental factors. Twothirds of preterm deliveries are spontaneous, and in nearly all these cases, threatened preterm labor (TPL) precedes delivery [4–6]. Pregnancy-associated plasma protein-A (PAPP-A) is a product of the placenta and decidua and is secreted into the maternal circulation during human pregnancy [7,8]. It has been recently identified as an IGF binding protein (IGFBP)- 4 protease. Presumed functions at the maternal–fetal interface are to proteolyze IGFBP-4 and thus increase IGF bioavailability locally in the placenta, to promote IGF-II-mediated trophoblast invasion into the maternal decidua, and to modulate IGF regulation of steroidogenesis and glucose and amino acid transport in the villi [9].
Throughout the pregnancy, PAPP-A concentration in serum correlated to gestational age significantly increases with pregnancy until term [10–13]. Maternal serum concentrations of PAPP-A ( pappalysin-1, EC 3.4.24.79) are used to predict the occurrence of Down syndrome in the first trimester [14,15]. From previous reports, PAPP-A levels in the first trimester have been found also predictive in adverse pregnancy outcomes like fetal growth restriction, premature delivery, and preeclampsia [16,17]. IGFs are believed to play an important role in the regulation of trophoblast invasion of the decidua. Impaired release of free IGFs may be a cause for poor placental perfusion, thereby affecting the fetal growth and the onset of other adverse pregnancy conditions [9,18]. PAPP-A expression has been shown to be regulated by inflammatory cytokines such as TNF-a, IL-1b [19]. These data provide a mechanism for the regulation of PAPP-A in response to injury and further implicate PAPP-A as an acute reactant in inflammatory processes, one of which may be preterm labor. The pathological processes implicated in the preterm birth syndrome include inflammatory intrauterine infection and non-inflammatory group, uterine ischaemia (maternal–placental vasculopathy, uterine overdistension, abnormal allogenic recognition, allergic-like reaction,
Correspondence: Alev Atis, Halkalı, Atakent mah.Soyak Olimpiakent sitesi.D:12 blok D:53, 34303,Ku¨c¸u¨kc¸ekmece/Istanbul,Turkey. Tel: þ905323851290. E-mail:
[email protected] ISSN 1476-7058 print/ISSN 1476-4954 online Ó 2011 Informa UK, Ltd. DOI: 10.3109/14767058.2010.531320
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A. Atis et al. Table I. Demographic variables of the participants in three groups.
Variables
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Age (year) Parity Gestational age (week) at admission Fetal weight (g) at birth Body mass index (kg/m2) Delivery week Rate of cesarean section (%)
Group 1 (n ¼ 41)
Group 2 (n ¼ 32)
Group 3 (n ¼ 31)
p
26.3 + 6.2 1.9 + 1.1 31.46 + 3.4 1988.8 + 841.6 27.3 + 4.5 33.8 + 4.7 26.83
26.2 + 4.8 2.1 + 1.2 31.46 + 2.8 1921.4 + 649.5 26.9 + 3.8 38.9 + 1.7 28.12
28.2 + 6.8 1.9 + 1.0 31.48 + 3.6 2022.2 + 865.4 27.9 + 4.6 39.8 + 2.1 32.25
0.41 0.99 1.0 0.43 0.64 0.03 0.87
cervical disease, and endocrine disorders [20,21]. PAPP-A may be affected in both groups of etiologies of preterm birth by means of IGFs and inflammatory cytokines. The predictive power of PAPP-A in the second trimester for preterm delivery is still under debate and previously studied by Grisaru-Granovsky et al. [22]. The purpose of the present study is to evaluate late, ‘at admission’, PAPP-A levels as a predictor of preterm birth in women with TPL.
Methods Study design This prospective cohort study was carried out at the Sisli Etfal Training and Research Hospital between July 2008 to November 2009. Three strictly, gestational agematched groups were constructed. Group 1; consisted of 41 women who attended to our hospital after 24 weeks with symptoms of preterm labor with intact membranes and at follow-up delivered preterm (537 week), Group 2; consisted of 32 women who attended with symptoms of preterm birth but did not deliver preterm at follow-up (TPL group) reached to term ( 37 week) and Group 3; consisted of 32 women who attended for monthly control of uncomplicated gestation and had term birth at our hospital at follow-up.
Figure 1. Mean plasma levels and ranges of PAPP-A according to groups.
Clinical definition Ages of women, parity, gravidity, pregnancy outcomes blood pressure, neonatal weights, maternal weight, and smoking status were recorded. Preterm labor was defined by the presence of regular of uterine contractions occurring at a frequency of at least two every 10 min associated with cervical change before 37 completed weeks of gestation that required hospitalization. Women with a complaint of regular, painful contractions and/or cervical dilatation of 43 cm and/or effacement of 80% were included. Women were excluded if they had a multiple pregnancy; a condition, such as diabetes, hypertension, pre-eclampsia, or placental hemorrhage, that had complicated the pregnancy; or concurrent infections or a major anomaly, or if the pregnancy outcome was unknown (i.e. if they did not deliver at our hospital). Gestational age was determined from the date of the last menstrual period (LMP) unless this differed by the ultrasound estimate by more than 7 days, in which case the ultrasound estimate was used. Women in the second group were followed up to term pregnancy at our outpatient clinic. If some of them deliver before 37 weeks, they were excluded from the group.
Figure 2. ROC curve of preterm-labor versus control group.
Sample collection The quantitative determination of PAPP-A in the maternal serum was performed with an Immulite/Immulite 1000 device using a solid phase, chemilimuminescence immunometric sandwich method and given as mIU/ml. Blood samples of control group was taken from outpatient pregnancy clinic of our hospital at the mean gestational age of other groups and all followed up to term.
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Late pregnancy associated plasma protein A in preterm labor Table II. Cutoff values of PAPP-A for prediction of preterm labor versus control. Cutoff value
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29.80 30.10 30.40 31.20 33.80
Sensitivity
Specificity
Likelihood ratio
PPV
NPV
0.70968 0.67742 0.64516 0.58065 0.54839
0.51220 0.51220 0.51220 0.51220 0.53659
1.45484 1.38871 1.32258 1.19032 1.18336
0.52381 0.51220 0.50000 0.47368 0.47222
0.70000 0.67742 0.65625 0.61765 0.61111
Maternal blood samples are obtained at admission and studied within 24 h to prevent misdata. One of the tocolysis options is used on hospitalization according to standard protocols. Cesarean sections were done according to standard obstetric indications. All participants gave informed consent and the study was approved by the Ethical Comittee of our hospital. The study was performed according to the institutional ethical committee (Helsinki Committee) guidelines and received approval from the IRB.
Statıstıcal analysis Three groups were compared. Student’s t-test for continuous variables normally distributed, and the Mann– Whitney U-test for variables without normal distribution. w2 test was used for comparison of mode of delivery. Data are presented as mean + SD. One way ANOVA and post hoc Tukey tests were used to compare the groups. Pearson correlation analysis was used to investigate the lineer relation with PAPP-A and gestational week, and PAPP-A and fetal weight. Receiver operator curve (ROC) was constructed to determine the specificity and sensitivity of PAPP-A levels at various cutoff values to predict preterm delivery and threatened preterm delivery. p 5 0.05 was accepted as significant at 95% confidence interval. Analyses were performed with NCSS 2007. Tests were considered statistically significant at a p-value (two-sided) 5 0.05.
Results During the study period 104 patients were enrolled. First group consisted 41 patients who delivered preterm, second group consisted 32 patients having symptoms of preterm labor but not delivered preterm (TPL), third group had 31 patients having neither symptoms of preterm labor nor delivered preterm (control). There were no statistically significant differences between the groups for maternal age, parity, antenatal care, and gestational age at enrollment (Table I). Rates of cesarean section were shown in Table I, were similar among three groups (p ¼ 0.87). Mean PAPP-A levels in preterm-labor and its matched control were 33.48 + 19.99 mIU/ml and 52.56 + 25.46 mIU/ml, respectively, and difference was statistically significant (p ¼ 0.003). Interestingly, mean PAPP-A level in TPL group was 47.60 + 25.33 mIU/ml and differences were significant compared to preterm-labor, but not significant compared to control groups (p ¼ 0.028 and p ¼ 0.74, respectively) (Figure 1). Mean gestational ages of preterm, TPL and control groups at delivery were; 33.8 + 4.7, 38.9 + 1.7, 39.8 + 2.1 weeks, respectively (p ¼ 0.03). There were significant, positive, and strong correlation between gestational age and PAPP-A level and also
Figure 3. ROC curve of preterm-labor versus threatened-pretermlabor group.
between fetal weight and PAPP-A levels (correlation coefficents ¼ 0.83 and 0.78, respectively). ROC analysis differentiating control versus preterm group, showed that 29.8 mIU/ml as cutoff value for PAPP-A has 70.9% sensitivity and 51.2% specificity with a positive predictive value of 52.3% and negative predictive value of 70% for prediction of preterm labor (Figure 2). Cutoff values of PAPP-A for prediction of preterm labor versus control are shown in Table II. ROC analysis manifested that cutoff value of 33.6 mIU/ ml has 68.7% sensitivity and 53.6% specificity with positive predictive value of 55.6% and negative predictive value of 68.7% in discrimination of TPL from preterm labor (Figure 3). Cutoff value of PAPP-A, predicting pretermlabor versus TPL was shown in Table III.
Discussion Preterm delivery, particularly before 34 weeks’ gestation, accounts for three-quarters of neonatal mortality and onehalf of long-term neurological impairment in children. Many of the surviving infants also suffer from other serious short-term and long-term morbidity. Preterm birth has a major and significant direct and indirect cost. There is a direct cost in terms intensive and often prolonged neonatal care and emotional, psychological and financial burdens on the parents [1,2,23]. There are also indirect costs to society where scarce public resources are used for long-term care of the handicapped premature child [1,3,24,25]. Honest et al. in their systematic preterm birth review evaluated 22 tests including ultrasonographic cervical length and funnelling; cervicovaginal fetal fibronectin, amniotic fluid C-reactive protein measurement, absence of fetal breathing movements, amniotic fluid interleukin-6
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A. Atis et al. Table III. Cutoff value of PAPP-A, predicting preterm-labor versus threatened-preterm-labor.
Cutoff value
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33.60 33.80 34.20 34.70 35.00 36.50
Sensitivity
Specificity
Likelihood ratio
PPV
NPV
0.68750 0.65625 0.65625 0.65625 0.65625 0.65625
0.53659 0.53659 0.56098 0.58537 0.60976 0.63415
1.48355 1.41612 1.49479 1.58272 1.68164 1.79375
0.53659 0.52500 0.53846 0.55263 0.56757 0.58333
0.68750 0.66667 0.67647 0.68571 0.69444 0.70270
(IL-6), matrix metalloprotease 9 and serum-reactive protein and cervicovaginal human chorionic gonadotrophine and reviewed quality of studies and accuracy of tests in prediction and found that generally they were poor and a few tests reviewed reached LR þ point estimates 4 5. The cost of the tests for both asymptomatic and symptomatic women varied, reaching to very high rates [26,27]. Recent years urocortin and CRF, a peptide sharing substantial sequence homology with urocortin when evaluated in symptomatic pregnancies, predicted delivery at less than 37 week gestation with acceptable ratios [28,29]. The incidence of first-time hospitalization for preterm labor was found 9% in a study of epidemiology of TPL, with most episodes not resulting in preterm birth [30]. Therefore, accurate prediction of the risk of preterm birth among asymptomatic pregnant women and those symptomatic with TPL may offer the opportunity to target care at those most likely to benefit. TPL appears to be the leading reason for antenatal maternal transfer and hospitalisation, management has changed in many important ways in recent years, especially in relation to the assessment of the risk of preterm delivery, development of new classes of tocolytic drugs, the generalised use of antenatal corticosteroid therapy [6,30]. So, we wanted to know whether late PAPP-A would meet the needs for predicting the preterm delivery and replace aforementioned tests. In a normal pregnancy, trophoblasts invade through the decidua and transform the small muscular walls of the maternal spiral arteries into larger, more elastic vessels to allow an increase in blood flow to the placenta. PAPP-A is most highly expressed in the syncytiotrophoblast of the placenta, which is the main source of circulating PAPP-A in pregnancy [11,12]. Impaired functions may be a cause for poor placental perfusion, thereby affecting adverse pregnancy conditions reflected in lower values. A number of studies have evaluated the effect of a low PAPP-A value on pregnancy outcome, among pregnancies with no chromosomal abnormality. Most studies have evaluated PAPP-A measurements conducted during first trimester screening and some have found associations between low PAPP-A and fetal loss, SGA, preterm birth, or preeclampsia [17,31,32], while others have not [33,34]. Factors such as gestational age (GA) at blood sampling, the definition of low PAPP-A, types of outcomes, sample sizes, and methods of statistical analyses could explain the varying degrees of associations or conflicting results between studies. This study evaluated whether a low level of PAPP-A measured in maternal serum in late pregnancy was associated with having a spontaneous preterm labor or TPL and to determine whether a late low PAPP-A value could be used to predict these outcomes. We found that 29.8 mIU/ml as cutoff value for PAPP-A has 70.9% sensitivity and 51.2% specificity with a positive predictive
value of 52.3% and negative predictive value of 70% for prediction of preterm labor, while cutoff value of 33.6 mIU/ ml has 68.7% sensitivity and 53.6% specificity with positive predictive value of 55.6% and negative predictive value of 68.7% in discrimination of TPL from preterm labor. A similar study of Granovsky et al. showed that values 5 30 mIU/ml at admission for evaluation of preterm birth had 88% specificity and 50% sensitivity with 81% positive predictive value, 62% negative predictive value for delivery 5 7 days [22]. We constructed our study in three groups discriminating real control from TPL group thinking some pathological mechanisms still persist even if TPL group accomplish to reach to 37 weeks. Confirming this, mean PAPP-A levels in preterm-labor, TPL, and control were 33.48 + 19.99 mIU/ml, 47.60 + 25.33 mIU/ ml, and 52.56 + 25.46 mIU/ml, respectively. Interestingly, mean PAPP-A level in TPL group was different from preterm and controls and the difference was significant compared to preterm-labor, (p ¼ 0.028). TPL group had higher PAPP-A values than preterm group significantly. In our study, among TPL group, PAPP-A cutoff at or 4 33.6 mIU/ml is more likely to deliver term while cutoff at or 5 29.8mIU/ml is more likely to deliver preterm with requiring more aggresive therapeutic approach. Our power of study comes from its prospective design that we followed up patients from admission to delivery. Our limiation is PAPP-A could not be found at different centers at various times, a predictive test should be reached easily and should not result falsely either by keeping or preserving conditions but in the future, these may change. A low level of PAPP-A in maternal blood early in pregnancy is believed to be an indication that a woman may develop one or more of the outcomes associated with poor placental perfusion, such as spontaneous fetal loss, stillbirth, preeclampsia, and small for gestational age infant [16,32]. So we point out that lower PAPP-A level also in late pregnancy is a possible determinant of preterm labor.
Acknowledgements Authors thank the head of Istanbul University Cerrahpasa Medical Faculty Biostatistics Department ‘Prof. Dr. Mustafa Senocak’ for statistical performance and interpretation. References 1. Smith R. Parturition. N Engl J Med 2007;356:271–283. 2. Gotsch F, Gotsch F, Romero R, Erez O, Vaisbuch E, Kusanovic JP, Mazaki-Tovi S, Kim SK, Hassan S, Yeo L. The preterm parturition syndrome and its implications for understanding the biology, risk assessment, diagnosis, treatment and prevention of preterm birth. J Matern Fetal Neonatal Med 2009;22 (Suppl 2):5–23.
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