Association of different serum PAPP A levels, in first trimester, with adverse pregnancy outcomes: a retrospective study

Association of different serum PAPP A levels, in first trimester, with adverse pregnancy outcomes: a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of different serum PAPP A levels, in first trimester, with adverse pregnancy outcomes: a retrospective study Dinçer Sümer, Ahmet Arif Filiz, Ramazan Berk Us, Arzu Kösem, Said Muhammed Rüzgar, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6985747/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The first trimester screening test for aneuploidy, including pregnancy-associated plasma protein A (PAPP A), has been used in clinical practice for over forty years. Studies have shown that in addition to screening for aneuploidy, PAPP A is also a potential early marker for adverse pregnancy outcomes. The aim of this study is to investigate different PAPP A levels and analyze the association with pregnancy outcomes. Methods A retrospective cohort study was designed for singleton pregnancies that underwent first trimester screening. A PAPP A value above 3.73 MoM (99th percentile) was defined as an extremely high PAPP A group. A low group was defined as PAPP A below 0.41 MoM (< 5th percentile), normal group defined as 0.42–2.50 MoM (between the 5th and 95th percentile) and high group defined as PAPP A value between 2.51 and 3.73 MoM (between the 95th and 99th percentile). Out of 16646 patients 55 (0.03%) had a PAPP A MoM level > 99th percentile and 43 of them were eligible for the study. The participants of the other groups matched the date of the screening test of the extremely high group participants. Results Fetal growth restriction, Gestational diabetes mellitus, birth weight, cesarean section rate and admission to Neonatal intensive care unit were significant for the low PAPP A group. Oligohydroamnios, polihydroamnios, preterm labor, preterm premature rupture of membranes, small for gestational age, gestational hypertension, preeclampsia, macrosomia, intrauterine demise after 22 weeks' gestation and placental abruption were not significant for the groups (p > 0.05). Conclusions PAPP A is produced by placental tissue and has the potential to be an indirect diagnostic tool for placental function and the prediction for adverse pregnancy outcomes. Clinicians and so patients feel distress if the screening test result report altered PAPP A levels. Low PAPP A concentrations appear to be associated with an adverse pregnancy outcome and gestational diabetes mellitus but high or extremely high PAPP A levels have no effect on obstetric and neonatal outcomes. Pregnancy-associated plasma protein A High PAPP A level Low PAPP A level Pregnancy outcomes Figures Figure 1 Figure 2 Introduction The first trimester screening test for aneuploidy, has been used in clinical practice for over forty years( 1 ). With the widespread use of the test over these years, more and more studies have shown that in addition to screening for aneuploidy, there is also a correlation between PAPP A levels and advers clinical outcomes. PAPP A is produced by placental tissue and has the potential to be an indirect diagnostic tool for placental function and the prediction for advers pregnancy outcomes( 2 ). Low PAPP A levels have been investigated and the results of many studies have confirmed that low serum levels can predict preterm birth, fetal growth restriction or gestational hypertensive disorders( 3 ). On the other hand, knowledge of the clinical significance of elevated Papp A levels, whether ubiquitous or not, is not as clear as for low levels. In the early 2000s, studies suggested that elevated levels had no effect on pregnancy outcome, but more recent studies are skeptical of this finding( 4 – 8 ) The aim of this study is to investigate and compare different PAPP A levels in the first trimester screening test and analyze the association with obstetric and neonatal outcomes. Material method Study design and patient selection A retrospective study was designed for singleton pregnancies that underwent first trimester screening test, Crown-rump length(CRL) between 45 and 84mm, between January 2023 and December 2024. During the study period, a total of 16646 patients underwent a screening test. The biochemical data were obtained from the database of the Department of Medical Biochemistry. A PAPP A value above 3.73 MoM (99th percentile) was defined as an extremely high PAPP A group. Fifty-five (0.03%) patients had a PAPP A MoM value above the 99th percentile. Forty-three of them were eligible for the study. Low group defined as PAPP A below 0.41 MoM (< 5th percentile), normal group defined as 0.42–2.50 MoM (between the 5th and 95th percentile) and high group defined as PAPP A value between 2.51 and 3.73 MoM (between the 95th and 99th percentile) ( 9 ). The participant of the groups matched the date of the screening test of the extremely high group. If more than one participant was available, the first eligible patient after the test of the index patient of the extremely high group was recorded in the database, was included in the study. 1:1 matched patients of the extremely high group were included in the other groups. The flowchart of the study is shown in Fig. 1 . Ultrasound measurements for first trimester screening were performed by obstetrics and gynecology specialists or perinatology clinic staff. Ultrasound examinations were performed (General Electrics Voluson S10, GEHealthcare, General Electric Company, USA), equipped with an abdominal 3.5 MHz convex transducer. All serum samples were analyzed using Siemens equipment (Immulite 2000 Xpi-2). Moms were corrected for weight, smoking, ethnicity and other variables as is standard practice in screening for trisomy 21. The result of the screening test was calculated using PRISCA® software. A risk of more than 1/270 was considered positive for trisomies. Fetal ultrasound screening for aneuploidy in the second trimester and examinations in the third trimester were performed by staff of the perinatology clinic. Data on maternal characteristics, obstetric history, medical history, and pregnancy outcomes were obtained from the perinatology clinic archives. Multiple pregnancies, history of vanishing twin in concurrent pregnancy, fetal demise before 22th gestational weeks and patients for whom obstetric and birth reports did not reached excluded from study. Definition of terms Preterm birth was defined as a delivery occurred before the 37th week of pregnancy( 10 ). Preterm premature rupture of membranes (PPROM) was defined as rupture of the fetal membranes before the onset of uterine contractions before 37 + 0 weeks of gestation( 11 ). Gestational hypertension is defined as a systolic blood pressure of 140 mm Hg or more or a diastolic blood pressure of 90 mm Hg or more or both after 20 weeks of gestation in a woman with a previously normal blood pressure according to the American College of Obstetricians and Gynecologists (ACOG)( 12 ). Pre-eclampsia was defined as new-onset proteinuria associated with gestational hypertension according to ACOG( 12 ).Fetal growth restriction (FGR) and small-for-gestational-age (SGA) fetuses were defined according to the Delphi consensus( 13 ). Fetuses weighing more than 4000 grams are considered macrosomia. Gestational diabetes mellitus (GDM) is defined and screened according to ACOG ( 14 ) and American Diabetes Association( 15 ) guidelines. Maximum vertical pocket method for amniotic fluid assessment is preferred for fetal examination in our hospital. Oligohydramnios is defined as a maximum vertical pocket of less than 2 cm and polyhydramnios is defined as a maximum vertical pocket of 8 cm or more or an amniotic fluid index of 24 cm or more according to the 2014 Fetal Ultrasound Imaging Workshop ( 16 ). Ultrasound findings of the fetus in the second trimester such as echogenic bowel, thickened nuchal fold, pyelectasia, echogenic intracardiac focus, single umbilical artery, choroid plexus cysts, shortened humerus or femur and absent or hypoplastic nasal bone defined as soft markers of aneuploidy. Otherwise, malformations that threaten fetal or neonatal life are defined as major structural anomalies( 16 – 18 ). Statistical analysis The Statistical Package for the Social Sciences Version 22.0 (IBM Corporation, Armonk, New York, US) was used to analyze the data, and the significance level was set at p < 0.05 for analysis. The Kolmogrov-Simirnov and Shapiro-Wilk test was used to determine the distribution of the data. Kruskall-Wallis test was used to compare the groups and the Mann-Whitney U-test, with Benforri correction, was used for post-hoc analysis. The significance level was set at p < 0.008 for post-hoc analysis. For non-normally distributed numerical data, median and interquartile ranges (median, Q1-Q3) were used. The relationships between categorical variables were analyzed using the Chi-square test or Fisher’s exact test. If there was significance, the group that appeared to differ from the others was excluded and the chi-square test was performed again for the other groups. Obtained insignificant result of reanalysis confirmed the significancy caused by the excluded group. For the categorical variables, descriptive analyzes were presented using frequency and percentage(n,%). Results Gravida, parity and body mass index were significantly different for groups (p < 0.05). Gravida was significantly lower in extremely high group than low group (p = 0.004). Parity was significantly higher in high group than low and normal papp-a groups (p = 0.006 and p = 0.004 respectively). Body mass index was significantly lower in high group than normal group(p = 0.002). The participants did not have pre-gestational diabetes or chronic hypertension. The demographic characteristics of the study participants are listed in Table 1 .. Table 1 Demographic characteristics of the study participants BMI: Body mass Index ART asisted reproduction technics, # median (Q1-Q3), & n (%), a Kruskall-Wallis test, b Fisher’s exact test *statistically significant Low PAPP A group n:43 Normal PAPP A group n:43 High PAPP A group n:43 Extremely high PAPP A group n: 43 p value Age(year) # 30(26–34) 27(25–32) 27(24–32) 26(23–34) 0.196 a Gravida # 2(2.0–3.0) 2(1.0–3.0) 2(1.0–3.0) 1(1.0–2.0) 0.039 a * Parity # 1(1.0–2.0) 1(1.0–2.0) 2(1.0–2.0) 1(1.0–2.0) 0.007 a * Abortus # 0(0–0) 0(0–0) 0(0–0) 0(0–0) 0.932 a BMI(kg/m 2 ) # 28(25.0–32.0) 28(26.0–32.0) 26(25.0–28.0) 27(25.0–30.0) 0.018 a * Smoking & 3(7%) 2(4.7%) 7(16.3%) 4 (9.3%) 0.364 b Consanguinity & 1(2.3%) 2 (4.7%) 5 (11.6%) 2 (4.7%) 1.0 b ART pregnancy & 0 (0%) 0 (0%) 1 (2.3%) 0 (0%) 1.0 b The median PAPP A value and MoM were significantly different for grops as expectantly (p < 0.05). Crown-rump length (CRL), Beta HCG level, Beta-HCG MoM level, Screening test positivity for Trisomi 21 were significatly different for groups (p < 0.05). CRL was significantly lower in normal group than high group(p < 0.001) and also significantly lower in low group than high and extremely high group (p < 0.001 and p < 0.001 respectively). Beta HCG level was significantly lower in low group than extremely high group (p = 0.002). Beta-HCG MoM level was significantly lower in low group than high and extremely high group(p = 0.001 and p < 0.001 respectively). The screening test was positive for Down syndrome for twenty-three participants. Low group had significantly higher positivitity rate than other groups (p = < 0.001). Fetal growth restriction (FGR) was significantly different for groups (p < 0.001). There was significantly more FGR in low group than other three groups. Gestational diabetes mellitus (GDM) was significant for groups(p = 0.010). Low group had significantly more GDM than other groups. Clinical characteristics of the study participants are shown in Table 2 . Table 2 Clinical characteristics of the study participants hCG , human chorionic gonadotrophin; MoM , multiple of the median; PAPP , pregnancy-associated plasma protein. # median (Q1-Q3), & n (%), a Kruskall-Wallis test, b Fisher’s exact test, c Chi square test *statistically significant Low PAPP A group n:43 Normal PAPP A group n:43 High PAPP A group n:43 Extremely high PAPP A group n: 43 P value PAPP A Mom level # 0.32(0.25–0.37) 1.40(0.72–2.04) 3.10 (2.81–3.46) 4.35(4.00-5.13) < 0.001 a * PAPP A level (mIU/mL) # 0.65(0.55–0.76) 4.5(1.80–11.90) 18.10(11.90–19.90) 20.70(18.20–24.50) < 0.001 a * Crown-rump length (mm) # 56.50(53.0–61.0) 65.0(53.0–71.0) 74.0 (69.5–77.5) 70.0(62.0–75.0) < 0.001 a * Nuchal transluency measurement(mm) # 1.10(0.90–1.40) 1.10(1.00-1.30) 1.20(0.97–1.60) 1.20 (1.00-1.40) 0.578 a Beta-HCG level (ng/mL) # 23.00(16.00–47.00) 30.00(19.00–56.00) 38.00 (27.00–62.00) 45.00(33.00–65.00) 0.002 a * Beta-HCG MoM level # 0.61(0.43–1.15) 0.84(0.57–1.68) 1.10 (0.80–1.70) 1.35 (0.96–1.77) < 0.001 a * First trimester TSH level (mIU/mL) # 1.63(1.35–2.24) 1.80(0.98–2.60) 1.49 (0.79–1.94) 1.43 (0.87–2.21) 0.386 a First trimester Hemoglobin level (g/dL) # 12.3(11.5–13.5) 12.6(12.0–13.0) 12.6(11.6–13.3) 12.7 (12.2–13.4) 0.423 a Screening test positivity for Trisomi 21 & 15(34.9%) 1(2.3%) 5 (11.6%) 2(4.7%) < 0.001 b * Screening test positivity for Trisomi 13 and 18 & 3(7%) 0(0%) 0(0%) 0(0%) 0.059 b Soft marker presence at Ultrasonography & 9(22.0%) 5(11.6%) 9 (20.9%) 12 (27.9%) 0.326 c Oligohydramnios & 2(4.9) 2 (4.7%) 2 (4.7%) 1 (2.3%) 1.0 b Polihydramnios & 1(2.4%) 3(7.0%) 2 (4.7%) 1 (2.3%) 0.838 b Preterm labor & 5(11.6%) 3 (7.0%) 4 (9.3%) 3 (7.0%) 0.933 b PPROM & 3(7.0%) 0(0%) 1 (2.3%) 1 (2.3%) 0.402 b Gestational Diabetes Mellitus (GDM) & 10(25%) 2 (4.7%) 2 (4.7%) 2 (4.7%) 0.010 b * Gestational hypertension & 1(2.4%) 1 (2.3%) 0(0%) 0(0%) 1,0 b Pre-eclampsia & 3 (7.0%) 1(2.3%) 0(0%) 2(4.7%) 0.517 b Fetal Growth Restriction (FGR) & 12(27.9%) 0(0%) 1(2.3%) 0(0%) < 0.001 b * Small for Gestational Age(SGA) & 9(20.9%) 3 (7.0%) 5 (11.6%) 3 (7.0%) 0.173 b Macrosomia & 2(4.9%) 2(4.7%) 1(2.3%) 0(0%) 0.757 b Intrauterine demise after 22 weeks pregnancy & 0(0%) 0(0%) 1(2.3%) 0(0%) 1.0 b Placental abruption & 0(0%) 0(0%) 2 (4.7%) 1(2.3%) 0.619 b Birth weight, admission to the NICU, mode of delivery were significant for the groups (p > 0.05). Birth weight was significantly lesser in low group than normal group (p = 0.002). Cesarean sectio were performed significantly more in low group than exremely high group (p < 0.001). NICU admission rate was significantly higher for low group than normal group (p = 0.002). Neonatal death was not observed in either group. The neonatal characteristics of the study participants are listed in Table 3 . Table 3 Neonatal characteristics of the study participants IQR , interquartile range NICU neonatal intensive care unit. # median (Q1-Q3), & n (%), a Kruskall-Wallis test, b Fisher’s exact test, c Chi square test *statistically significant Low PAPP A group n:43 Normal PAPP A group n:43 High PAPP A group n:43 Extremely high PAPP A group n: 43 P value Birth weight (gram) # 2960(2510–3300) 3270(3100–3520) 3200 (2950–3380) 3300 (2950–3560) 0.008 a * Gestational age at delivery (week) # 38.0(38.0–39.0) 39.0 (38–40) 39.0 (38–40) 39.0 (38–40) 0.103 a Cesarean Sectio & 30(73.2%) 24(55.8%) 21(48.8%) 12 (27.9%) 0.001 c * Gender & Female22 (53.7%) Male 19(46.3%) Female 19(44.2%) Male 24(55.8%) Female 24(55.8%) Male 19(44.2%) Female 26(60.5%) Male 17(39.5%) 0.488 c NICU admission & 8(19.5%) 0(0%) 4 (9.3%) 3 (7.0%) 0.015 b * Receiver Operating characteristics (ROC) analysis was performed to determine the value of PAPP A MOM level in predicting FGR, GDM and NICU admission of the newborn( Fig. 2 ). Area Under Curve (AUC) analysis of PAPP A MOM for estimation of FGR was 0.866(p = < 0.001, 95% CI = 0.789–0.943), GDM was 0.715 ( p = 0.005, 95% CI = 0.563–0.866), admission to the NICU was 0.650(p = 0.055, 95% CI = 0.487–0.813). The optimal threshold value for PAPP A MOM was determined for prediction of FGR as 0.395 (with 83.4% sensitivity and 85.7% specificity) and of GDM as 0.735(with 72.9% sensitivity and 68.7% specificity). Discussion Our study shows that low PAPP A levels are associated with FGR, GDM, lower birth weight, increased cesarean section rate and admission to the neonatal intensive care unit. High or extremely high PAPP A levels have no effect on obstetric and neonatal outcomes. Gomes MS et al. examined extreme values of PAPP A in 916 patients and reported that PAPP-A values above the 10th percentile were not associated with an increased risk for adverse outcomes, and below the 10th percentile there was a fourfold increased risk of preeclampsia, a threefold increased risk of FGR, and a fiftyfold increased risk of abrupsio plasentae( 3 ). Another study analyzed maternal serum PAPP A levels in the first trimester and obstetric outcomes of 34,271 pregnancies and found an association between low levels and adverse pregnancy outcomes in their study. They pointed out that an elevated PAPP A level has no negative consequences( 5 ). Krantz D et al. analyzed extreme maternal serum biochemistry levels in the first trimester and adverse pregnancy outcomes in 8514 patients in the first trimester. In their study, 79 patients had PAPP A levels above the 99th percentile, and fetal anomalies, intrauterine growth retardation, and preterm birth were not significant in the group with extremely elevated PAPP A levels. They mentioned an association between FGR and first trimester PAPP A and also a significant association between low first trimester PAPP A levels and preterm birth( 19 ). Uriel M et al. analyzed and compared maternal serum PAPP A levels in the first trimester in 422 singleton pregnancies complicated by impaired placental diseases, such as preeclampsia, fetal growth restriction, and gestational hypertension with those of pregnancies in which none of these disorders occurred. 360 patients had a normal pregnancy without developing disturbed placental disease, 32 developed pre-eclampsia, 14 developed FGR and 16 developed GH in their study. They concluded that PAPP A levels were significantly higher in the patients who developed PE than in the FGR and GH groups( 8 ). Another study retrospectively studied newborns admitted to NICU and reported that low PAPP A was associated with increased NICU admissions and lower Apgar scores( 20 ). Boutin A et al investigated PAPP A and adverse pregnancy outcome and reported that PAPP A was moderately associated with PE and SGA, but not with fetal death. And suggested that low PAPP A levels should be used for the prediction of PE, SGA or fetal death( 21 ). Bilagi A et al reported in their large cohort study that low PAPP A levels were associated with an increased likelihood of SGA, stillbirth, pre-eclampsia and preterm birth( 22 ). In this study, FGR, lower birth weight, cesarean section rate and NICU admission were significantly higher with low PAPP A. The incidence of oligohydramnios, polihydramnios, preterm labor, SGA, placental abruption, fetal demise after 22 weeks' gestation and macrosomia were not significant between the groups. Pre-eclampsia occurred in two participants in the extremely high group, one in the normal group and three in the low group, and difference was not significant in either the low, high or extremely high group. Saletra-Bielińska A et al. investigated the PAPP A concentration in the first trimester in twin pregnancies. Their study included 304 patients and 28 of them had PAPP A levels above the 90th percentile. They showed that there was a significant association between high PAPP A levels and deliveries below 34 weeks and below 32 weeks. And they emphasize that an elevated value increases the number of premature births by a factor of two. The intrauterine mortality rate also increases significantly in the group with elevated PAPP A ( 6 ). In another study, which examined 3707 euploid singleton pregnancies in the first trimester, it was reported that a PAPP A level above 2.90 mom was associated with a higher rate of meconium-stained amniotic fluid ( 7 ). Multiple pregnancies were not included in this study. The incidence of preterm labor, pprom, intrauterine demise after 22 weeks were not significant for the groups. The presence of meconium in the amniotic fluid was not analyzed in this study, but neonatal outcomes did not differ at high or extremely high PAPP A levels. Cuckle H et al. analyzed 79 patients with PAPP A levels above 5.0 mom in a multicenter study and reported one fetus with Noonan syndrome, one infant with gastroschisis, and five obstetric complications. He concluded that women should be informed that there is no reason to believe that the outcome of the pregnancy will be different from that of women with normal values, especially if all other markers are normal( 4 ). In this study, soft markers for aneuploidy were detected in 35 fetuses, and most were echogenic intracardiac foci. No major congenital anomalies were found. The frequency of the presence of markers was not significant for the groups. There were a total of twenty-six participants positive for screening test. Diagnostic tests were offered all of the test positive participants, two of them been performed chorion villus sampling, two of them been performed amniocentesis. Five patient performed non- invasive prenatal test. Chromosomal analysis and non invasive test revealed euploidy for the fetuses. Both newborns were examined by the neonatologist at birth and appeared to be normal. Shyu IL et al reported in their systematic review and meta-analysis that low PAPP A levels are associated with an increased risk of GDM. They suggested that PAPP-A assessment can be included in the clinical assessment of GDM risk in addition to traditional maternal risk factors( 23 ). Another study investigated PAPP A level for predicting GDM and showed in their meta-analysis that the predictive value of PAPP A for GDM has a sensitivity of 55% and a specificity of 90%. They mentioned that the PAPP A score has a low predictive accuracy overall, but can be useful in combination with other tests ( 24 ). Our results confirm these studies and show a higher rate of GDM in the low PAPP A group. Limitations This study has several limitations. This was a retrospective analysis of 172 consecutive patients in a single center. The non-randomized study design and the matched sampling method are the main limitations of this study. A larger randomized study with more patients would be necessary. Conclusions PAPP A is produced by placental tissue and has the potential to be an indirect diagnostic tool for placental function and the prediction for adverse pregnancy outcomes. Clinicians and so patients feel distress if the screening test result report altered PAPP A levels. Low PAPP A concentrations appear to be associated with an adverse pregnancy outcome and gestational diabetes mellitus but high or extremely high PAPP A levels have no effect on obstetric and neonatal outcomes. Declarations Ethics approval and consent to participate This retrospective research was carried out in compliance with the Helsinki Declaration. The data were based on clinical records and owing to the retrospective cohort study design this study, so informed consent was not required. Ethical approval was obtained from the ethics committee of the Etlik City Hospital, Ankara, Türkiye ( Approval number AEŞH-BADEK-2025-046) Consent for publication Not applicable Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgements Not applicable Author contributions Dr. Us , Dr. Öktem and Dr. Rüzgar defined the research goals and objectives and worked in data curation. Dr. Filiz and Dr Akbulut analysed the study data. Dr.Sümer developed the methodology and wrote the initial draft. Dr. Yılmaz reviewed the draft and reviewed the manuscript. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol. 2004 Jul;191(1):45-67. doi: 10.1016/j.ajog.2004.03.090. Goetzl L. Adverse pregnancy outcomes after abnormal first-trimester screening for aneuploidy. Clin Lab Med. 2010 Sep;30(3):613-28. doi: 10.1016/j.cll.2010.04.003. 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Ultrasound Obstet Gynecol. 2016 Sep;48(3):333-9. doi: 10.1002/uog.15884. American College of Obstetricians and Gynecologists. Practice Bulletin No. 190: Gestational diabetes mellitus. Committee on Practice Bulletins—Obstetrics. Obstet Gynecol 2018; 131:e49 American Diabetes Association. Standards of Medical Care in Diabetes 2011. Diabetes Care 2011; 34:S11 Reddy UM, Abuhamad AZ, Levine D, Saade GR; Fetal Imaging Workshop Invited Participants*. Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. Obstet Gynecol. 2014 May;123(5):1070-1082. doi: 10.1097/AOG.0000000000000245. Prabhu, Malavika et al. Society for Maternal-Fetal Medicine Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester American Journal of Obstetrics & Gynecology, Volume 225, Issue 4, B2 - B15 https://archive.cdc.gov/#/details?url=https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/chapters/chapter-1/chapter1-4.html Access date 17.05.2025 Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, Silver R, Pergament E, Platt LD, Filkins K, Johnson A, Mahoney M, Hogge WA, Wilson RD, Mohide P, Hershey D, Wapner R; First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. Am J Obstet Gynecol. 2004 Oct;191(4):1452-8. doi: 10.1016/j.ajog.2004.05.068. Elmas B, Laleli Koç B, Tuğrul Ersak D, Zorlu U, Aydoğdu E, Yılmaz G, Üreyen Özdemir E, Hançerlioğulları N, Moraloğlu Tekin Ö. The relationship between the first trimester maternal serum PAPP-A and β-hCG values and newborn intensive care needs in low-risk pregnancies. Turk J Obstet Gynecol. 2022 Dec 13;19(4):287-294. doi: 10.4274/tjod.galenos.2022.48861. Boutin A, Gasse C, Demers S, Blanchet G, Giguère Y, Bujold E. Does Low PAPP-A Predict Adverse Placenta-Mediated Outcomes in a Low-Risk Nulliparous Population? the Great Obstetrical Syndromes (GOS) Study. J Obstet Gynaecol Can. 2018 Jun;40(6):663-668. doi: 10.1016/j.jogc.2017.08.047. Epub 2017 Dec 21. Bilagi A, Burke DL, Riley RD, Mills I, Kilby MD, Katie Morris R. Association of maternal serum PAPP-A levels, nuchal translucency and crown-rump length in first trimester with adverse pregnancy outcomes: retrospective cohort study. Prenat Diagn. 2017 Jul;37(7):705-711. doi: 10.1002/pd.5069. Epub 2017 Jun 16. Shyu IL, Tsai YC, Kuo TN, Shiue YL. Prognostic Impact of Pregnancy-Associated Plasma Protein-A (PAPP-A) for Gestational Diabetes Mellitus (GDM): An Updated Systematic Review and Meta-Analysis of More Than 90 000 Pregnancies. Am J Reprod Immunol. 2025 Jun;93(6):e70087. doi: 10.1111/aji.70087. Talasaz ZH, Sadeghi R, Askari F, Dadgar S, Vatanchi A. First trimesters Pregnancy-Associated Plasma Protein-A levels value to Predict Gestational diabetes Mellitus: A systematic review and meta-analysis of the literature. Taiwan J Obstet Gynecol. 2018 Apr;57(2):181-189. doi: 10.1016/j.tjog.2018.02.003. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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09:19:48","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":100689,"visible":true,"origin":"","legend":"","description":"","filename":"a5943cdcdbb44e59ad5ca1984b283c981structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-6985747/v1/1e7017c808a82e1ecda332dd.xml"},{"id":91832389,"identity":"a8c76612-f2de-4eb9-b5a0-57538b8caf4d","added_by":"auto","created_at":"2025-09-22 09:19:48","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":106756,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-6985747/v1/c6ff94795bb469545d63daaa.html"},{"id":91834858,"identity":"1d9a700c-1b7c-4c25-9c5b-921450e96845","added_by":"auto","created_at":"2025-09-22 09:27:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":17090,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6985747/v1/551dec8277846fb096acdbf7.png"},{"id":91832383,"identity":"d58ba066-5aa1-4246-9f42-367b056575b6","added_by":"auto","created_at":"2025-09-22 09:19:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24245,"visible":true,"origin":"","legend":"\u003cp\u003eROC analysis for sensitivity, specificity of PAPP A MOM in FGR, GDM and NICU admission.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6985747/v1/77a9c90efd947b2a68d45efc.png"},{"id":98440838,"identity":"647d0af8-194d-4ce8-86b9-f9b78b0e2984","added_by":"auto","created_at":"2025-12-17 17:04:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":856365,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6985747/v1/dbbeaed6-433d-4717-80a1-95c3c033c8aa.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of different serum PAPP A levels, in first trimester, with adverse pregnancy outcomes: a retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe first trimester screening test for aneuploidy, has been used in clinical practice for over forty years(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). With the widespread use of the test over these years, more and more studies have shown that in addition to screening for aneuploidy, there is also a correlation between PAPP A levels and advers clinical outcomes. PAPP A is produced by placental tissue and has the potential to be an indirect diagnostic tool for placental function and the prediction for advers pregnancy outcomes(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Low PAPP A levels have been investigated and the results of many studies have confirmed that low serum levels can predict preterm birth, fetal growth restriction or gestational hypertensive disorders(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). On the other hand, knowledge of the clinical significance of elevated Papp A levels, whether ubiquitous or not, is not as clear as for low levels. In the early 2000s, studies suggested that elevated levels had no effect on pregnancy outcome, but more recent studies are skeptical of this finding(\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThe aim of this study is to investigate and compare different PAPP A levels in the first trimester screening test and analyze the association with obstetric and neonatal outcomes.\u003c/p\u003e"},{"header":"Material method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and patient selection\u003c/h2\u003e\u003cp\u003eA retrospective study was designed for singleton pregnancies that underwent first trimester screening test, Crown-rump length(CRL) between 45 and 84mm, between January 2023 and December 2024. During the study period, a total of 16646 patients underwent a screening test. The biochemical data were obtained from the database of the Department of Medical Biochemistry. A PAPP A value above 3.73 MoM (99th percentile) was defined as an extremely high PAPP A group. Fifty-five (0.03%) patients had a PAPP A MoM value above the 99th percentile. Forty-three of them were eligible for the study. Low group defined as PAPP A below 0.41 MoM (\u0026lt;\u0026thinsp;5th percentile), normal group defined as 0.42\u0026ndash;2.50 MoM (between the 5th and 95th percentile) and high group defined as PAPP A value between 2.51 and 3.73 MoM (between the 95th and 99th percentile) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The participant of the groups matched the date of the screening test of the extremely high group. If more than one participant was available, the first eligible patient after the test of the index patient of the extremely high group was recorded in the database, was included in the study. 1:1 matched patients of the extremely high group were included in the other groups. The flowchart of the study is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Ultrasound measurements for first trimester screening were performed by obstetrics and gynecology specialists or perinatology clinic staff. Ultrasound examinations were performed (General Electrics Voluson S10, GEHealthcare, General Electric Company, USA), equipped with an abdominal 3.5 MHz convex transducer. All serum samples were analyzed using Siemens equipment (Immulite 2000 Xpi-2). Moms were corrected for weight, smoking, ethnicity and other variables as is standard practice in screening for trisomy 21. The result of the screening test was calculated using PRISCA\u0026reg; software. A risk of more than 1/270 was considered positive for trisomies. Fetal ultrasound screening for aneuploidy in the second trimester and examinations in the third trimester were performed by staff of the perinatology clinic. Data on maternal characteristics, obstetric history, medical history, and pregnancy outcomes were obtained from the perinatology clinic archives. Multiple pregnancies, history of vanishing twin in concurrent pregnancy, fetal demise before 22th gestational weeks and patients for whom obstetric and birth reports did not reached excluded from study.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDefinition of terms\u003c/h3\u003e\n\u003cp\u003ePreterm birth was defined as a delivery occurred before the 37th week of pregnancy(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Preterm premature rupture of membranes (PPROM) was defined as rupture of the fetal membranes before the onset of uterine contractions before 37\u0026thinsp;+\u0026thinsp;0 weeks of gestation(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Gestational hypertension is defined as a systolic blood pressure of 140 mm Hg or more or a diastolic blood pressure of 90 mm Hg or more or both after 20 weeks of gestation in a woman with a previously normal blood pressure according to the American College of Obstetricians and Gynecologists (ACOG)(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Pre-eclampsia was defined as new-onset proteinuria associated with gestational hypertension according to ACOG(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).Fetal growth restriction (FGR) and small-for-gestational-age (SGA) fetuses were defined according to the Delphi consensus(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Fetuses weighing more than 4000 grams are considered macrosomia. Gestational diabetes mellitus (GDM) is defined and screened according to ACOG (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and American Diabetes Association(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) guidelines. Maximum vertical pocket method for amniotic fluid assessment is preferred for fetal examination in our hospital. Oligohydramnios is defined as a maximum vertical pocket of less than 2 cm and polyhydramnios is defined as a maximum vertical pocket of 8 cm or more or an amniotic fluid index of 24 cm or more according to the 2014 Fetal Ultrasound Imaging Workshop (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Ultrasound findings of the fetus in the second trimester such as echogenic bowel, thickened nuchal fold, pyelectasia, echogenic intracardiac focus, single umbilical artery, choroid plexus cysts, shortened humerus or femur and absent or hypoplastic nasal bone defined as soft markers of aneuploidy. Otherwise, malformations that threaten fetal or neonatal life are defined as major structural anomalies(\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe Statistical Package for the Social Sciences Version 22.0 (IBM Corporation, Armonk, New York, US) was used to analyze the data, and the significance level was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for analysis. The Kolmogrov-Simirnov and Shapiro-Wilk test was used to determine the distribution of the data. Kruskall-Wallis test was used to compare the groups and the Mann-Whitney U-test, with Benforri correction, was used for post-hoc analysis. The significance level was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.008 for post-hoc analysis. For non-normally distributed numerical data, median and interquartile ranges (median, Q1-Q3) were used. The relationships between categorical variables were analyzed using the Chi-square test or Fisher\u0026rsquo;s exact test. If there was significance, the group that appeared to differ from the others was excluded and the chi-square test was performed again for the other groups. Obtained insignificant result of reanalysis confirmed the significancy caused by the excluded group. For the categorical variables, descriptive analyzes were presented using frequency and percentage(n,%).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eGravida, parity and body mass index were significantly different for groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Gravida was significantly lower in extremely high group than low group (p\u0026thinsp;=\u0026thinsp;0.004). Parity was significantly higher in high group than low and normal papp-a groups (p\u0026thinsp;=\u0026thinsp;0.006 and p\u0026thinsp;=\u0026thinsp;0.004 respectively). Body mass index was significantly lower in high group than normal group(p\u0026thinsp;=\u0026thinsp;0.002). The participants did not have pre-gestational diabetes or chronic hypertension. The demographic characteristics of the study participants are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e..\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic characteristics of the study participants BMI: Body mass Index ART asisted reproduction technics, \u003csup\u003e#\u003c/sup\u003emedian (Q1-Q3), \u003csup\u003e\u0026amp;\u003c/sup\u003e n (%), \u003csup\u003ea\u003c/sup\u003e Kruskall-Wallis test, \u003csup\u003eb\u003c/sup\u003e Fisher\u0026rsquo;s exact test *statistically significant\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eExtremely high PAPP A group\u003c/p\u003e\u003cp\u003en: 43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge(year)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30(26\u0026ndash;34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27(25\u0026ndash;32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27(24\u0026ndash;32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e26(23\u0026ndash;34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.196\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGravida\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(2.0\u0026ndash;3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(1.0\u0026ndash;3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.0\u0026ndash;3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1(1.0\u0026ndash;2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.039\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParity\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(1.0\u0026ndash;2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(1.0\u0026ndash;2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2(1.0\u0026ndash;2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1(1.0\u0026ndash;2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbortus\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0(0\u0026ndash;0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0\u0026ndash;0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0(0\u0026ndash;0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0(0\u0026ndash;0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.932\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28(25.0\u0026ndash;32.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28(26.0\u0026ndash;32.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26(25.0\u0026ndash;28.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e27(25.0\u0026ndash;30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoking\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3(7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7(16.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (9.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.364\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConsanguinity\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (11.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.0\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eART pregnancy\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.0\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe median PAPP A value and MoM were significantly different for grops as expectantly (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Crown-rump length (CRL), Beta HCG level, Beta-HCG MoM level, Screening test positivity for Trisomi 21 were significatly different for groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). CRL was significantly lower in normal group than high group(p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and also significantly lower in low group than high and extremely high group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 respectively). Beta HCG level was significantly lower in low group than extremely high group (p\u0026thinsp;=\u0026thinsp;0.002). Beta-HCG MoM level was significantly lower in low group than high and extremely high group(p\u0026thinsp;=\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 respectively). The screening test was positive for Down syndrome for twenty-three participants. Low group had significantly higher positivitity rate than other groups (p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Fetal growth restriction (FGR) was significantly different for groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was significantly more FGR in low group than other three groups. Gestational diabetes mellitus (GDM) was significant for groups(p\u0026thinsp;=\u0026thinsp;0.010). Low group had significantly more GDM than other groups. Clinical characteristics of the study participants are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of the study participants \u003cem\u003ehCG\u003c/em\u003e, human chorionic gonadotrophin; \u003cem\u003eMoM\u003c/em\u003e, multiple of the median; \u003cem\u003ePAPP\u003c/em\u003e, pregnancy-associated plasma protein. \u003csup\u003e#\u003c/sup\u003emedian (Q1-Q3), \u003csup\u003e\u0026amp;\u003c/sup\u003e n (%), \u003csup\u003ea\u003c/sup\u003e Kruskall-Wallis test, \u003csup\u003eb\u003c/sup\u003e Fisher\u0026rsquo;s exact test, \u003csup\u003ec\u003c/sup\u003e Chi square test *statistically significant\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal PAPP A group n:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eExtremely high PAPP A group n: 43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePAPP A Mom level\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.32(0.25\u0026ndash;0.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.40(0.72\u0026ndash;2.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.10 (2.81\u0026ndash;3.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.35(4.00-5.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePAPP A level (mIU/mL)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.65(0.55\u0026ndash;0.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.5(1.80\u0026ndash;11.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18.10(11.90\u0026ndash;19.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20.70(18.20\u0026ndash;24.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCrown-rump length (mm)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56.50(53.0\u0026ndash;61.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65.0(53.0\u0026ndash;71.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e74.0 (69.5\u0026ndash;77.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e70.0(62.0\u0026ndash;75.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNuchal transluency measurement(mm)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.10(0.90\u0026ndash;1.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.10(1.00-1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.20(0.97\u0026ndash;1.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.20 (1.00-1.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.578\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBeta-HCG level (ng/mL)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.00(16.00\u0026ndash;47.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.00(19.00\u0026ndash;56.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38.00 (27.00\u0026ndash;62.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e45.00(33.00\u0026ndash;65.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBeta-HCG MoM level\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.61(0.43\u0026ndash;1.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.84(0.57\u0026ndash;1.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.10 (0.80\u0026ndash;1.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.35 (0.96\u0026ndash;1.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst trimester TSH level (mIU/mL)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.63(1.35\u0026ndash;2.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.80(0.98\u0026ndash;2.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.49 (0.79\u0026ndash;1.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.43 (0.87\u0026ndash;2.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.386\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst trimester Hemoglobin level (g/dL)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.3(11.5\u0026ndash;13.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.6(12.0\u0026ndash;13.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12.6(11.6\u0026ndash;13.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12.7 (12.2\u0026ndash;13.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.423\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScreening test positivity for Trisomi 21\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15(34.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (11.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2(4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScreening test positivity for Trisomi 13 and 18\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3(7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.059\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSoft marker presence at Ultrasonography\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9(22.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5(11.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (20.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 (27.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.326\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOligohydramnios\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(4.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.0\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePolihydramnios\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.838\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreterm labor\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5(11.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (9.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.933\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePPROM\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3(7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.402\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGestational Diabetes Mellitus (GDM) \u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.010\u003c/b\u003e\u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGestational hypertension\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,0\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePre-eclampsia\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2(4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.517\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFetal Growth Restriction (FGR) \u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12(27.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmall for Gestational Age(SGA) \u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9(20.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (11.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.173\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMacrosomia\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(4.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.757\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntrauterine demise after 22 weeks pregnancy\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.0\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlacental abruption\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1(2.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.619\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBirth weight, admission to the NICU, mode of delivery were significant for the groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Birth weight was significantly lesser in low group than normal group (p\u0026thinsp;=\u0026thinsp;0.002). Cesarean sectio were performed significantly more in low group than exremely high group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). NICU admission rate was significantly higher for low group than normal group (p\u0026thinsp;=\u0026thinsp;0.002). Neonatal death was not observed in either group. The neonatal characteristics of the study participants are listed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eNeonatal characteristics of the study participants \u003cem\u003eIQR\u003c/em\u003e, interquartile range NICU neonatal intensive care unit. \u003csup\u003e#\u003c/sup\u003emedian (Q1-Q3), \u003csup\u003e\u0026amp;\u003c/sup\u003e n (%), \u003csup\u003ea\u003c/sup\u003e Kruskall-Wallis test, \u003csup\u003eb\u003c/sup\u003e Fisher\u0026rsquo;s exact test, \u003csup\u003ec\u003c/sup\u003e Chi square test *statistically significant\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh PAPP A group\u003c/p\u003e\u003cp\u003en:43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eExtremely high PAPP A group\u003c/p\u003e\u003cp\u003en: 43\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBirth weight (gram) \u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2960(2510\u0026ndash;3300)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3270(3100\u0026ndash;3520)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3200 (2950\u0026ndash;3380)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3300 (2950\u0026ndash;3560)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGestational age at delivery (week) \u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38.0(38.0\u0026ndash;39.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39.0 (38\u0026ndash;40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39.0 (38\u0026ndash;40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39.0 (38\u0026ndash;40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.103\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCesarean Sectio\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30(73.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24(55.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21(48.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 (27.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale22 (53.7%)\u003c/p\u003e\u003cp\u003eMale 19(46.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale 19(44.2%)\u003c/p\u003e\u003cp\u003eMale 24(55.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFemale 24(55.8%)\u003c/p\u003e\u003cp\u003eMale 19(44.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFemale 26(60.5%)\u003c/p\u003e\u003cp\u003eMale 17(39.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.488\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNICU admission \u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8(19.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (9.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eReceiver Operating characteristics (ROC) analysis was performed to determine the value of PAPP A MOM level in predicting FGR, GDM and NICU admission of the newborn( Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Area Under Curve (AUC) analysis of PAPP A MOM for estimation of FGR was 0.866(p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 95% CI\u0026thinsp;=\u0026thinsp;0.789\u0026ndash;0.943), GDM was 0.715 (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.005, 95% CI\u0026thinsp;=\u0026thinsp;0.563\u0026ndash;0.866), admission to the NICU was 0.650(p\u0026thinsp;=\u0026thinsp;0.055, 95% CI\u0026thinsp;=\u0026thinsp;0.487\u0026ndash;0.813). The optimal threshold value for PAPP A MOM was determined for prediction of FGR as 0.395 (with 83.4% sensitivity and 85.7% specificity) and of GDM as 0.735(with 72.9% sensitivity and 68.7% specificity).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study shows that low PAPP A levels are associated with FGR, GDM, lower birth weight, increased cesarean section rate and admission to the neonatal intensive care unit. High or extremely high PAPP A levels have no effect on obstetric and neonatal outcomes.\u003c/p\u003e\u003cp\u003eGomes MS et al. examined extreme values of PAPP A in 916 patients and reported that PAPP-A values above the 10th percentile were not associated with an increased risk for adverse outcomes, and below the 10th percentile there was a fourfold increased risk of preeclampsia, a threefold increased risk of FGR, and a fiftyfold increased risk of abrupsio plasentae(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Another study analyzed maternal serum PAPP A levels in the first trimester and obstetric outcomes of 34,271 pregnancies and found an association between low levels and adverse pregnancy outcomes in their study. They pointed out that an elevated PAPP A level has no negative consequences(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Krantz D et al. analyzed extreme maternal serum biochemistry levels in the first trimester and adverse pregnancy outcomes in 8514 patients in the first trimester. In their study, 79 patients had PAPP A levels above the 99th percentile, and fetal anomalies, intrauterine growth retardation, and preterm birth were not significant in the group with extremely elevated PAPP A levels. They mentioned an association between FGR and first trimester PAPP A and also a significant association between low first trimester PAPP A levels and preterm birth(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Uriel M et al. analyzed and compared maternal serum PAPP A levels in the first trimester in 422 singleton pregnancies complicated by impaired placental diseases, such as preeclampsia, fetal growth restriction, and gestational hypertension with those of pregnancies in which none of these disorders occurred. 360 patients had a normal pregnancy without developing disturbed placental disease, 32 developed pre-eclampsia, 14 developed FGR and 16 developed GH in their study. They concluded that PAPP A levels were significantly higher in the patients who developed PE than in the FGR and GH groups(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Another study retrospectively studied newborns admitted to NICU and reported that low PAPP A was associated with increased NICU admissions and lower Apgar scores(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Boutin A et al investigated PAPP A and adverse pregnancy outcome and reported that PAPP A was moderately associated with PE and SGA, but not with fetal death. And suggested that low PAPP A levels should be used for the prediction of PE, SGA or fetal death(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Bilagi A et al reported in their large cohort study that low PAPP A levels were associated with an increased likelihood of SGA, stillbirth, pre-eclampsia and preterm birth(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In this study, FGR, lower birth weight, cesarean section rate and NICU admission were significantly higher with low PAPP A. The incidence of oligohydramnios, polihydramnios, preterm labor, SGA, placental abruption, fetal demise after 22 weeks' gestation and macrosomia were not significant between the groups. Pre-eclampsia occurred in two participants in the extremely high group, one in the normal group and three in the low group, and difference was not significant in either the low, high or extremely high group.\u003c/p\u003e\u003cp\u003eSaletra-Bielińska A et al. investigated the PAPP A concentration in the first trimester in twin pregnancies. Their study included 304 patients and 28 of them had PAPP A levels above the 90th percentile. They showed that there was a significant association between high PAPP A levels and deliveries below 34 weeks and below 32 weeks. And they emphasize that an elevated value increases the number of premature births by a factor of two. The intrauterine mortality rate also increases significantly in the group with elevated PAPP A (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In another study, which examined 3707 euploid singleton pregnancies in the first trimester, it was reported that a PAPP A level above 2.90 mom was associated with a higher rate of meconium-stained amniotic fluid (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Multiple pregnancies were not included in this study. The incidence of preterm labor, pprom, intrauterine demise after 22 weeks were not significant for the groups. The presence of meconium in the amniotic fluid was not analyzed in this study, but neonatal outcomes did not differ at high or extremely high PAPP A levels.\u003c/p\u003e\u003cp\u003eCuckle H et al. analyzed 79 patients with PAPP A levels above 5.0 mom in a multicenter study and reported one fetus with Noonan syndrome, one infant with gastroschisis, and five obstetric complications. He concluded that women should be informed that there is no reason to believe that the outcome of the pregnancy will be different from that of women with normal values, especially if all other markers are normal(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In this study, soft markers for aneuploidy were detected in 35 fetuses, and most were echogenic intracardiac foci. No major congenital anomalies were found. The frequency of the presence of markers was not significant for the groups. There were a total of twenty-six participants positive for screening test. Diagnostic tests were offered all of the test positive participants, two of them been performed chorion villus sampling, two of them been performed amniocentesis. Five patient performed non- invasive prenatal test. Chromosomal analysis and non invasive test revealed euploidy for the fetuses. Both newborns were examined by the neonatologist at birth and appeared to be normal.\u003c/p\u003e\u003cp\u003eShyu IL et al reported in their systematic review and meta-analysis that low PAPP A levels are associated with an increased risk of GDM. They suggested that PAPP-A assessment can be included in the clinical assessment of GDM risk in addition to traditional maternal risk factors(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Another study investigated PAPP A level for predicting GDM and showed in their meta-analysis that the predictive value of PAPP A for GDM has a sensitivity of 55% and a specificity of 90%. They mentioned that the PAPP A score has a low predictive accuracy overall, but can be useful in combination with other tests (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Our results confirm these studies and show a higher rate of GDM in the low PAPP A group.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThis study has several limitations. This was a retrospective analysis of 172 consecutive patients in a single center. The non-randomized study design and the matched sampling method are the main limitations of this study. A larger randomized study with more patients would be necessary.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePAPP A is produced by placental tissue and has the potential to be an indirect diagnostic tool for placental function and the prediction for adverse pregnancy outcomes. Clinicians and so patients feel distress if the screening test result report altered PAPP A levels. Low PAPP A concentrations appear to be associated with an adverse pregnancy outcome and gestational diabetes mellitus but high or extremely high PAPP A levels have no effect on obstetric and neonatal outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003eThis retrospective research was carried out in compliance with the Helsinki Declaration. The data were based on clinical records and owing to the retrospective cohort study design this study, so informed consent was not required. Ethical approval was obtained from the ethics committee of the\u0026nbsp;Etlik City Hospital, Ankara, T\u0026uuml;rkiye ( Approval number AEŞH-BADEK-2025-046)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e Dr. Us , Dr. \u0026Ouml;ktem and Dr. R\u0026uuml;zgar defined the research goals and objectives and worked in data curation. Dr. Filiz and Dr Akbulut analysed the study data. Dr.S\u0026uuml;mer developed the methodology and wrote the initial draft. \u0026nbsp; Dr. Yılmaz reviewed the draft and reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol. 2004 Jul;191(1):45-67. doi: 10.1016/j.ajog.2004.03.090. \u003c/li\u003e\n\u003cli\u003eGoetzl L. Adverse pregnancy outcomes after abnormal first-trimester screening for aneuploidy. Clin Lab Med. 2010 Sep;30(3):613-28. doi: 10.1016/j.cll.2010.04.003. \u003c/li\u003e\n\u003cli\u003eG\u0026oacute;rczewski W, G\u0026oacute;recka J, Massalska-Wolska M, Staśkiewicz M, Borowski D, Huras H, Rybak-Krzyszkowska M. Role of First Trimester Screening Biochemical Markers to Predict Hypertensive Pregnancy Disorders and SGA Neonates-A Narrative Review. Healthcare (Basel). 2023 Sep 1;11(17):2454. doi: 10.3390/healthcare11172454.\u003c/li\u003e\n\u003cli\u003eCuckle H, Arbuzova S, Spencer K, Crossley J, Barkai G, Krantz D, Muller F, Nikolenko M, Aitken D, Hallahan T, Macri J, Buchanan PD. Frequency and clinical consequences of extremely high maternal serum PAPP-A levels. Prenat Diagn. 2003 May;23(5):385-8. doi: 10.1002/pd.600. \u003c/li\u003e\n\u003cli\u003eDugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, Hankins G, Berkowitz RL, Merkatz I, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Vidaver J, D\u0026apos;Alton ME. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol. 2004 Oct;191(4):1446-51. doi: 10.1016/j.ajog.2004.06.052.\u003c/li\u003e\n\u003cli\u003eSaletra-Bielińska A, Kosińska-Kaczyńska K, Szymusik I, Kaczyński B, Brawura-Biskupski-Samaha R, Kozłowski S, Jarmużek P, Walasik I, Wielgoś M. Both Low and High PAPP-A Concentrations in the First Trimester of Pregnancy Are Associated with Increased Risk of Delivery before 32 Weeks in Twin Gestation. J Clin Med. 2020 Jul 3;9(7):2099. doi: 10.3390/jcm9072099. \u003c/li\u003e\n\u003cli\u003eSriram C. Perni, Mladen Predanic, Kristin Cox, Tania Portillo, Robin B. Kalish, Stephen T. Chasen, The association between first-trimester levels of PAPP-A and perinatal complications, Volume 2880, Issue 1006, 12/2004, Pages S1-S208, ISSN 0002-9378, http://dx.doi.org/10.1016/j.ajog.2004.10.155\u003c/li\u003e\n\u003cli\u003eUriel M, Romero Infante XC, Rinc\u0026oacute;n Franco S, Ib\u0026aacute;\u0026ntilde;ez Pinilla EA, Rojas NA. Higher PAPP-A Values in Pregnant Women Complicated with Preeclampsia Than with Gestational Hypertension. Reprod Sci. 2023 Aug;30(8):2503-2511. doi: 10.1007/s43032-023-01176-1. Epub 2023 Mar 14. \u003c/li\u003e\n\u003cli\u003eGomes MS, Carlos-Alves M, Trocado V, Arteiro D, Pinheiro P. Prediction of adverse pregnancy outcomes by extreme values of first trimester screening markers. Obstet Med. 2017 Sep;10(3):132-137. doi: 10.1177/1753495X17704799. Epub 2017 May 16. \u003c/li\u003e\n\u003cli\u003ehttps://www.who.int/news-room/fact-sheets/detail/preterm-birth Accessed 20 June 2025\u003c/li\u003e\n\u003cli\u003eACOG Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 80: premature rupture of membranes. Clinical management guidelines for obstetrician-gynecologists. Obstet Gynecol. 2007 Apr;109(4):1007-19. doi: 10.1097/01.AOG.0000263888.69178.1f. \u003c/li\u003e\n\u003cli\u003eGestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstet Gynecol. 2020 Jun;135(6):e237-e260. doi: 10.1097/AOG.0000000000003891. \u003c/li\u003e\n\u003cli\u003eGordijn SJ, Beune IM, Thilaganathan B, Papageorghiou A, Baschat AA, Baker PN, Silver RM, Wynia K, Ganzevoort W. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound Obstet Gynecol. 2016 Sep;48(3):333-9. doi: 10.1002/uog.15884. \u003c/li\u003e\n\u003cli\u003eAmerican College of Obstetricians and Gynecologists. Practice Bulletin No. 190: Gestational diabetes mellitus. Committee on Practice Bulletins\u0026mdash;Obstetrics. Obstet Gynecol 2018; 131:e49\u003c/li\u003e\n\u003cli\u003eAmerican Diabetes Association. Standards of Medical Care in Diabetes 2011. Diabetes Care 2011; 34:S11\u003c/li\u003e\n\u003cli\u003eReddy UM, Abuhamad AZ, Levine D, Saade GR; Fetal Imaging Workshop Invited Participants*. Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. Obstet Gynecol. 2014 May;123(5):1070-1082. doi: 10.1097/AOG.0000000000000245.\u003c/li\u003e\n\u003cli\u003ePrabhu, Malavika et al. Society for Maternal-Fetal Medicine Consult Series #57: Evaluation and management of isolated soft ultrasound markers for aneuploidy in the second trimester American Journal of Obstetrics \u0026amp; Gynecology, Volume 225, Issue 4, B2 - B15\u003c/li\u003e\n\u003cli\u003ehttps://archive.cdc.gov/#/details?url=https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/chapters/chapter-1/chapter1-4.html Access date 17.05.2025\u003c/li\u003e\n\u003cli\u003eKrantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, Silver R, Pergament E, Platt LD, Filkins K, Johnson A, Mahoney M, Hogge WA, Wilson RD, Mohide P, Hershey D, Wapner R; First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. Am J Obstet Gynecol. 2004 Oct;191(4):1452-8. doi: 10.1016/j.ajog.2004.05.068.\u003c/li\u003e\n\u003cli\u003eElmas B, Laleli Ko\u0026ccedil; B, Tuğrul Ersak D, Zorlu U, Aydoğdu E, Yılmaz G, \u0026Uuml;reyen \u0026Ouml;zdemir E, Han\u0026ccedil;erlioğulları N, Moraloğlu Tekin \u0026Ouml;. The relationship between the first trimester maternal serum PAPP-A and \u0026beta;-hCG values and newborn intensive care needs in low-risk pregnancies. Turk J Obstet Gynecol. 2022 Dec 13;19(4):287-294. doi: 10.4274/tjod.galenos.2022.48861. \u003c/li\u003e\n\u003cli\u003eBoutin A, Gasse C, Demers S, Blanchet G, Gigu\u0026egrave;re Y, Bujold E. Does Low PAPP-A Predict Adverse Placenta-Mediated Outcomes in a Low-Risk Nulliparous Population? the Great Obstetrical Syndromes (GOS) Study. J Obstet Gynaecol Can. 2018 Jun;40(6):663-668. doi: 10.1016/j.jogc.2017.08.047. Epub 2017 Dec 21.\u003c/li\u003e\n\u003cli\u003eBilagi A, Burke DL, Riley RD, Mills I, Kilby MD, Katie Morris R. Association of maternal serum PAPP-A levels, nuchal translucency and crown-rump length in first trimester with adverse pregnancy outcomes: retrospective cohort study. Prenat Diagn. 2017 Jul;37(7):705-711. doi: 10.1002/pd.5069. Epub 2017 Jun 16.\u003c/li\u003e\n\u003cli\u003eShyu IL, Tsai YC, Kuo TN, Shiue YL. Prognostic Impact of Pregnancy-Associated Plasma Protein-A (PAPP-A) for Gestational Diabetes Mellitus (GDM): An Updated Systematic Review and Meta-Analysis of More Than 90 000 Pregnancies. Am J Reprod Immunol. 2025 Jun;93(6):e70087. doi: 10.1111/aji.70087.\u003c/li\u003e\n\u003cli\u003eTalasaz ZH, Sadeghi R, Askari F, Dadgar S, Vatanchi A. First trimesters Pregnancy-Associated Plasma Protein-A levels value to Predict Gestational diabetes Mellitus: A systematic review and meta-analysis of the literature. Taiwan J Obstet Gynecol. 2018 Apr;57(2):181-189. doi: 10.1016/j.tjog.2018.02.003.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pregnancy-associated plasma protein A, High PAPP A level, Low PAPP A level, Pregnancy outcomes","lastPublishedDoi":"10.21203/rs.3.rs-6985747/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6985747/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe first trimester screening test for aneuploidy, including pregnancy-associated plasma protein A (PAPP A), has been used in clinical practice for over forty years. Studies have shown that in addition to screening for aneuploidy, PAPP A is also a potential early marker for adverse pregnancy outcomes. The aim of this study is to investigate different PAPP A levels and analyze the association with pregnancy outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA retrospective cohort study was designed for singleton pregnancies that underwent first trimester screening. A PAPP A value above 3.73 MoM (99th percentile) was defined as an extremely high PAPP A group. A low group was defined as PAPP A below 0.41 MoM (\u0026lt;\u0026thinsp;5th percentile), normal group defined as 0.42\u0026ndash;2.50 MoM (between the 5th and 95th percentile) and high group defined as PAPP A value between 2.51 and 3.73 MoM (between the 95th and 99th percentile). Out of 16646 patients 55 (0.03%) had a PAPP A MoM level\u0026thinsp;\u0026gt;\u0026thinsp;99th percentile and 43 of them were eligible for the study. The participants of the other groups matched the date of the screening test of the extremely high group participants.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFetal growth restriction, Gestational diabetes mellitus, birth weight, cesarean section rate and admission to Neonatal intensive care unit were significant for the low PAPP A group. Oligohydroamnios, polihydroamnios, preterm labor, preterm premature rupture of membranes, small for gestational age, gestational hypertension, preeclampsia, macrosomia, intrauterine demise after 22 weeks' gestation and placental abruption were not significant for the groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePAPP A is produced by placental tissue and has the potential to be an indirect diagnostic tool for placental function and the prediction for adverse pregnancy outcomes. Clinicians and so patients feel distress if the screening test result report altered PAPP A levels. Low PAPP A concentrations appear to be associated with an adverse pregnancy outcome and gestational diabetes mellitus but high or extremely high PAPP A levels have no effect on obstetric and neonatal outcomes.\u003c/p\u003e","manuscriptTitle":"Association of different serum PAPP A levels, in first trimester, with adverse pregnancy outcomes: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 09:19:43","doi":"10.21203/rs.3.rs-6985747/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"07824157-ed15-436e-8a00-8089ffd8649f","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-17T07:54:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 09:19:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6985747","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6985747","identity":"rs-6985747","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}