The association of first and second-trimester serum biomarkers with adverse perinatal outcomes in late-preterm and term deliveries: a retrospective cohort study

Şebnem Karagün; Ahmet Zeki Nessar; Hamza Yıldız; Yusuf Dal; Sefanur Gamze Karaca; Ayhan Coşkun

doi:10.1186/s12884-026-08758-2

. 2026 Feb 4;26:200. doi: 10.1186/s12884-026-08758-2

The association of first and second-trimester serum biomarkers with adverse perinatal outcomes in late-preterm and term deliveries: a retrospective cohort study

Şebnem Karagün ^1,^✉, Ahmet Zeki Nessar ¹, Hamza Yıldız ², Yusuf Dal ¹, Sefanur Gamze Karaca ¹, Ayhan Coşkun ¹

PMCID: PMC12930652 PMID: 41639641

Abstract

Background

Maternal serum biomarkers, primarily introduced for aneuploidy screening, have also been investigated as predictors of adverse pregnancy outcomes. However, their value in late-preterm and term pregnancies remains unclear.

Methods

In this retrospective cohort study, 592 singleton pregnancies screened at a tertiary perinatology center between 2020 and 2025 were analyzed. Participants underwent either the first-trimester combined test (n = 461) or the second-trimester triple test (n = 131). Serum biomarker multiples of the median (MoM) were categorized as low (< 0.5), normal (0.5–2.0), or high (> 2.0). Perinatal outcomes—including Apgar scores, umbilical artery pH, neonatal intensive care unit (NICU) admission, and preterm premature rupture of membranes (PPROM)—were assessed using predefined group comparisons, multivariate adjustment, and ROC curve analysis.

Results

Low first-trimester free β-hCG was significantly associated with reduced Apgar scores at 1 and 5 min in term neonates (p = 0.025 and p = 0.005, respectively). In the second trimester, infants with normal AFP levels demonstrated lower umbilical artery pH compared to those with elevated AFP (p = 0.013), and low AFP was associated with an increased risk of NICU admission (p = 0.041). ROC analysis identified an AFP threshold ≥ 1.075 MoM as predictive of PPROM with 75.0% sensitivity and 69.3% specificity (AUC = 0.723, p = 0.035). No significant associations were observed for PAPP-A.

Conclusions

First-trimester low free β-hCG and second-trimester AFP abnormalities showed modest associations with neonatal outcomes and PPROM in late-preterm and term pregnancies, whereas PAPP-A did not. These findings suggest limited standalone predictive capacity of serum biomarkers, underscoring the need for integrated multiparametric models in risk stratification.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12884-026-08758-2.

Keywords: PAPP-A, β-hCG, AFP, Maternal serum screening, Perinatal outcomes, NICU admission, Apgar score, PPROM

Introduction

The prediction of adverse pregnancy outcomes is a key component of modern obstetric care, aiming to optimize maternal–fetal surveillance and improve perinatal health [1–3]. In this context, serum markers originally developed for aneuploidy screening have increasingly been explored within risk-based and personalized medicine approaches, not only for chromosomal risk estimation but also as potential predictors of perinatal complications [4–7]. Although cell-free DNA testing offers superior accuracy for common aneuploidies, the first-trimester combined test provides indispensable clinical information including accurate pregnancy dating, early detection of major fetal structural anomalies, identification of multiple pregnancies, and risk assessment for early-onset preeclampsia—capabilities not afforded by NIPT alone [8, 9]. Conventional serum screening thus remains still a cost-effective strategy and a valuable tool for investigating biomarkers linked to adverse perinatal outcomes beyond aneuploidy [10].

While several studies have reported associations between first-trimester biomarkers and adverse perinatal outcomes—most notably linking low pregnancy-associated plasma protein- (PAPP-A) (< 0.4 MoM) to small-for-gestational-age (SGA) infants, preterm birth (PTB), and composite outcomes including hypertensive disorders of pregnancy—other investigations have found no significant correlation between elevated PAPP-A or free human chorionic gonadotropin (hCG) levels (> 2.0 MoM) and obstetric complications [11–13]. This inconsistency is further emphasized by a recent systematic review, which concluded that first-trimester screening, whether based on serum or ultrasound markers, exhibits limited positive predictive value for reliably forecasting preeclampsia, fetal growth restriction (FGR), PTB, or stillbirth [14]. Such discrepancies highlight the need for population-specific research to delineate the clinical utility of these biomarkers within risk stratification frameworks.

Despite these accumulating findings, considerable heterogeneity and conflicting data persist in the literature regarding the predictive utility of first- and second-trimester biomarkers for adverse perinatal outcomes, particularly in term and late-preterm populations. We therefore designed this retrospective cohort study to test the specific hypothesis that extreme deviations in first- and second-trimester serum biomarker levels (defined a priori as < 0.5 or > 2.0 MoM) are associated with an increased risk of adverse perinatal outcomes in a rigorously defined cohort of late-preterm and term deliveries from a Turkish population. Crucially, much of the existing literature combines preterm and term populations, potentially conflating associations driven by early, severe placental disease with those relevant to the majority of pregnancies delivering at term. A significant evidence gap exists regarding the predictive utility of these biomarkers specifically in late-preterm and term cohorts (≥ 34 weeks), which is precisely the population where their clinical application is most uncertain. Our study was designed to address this gap. Ultimately, our goal was to investigate whether these prenatal screening biomarkers could offer any small, yet valuable, contribution to the management of pregnancy in terms of adverse outcomes, and to refine the clinical approach for pregnancies with abnormal screening parameters (> 2.0 MoM or < 0.5 MoM). By employing multivariate adjustment and predefined test accuracy metrics, our aim was to move beyond exploratory associations and provide a rigorous assessment of their standalone predictive value in this understudied population.

Materials and methods

Study design and population

This retrospective cohort study included 592 singleton pregnancies who underwent first- or second-trimester prenatal screening at Mersin University Hospital, a tertiary perinatology center from January 2020 to December 2025. The study protocol received approval from the Mersin University Clinical Research Ethics Committee (Decision No: 2024/346) and was conducted in accordance with the Declaration of Helsinki. The study was designed as a retrospective cohort analysis based on routinely collected clinical and laboratory data. All data were fully anonymized prior to analysis, and no identifying personal information was accessed or used at any stage of the study. Due to the retrospective nature of the study and the use of anonymized patient records, the requirement for obtaining informed consent was reviewed by the Institutional Review Board and deemed unnecessary. This decision was made in accordance with applicable national legislation and institutional regulations governing retrospective observational research.

According to our institutional protocol, all women requesting prenatal screening are first counseled regarding the option of cell-free DNA testing [15], which is not reimbursed by the national health insurance system in Turkey. For those who cannot access or decline cell-free DNA testing, the first-trimester combined test—fully covered by social insurance—is recommended. Women presenting later in gestation (15–20 weeks) who have not undergone cell-free DNA testing are offered the second-trimester triple test, with explicit counseling about its lower detection rate, since the quadruple test is not available in our institution. The combined test consists of sonographic assessment of nuchal translucency (NT) together with maternal serum levels of PAPP-Aand free hCG, performed between 11 + 0 and 13 + 6 weeks of gestation. The triple test, which includes maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), and hCG in combination with maternal age, is therefore reserved for women presenting beyond the recommended time window for the combined test.

All biochemical markers were adjusted for maternal weight and smoking status, with results expressed as multiples of the median (MoM) specific to gestational age. For the purpose of evaluating associations between biomarker levels and perinatal outcomes, MoM values were categorized as follows: >2.0 was considered high, < 0.5 was considered low, and values between 0.5 and 2.0 were classified as normal. Biomarker MoM values were categorized into low (< 0.5 MoM), normal (0.5–2.0 MoM), and high (> 2.0 MoM) groups based on clinically established thresholds widely used in previous literature to identify clinically meaningful extreme deviations [16, 17]. The purpose of this categorization was to examine whether extreme biomarker values confer an incremental risk in late-preterm and term deliveries. This categorization was applied consistently across all analyzed biomarkers.

The study cohort was derived from the population of patients who underwent first or second-trimester serum screening at our center. The final analysis was restricted to those with complete perinatal outcome data available from delivery at our institution, as many patients with low-risk screening results returned to their primary care facilities for delivery. Accordingly, 461 pregnancies underwent the combined first-trimester test, whereas 131 women who presented later and could not undergo cell-free DNA or combined testing were subsequently screened with the second-trimester triple test. Measurements were performed using a Samsung HS60 ultrasound machine (Samsung Medison, Seoul, Korea) equipped with a 2–5 MHz convex transducer. All scans were performed by certified maternal-fetal medicine specialists in accordance with standardized guidelines for fetal biometry and nuchal translucency measurement [18, 19].

The statistical plan was structured to test our primary hypothesis regarding extreme biomarker values. Analyses were not data-driven or exploratory; rather, they followed a predefined sequence: (1) Group comparisons based on prespecified MoM categories, (2) Multivariate modeling to adjust for key confounders, and (3) Test performance evaluation (ROC analysis) for outcomes showing univariate significance.

Outcome data

For the analysis of perinatal outcomes, only pregnancies delivering beyond 34 weeks of gestation were included; these were categorized as late preterm (34 + 0 to 36 + 6 weeks) and term (≥ 37 weeks) deliveries. Pregnancies with major fetal chromosomal or structural anomalies, multiple gestations, and those with missing outcome data were excluded. All included patients received their prenatal care, delivery, and postnatal care at our clinic, and the data were obtained anonymously from the hospital database. The following data were collected for analysis: maternal characteristics (age, body mass index (BMI), gravida, parity), first-trimester biochemical markers (PAPP-A, free β-hCG MoM values), second-trimester biochemical markers (AFP, uE3, total hCG MoM values), and pregnancy outcomes (preterm birth, birth weight, 1-minute and 5-minute Apgar scores, umbilical artery pH, and neonatal intensive care unit admission (NICU)). The primary outcome for this analysis was to determine the association between abnormal first and second-trimester serum biomarker levels (MoM values) and adverse perinatal outcomes, and to calculate predictive MoM thresholds where significant associations were found.

Definition of perinatal outcomes

Low Apgar score was defined as a 1- or 5-minute score < 7, as values ≤ 6 typically require neonatal evaluation [20]. Abnormal umbilical artery pH was defined as < 7.10, a clinically relevant threshold indicating possible intrapartum hypoxia (pH < 7.0 strongly suggests hypoxia, whereas pH > 7.20 makes it unlikely) [20]. FGR be defined as an ultrasonographic estimated fetal weight or abdominal circumference below the 10th percentile for gestational age [21]. Prenatal premature rupture of membranes (PPROM) refers to rupture of membranes occurring before the onset of uterine contractions at 37 0/7 weeks gestation [22]. NICU admission was defined as admission for any indication beyond routine observation. All first and second-trimester serum biomarker levels (PAPP-A, free β-hCG, AFP, uE3) are expressed as Multiples of the Median (MoM), which are unitless, gestational-age-adjusted values.

An a priori sample size calculation was performed for a comparison of two proportions. Based on effect sizes reported in similar study [23], a relative risk of 2.0 was assumed for a key outcome (NICU admission). Assuming a 10% incidence in the normal biomarker group and a 20% incidence in the at-risk group, a calculation with an alpha error of 0.05 and 90% power yielded a minimum required sample size of 532 participants. Our final cohort of 592 participants exceeded this requirement.

Statistical analysis

Statistical analyses were performed using SPSS 25.0. Continuous variables were presented as mean ± SD, and categorical variables as numbers and percentages. Normality was assessed by Kolmogorov–Smirnov and Shapiro–Wilk tests, histogram and Q–Q plots. Comparisons between groups were made using independent t-test, One-Way ANOVA, Fisher’s exact test, or Fisher–Freeman–Halton test, as appropriate. Pearson correlation coefficients were calculated for continuous variables. Receiver operating characteristic (ROC) curve analysis was used to determine the predictive value of screening test parameters for adverse maternal and neonatal outcomes. A p-value < 0.05 was considered statistically significant. ROC curve analysis was used to determine the predictive value of all first and second-trimester screening parameters (PAPP-A, free β-hCG, AFP, uE3, NT in mm and MoM) for key adverse perinatal outcomes (NICU admission, preterm birth, FGR, and PPROM). For each biomarker-outcome pair, the area under the curve (AUC), the optimal cut-off value, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The complete results of these analyses are provided in Supplementary Table 1. To evaluate whether the associations between serum biomarker categories and adverse perinatal outcomes were independent of confounding factors, multivariate logistic regression analyses were performed. Maternal age, BMI, and parity were included as covariates in all models. Adjusted odds ratios (aORs) with 95% confidence intervals (CI) were reported. A p-value < 0.05 was considered statistically significant. For all ANOVA analyses, post-hoc Tukey HSD testing was applied to determine which specific biomarker groups differed significantly.

Results

A total of 592 pregnant women who underwent either the combined first-trimester test or the second-trimester triple test were included in the study (Fig. 1) Of these, 461 women underwent the combined test and 131 women underwent the triple test. The mean maternal age was 31.52 ± 5.55 years.

Fig. 1 — Flowchart of study population selection

According to the first-trimester combined test results, the distribution of late preterm and term perinatal outcomes is presented in Table 1. Among term pregnancies, 1- and 5-minute Apgar scores were significantly lower in the low free β-hCG group compared with those with normal free β-hCG levels (p = 0.025 and p = 0.005, respectively).

Table 1.

Perinatal outcomes according to first-trimester combined test results

	Late preterm (n=46)						Term (n=415)
	PAPP-A			Free BHCG			PAPP-A			Free BHCG
MoM	Low	Normal	High	Low	Normal	High	Low	Normal	High	Low	Normal	High
GA at delivery (wk)	35,52±1,07	35,71±0,80	35,06±0,79	34,86±0,98	35,64±0,84	35,77±0,88	38,40±0,61	38,58±0,93	38,58±0,71	38,40±0,47	38,54±0,84	38,73±1,18
p	0,278 ^a			0,296^a			0,285^a			0,271^a
Fetal weight (gr)	2803,75±469,55	2580,97±456,05	2324,00±641,53	2500,00±229,12	2562,36±506,48	2947,50±222,76	3297,97±446,74	3315,21±414,30	3266,88±451,80	3331,96±404,77	3304,65±417,64	3335,35±468,42
p	0,218^a			0,307^a			0,836^a			0,873^a
Weight percentile	57,00±51,84	38,97±35,35	35,60±34,26	46,33±7,23	38,56±33,75	69,25±33,88	54,69±29,72	54,06±28,20	48,71±30,32	57,65±27,35	53,87±28,59	51,77±29,35
p	0,365^a			0,214^a			0,652^a			0,728^a
Apgar 1 min	6,50±1,19	6,76±1,85	7,40±1,14	6,00±1,00	6,72±1,74	8,00±0,81	7,77±1,17	7,98±1,32	7,79±1,06	7,30±1,84	8,00±1,19	7,93±1,28
p	0,647^a			0,252^a			0,373^a			0,025^a; Low<Normal
Apgar 5 min	8,63±0,91	8,33±1,26	8,60±0,89	8,00±1,00	8,38±1,20	9,00±0,81	9,11±0,88	9,25±1,03	9,22±0,99	8,61±1,87	9,27±0,88	9,09±1,04
p	0,769^a			0,503^a			0,489^a			0,005^a; Low<Normal
PPROM	1 (12,5)	5 (15,2)	2 (40,0)	0	8 (20,5)	0	2 (2,7)	14 (4,4)	1 (4,2)	1 (4,3)	15 (4,3)	1 (2,3)
p	0,371^b			1,000^b			0,902^b			1,000^b
FGR	5 (62,5)	21 (63,6)	3 (60,0)	3 (100,0)	24 (61,5)	2 (50,0)	7 (9,5)	28 (8,8)	4 (16,7)	1 (4,3)	32 (9,2)	6 (14,0)
p	1,000^b			0,569^b			0,401^b			0,427^b
Umbilical artery pH	7,29±0,04	7,27±0,02	7,29±0,04	7,31±0,03	7,29±0,04	7,30±0,04	7,32±0,04	7,32±0,04	7,31±0,04	7,31±0,04	7,32±0,04	7,32±0,05
p	0,672^a			0,623^a			0,840^a			0,629^a
NICU admission	3 (37,5)	23 (69,7)	5 (100,0)	2 (66,7)	28 (71,8)	1 (25,0)	8 (10,8)	27 (8,5)	0	4 (17,4)	26 (7,4)	5 (11,6)
p	0,064^b			0,123^b			0,277^b			0,129^b

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Data are presented as mean ± standard deviation or n (%)

GA gestational age, PPROM preterm rupture of membranes, FGR fetal growth restriction, NICU neonatal intensive care unit, PAPP-A pregnancy-associated plasma protein A

^aOne-way ANOVA test

^bFisher-Halton-Freeman test

^cFisher's exact test

Table 2 presents the distribution of fetal outcomes in late-preterm and term deliveries according to triple test results. Umbilical artery pH levels were significantly lower in term infants with normal AFP levels compared to those with elevated AFP (p = 0.013). Additionally, the rate of NICU admission was significantly higher among cases with low AFP levels (p = 0.041).

Table 2.

Perinatal outcomes according to second-trimester triple test results

Outcome	Low	Normal	High	p
A. Late-preterm deliveries
AFP
Gestational age	36.60	35.70 ± 0.71	34.90 ± 0.84	0.182
Fetal weight (g)	3470	2924 ± 358	2855 ± 64	0.319
Weight percentile	93.0	68.2 ± 27.8	71.5 ± 26.1	0.569
Apgar 1 min	6.00	6.54 ± 1.61	7.00 ± 1.41	0.872
Apgar 5 min	8.00	8.46 ± 1.12	7.50 ± 2.12	0.583
Umbilical artery pH	7.30	7.31 ± 0.04	7.35 ± 0.04	0.530
NICU admission	0	5 (41.7)	2 (100)	0.323
B. Term deliveries
AFP
Gestational age	38.21 ± 0.16	38.45 ± 0.92	39.00 ± 0.70	0.566
Fetal weight (g)	3053 ± 736	3207 ± 405	3185 ± 205	0.686
Weight percentile	46.5 ± 38.6	47.27 ± 28.46	35.0 ± 9.89	0.837
Apgar 1 min	7.17 ± 2.13	7.95 ± 1.22	8.00 ± 1.41	0.341
Apgar 5 min	9.17 ± 1.16	9.28 ± 0.88	9.00 ± 1.41	0.875
Umbilical artery pH	7.33 ± 0.06	7.30 ± 0.04	7.39 ± 0.03	0.013*
NICU admission	3 (50.0)	12 (10.8)	0	0.041

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Data shown as mean ± SD or n (%). Statistical tests: ANOVA and Fisher–Freeman–Halton test. Bold values indicate statistically significant differences among groups (p < 0.05)

AFP alpha-fetoprotein, β-hCG beta-human chorionic gonadotropin, uE3 unconjugated estriol, FGR fetal growth restriction, NICU neonatal intensive care unit, PPROM preterm premature rupture of membranes. Bold values indicate statistically significant differences (p < 0.05)

Additionally, independent t-test analyses performed for variables with two-group comparisons did not identify any statistically significant differences (all p > 0.05). Likewise, Pearson correlation analysis demonstrated no meaningful correlations between maternal serum marker MoM values and perinatal outcomes (all r < 0.30, p > 0.05).

Post-hoc Tukey analysis showed that term pregnancies with low free β-hCG had significantly lower 1- and 5-minute Apgar scores compared with the normal group (p = 0.025 and p = 0.005, respectively). No other pairwise comparisons were statistically significant. For AFP, post-hoc analysis demonstrated that umbilical artery pH was significantly lower in the normal AFP group compared with the high AFP group (p = 0.013). No significant differences were observed between low and normal or low and high groups.

To evaluate the predictive capacity of screening test parameters for perinatal outcomes, receiver operating characteristic (ROC) curve analysis was performed. An AFP level ≥ 1.075 MoM was identified as predictive of preterm premature rupture of membranes (PPROM) with 75.0% sensitivity and 69.3% specificity (AUC = 0.723; 95% CI: 0.594–0.852; p = 0.035) (Fig. 2).

Fig. 2 — Receiver operating characteristic (ROC) curve of second-trimester maternal serum alpha-fetoprotein (AFP) for the prediction of preterm premature rupture of membranes (PPROM) in term deliveries among women who underwent the second-trimester triple test. AUC, area under the curve; CI, confidence interval

Multivariate logistic regression analysis demonstrated that maternal age (OR = 1.138; 95% CI: 1.017–1.274; p = 0.024) and BMI (OR = 0.806; 95% CI: 0.678–0.957; p = 0.014) were independently associated with preterm birth. However, first-trimester serum biomarkers—including PAPP-A MoM (p = 0.574), free β-hCG MoM (p = 0.573), NT MoM (p = 0.677), and parity (p = 0.242) were not identified as independent predictors. Likewise, for NICU admission, FGR, and PPROM, none of the biomarkers demonstrated independent predictive value after adjustment for maternal age, BMI, and parity (all p > 0.05). Although PAPP-A showed a marginal trend toward increased risk of PPROM (aOR = 1.826), this did not reach statistical significance (p = 0.095). These findings indicate that first-trimester serum markers do not provide independent predictive utility for adverse perinatal outcomes once maternal characteristics are taken into account. This finding underscores that the observed univariate associations do not translate into independent predictive utility once maternal characteristics are taken into account.

Discussion

The prediction of adverse perinatal outcomes remains a significant challenge in obstetrics. First and second-trimester serum biomarkers, routinely collected for aneuploidy screening, represent a promising tool for risk stratification. The present study was designed to investigate the association between first- and second-trimester maternal serum screening markers and adverse perinatal outcomes in pregnancies delivered beyond 34 weeks of gestation. Our principal finding was that low free β-hCG in the first-trimester was associated with significantly lower Apgar scores at both 1 and 5 min in term neonates. In addition, second-trimester analyses revealed that term pregnancies with normal AFP levels were more likely to have lower umbilical cord pH compared to those with elevated AFP, while low AFP was associated with a higher rate of NICU admission. In the late preterm group, uE3 levels showed a strong negative correlation with umbilical cord pH.

Aberrations in both PAPP-A and free β-hCG levels have been widely regarded as indicators of early placental dysfunction [24–26]. However, in a multicenter study, extremely high PAPP-A and free β-hCG levels (> 2.0 MoM) were not associated with a higher prevalence of pregnancy complications [12]. Our study confirms these findings, as we detected no significant differences in fetal weight percentile, FGR, NICU admission, 1- and 5-minute Apgar scores, or umbilical artery pH between groups with high and normal first-trimester MoM values in either late-preterm or term deliveries. The association between low first-trimester free β-hCG and reduced Apgar scores may reflect a suboptimal trophoblastic invasion, leading to a relative placental insufficiency that becomes evident during the stress of labor, impacting fetal oxygenation and vitality at birth.

In the study by Świercz and colleagues, newborns with a 1-minute Apgar score < 8 exhibited significantly lower concentrations of PAPP-A MoM in the first trimester. In another study, PAPP-A < 0.4 MoM in postterm pregnancies was associated with a 5.4-fold increased risk of a 5-minute Apgar score < 7 [27]. Interestingly, however, our analysis did not identify a significant association between PAPP-A levels and Apgar scores; instead, we found that low free β-hCG MoM levels were significantly associated with lower 1- and 5-minute Apgar scores in term infants. Similar associations have been described by Sirikunalai et al., who found that low first-trimester β-hCG levels significantly increased the risk of low Apgar scores [28]. This is partially consistent with the findings of Świercz et al., who also reported an increased NICU admission rate among neonates with low first-trimester free β-hCG concentrations [27]. In contrast, Zizzo et al. observed that in postterm pregnancies, PAPP-A < 0.4 MoM was associated with an adjusted odds ratio of 1.5 for NICU admission [29]. In our cohort, which focused on late-term and term deliveries, no significant association was found between first-trimester free β-hCG or PAPP-A levels and NICU admission. However, we demonstrated a significantly higher rate of NICU admission among cases with low second-trimester AFP levels.

Our first-trimester marker findings are consistent with those of Kirkegaard et al., who similarly found no significant association between low PAPP-A or low free β-hCG and adverse neonatal outcomes—including NICU admission, neonatal hypoglycemia, jaundice, or low Apgar score—in their subgroup analysis of term deliveries [30]. The discrepancy between studies focusing specifically on term pregnancies and those including preterm deliveries suggests that the predictive value of first-trimester biomarkers may be more relevant for preterm or early-onset complications. This highlights the importance of gestational age-specific analysis when evaluating biomarker performance. The available literature indicates a need for further large-scale, prospective studies designed specifically to evaluate the relationship between first-trimester screening markers and perinatal outcomes in term pregnancies, in order to clarify their clinical utility in this population.

In a large prospective cohort, Sovio et al. demonstrated that lower first-trimester PAPP-A levels and elevated AFP were associated with FGR, small-for-gestational-age (SGA) neonates, and preterm birth [31]. In contrast, in our study, neither PAPP-A nor AFP showed significant associations with birth weight, birth weight percentiles, or the development of FGR among late preterm and term pregnancies. This discrepancy may be explained by our exclusion of early preterm deliveries (< 34 weeks), which potentially removed the subgroup at highest risk of growth-related complications. Consistent with our findings, Côté et al. also reported that isolated low PAPP-A should not be considered an independent risk factor for adverse pregnancy outcomes [32]. While elevated second-trimester AFP (> 2.5 MoM) is a well-established marker for placental dysfunction and adverse outcomes [33], the significantly lower umbilical artery pH observed in term infants with normal AFP levels compared to those with elevated AFP in our cohort suggests a complex, non-linear relationship between AFP and fetal acid-base status, potentially indicating that markedly elevated AFP may reflect chronic placental changes that do not acutely precipitate intrapartum acidosis. This counterintuitive finding may reflect residual confounding, chance due to small subgroup size, or a non-linear biological relationship rather than a clinically meaningful effect. Importantly, this isolated observation should be interpreted cautiously and requires confirmation in independent cohorts before any clinical inference can be made.

ROC curve analysis in our cohort demonstrated that an AFP threshold of ≥ 1.075 MoM predicted PPROM with moderate accuracy (AUC 0.723), suggesting that second-trimester AFP may hold value as a predictive marker of membrane rupture risk. In the study by Bartkute et al., elevated maternal serum AFP was associated with adverse outcomes in 26.1% of pregnancies, including fetal malformations, SGA neonates, and intrauterine fetal demise [34]. Similarly, Dai et al. reported that placenta previa, PPROM, advanced maternal age (≥ 35 years) and increased free β-hCG MoM, were significant risk factors for adverse pregnancy outcomes in the elevated AFP group [35].

Our results, showing modest associations, align with meta-analyses that conclude the standalone predictive value of these biomarkers is low [36]. This reinforces that their potential utility lies not in standalone prediction but in contributing to a broader clinical assessment. In clinical practice, extreme biomarker values may warrant heightened awareness and integration with maternal risk factors and routine obstetric surveillance; however, they should not independently alter management strategies in otherwise low-risk late-preterm or term pregnancies. Future research should explore the potential of combining multiple biomarkers with maternal characteristics to develop integrated predictive models for PPROM and other adverse outcomes. Although the predictive capacity of AFP remains preliminary, integration into comprehensive risk stratification models, particularly when combined with maternal characteristics and other clinical parameters, may enhance identification of women at increased risk of obstetric complications. Importantly, the absence of independent predictive value in multivariate models suggests that these serum biomarkers should not be interpreted as causal or standalone prognostic indicators.

Strengths and limitations

The strengths of this study include the use of a clearly defined cohort from a tertiary referral center, the standardized application of both first- and second-trimester screening protocols, and comprehensive follow-up of maternal and neonatal outcomes within a single institution. The relatively large sample size for a single-center study, combined with the exclusion of confounding factors such as multiple gestations and congenital anomalies, enhances the internal validity of our findings.

Nevertheless, several limitations must be acknowledged. The retrospective and single-center design may limit the generalizability of results, particularly across diverse populations and health care systems. Our study is subject to potential selection bias. As a tertiary referral center, a large proportion of patients undergo screening at our clinic but deliver at their local hospitals. Our results are therefore based on the subset of women who delivered at our institution, which may limit the generalizability of our findings. Although the overall sample size exceeded the a priori calculated requirement, some subgroup analyses—particularly those involving rare biomarker categories such as low second-trimester AFP—may remain underpowered. Therefore, these findings should be interpreted cautiously and considered hypothesis-generating rather than definitive.

The exclusion of preterm deliveries before 34 weeks may have eliminated the highest-risk pregnancies, potentially underestimating the true predictive value of the biomarkers for severe placental dysfunction. Additionally, the lack of data on placental pathology, uterine artery Doppler indices, or serial biomarker measurements limited our ability to explore underlying mechanisms or dynamic changes in biomarker levels. Although composite adverse perinatal outcomes are frequently used to increase statistical power, we deliberately chose to analyze individual outcomes separately to avoid masking clinically distinct entities, particularly in a cohort limited to late-preterm and term deliveries. Finally, the use of categorical cut-offs, while clinically practical, may have obscured more subtle dose-response relationships.

Conclusions

In this retrospective cohort of pregnancies delivered beyond 34 weeks, we identified an association between low first-trimester free β-hCG and reduced Apgar scores in term neonates, while second-trimester analyses revealed links between AFP abnormalities and both NICU admission and umbilical cord pH. In contrast, PAPP-A did not demonstrate significant associations with adverse outcomes in late preterm or term deliveries. ROC analysis further suggested that AFP may hold predictive value for PPROM, highlighting a potentially novel role for this marker beyond its conventional applications.

Taken together, these findings suggest that while first- and second-trimester serum markers may reflect placental function, their predictive utility for perinatal outcomes appears limited in term pregnancies. The translational implication is that abnormal biomarker results should not, in isolation, drive clinical management decisions for otherwise low-risk women at term. Future multicenter prospective studies, incorporating biochemical, clinical, and sonographic variables into integrated risk models, are warranted to clarify the clinical value of these screening markers and to improve individualized obstetric care.

Supplementary Information

Supplementary Material 1.^{(155.5KB, pdf)}

Acknowledgements

AcknowledgmentsThe authors would like to thank the staff of the Department of Obstetrics and Gynecology and the Pernatology Clinic at Mersin University Hospital for their support in data collection and patient care. We also extend our gratitude to the medical records department for their assistance in data retrieval.

Abbreviations

AFP: Alpha-fetoprotein
β-hCG: Beta-human chorionic gonadotropin
PAPP-A: Pregnancy-associated plasma protein A
MoM: Multiple of the median
NICU: Neonatal intensive care unit
PPROM: Preterm premature rupture of membranes
FGR: Fetal growth restriction
GA: Gestational age

Authors’ contributions

Şebnem Karagün: Conceptualization, Methodology, Formal Analysis, Investigation, Data Curation, Writing – Original Draft, Writing – Review & Editing, Project Administration.Ahmet Zeki Nessar: Investigation, Resources, Data Curation, Writing – Review & Editing.Hamza Yıldız: Software, Formal Analysis, Visualization, Writing – Review & Editing.Yusuf Dal: Investigation, Methodology, Resources, Validation.Sefanur Gamze Karaca: Investigation, Data Curation, Validation.Ayhan Coşkun: Supervision, Methodology, Writing – Review & Editing.

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 generated and/or analyzed during the current study are not publicly available due to patient privacy and ethical restrictions but are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the principles of the Declaration of Helsinki and relevant national regulations, including the Regulation on Clinical Trials of New Medicinal Products for Human Use (Official Gazette dated 27.05.2023, No. 32203). Ethical approval was obtained from the Institutional Review Board (IRB) of Mersin University Clinical Research Ethics Committee (Decision No: 2024/346). The study was designed as a retrospective cohort study using routinely collected clinical and laboratory data. All data were fully anonymized prior to analysis, and no identifying personal information was accessed or used. In accordance with the above regulation and national legislation, the requirement for obtaining informed consent was reviewed by the Institutional Review Board and deemed unnecessary, given the retrospective nature of the study and the use of anonymized data.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1.van Eekhout JCA, Becking EC, Scheffer PG, Koutsoliakos I, Bax CJ, Henneman L, et al. First-Trimester prediction models based on maternal characteristics for adverse pregnancy outcomes: A systematic review and Meta-Analysis. BJOG. 2025;132(3):243–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Kleinrouweler CE, Cheong-See FM, Collins GS, Kwee A, Thangaratinam S, Khan KS, et al. Prognostic models in obstetrics: available, but Far from applicable. Am J Obstet Gynecol. 2016;214(1):79–e9036. [DOI] [PubMed] [Google Scholar]
3.Meertens L, Smits L, van Kuijk S, Aardenburg R, van Dooren I, Langenveld J, et al. External validation and clinical usefulness of first-trimester prediction models for small- and large-for-gestational-age infants: a prospective cohort study. BJOG. 2019;126(4):472–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Hui D, Okun N, Murphy K, Kingdom J, Uleryk E, Shah PS. Combinations of maternal serum markers to predict preeclampsia, small for gestational age, and stillbirth: a systematic review. J Obstet Gynaecol Can. 2012;34(2):142–53. [DOI] [PubMed] [Google Scholar]
5.Morris RK, Cnossen JS, Langejans M, Robson SC, Kleijnen J, Ter Riet G, et al. Serum screening with down’s syndrome markers to predict pre-eclampsia and small for gestational age: systematic review and meta-analysis. BMC Pregnancy Childbirth. 2008;8:33. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Godbole K, Kulkarni A, Kanade A, Kulkarni S, Godbole G, Wakankar A. Maternal serum aneuploidy screen and adverse pregnancy outcomes. J Obstet Gynaecol India. 2016;66(Suppl 1):141–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Canini S, Prefumo F, Pastorino D, Crocetti L, Afflitto CG, Venturini PL, et al. Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Fertil Steril. 2008;89(1):174–8. [DOI] [PubMed] [Google Scholar]
8.Suciu I, Galeva S, Abdel Azim S, Pop L, Toader O. First-trimester screening-biomarkers and cell-free DNA. J Matern Fetal Neonatal Med. 2021;34(23):3983–9. [DOI] [PubMed] [Google Scholar]
9.Sebire E, Rodrigo CH, Bhattacharya S, Black M, Wood R, Vieira R. The implementation and impact of non-invasive prenatal testing (NIPT) for down’s syndrome into antenatal screening programmes: A systematic review and meta-analysis. PLoS ONE. 2024;19(5):e0298643. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Nshimyumukiza L, Menon S, Hina H, Rousseau F, Reinharz D. Cell-free DNA noninvasive prenatal screening for aneuploidy versus conventional screening: A systematic review of economic evaluations. Clin Genet. 2018;94(1):3–21. [DOI] [PubMed] [Google Scholar]
11.Kantomaa T, Vääräsmäki M, Gissler M, Sairanen M, Nevalainen J. First trimester low maternal serum pregnancy associated plasma protein-A (PAPP-A) as a screening method for adverse pregnancy outcomes. J Perinat Med. 2023;51(4):500–9. [DOI] [PubMed] [Google Scholar]
12.Kosinski P, Frühauf A, Lipa M, Szczepkowska A, Luterek K, Falis M, et al. Clinical consequences of maternal serum PAPP-A and free beta hCG levels above 2.0 multiple of median in the first trimester screening. Eur J Obstet Gynecol Reprod Biol. 2023;282:101–4. [DOI] [PubMed] [Google Scholar]
13.Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. 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;191(4):1446–51. [DOI] [PubMed] [Google Scholar]
14.Halscott TL, Ramsey PS, Reddy UM. First trimester screening cannot predict adverse outcomes yet. Prenat Diagn. 2014;34(7):668–76. [DOI] [PubMed] [Google Scholar]
15.Screening for Fetal Chromosomal Abnormalities. ACOG practice Bulletin, number 226. Obstet Gynecol. 2020;136(4):e48–69. [DOI] [PubMed] [Google Scholar]
16.Genc S, Ozer H, Emeklioglu CN, Cingillioglu B, Sahin O, Akturk E, et al. Relationship between extreme values of first trimester maternal pregnancy associated plasma Protein-A, free-β-human chorionic gonadotropin, nuchal translucency and adverse pregnancy outcomes. Taiwan J Obstet Gynecol. 2022;61(3):433–40. [DOI] [PubMed] [Google Scholar]
17.Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr-Urtreger A. Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome. Prenat Diagn. 2002;22(9):778–82. [DOI] [PubMed] [Google Scholar]
18.Bilardo CM, Chaoui R, Hyett JA, Kagan KO, Karim JN, Papageorghiou AT, et al. ISUOG practice guidelines (updated): performance of 11-14-week ultrasound scan. Ultrasound Obstet Gynecol. 2023;61(1):127–43. [DOI] [PubMed] [Google Scholar]
19.Salomon LJ, Alfirevic Z, Berghella V, Bilardo CM, Chalouhi GE, Da Silva Costa F, et al. ISUOG practice guidelines (updated): performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol. 2022;59(6):840–56. [DOI] [PubMed] [Google Scholar]
20.Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet Gynecol. 2014 Apr;123(4):896-901.10.1097/01.AOG.0000445580.65983.d2. [DOI] [PubMed]
21.Martins JG, Biggio JR, Abuhamad A. Society for Maternal-Fetal medicine consult series #52: diagnosis and management of fetal growth restriction: (Replaces clinical guideline number 3, April 2012). Am J Obstet Gynecol. 2020;223(4):B2–17. [DOI] [PubMed] [Google Scholar]
22.Ronzoni S, Boucoiran I, Yudin MH, Coolen J, Pylypjuk C, Melamed N, et al. Guideline 430: diagnosis and management of preterm prelabour rupture of membranes. J Obstet Gynaecol Can. 2022;44(11):1193–e2081. [DOI] [PubMed] [Google Scholar]
23.Alizadeh-Dibazari Z, Alizadeh-Ghodsi Z, Fathnezhad-Kazemi A. Association between serum markers used in the routine prenatal screening with pregnancy outcomes: A cohort study. J Obstet Gynaecol India. 2022;72(Suppl 1):6–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Cignini P, Maggio Savasta L, Gulino FA, Vitale SG, Mangiafico L, Mesoraca A, et al. Predictive value of pregnancy-associated plasma protein-A (PAPP-A) and free beta-hCG on fetal growth restriction: results of a prospective study. Arch Gynecol Obstet. 2016;293(6):1227–33. [DOI] [PubMed] [Google Scholar]
25.Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, et al. 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;191(4):1452–8. [DOI] [PubMed] [Google Scholar]
26.Sruthi RS, Sarita P, Marandi S, Nayak S, Pati T. Early trimester maternal serum β-hCG and PAPP-A levels as predictor of hypertensive disorders of pregnancy. J Obstet Gynaecol India. 2024;74(3):231–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Swiercz G, Zmelonek-Znamirowska A, Szwabowicz K, Armanska J, Detka K, Mlodawska M, et al. Navigating Uncertain Waters: First-Trimester Screening's Role in Identifying Neonatal Complications. J Clin Med. 2024 Mar 29;13(7):1982. 10.3390/jcm13071982. [DOI] [PMC free article] [PubMed]
28.Sirikunalai P, Wanapirak C, Sirichotiyakul S, Tongprasert F, Srisupundit K, Luewan S, et al. Associations between maternal serum free beta human chorionic gonadotropin (β-hCG) levels and adverse pregnancy outcomes. J Obstet Gynaecol. 2016;36(2):178–82. [DOI] [PubMed] [Google Scholar]
29.Zizzo AR, Kirkegaard I, Henriksen TB, Ulbjerg N. Pregnancy-associated plasma protein A levels and neonatal complications in post-date pregnancies. Prenat Diagn. 2013;33(10):965–72. [DOI] [PubMed] [Google Scholar]
30.Kirkegaard I, Uldbjerg N, Henriksen TB. PAPP-A and free β-hCG in relation to admission to neonatal intensive care unit and neonatal disease. Prenat Diagn. 2011;31(12):1169–75. [DOI] [PubMed] [Google Scholar]
31.Sovio U, Gaccioli F, Cook E, Charnock-Jones DS, Smith GCS. Association between adverse pregnancy outcome and placental biomarkers in the first trimester: A prospective cohort study. BJOG. 2024;131(6):823–31. [DOI] [PubMed] [Google Scholar]
32.Côté ML, Giguère Y, Forest JC, Audibert F, Johnson JA, Okun N, et al. First-Trimester PlGF and PAPP-A and the risk of Placenta-Mediated complications: PREDICTION prospective study. J Obstet Gynaecol Can. 2025;47(2):102732. [DOI] [PubMed] [Google Scholar]
33.Gagnon A, Wilson RD. Obstetrical complications associated with abnormal maternal serum markers analytes. J Obstet Gynaecol Can. 2008;30(10):918–32. [DOI] [PubMed] [Google Scholar]
34.Bartkute K, Balsyte D, Wisser J, Kurmanavicius J. Pregnancy outcomes regarding maternal serum AFP value in second trimester screening. J Perinat Med. 2017;45(7):817–20. [DOI] [PubMed] [Google Scholar]
35.Dai X, Zhang H, Wu B, Ning W, Chen Y, Chen Y. Correlation between elevated maternal serum alpha-fetoprotein and ischemic placental disease: a retrospective cohort study. Clin Exp Hypertens. 2023;45(1):2175848. [DOI] [PubMed] [Google Scholar]
36.Morris RK, Bilagi A, Devani P, Kilby MD. Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis. Prenat Diagn. 2017;37(3):253–65. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1.^{(155.5KB, pdf)}

Data Availability Statement

[CR1] 1.van Eekhout JCA, Becking EC, Scheffer PG, Koutsoliakos I, Bax CJ, Henneman L, et al. First-Trimester prediction models based on maternal characteristics for adverse pregnancy outcomes: A systematic review and Meta-Analysis. BJOG. 2025;132(3):243–65. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR2] 2.Kleinrouweler CE, Cheong-See FM, Collins GS, Kwee A, Thangaratinam S, Khan KS, et al. Prognostic models in obstetrics: available, but Far from applicable. Am J Obstet Gynecol. 2016;214(1):79–e9036. [DOI] [PubMed] [Google Scholar]

[CR3] 3.Meertens L, Smits L, van Kuijk S, Aardenburg R, van Dooren I, Langenveld J, et al. External validation and clinical usefulness of first-trimester prediction models for small- and large-for-gestational-age infants: a prospective cohort study. BJOG. 2019;126(4):472–84. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR4] 4.Hui D, Okun N, Murphy K, Kingdom J, Uleryk E, Shah PS. Combinations of maternal serum markers to predict preeclampsia, small for gestational age, and stillbirth: a systematic review. J Obstet Gynaecol Can. 2012;34(2):142–53. [DOI] [PubMed] [Google Scholar]

[CR5] 5.Morris RK, Cnossen JS, Langejans M, Robson SC, Kleijnen J, Ter Riet G, et al. Serum screening with down’s syndrome markers to predict pre-eclampsia and small for gestational age: systematic review and meta-analysis. BMC Pregnancy Childbirth. 2008;8:33. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR6] 6.Godbole K, Kulkarni A, Kanade A, Kulkarni S, Godbole G, Wakankar A. Maternal serum aneuploidy screen and adverse pregnancy outcomes. J Obstet Gynaecol India. 2016;66(Suppl 1):141–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR7] 7.Canini S, Prefumo F, Pastorino D, Crocetti L, Afflitto CG, Venturini PL, et al. Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Fertil Steril. 2008;89(1):174–8. [DOI] [PubMed] [Google Scholar]

[CR8] 8.Suciu I, Galeva S, Abdel Azim S, Pop L, Toader O. First-trimester screening-biomarkers and cell-free DNA. J Matern Fetal Neonatal Med. 2021;34(23):3983–9. [DOI] [PubMed] [Google Scholar]

[CR9] 9.Sebire E, Rodrigo CH, Bhattacharya S, Black M, Wood R, Vieira R. The implementation and impact of non-invasive prenatal testing (NIPT) for down’s syndrome into antenatal screening programmes: A systematic review and meta-analysis. PLoS ONE. 2024;19(5):e0298643. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR10] 10.Nshimyumukiza L, Menon S, Hina H, Rousseau F, Reinharz D. Cell-free DNA noninvasive prenatal screening for aneuploidy versus conventional screening: A systematic review of economic evaluations. Clin Genet. 2018;94(1):3–21. [DOI] [PubMed] [Google Scholar]

[CR11] 11.Kantomaa T, Vääräsmäki M, Gissler M, Sairanen M, Nevalainen J. First trimester low maternal serum pregnancy associated plasma protein-A (PAPP-A) as a screening method for adverse pregnancy outcomes. J Perinat Med. 2023;51(4):500–9. [DOI] [PubMed] [Google Scholar]

[CR12] 12.Kosinski P, Frühauf A, Lipa M, Szczepkowska A, Luterek K, Falis M, et al. Clinical consequences of maternal serum PAPP-A and free beta hCG levels above 2.0 multiple of median in the first trimester screening. Eur J Obstet Gynecol Reprod Biol. 2023;282:101–4. [DOI] [PubMed] [Google Scholar]

[CR13] 13.Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. 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;191(4):1446–51. [DOI] [PubMed] [Google Scholar]

[CR14] 14.Halscott TL, Ramsey PS, Reddy UM. First trimester screening cannot predict adverse outcomes yet. Prenat Diagn. 2014;34(7):668–76. [DOI] [PubMed] [Google Scholar]

[CR15] 15.Screening for Fetal Chromosomal Abnormalities. ACOG practice Bulletin, number 226. Obstet Gynecol. 2020;136(4):e48–69. [DOI] [PubMed] [Google Scholar]

[CR16] 16.Genc S, Ozer H, Emeklioglu CN, Cingillioglu B, Sahin O, Akturk E, et al. Relationship between extreme values of first trimester maternal pregnancy associated plasma Protein-A, free-β-human chorionic gonadotropin, nuchal translucency and adverse pregnancy outcomes. Taiwan J Obstet Gynecol. 2022;61(3):433–40. [DOI] [PubMed] [Google Scholar]

[CR17] 17.Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr-Urtreger A. Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome. Prenat Diagn. 2002;22(9):778–82. [DOI] [PubMed] [Google Scholar]

[CR18] 18.Bilardo CM, Chaoui R, Hyett JA, Kagan KO, Karim JN, Papageorghiou AT, et al. ISUOG practice guidelines (updated): performance of 11-14-week ultrasound scan. Ultrasound Obstet Gynecol. 2023;61(1):127–43. [DOI] [PubMed] [Google Scholar]

[CR19] 19.Salomon LJ, Alfirevic Z, Berghella V, Bilardo CM, Chalouhi GE, Da Silva Costa F, et al. ISUOG practice guidelines (updated): performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol. 2022;59(6):840–56. [DOI] [PubMed] [Google Scholar]

[CR20] 20.Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. Obstet Gynecol. 2014 Apr;123(4):896-901.10.1097/01.AOG.0000445580.65983.d2. [DOI] [PubMed]

[CR21] 21.Martins JG, Biggio JR, Abuhamad A. Society for Maternal-Fetal medicine consult series #52: diagnosis and management of fetal growth restriction: (Replaces clinical guideline number 3, April 2012). Am J Obstet Gynecol. 2020;223(4):B2–17. [DOI] [PubMed] [Google Scholar]

[CR22] 22.Ronzoni S, Boucoiran I, Yudin MH, Coolen J, Pylypjuk C, Melamed N, et al. Guideline 430: diagnosis and management of preterm prelabour rupture of membranes. J Obstet Gynaecol Can. 2022;44(11):1193–e2081. [DOI] [PubMed] [Google Scholar]

[CR23] 23.Alizadeh-Dibazari Z, Alizadeh-Ghodsi Z, Fathnezhad-Kazemi A. Association between serum markers used in the routine prenatal screening with pregnancy outcomes: A cohort study. J Obstet Gynaecol India. 2022;72(Suppl 1):6–18. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR24] 24.Cignini P, Maggio Savasta L, Gulino FA, Vitale SG, Mangiafico L, Mesoraca A, et al. Predictive value of pregnancy-associated plasma protein-A (PAPP-A) and free beta-hCG on fetal growth restriction: results of a prospective study. Arch Gynecol Obstet. 2016;293(6):1227–33. [DOI] [PubMed] [Google Scholar]

[CR25] 25.Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, et al. 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;191(4):1452–8. [DOI] [PubMed] [Google Scholar]

[CR26] 26.Sruthi RS, Sarita P, Marandi S, Nayak S, Pati T. Early trimester maternal serum β-hCG and PAPP-A levels as predictor of hypertensive disorders of pregnancy. J Obstet Gynaecol India. 2024;74(3):231–5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR27] 27.Swiercz G, Zmelonek-Znamirowska A, Szwabowicz K, Armanska J, Detka K, Mlodawska M, et al. Navigating Uncertain Waters: First-Trimester Screening's Role in Identifying Neonatal Complications. J Clin Med. 2024 Mar 29;13(7):1982. 10.3390/jcm13071982. [DOI] [PMC free article] [PubMed]

[CR28] 28.Sirikunalai P, Wanapirak C, Sirichotiyakul S, Tongprasert F, Srisupundit K, Luewan S, et al. Associations between maternal serum free beta human chorionic gonadotropin (β-hCG) levels and adverse pregnancy outcomes. J Obstet Gynaecol. 2016;36(2):178–82. [DOI] [PubMed] [Google Scholar]

[CR29] 29.Zizzo AR, Kirkegaard I, Henriksen TB, Ulbjerg N. Pregnancy-associated plasma protein A levels and neonatal complications in post-date pregnancies. Prenat Diagn. 2013;33(10):965–72. [DOI] [PubMed] [Google Scholar]

[CR30] 30.Kirkegaard I, Uldbjerg N, Henriksen TB. PAPP-A and free β-hCG in relation to admission to neonatal intensive care unit and neonatal disease. Prenat Diagn. 2011;31(12):1169–75. [DOI] [PubMed] [Google Scholar]

[CR31] 31.Sovio U, Gaccioli F, Cook E, Charnock-Jones DS, Smith GCS. Association between adverse pregnancy outcome and placental biomarkers in the first trimester: A prospective cohort study. BJOG. 2024;131(6):823–31. [DOI] [PubMed] [Google Scholar]

[CR32] 32.Côté ML, Giguère Y, Forest JC, Audibert F, Johnson JA, Okun N, et al. First-Trimester PlGF and PAPP-A and the risk of Placenta-Mediated complications: PREDICTION prospective study. J Obstet Gynaecol Can. 2025;47(2):102732. [DOI] [PubMed] [Google Scholar]

[CR33] 33.Gagnon A, Wilson RD. Obstetrical complications associated with abnormal maternal serum markers analytes. J Obstet Gynaecol Can. 2008;30(10):918–32. [DOI] [PubMed] [Google Scholar]

[CR34] 34.Bartkute K, Balsyte D, Wisser J, Kurmanavicius J. Pregnancy outcomes regarding maternal serum AFP value in second trimester screening. J Perinat Med. 2017;45(7):817–20. [DOI] [PubMed] [Google Scholar]

[CR35] 35.Dai X, Zhang H, Wu B, Ning W, Chen Y, Chen Y. Correlation between elevated maternal serum alpha-fetoprotein and ischemic placental disease: a retrospective cohort study. Clin Exp Hypertens. 2023;45(1):2175848. [DOI] [PubMed] [Google Scholar]

[CR36] 36.Morris RK, Bilagi A, Devani P, Kilby MD. Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis. Prenat Diagn. 2017;37(3):253–65. [DOI] [PubMed] [Google Scholar]

PERMALINK

The association of first and second-trimester serum biomarkers with adverse perinatal outcomes in late-preterm and term deliveries: a retrospective cohort study

Şebnem Karagün

Ahmet Zeki Nessar

Hamza Yıldız

Yusuf Dal

Sefanur Gamze Karaca

Ayhan Coşkun

Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Introduction

Materials and methods

Study design and population

Outcome data

Definition of perinatal outcomes

Statistical analysis

Results

Fig. 1.

Table 1.

Table 2.

Fig. 2.

Discussion

Strengths and limitations

Conclusions

Supplementary Information

Acknowledgements

Abbreviations

Authors’ contributions

Funding

Data availability

Declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Footnotes

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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