Background: It is well established in the literature that pregnancy-associated plasma protein-A (PAPP-A) is linked to several adverse pregnancy outcomes, including pre-eclampsia (PE), fetal growth restriction (FGR), and preterm birth (PTB) in singleton pregnancies. However, data regarding such an association in twin pregnancies are lacking. The primary goal of this systematic review and meta-analysis was to assess the potential value of low PAPP-A levels in the prediction of the subsequent development of hypertensive disorders of pregnancy (HDPs), PTB, and small for gestational age (SGA)/FGR fetuses in twin pregnancies and investigate its association with the development of gestational diabetes, intrauterine death (IUD) of at least one twin, and birth weight discordance (BWD) among the fetuses. Methods: Medline, Scopus, CENTRAL, Clinicaltrials.gov, and Google Scholar databases were systematically searched from inception until 31 July 2024. All observational studies reporting low PAPP-A levels after the performance of the first-trimester combined test as part of the screening for chromosomal abnormalities with reported adverse pregnancy outcomes were included. Results: The current systematic review encompassed a total of 11 studies (among which 6 were included in the current meta-analysis) that enrolled a total of 3741 patients. Low PAPP-A levels were not associated with HDPs (OR 1.25, 95% CI 0.78, 2.02, I-square test: 13%). Low PAPP-A levels were positively associated with both the development of preterm birth prior to 32 (OR 2.85, 95% CI 1.70, 4.77, I-square test: 0%) and 34 weeks of gestational age (OR 2.09, 95% CI 1.34, 3.28, I-square test: 0%). Furthermore, low PAPP-A levels were positively associated with SGA/FGR (OR 1.58, 95% CI 1.04, 2.41, I-square test: 0%). Prediction intervals indicated that the sample size that was used did not suffice to support these findings in future studies. Conclusions: Our study indicated that low PAPP-A levels are correlated with an increased incidence of adverse perinatal outcomes in twin pregnancies. Identifying women at elevated risk for such adversities in twin pregnancies may facilitate appropriate management and potential interventions, but additional studies are required to identify the underlying mechanism linking PAPP-A with those obstetrical complications.

Background/Objectives: It is well established in the modern literature that newborns delivered from multiple gestations are more predisposed to low birthweight in comparison to their singleton equivalents. In this study, we sought to explore the potential of first-trimester biochemical (PAPP-A and free β-hCG) and biophysical indices (uterine artery Doppler) to predict low birthweight in one or both twins. Methods: This is a retrospective cohort analysis of 400 twin viable pregnancies presenting for routine first-trimester assessment in four fetal medicine centers between 2014 and 2025. The examination included the recording of maternal demographic characteristics and medical history, the assessment of markers of aneuploidy and the fetal anatomy, the measurement of mean arterial pressure, the assessment of uterine arteries and the measurement of serum concentration of PAPP-A and free β-hCG. The evaluated outcomes included BW ≤ 3rd centile and BW ≤ 10th centile in one or both twins based on local population birthweight reference charts. Results: The study cohort consisted of 400 twin pregnancies. BW ≤ 3rd centile in one or both twins was reported in 1.5 and 3.8% of cases, respectively, and there was no association of BW ≤ 3rd centile with any of the studied parameters. BW ≤ 10th centile in one or both twins was reported in 14.8 and 9.8% of the cases, respectively. PAPP-A MoM values were significantly lower in cases complicated by BW ≤ 10th centile in one and in both twins, remaining statistically significant even after the appropriate multiple logistic regression. PAPP-A MoM demonstrated statistically significant but low prognostic value for BW ≤ 10th centile in either one or both twins. Conclusions: Low PAPP-A levels were associated with BW ≤ 10th centile in one and both twins and its significant value as a risk marker was demonstrated. Higher PAPP-A MoM halves the risk of having at least one twin with low BW. Other maternal biophysical and biochemical indices did not seem to be predictive of low birthweight.