Low PAPPA and Its Association with Adverse Pregnancy Outcomes in Twin Pregnancies: A Systematic Review of the...

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.