First-trimester maternal serum PAPP-A levels and hyperemesis gravidarum: unraveling the link – a meta-analysis

Objectives Hyperemesis gravidarum is a severe form of nausea and vomiting that affects approximately 0.3–2 % of pregnancies, leading to significant perinatal complications. This systematic review and meta-analysis aims to investigate the potential link between hyperemesis gravidarum and maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels in the first trimester. Methods A thorough literature search of PubMed/MEDLINE, ScienceDirect, the Cochrane Library, and Google Scholar was conducted to identify relevant studies comparing PAPP-A levels in pregnant women diagnosed with hyperemesis gravidarum compared to healthy controls. Six studies met the inclusion criteria, with a total of 1,049 participants. Meta-analysis was performed to estimate the pooled mean difference in PAPP-A levels between hyperemesis gravidarum and control groups. A p-curve analysis and funnel plot assessment were conducted to evaluate publication bias and statistical power. Results The meta-analysis demonstrated a pooled mean difference of 0.16 (95 % CI: 0.07–0.25), indicating that PAPP-A levels were significantly higher in pregnancies affected by HG. The heterogeneity statistic (I 2 =46 %) suggested moderate variability among studies. P-curve analysis showed a right-skewed distribution of significant p-values (p=0.033), suggesting evidential value and ruling out selective reporting bias. However, the prediction interval (−0.08–0.4) indicated that some future studies might yield non-significant or even negative findings. Funnel plot analysis revealed minimal publication bias, though a slight asymmetry suggested potential underrepresentation of small, non-significant studies. Conclusions This study provides evidence that PAPP-A levels are elevated in pregnancies complicated by hyperemesis gravidarum, implicating potential placental dysfunction and hormonal influences in its pathogenesis. While the findings are statistically significant and robust against publication bias, moderate heterogeneity highlights the need for larger prospective studies with standardized methodologies to confirm this association and explore possible underlying mechanisms. Understanding the role of PAPP-A in hyperemesis gravidarum may contribute to improved screening and management strategies for affected pregnancies and as a result, improved perinatal care.