First trimester prenatal screening biomarkers and gestational diabetes mellitus: A systematic review and meta-analysis

Biomarkers commonly assessed in prenatal screening have been associated with a number of adverse perinatal and birth outcomes. However, it is not clear whether first trimester measurements of prenatal screening biomarkers are associated with subsequent risk of gestational diabetes mellitus (GDM). We aimed to systematically review and statistically summarize studies assessing the relationship between first trimester prenatal screening biomarker levels and GDM development. We comprehensively searched PubMed/MEDLINE, EMBASE, CINAHL, and Scopus (from inception through January 2018) and manually searched the reference lists of all relevant articles. We included original, published, observational studies examining the association of first trimester pregnancy associated plasma protein- A (PAPP-A) and/or free beta-human chorionic gonadotropin (free beta-hCG) levels with GDM diagnosis. Mean differences were calculated comparing PAPP-A and free beta-hCG multiples of median (MoM) levels between women who developed GDM and those who did not and were subsequently pooled using two-sided random-effects models. Our meta-analysis of 13 studies on PAPP-A and nine studies on free beta-hCG indicated that first trimester MoM levels for both biomarkers were lower in women who later developed GDM compared to women who remained normoglycemic throughout pregnancy (MD -0.17; 95% CI -0.24, -0.10; MD -0.04; 95% CI -0.07 +/- 0.01). There was no evidence for between-study heterogeneity among studies on free beta-hCG (I-2 = 0%). A high level of between-study heterogeneity was detected among the studies reporting on PAPP-A (I-2 = 90%), but was reduced after stratifying by geographic location, biomarker assay method, and timing of GDM diagnosis. Our meta-analysis indicates that women who are diagnosed with GDM have lower first trimester levels of both PAPP-A and free beta-hCG than women who remain normoglycemic throughout pregnancy. Further assessment of the predictive capacity of these biomarkers within large, diverse populations is needed.