Placental protein levels in maternal serum are associated with adverse pregnancy outcomes in nulliparous patients

Abstract

Background The NICHD Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) was established to investigate the underlying causes and pathophysiologic pathways associated with adverse pregnancy outcomes in nulliparous gravidas. Objective Our objectives were to study placental physiology and identify novel biomarkers in relation to adverse pregnancy outcomes, including preterm birth (medically-indicated and spontaneous), preeclampsia, small for gestational age (SGA) neonates, and stillbirth. We measured levels of placental proteins in the maternal circulation in the first two trimesters of pregnancy. Materials and Methods Maternal serum samples were collected at two study visits (6-13 weeks and 16-21 weeks), and levels of nine analytes were measured. The analytes we measured were vascular endothelial growth factor (VEGF), placental growth factor (PlGF), endoglin (Eng), soluble fms-like tyrosine kinase-1 (sFlt-1), A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A), free β human chorionic gonadotropin (βhCG), inhibin A, and alpha-fetoprotein (AFP). The primary outcome was preterm birth between 20 weeks 0 days and 36 weeks 6 days gestation. Secondary outcomes were spontaneous preterm births, medically-indicated preterm births, preeclampsia, SGA neonates, and stillbirth. Results A total of 10,038 eligible gravidas were enrolled into the nuMoM2b cohort, from which a nested case-control study was performed comparing 800 cases with preterm birth (466 spontaneous preterm births, 330 medically-indicated preterm births, and 4 unclassified preterm births), 568 with preeclampsia, 406 with SGA birth, and 49 with stillbirth, with 911 controls who delivered at term without complications. Although levels of each analyte generally differed between cases and controls at one or both visits, the odds ratios revealed a less than two-fold difference between cases and controls in all comparisons. Receiver operating characteristic curves, generated to determine the relationship between analyte levels and preterm birth and the other adverse pregnancy outcomes, resulted in areas under the curves (AUCs) that were relatively low (range 0.50-0.64) for each analyte. Logistic regression modeling demonstrated that AUCs for predicting adverse pregnancy outcomes were greater using baseline clinical characteristics and combinations of analytes compared to baseline characteristics alone, but AUCs remained relatively low for each outcome (0.65-0.78). Conclusion We have found significant associations between maternal serum levels of analytes evaluated early in pregnancy and subsequent adverse pregnancy outcomes in nulliparous gravidas. However, the test characteristics for these analytes do not support their use as clinical biomarkers to predict adverse pregnancy outcomes, either alone or in combination with maternal clinical characteristics.