Evidence of placental hemorrhage: Relations with preterm delivery, polymorphisms in vascular function genes, and intrauterine infection

Bleeding has been identified as a major etiologic pathway to preterm delivery (PTD). We hypothesized that placental abruption may be an extreme manifestation of this pathway, while early pregnancy vaginal bleeding and placental pathology findings may identify early or subclinical manifestations, respectively. We aimed (1) to evaluate multiple indicators of placental hemorrhage as potential components of a common bleeding pathway, (2) to assess the associations between maternal gene polymorphisms in thrombophilia and renin-angiotensin system pathways and PTD subtypes defined by evidence of placental hemorrhage, and (3) to evaluate risk of histologic chorioamnionitis and clinical chorioamnionitis in relation to early and late evidence of placental hemorrhage.;A subcohort (N=1371) of pregnant women were recruited at midtrimester (15-27 weeks' gestation) as part of a prospective cohort study (1998-2004). Data were ascertained by interviews conducted at enrollment, detailed medical chart abstraction, maternal blood assays and placental pathology examinations. We analyzed data on 996 black or white subcohort women who had complete placenta data and did not have placenta previa. Data on functional polymorphisms in candidate genes (methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, Factor V G1691A (Leiden, FVL), and angiotensinogen (AGT) G-6A) were available on 959 of these women. Information derived from the gross and microscopic placental examinations included histologic chorioamnionitis, disc-impacting blood dots, and Maternal Vascular - Disturbance of Integrity (MV-I) scores. Four manifestations of placental hemorrhage, i.e. placental abruption, disc-impacting blood dots, top quintile of MV-I scores, and first trimester bleeding, differed in their associations with some maternal characteristics and were not highly concordant with one another. Subclinical evidence of placental hemorrhage identified through placental pathology exams was associated with increased odds of PTD, particularly PTD at <35 weeks, after accounting for clinically evident bleeding in a multivariable model. Women who were heterozygous for FVL or the AGT-6 A allele were at increased risk of PTD with evidence of placental hemorrhage, whereas they were not at increased risk of PTD without evidence of placental hemorrhage. Placental abruption and disc-impacting blood dots were associated with clinical chorioamnionitis, while bleeding in the first and second trimesters was associated with the histologic chorioamnionitis, although there was evidence of an interaction with delivery timing for histologic chorioamnionitis.;Multiple clinical and subclinical indicators of placental hemorrhage are related to PTD. However, because associations with maternal characteristics, gene polymorphisms, and intrauterine infection differed among measures of placental hemorrhage we conclude that heterogeneity exists even within the "bleeding pathway." PTD may be marked by early or late bleeding for a number of reasons. Greater insight into bleeding-related pathways may be achieved by incorporating information on subclinical hemorrhage.