Agnostic identification of plasma biomarkers for postpartum hemorrhage risk.

BACKGROUND: Postpartum hemorrhage (PPH) is difficult to predict, is associated with significant maternal morbidity, and is the leading cause of maternal mortality worldwide. The identification of maternal biomarkers that can predict increased PPH risk would enhance clinical care and may uncover mechanisms that lead to PPH. OBJECTIVE: This retrospective case-control study employed agnostic proteomic profiling of maternal plasma samples to identify differentially abundant proteins in controls and PPH cases. STUDY DESIGN: Maternal plasma samples were procured from a cohort of >60,000 participants in a single institution's perinatal repository. PPH was defined as a decrease in hematocrit of ≥10% or receipt of transfusion within 24 hours of delivery. PPH cases (N=30) were matched by maternal age and delivery mode (vaginal or cesarean) with controls (N=56). Mass spectrometry was used to identify differentially abundant proteins using integrated peptide peak areas. Statistically significant differences between groups were defined by a p-value of <0.05 after controlling for multiple comparisons. RESULTS: By study design, cases and controls did not differ in race, ethnicity, gestational age at delivery, blood type, or pre-delivery platelet count. Cases had slightly, but significantly lower pre- and post-delivery hematocrit and hemoglobin. Mass spectrometry detected 1140 proteins, including 77 proteins for which relative abundance differed significantly between cases and controls (fold change >1.15, P<0.05). Of these differentially abundant plasma proteins, most had likely liver or placental origins. Gene ontology term analysis mapped to protein clusters involved in responses to wound healing, stress response, and host immune defense. Significantly differentially abundant proteins with the highest fold change (prostaglandin D2 synthase, periostin, and several serine protease inhibitors) did not correlate with pre-delivery hematocrit or hemoglobin, but identified PPH cases with logistic regression modeling revealing good-to-excellent area under the operator receiver characteristic curves (AUROC 0.802-0.874). Incorporating pre-delivery hemoglobin with these candidate proteins further improved identification of PPH cases. CONCLUSION: Agnostic analysis of maternal plasma samples identified differentially abundant proteins in controls and PPH cases. Several of these proteins are known to participate in biologically plausible pathways for PPH risk and have potential value for predicting PPH. These findings identify candidate protein biomarkers for future validation and mechanistic studies.

Fetal sex and the development of gestational diabetes mellitus in gravidae with multiple gestation pregnancies.

INTRODUCTION: There is an increasing incidence of pregnancies with twin gestations. One outcome more likely to occur with multiple gestations is gestational diabetes mellitus. Studies have suggested that in singleton pregnancies, fetal sex may affect insulin resistance. However, the effects of fetal sex in twins and the development of gestational diabetes mellitus are unknown. We hypothesized that rates of gestational diabetes mellitus and degree of insulin resistance might vary in twin gestations based on the fetal sex pairing: male-male, male-female or female-female. We aimed to employ a large population-based database to ascertain any correlations between fetal sex and gestational diabetes mellitus in multifetal gestations. MATERIAL AND METHODS: A two-hospital, single academic institution database comprised of over 39 000 participants with pregnancy data from August 2011 to January 2022 was employed. All twin deliveries of live-born neonates >24 weeks' gestational age from gravidae without preexisting diabetes or twin-twin transfusion syndrome were included. Entries were then grouped based on the fetal sex of the pairing. The presence or absence of gestational diabetes and type of gestational diabetes - diet-controlled (gestational diabetes mellitus classification A1) vs medication-controlled (gestational diabetes mellitus classification A2) - were identified. Statistical analysis was performed using a generalized linear mixed method, and a P-value ≤0.05 was considered statistically significant. RESULTS: We identified 1924 twin deliveries that met the inclusion criteria in our database (male-male =652; male-female = 638; female-female = 634). We found no association between fetal sex pairing and the development of gestational diabetes mellitus. There was a significant association between the fetal sex pairing and the type of gestational diabetes mellitus developed, with 32.0% of male-male twins, 33.3% of male-female twins and 58.3% of the female-female twin deliveries associated with medication-controlled gestational diabetes classification A2: male-female vs female-female (P = 0.05) and male-male vs female-female (P = 0.046). CONCLUSIONS: While gestational diabetes mellitus is of multifactorial origin, we found a significant association between the fetal sex pairing and the treatment needed for gravidae with twins who develop gestational diabetes mellitus. A higher proportion of female-female twins was associated with gestational diabetes classification A2 compared with male-female or male-male deliveries. Further research on the physiology driving this association is warranted.

Fetal sex and the development of gestational diabetes mellitus in polycystic ovarian syndrome gravidae.

BACKGROUND: Polycystic ovarian syndrome is characterized by elevated androgens and is a well-known risk factor for the occurrence of gestational diabetes mellitus. Androgens (particularly dehydroepiandrosterone-sulfate) are crucial for the development and characteristics of the male reproductive tract during fetal life, and fetal dehydroepiandrosterone-sulfate enters the placenta where it is metabolized and functions as an estrogen substrate. Given this unique sex-specific relationship with androgens and the association of serum dehydroepiandrosterone-sulfate concentration with insulin resistance, we hypothesized that metabolic comorbidities in pregnancy might differ by fetal sex in gravidae with polycystic ovarian syndrome, notably in those with infertility. OBJECTIVE: This study aimed to evaluate the data in a large population-based database to explore if fetal sex was significantly associated with gestational diabetes mellitus in gravidae with infertility and polycystic ovarian syndrome after controlling for confounders. STUDY DESIGN: This study was designed to evaluate the risk for the occurrence and rates of gestational diabetes mellitus among gravidae with infertility and a history of polycystic ovarian syndrome. We used a 2-hospital, single academic institution database comprising more than 30,000 subjects enrolled from September 2011 to June 2021 to identify all gravidae with diagnoses of infertility and polycystic ovarian syndrome at the time of delivery and to compare them with gravidae who lacked these comorbidities. Data on covariates, including but not limited to maternal age, body mass index, fetal sex, race, ethnicity, presence or absence of hypertensive disease, and presence or absence of gestational diabetes were identified. Unadjusted and adjusted odds rations were calculated. RESULTS: We found a statistically significant association between fetal female sex and the development of gestational diabetes mellitus in gravidae with polycystic ovarian syndrome (odds ratio for female vs male, 2.13; 95% confidence interval, 1.06-4.32; P=.03). After adjusting for potential confounders identified in our univariate analyses, there continued to be a statistically significant association between female fetuses and the development of gestational diabetes mellitus (adjusted odds ratio for female vs male, 2.10; 95% confidence interval, 1.04-4.41; P=.04). In contrast, there was no significant association between fetal sex and the development of gestational diabetes mellitus in our similar analysis of gravidae without infertility and polycystic ovarian syndrome (P=.99). CONCLUSION: Although the origin of gestational diabetes mellitus is multifactorial, we found that female fetal sex is associated with gestational diabetes mellitus in gravidae with infertility and polycystic ovarian syndrome but not in their comparative controls. Further research on the molecular mechanisms driving the association between female fetuses and the development of gestational diabetes mellitus in the context of maternal polycystic ovarian syndrome is warranted.

Crucial nuances in understanding (mis)associations between the neonatal microbiome and Cesarean delivery.

As rates of Cesarean delivery and common non-communicable disorders (NCDs), such as obesity, metabolic disease, and atopy/asthma, have concomitantly increased in recent decades, investigators have attempted to discern a causal link. One line of research has led to a hypothesis that Cesarean birth disrupts the presumed normal process of colonization of the neonatal microbiome with vaginal microbes, yielding NCDs later in life. However, a direct link between a disrupted microbiota transfer at time of delivery and acute and/or chronic illness in infants born via Cesarean has not been causally established. Microbiota seeding from maternal vaginal or stool sources has been preliminarily evaluated as an intervention designed to compensate for the lack of (or limited) exposure to such sources among Cesarean-delivered neonates. However, to date, clinical trials have yet to show a clear health benefit with neonatal 'vaginal seeding' practices. Until the long-term effects of these microbiome alterations can be fully determined, it is paramount to conduct parallel meaningful and mechanistic-minded interrogations of the impact of clinically modifiable maternal, nutritional, or environmental exposure on the functional microbiome over the duration of pregnancy and lactation to determine their role in the mitigation of childhood and adult NCDs.

Developmental effects of in utero metformin exposure.

According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, the intrauterine environment influences fetal programming and development, affecting offspring disease susceptibility in adulthood. In recent years, therapeutic use of the Type 2 diabetes drug metformin has expanded to the treatment of pre-diabetes, polycystic ovarian syndrome, and gestational diabetes. Because metformin both undergoes renal excretion and binds to receptors on the placenta, the fetus receives equivalent maternal dosing. Although no teratogenic nor short-term harmful fetal impact of metformin is known to occur, the effects of metformin exposure on longer-range offspring development have not yet been fully elucidated. This review encapsulates the (albeit limited) existing knowledge regarding the potential longer-term impact of intrauterine metformin exposure on the development of key organs including the liver, central nervous system, heart, gut, and endocrine pancreas in animal models and humans. We discuss molecular and cellular mechanisms that would be altered in response to treatment and describe the potential consequences of these developmental changes on postnatal health. Further studies regarding the influence of metformin exposure on fetal programming and adult metabolic health will provide necessary insight to its long-term risks, benefits, and limitations in order to guide decisions for use of metformin during pregnancy.