Management of Women with Polycystic Ovary Syndrome During Pregnancy.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women and is associated with subfertility and adverse perinatal outcomes, which may include early pregnancy loss, gestational diabetes mellitus, hypertensive spectrum disorder, preterm birth, fetal growth disorders, and cesarean deliveries. The phenotypic heterogeneity, different diagnostic criteria, and PCOS-related conditions that women enter pregnancy with have limited evidenced-based studies and guidelines to reduce pregnancy complications among this high-risk population. This review summarizes the available evidence on the approach and management of women with PCOS preconception, prenatal, and postpartum.

Single Cell RNA Sequencing of Human Milk-Derived Cells Reveals Sub-Populations of Mammary Epithelial Cells with Molecular Signatures of Progenitor and Mature States: a Novel, Non-invasive Framework for Investigating Human Lactation Physiology.

Cells in human milk are an untapped source, as potential "liquid breast biopsies", of material for investigating lactation physiology in a non-invasive manner. We used single cell RNA sequencing (scRNA-seq) to identify milk-derived mammary epithelial cells (MECs) and their transcriptional signatures in women with diet-controlled gestational diabetes (GDM) with normal lactation. Methodology is described for coordinating milk collections with single cell capture and library preparation via cryopreservation, in addition to scRNA-seq data processing and analyses of MEC transcriptional signatures. We comprehensively characterized 3740 cells from milk samples from two mothers at two weeks postpartum. Most cells (>90%) were luminal MECs (luMECs) expressing lactalbumin alpha and casein beta and positive for keratin 8 and keratin 18. Few cells were keratin 14+ basal MECs and a small immune cell population was present (<10%). Analysis of differential gene expression among clusters identified six potentially distinct luMEC subpopulation signatures, suggesting the potential for subtle functional differences among luMECs, and included one cluster that was positive for both progenitor markers and mature milk transcripts. No expression of pluripotency markers POU class 5 homeobox 1 (POU5F1, encoding OCT4) SRY-box transcription factor 2 (SOX2) or nanog homeobox (NANOG), was observed. These observations were supported by flow cytometric analysis of MECs from mature milk samples from three women with diet-controlled GDM (2-8 mo postpartum), indicating a negligible basal/stem cell population (epithelial cell adhesion molecule (EPCAM)-/integrin subunit alpha 6 (CD49f)+, 0.07%) and a small progenitor population (EPCAM+/CD49f+, 1.1%). We provide a computational framework for others and future studies, as well as report the first milk-derived cells to be analyzed by scRNA-seq. We discuss the clinical potential and current limitations of using milk-derived cells as material for characterizing human mammary physiology.

Universal early pregnancy glycosylated hemoglobin A1c as an adjunct to Carpenter-Coustan screening: an observational cohort study.

BACKGROUND: Early pregnancy screening for preexisting and gestational diabetes mellitus is widely recommended, but the details of screening (eg, targeted vs universal screening, criteria to identify women requiring early screening, specific screening strategy) remain controversial and poorly defined. OBJECTIVE: The objective of the study was to determine the utility of universal early glycosylated hemoglobin A1c obtained at the first prenatal visit in diagnosing preexisting diabetes and high-risk gestational diabetes mellitus (early glycosylated hemoglobin A1c, 5.9-6.4%). We further sought to determine whether early glycosylated hemoglobin A1c could replace routine Carpenter-Coustan testing and to determine the correlation between early glycosylated hemoglobin A1c and maternal and neonatal morbidity and mortality. STUDY DESIGN: This was an observational cohort study of women delivering from May 2016 to July 2017 (14 months) at a single county teaching hospital. Multiple gestations and second deliveries during the study interval were excluded. Women with an early glycosylated hemoglobin A1c of ≥ 6.5% were diagnosed with preexisting diabetes. Women with early glycosylated hemoglobin A1c of 5.9-6.4% underwent immediate 3 hour glucose tolerance testing, which if abnormal diagnosed gestational diabetes mellitus and if normal was repeated at 24-28 weeks. Women with early glycosylated hemoglobin A1c <5.9% underwent routine Carpenter-Coustan screening at 24-28 weeks. Receiver-operator curve methodology was used to evaluate the diagnostic properties of early glycosylated hemoglobin A1c for gestational diabetes mellitus. The correlation between early glycosylated hemoglobin A1c and composite measures of maternal and neonatal morbidity and mortality were calculated. RESULTS: A total of 4144 deliveries remained after exclusions. Median gestational age at early glycosylated hemoglobin A1c draw was 9 weeks (interquartile range, 7-12). Early glycosylated hemoglobin A1c diagnosed 26 women with preexisting diabetes (0.8% of all patients, 37.7% of all preexisting diabetes). A total of 41.9% of 93 women with early glycosylated hemoglobin A1c of 5.9-6.4% had an early diagnosis of gestational diabetes mellitus, accounting for 25.8% of total gestational diabetes mellitus cases. Based on receiver-operator curve analysis, no early glycosylated hemoglobin A1c cutoff had sufficient sensitivity and positive predictive value to diagnose gestational diabetes mellitus. An early glycosylated hemoglobin A1c ≤5.0% (29.2% of patients) had a 98% negative predictive value for gestational diabetes mellitus, suggesting women with an early glycosylated hemoglobin A1c ≤5.0% in a similar-risk population could potentially forego further testing. The per-patient incremental cost for the glycosylated hemoglobin A1c was $3.72. CONCLUSION: Early glycosylated hemoglobin A1c correlates with maternal and neonatal morbidity and mortality but cannot entirely replace routine Carpenter-Coustan testing because of poor sensitivity. Rather, its use as an adjunct to Carpenter-Coustan testing, with reflex to early 3 hour glucose tolerance testing for those with values 5.9-6.4%, is an inexpensive and simple method that identifies women with preexisting diabetes and high-risk gestational diabetes mellitus early in pregnancy, allowing early intervention and the prospect of improved outcomes.

Nicotinamide Promotes Adipogenesis in Umbilical Cord-Derived Mesenchymal Stem Cells and Is Associated with Neonatal Adiposity: The Healthy Start BabyBUMP Project.

The cellular mechanisms whereby excess maternal nutrition during pregnancy increases adiposity of the offspring are not well understood. However, nicotinamide (NAM), a fundamental micronutrient that is important in energy metabolism, has been shown to regulate adipogenesis through inhibition of SIRT1. Here we tested three novel hypotheses: 1) NAM increases the adipogenic response of human umbilical cord tissue-derived mesenchymal stem cells (MSCs) through a SIRT1 and PPARγ pathway; 2) lipid potentiates the NAM-enhanced adipogenic response; and 3) the adipogenic response to NAM is associated with increased percent fat mass (%FM) among neonates. MSCs were derived from the umbilical cord of 46 neonates born to non-obese mothers enrolled in the Healthy Start study. Neonatal %FM was measured using air displacement plethysmography (Pea Pod) shortly after birth. Adipogenic differentiation was induced for 21 days in the 46 MSC sets under four conditions, +NAM (3mM)/-lipid (200 µM oleate/palmitate mix), +NAM/+lipid, -NAM/+lipid, and vehicle-control (-NAM/-lipid). Cells incubated in the presence of NAM had significantly higher PPARγ protein (+24%, p <0.01), FABP4 protein (+57%, p <0.01), and intracellular lipid content (+51%, p <0.01). Lipid did not significantly increase either PPARγ protein (p = 0.98) or FABP4 protein content (p = 0.82). There was no evidence of an interaction between NAM and lipid on adipogenic response of PPARγ or FABP4 protein (p = 0.99 and p = 0.09). In a subset of 9 MSC, SIRT1 activity was measured in the +NAM/-lipid and vehicle control conditions. SIRT1 enzymatic activity was significantly lower (-70%, p <0.05) in the +NAM/-lipid condition than in vehicle-control. In a linear model with neonatal %FM as the outcome, the percent increase in PPARγ protein in the +NAM/-lipid condition compared to vehicle-control was a significant predictor (ß = 0.04, 95% CI 0.01-0.06, p <0.001). These are the first data to support that chronic NAM exposure potentiates adipogenesis in human MSCs in-vitro, and that this process involves PPARγ and SIRT1.

Chronically increased S6K1 is associated with impaired IRS1 signaling in skeletal muscle of GDM women with impaired glucose tolerance postpartum.

CONTEXT: The rapidly increasing prevalence of gestational diabetes mellitus (GDM) globally places a growing population at risk for developing type 2 diabetes mellitus (T2DM), particularly those with persistent impaired glucose tolerance (IGT) postpartum. OBJECTIVE: We sought to 1) identify dynamic insulin signaling abnormalities in vivo in a prospective, longitudinal study of GDM women compared to weight-matched pregnant controls both antepartum and postpartum; and 2) determine abnormalities that might distinguish GDM women who normalize their glucose tolerance postpartum from those with persistent IGT. DESIGN: Skeletal muscle biopsies were obtained before and after a 75-g glucose load in nine overweight to obese GDM women and 10 weight-matched pregnant controls antepartum and postpartum. Postpartum biopsies were collected in five weight-matched GDM women with IGT (GDM/IGT). RESULTS: GDM women had decreased skeletal muscle insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine activation and reduced IRS1, concomitant with increased basal IRS1 serine phosphorylation and basal p70 S6-kinase (S6K1) activation, which resolved postpartum. However, GDM/IGT subjects had a persistent impairment in IRS1 activation and increased S6K1 phosphorylation compared to GDM subjects with normal glucose tolerance. CONCLUSIONS: This study reveals that women with GDM demonstrate impaired IRS1 signaling associated with increased S6K1 activation in skeletal muscle in vivo. This defect is maintained postpartum in GDM/IGT subjects, despite similar body weights and cytokine levels. Given that GDM women with persistent IGT are at a high risk of developing T2DM, understanding how the nutrient-sensitive mammalian target of rapamycin/S6K1 pathway is chronically activated in GDM may lead to important therapies that could prevent the progression to T2DM.

Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline.

OBJECTIVE: The objective is to provide clinical guidelines for the management of thyroid problems present during pregnancy and in the postpartum. PARTICIPANTS: The Chair was selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society. The Chair requested participation by the Latin American Thyroid Society, the Asia and Oceania Thyroid Society, the American Thyroid Association, the European Thyroid Association, and the American Association of Clinical Endocrinologists, and each organization appointed a member to the task force. Two members of The Endocrine Society were also asked to participate. The group worked on the guidelines for 2 yr and held two meetings. There was no corporate funding, and no members received remuneration. EVIDENCE: Applicable published and peer-reviewed literature of the last two decades was reviewed, with a concentration on original investigations. The grading of evidence was done using the United States Preventive Services Task Force system and, where possible, the GRADE system. CONSENSUS PROCESS: Consensus was achieved through conference calls, two group meetings, and exchange of many drafts by E-mail. The manuscript was reviewed concurrently by the Society's CGS, Clinical Affairs Committee, members of The Endocrine Society, and members of each of the collaborating societies. Many valuable suggestions were received and incorporated into the final document. Each of the societies endorsed the guidelines. CONCLUSIONS: Management of thyroid diseases during pregnancy requires special considerations because pregnancy induces major changes in thyroid function, and maternal thyroid disease can have adverse effects on the pregnancy and the fetus. Care requires coordination among several healthcare professionals. Avoiding maternal (and fetal) hypothyroidism is of major importance because of potential damage to fetal neural development, an increased incidence of miscarriage, and preterm delivery. Maternal hyperthyroidism and its treatment may be accompanied by coincident problems in fetal thyroid function. Autoimmune thyroid disease is associated with both increased rates of miscarriage, for which the appropriate medical response is uncertain at this time, and postpartum thyroiditis. Fine-needle aspiration cytology should be performed for dominant thyroid nodules discovered in pregnancy. Radioactive isotopes must be avoided during pregnancy and lactation. Universal screening of pregnant women for thyroid disease is not yet supported by adequate studies, but case finding targeted to specific groups of patients who are at increased risk is strongly supported.