Pathophysiology from preconception, during pregnancy, and beyond.

Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond.

Epidemiology and management of gestational diabetes.

Gestational diabetes is defined as hyperglycaemia first detected during pregnancy at glucose concentrations that are less than those of overt diabetes. Around 14% of pregnancies globally are affected by gestational diabetes; its prevalence varies with differences in risk factors and approaches to screening and diagnosis; and it is increasing in parallel with obesity and type 2 diabetes. Gestational diabetes direct costs are US$1·6 billion in the USA alone, largely due to complications including hypertensive disorders, preterm delivery, and neonatal metabolic and respiratory consequences. Between 30% and 70% of gestational diabetes is diagnosed in early pregnancy (ie, early gestational diabetes defined by hyperglycaemia before 20 weeks of gestation). Early gestational diabetes is associated with worse pregnancy outcomes compared with women diagnosed with late gestational diabetes (hyperglycaemia from 24 weeks to 28 weeks of gestation). Randomised controlled trials show benefits of treating gestational diabetes from 24 weeks to 28 weeks of gestation. The WHO 2013 recommendations for diagnosing gestational diabetes (one-step 75 gm 2-h oral glucose tolerance test at 24-28 weeks of gestation) are largely based on the Hyperglycemia and Adverse Pregnancy Outcomes Study, which confirmed the linear association between pregnancy complications and late-pregnancy maternal glycaemia: a phenomenon that has now also been shown in early pregnancy. Recently, the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) trial showed benefit in diagnosis and treatment of early gestational diabetes for women with risk factors. Given the diabesity epidemic, evidence for gestational diabetes heterogeneity by timing and subtype, and advances in technology, a life course precision medicine approach is urgently needed, using evidence-based prevention, diagnostic, and treatment strategies.

Impact of hypertensive disorders of pregnancy and gestational diabetes mellitus on offspring cardiovascular health in early adolescence.

BACKGROUND: Adverse pregnancy outcomes, including hypertensive disorders of pregnancy and gestational diabetes mellitus, influence maternal cardiovascular health long after pregnancy, but their relationship to offspring cardiovascular health following in-utero exposure remains uncertain. OBJECTIVE: To examine associations of hypertensive disorders of pregnancy or gestational diabetes mellitus with offspring cardiovascular health in early adolescence. STUDY DESIGN: This analysis used data from the prospective Hyperglycemia and Adverse Pregnancy Outcome Study from 2000 to 2006 and the Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study from 2013 to 2016. This analysis included 3317 mother-child dyads from 10 field centers, comprising 70.8% of Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study participants. Those with pregestational diabetes and chronic hypertension were excluded. The exposures included having any hypertensive disorders of pregnancy or gestational diabetes mellitus vs not having hypertensive disorders of pregnancy or gestational diabetes mellitus, respectively (reference). The outcome was offspring cardiovascular health when aged 10-14 years, on the basis of 4 metrics: body mass index, blood pressure, total cholesterol level, and glucose level. Each metric was categorized as ideal, intermediate, or poor using a framework provided by the American Heart Association. The primary outcome was defined as having at least 1 cardiovascular health metric that was nonideal vs all ideal (reference), and the second outcome was the number of nonideal cardiovascular health metrics (ie, at least 1 intermediate metric, 1 poor metric, or at least 2 poor metrics vs all ideal [reference]). Modified poisson regression with robust error variance was used and adjusted for covariates at pregnancy enrollment, including field center, parity, age, gestational age, alcohol or tobacco use, child's assigned sex at birth, and child's age at follow-up. RESULTS: Among 3317 maternal-child dyads, the median (interquartile) ages were 30.4 (25.6-33.9) years for pregnant individuals and 11.6 (10.9-12.3) years for children. During pregnancy, 10.4% of individuals developed hypertensive disorders of pregnancy, and 14.6% developed gestational diabetes mellitus. At follow-up, 55.5% of offspring had at least 1 nonideal cardiovascular health metric. In adjusted models, having hypertensive disorders of pregnancy (adjusted risk ratio, 1.14 [95% confidence interval, 1.04-1.25]) or having gestational diabetes mellitus (adjusted risk ratio, 1.10 [95% confidence interval, 1.02-1.19]) was associated with a greater risk that offspring developed less-than-ideal cardiovascular health when aged 10-14 years. The above associations strengthened in magnitude as the severity of adverse cardiovascular health metrics increased (ie, with the outcome measured as ≥1 intermediate, 1 poor, and ≥2 poor adverse metrics), albeit the only statistically significant association was with the "1-poor-metric" exposure. CONCLUSION: In this multinational prospective cohort, pregnant individuals who experienced either hypertensive disorders of pregnancy or gestational diabetes mellitus were at significantly increased risk of having offspring with worse cardiovascular health in early adolescence. Reducing adverse pregnancy outcomes and increasing surveillance with targeted interventions after an adverse pregnancy outcome should be studied as potential avenues to enhance long-term cardiovascular health in the offspring exposed in utero.

Barriers to implementing good nutrition in pregnancy and early childhood: Creating equitable national solutions.

Exposure to deleterious stressors in early life, such as poor nutrition, underlies most adult-onset chronic diseases. As rates of chronic disease continue to climb in the United States, a focus on good nutrition before and during pregnancy, lactation, and early childhood provides a potential opportunity to reverse this trend. This report provides an overview of nutrition investigations in pregnancy and early childhood and addresses racial disparities and health outcomes, current national guidelines, and barriers to achieving adequate nutrition in pregnant individuals and children. Current national policies and community interventions to improve nutrition, as well as the current state of nutrition education among healthcare professionals and students, are discussed. Major gaps in knowledge and implementation of nutrition practices during pregnancy and early childhood were identified and action goals were constructed. The action goals are intended to guide the development and implementation of critical nutritional strategies that bridge these gaps. Such goals create a national blueprint for improving the health of mothers and children by promoting long-term developmental outcomes that improve the overall health of the US population.

Racial and ethnic differences in the association between pregnancy dysglycemia and cardiometabolic risk factors 10-14 years' postpartum in the HAPO follow-up study.

Associations between pregnancy dysglycemia and subsequent maternal cardiometabolic factors 10-14 years postpartum were largely similar across self-identified racial and ethnic groups among birthing people in the U.S. enrolled in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Follow-up Study.

Mid-pregnancy sleep disturbances are not associated with mid-pregnancy maternal glycemia.

Background: In pregnancy, epidemiological data have consistently shown strong associations between sleep quality and duration and maternal glycemia. However, other sleep disturbances such as difficulty falling asleep and staying asleep are common in pregnancy. They may contribute to impaired maternal glycemia through sympathetic nervous system activity, systemic inflammation, and hormonal pathways. However, there is little research examining associations between these specific sleep disturbances and maternal glycemia. Objective: This study aimed to investigate the associations of sleep disturbances during mid-pregnancy and mid-pregnancy maternal glycemia and gestational diabetes subtypes. Study Design: This is a secondary data analysis of the Comparison of Two Screening Strategies for Gestational Diabetes trial. Participants (n = 828) self-reported the frequency of sleep disturbances (i.e., trouble falling asleep, trouble staying asleep, waking several times per night, and waking feeling tired or worn out) in mid-pregnancy. Gestational diabetes was diagnosed using either the International Associations of Diabetes and Pregnancy Study Groups or Carpenter-Coustan approach. We defined gestational diabetes subtypes based on the degree of insulin resistance and beta-cell dysfunction. We used multinomial logistic regression to examine associations of sleep disturbances with gestational diabetes status (i.e., normal, mild glycemic dysfunction, and gestational diabetes) and gestational diabetes subtypes (i.e., neither insulin resistance or beta-cell dysfunction, insulin resistance only, beta-cell dysfunction only, and insulin resistance and beta-cell dysfunction). Results: A total of 665 participants (80%) had normal glycemia, 81 (10%) mild hyperglycemia, and 80 (10%) had gestational diabetes. Among participants with gestational diabetes, 62 (78%) had both insulin resistance and beta-cell dysfunction, 15 (19 %) had insulin resistance only, and 3 had beta-cell dysfunction only or neither insulin resistance nor beta-cell dysfunction. Sleep disturbance frequency was not associated with maternal glycemia or gestational diabetes subtypes. Conclusions: Sleep disturbances in mid-pregnancy were not associated with maternal glycemia during mid-pregnancy. Future research should collect data on sleep disturbances at multiple time points in pregnancy and in combination with other sleep disturbances to determine whether sleep plays any role in maternal glycemic control.

The roles of newborn anthropometrics in the association between maternal weight gain and childhood cardiovascular risks.

OBJECTIVE: The aim was to study the association between newborn anthropometrics and childhood cardiovascular risks and whether newborn anthropometrics mediate the effect of maternal gestational weight gain (GWG) on childhood risks. METHODS: Data of 926 mother-child dyads from the Hyperglycemia and Adverse Pregnancy Outcomes study were analyzed. Newborn anthropometrics were treated as predictors and mediators by using a regression model and causal mediation model, respectively. RESULTS: Newborn sum of skinfolds (SSF) was associated with childhood diastolic blood pressure (DBP) and pulse wave velocity (coefficients [95% CI]: 0.13 [0.06 to 0.20]; 0.08 [0.004 to 0.15]), whereas newborn ponderal index (PI) was inversely associated with childhood systolic blood pressure (SBP), DBP, and pulse wave velocity (-0.08 [-0.15 to -0.01]; -0.08 [-0.14 to -0.008]; -0.09 [-0.16 to -0.03]). Newborn SSF mediated the effects of maternal excessive GWG on childhood SSF and DBP (proportion of total effect 9% and 8%, respectively). In contrast, a significant negative mediation through newborn PI was found for the effect of maternal excessive GWG on childhood DBP (-8%) and its effect on childhood SBP through birth weight (-27%). CONCLUSIONS: Childhood cardiovascular risks are positively associated with newborn SSF but inversely associated with newborn PI. Newborn SSF mediates the impact of excessive maternal GWG on childhood BP, but birth weight and newborn PI negatively mediate it.

Obesity, Pregnancy and the Social Contract with Today's Adolescents.

Adolescent health and well-being are of great concern worldwide, and adolescents encounter particular challenges, vulnerabilities and constraints. The dual challenges of adolescent parenthood and obesity are of public health relevance because of the life-altering health and socioeconomic effects on both the parents and the offspring. Prevention and treatment strategies at the individual and population levels have not been successful in the long term, suggesting that adolescent pregnancy and obesity cannot be managed by more of the same. Here, we view adolescent obese pregnancy through the lens of the social contract with youth. The disruption of this contract is faced by today's adolescents, with work, social and economic dilemmas which perpetuate socioeconomic and health inequities across generations. The lack of employment, education and social opportunities, together with obesogenic settings, increase vulnerability and exposure to lifelong health risks, affecting their offspring's life chances too. To break such vicious circles of disadvantage and achieve sustainable solutions in real-world settings, strong efforts on the part of policymakers, healthcare providers and the community must be oriented towards guaranteeing equity and healthy nutrition and environments for today's adolescents. The involvement of adolescents themselves in developing such programs is paramount, not only so that they feel a sense of agency but also to better meet their real life needs.

Comparing IADPSG and NICE Diagnostic Criteria for GDM in Predicting Adverse Pregnancy Outcomes.

OBJECTIVE: To compare the performance of diagnostic criteria for gestational diabetes mellitus (GDM) proposed by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) with those endorsed by the National Institute for Health and Care Excellence (NICE) in predicting adverse pregnancy outcomes. RESEARCH DESIGN AND METHODS: We performed a secondary data analysis of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study participants in five study centers. Logistic regression analyses were performed, and Akaike information criterion were applied for the comparison of different statistical prediction models. We further analyzed the performance by four racial/ethnic subgroups, namely, Whites, Hispanics, Asians, and Blacks. RESULTS: Among all, IADPSG criteria diagnosed 267 (4.1%) more women with GDM, but predicted primary caesarean section (CS) and large for gestational age (LGA) and neonatal adiposity better than did NICE criteria after adjustment for potential confounders. Among Whites, IADPSG criteria diagnosed 65 (2.5%) more subjects with GDM and predicted LGA and neonatal adiposity better, but predicted hypertensive disorders, primary CS and clinical neonatal hypoglycemia worse. Among Hispanics, the IADPSG criteria diagnosed 203 (12.1%) more with GDM but performed better in predicting hypertensive disorders, LGA, neonatal adiposity, and hyperinsulinemia. Among Asians, the IADPSG criteria diagnosed 34 (2.0%) fewer subjects with GDM but predicted hypertensive disorders better in the unadjusted model. In Blacks, IADPSG criteria diagnosed 34 (10.5%) more women with GDM. CONCLUSIONS: IADPSG criteria appear to be more favorable than NICE for identification of adverse pregnancy outcomes among Hispanic and Asian women, while they are comparable to NICE among White women.

Maternal Lipid Metabolism Is Associated With Neonatal Adiposity: A Longitudinal Study.

CONTEXT: Pregnancy is characterized by progressive decreases in glucose insulin sensitivity. Low insulin sensitivity resulting in hyperglycemia is associated with higher neonatal adiposity. However, less is known regarding lipid metabolism, particularly lipid insulin sensitivity in pregnancy and neonatal adiposity. OBJECTIVE: Because higher maternal prepregnancy body mass index is strongly associated with both hyperlipidemia and neonatal adiposity, we aimed to examine the longitudinal changes in basal and clamp maternal lipid metabolism as contributors to neonatal adiposity. METHODS: Twelve women planning a pregnancy were evaluated before pregnancy, in early (12-14 weeks), and late (34-36 weeks) gestation. Body composition was estimated using hydrodensitometry. Basal and hyperinsulinemic-euglycemic clamp glucose and glycerol turnover (GLYTO) were measured using 2H2-glucose and 2H5-glycerol and substrate oxidative/nonoxidative metabolism with indirect calorimetry. Total body electrical conductivity was used to estimate neonatal body composition. RESULTS: Basal free-fatty acids decreased with advancing gestation (P = 0.0210); however, basal GLYTO and nonoxidative lipid metabolism increased over time (P = 0.0046 and P = 0.0052, respectively). Further, clamp GLYTO and lipid oxidation increased longitudinally over time (P = 0.0004 and P = 0.0238, respectively). There was a median 50% increase and significant positive correlation during both basal and clamp GLYTO from prepregnancy through late gestation. Neonatal adiposity correlated with late pregnancy basal and clamp GLYTO (r = 0.6515, P = 0.0217; and r = 0.6051, P = 0.0371). CONCLUSIONS: Maternal prepregnancy and late pregnancy measures of basal and clamp lipid metabolism are highly correlated. Late pregnancy basal and clamp GLYTO are significantly associated with neonatal adiposity and account for ~40% of the variance in neonatal adiposity. These data emphasize the importance of maternal lipid metabolism relating to fetal fat accrual.

Changes in Visceral and Ectopic Adipose Tissue Stores Across Pregnancy and Their Relationship to Gestational Weight Gain.

BACKGROUND: Excessive gestational weight gain has been associated with increased total body fat (TBF), metabolic syndrome, and abdominal obesity. However, little is known about the relationship of gestational weight gain with changes in metabolically active visceral or ectopic (hepatic and skeletal muscle) lipid stores. OBJECTIVES: In a prospective study of 50 healthy, pregnant women, we assessed whether changes in weight were associated with changes in total, visceral, and ectopic lipid stores. METHODS: Participants (ages 19-39) were primarily White (84%). The mean preconception BMI was 25.8 kg/m2 (SD, 4.5 kg/m2; min-max, 17.1-35.9 kg/m2). Measurements were completed at visits 1 and 2 at means of 16 and 34 weeks gestation, respectively, and included TBF using BOD POD; abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) using MRI; and intrahepatic lipids (IHL), intramyocellular lipids (IMCL), and extramyocellular lipids (EMCL) using magnetic resonance spectroscopy. We used paired t-tests to examine changes in adipose tissue and Pearson's correlation to examine associations of adipose tissue changes and weight changes. We also examined whether changes in adipose tissue stores differed by preconception BMI (normal, overweight, and obese), using 1-way ANOVA. RESULTS: The TBF (mean change, +3.5 kg; 95% CI: 2.4-4.6 kg), SAT (mean change, +701 cm3; 95% CI: 421-981 cm3), VAT (mean change, +275 cm3; 95% CI: 170-379 cm3), and IHL (percentage water peak; median, +0.15; IQR = -0.01 to 0.32) values increased significantly; the IMCL and EMCL values did not change. Changes varied by BMI strata, with the least increase (or, for SAT, net loss) among women with obesity. Weight change was positively correlated with changes in TBF (r = 0.83; P < 0.001), SAT (r = 0.74; P < 0.001), and VAT (r = 0.63; P < 0.001) but not significantly correlated with changes in ectopic lipids (IHL, IMCL, and EMCL; -0.14 < r < 0.26). CONCLUSIONS: Preferential deposition of adipose tissue to the viscera in pregnancy, as seen in our sample, could serve an important metabolic function; however, excessive deposition in this region could negatively affect maternal health.

Association between sleep disordered breathing in early pregnancy and glucose metabolism.

STUDY OBJECTIVES: To examine the association between maternal sleep disordered breathing (SDB) and glucose metabolism in early gestation. METHODS: Women with body mass index (BMI) ≥27 kg/m2 and singleton pregnancies underwent in-home sleep study (HSAT) and homeostatic model assessment (HOMA) in early pregnancy. Insulin resistance (HOMA-IR) and ß-cell function (HOMA %B) were derived. Exclusion criteria included pregestational diabetes, use of continuous positive airway pressure and chronic steroid therapy. We performed linear regression analyses to evaluate the association between continuous measures of SDB (respiratory event index (REI), and oxygen desaturation index (ODI)) and glucose metabolism parameters (HOMA-IR and HOMA %B). Analyses were adjusted for a set of a priori selected variables which included gestational age, maternal age, BMI, ethnicity, race, and parity. RESULTS: One hundred and ninety-two pregnant women with median (interquartile range) BMI of 35.14 (8.30) kg/m2 underwent HSAT and HOMA assessment at 11.14 (3) and 15.35 (4.14) gestational weeks, respectively. REI and ODI, as continuous values, were associated with HOMA-IR after adjusting for covariates. OSA (obstructive sleep apnea) diagnosis (REI > 5 events per hour) was not associated with HOMA-IR after adjusting for BMI (p ≥ 0.05). None of the parameters were associated with HOMA %B (p > 0.07). CONCLUSIONS: SDB and insulin resistance are associated in early pregnancy, with a dose response association between respiratory event index severity and insulin resistance. Further studies are needed to establish if pregnant women with overweight and obesity may benefit from early SDB screening to improve glucose metabolic outcome. Clinical trials: NCT02412696, Positive Airway Pressure, Sleep Apnea, and the Placenta (PAP-SAP) https://clinicaltrials.gov/ct2/show/NCT02412696?term=Bourjeily&draw=2&rank=2 and NCT02917876, Predictors of De-novo Development of Obstructive Sleep Apnea in Pregnancy (Predictors) https://clinicaltrials.gov/ct2/show/NCT02917876?term=Bourjeily&draw=2&rank=1.

Oral Glucose Tolerance Test-based Measures of Insulin Secretory Response in Pregnancy.

BACKGROUND: Oral glucose tolerance test (OGTT)-based measures of insulin secretory response have not been validated in pregnancy. METHODS: In a secondary analysis of a longitudinal study, participants were studied prepregnancy (n = 40), in early pregnancy (n = 36; 12-14 weeks' gestation), and in late pregnancy (n = 36; 34-36 weeks' gestation). Participants underwent an OGTT, an intravenous glucose tolerance test (IVGTT), and a hyperinsulinemic-euglycemic clamp at each timepoint. We calculated homeostatic model assessment of beta-cell function (HOMA-2B), insulinogenic index (IGI), corrected insulin response (CIR), ratio of the area under the insulin curve and the area under the glucose curve (AUCins/AUCglu), and Stumvoll first-phase estimate (Stumvoll) from OGTT insulin and glucose levels. We used Pearson correlation to compare measures from OGTT and IVGTT. We used mixed effects models to examine longitudinal changes in insulin secretory response. RESULTS: Stumvoll was the only OGTT-based measure that was significantly correlated with first-phase insulin response prior to and across gestation (prepregnancy: r = 0.44, P = 0.01; early pregnancy: r = 0.67, P = 0.0001; late pregnancy: r = 0.67, P = 0.0001). In early and late pregnancy, AUCins/AUCglu had the strongest correlation with first-phase insulin response (early pregnancy: r = 0.79, P < 0.0001; late pregnancy: r = 0.69, P < 0.0001) but was not significantly correlated prepregnancy. IGI and CIR were significantly correlated with first-phase insulin response prepregnancy (IGI: r = 0.50, P = 0.005; CIR r = 0.47, P = 0.008) and in late pregnancy (IGI: r = 0.68, P = 0.0001; CIR r = 0.57, P = 0.002) but not in early pregnancy. HOMA-2B was the weakest correlate of first-phase insulin response. Stumvoll and AUCins/AUCglu recapitulated the longitudinal changes in insulin secretory response observed by IVGTT. CONCLUSIONS: Stumvoll and AUCins/AUCglu are valid OGTT-based insulin secretory response measures for pregnancy studies.

The importance of nutrition in pregnancy and lactation: lifelong consequences.

Most women in the United States do not meet the recommendations for healthful nutrition and weight before and during pregnancy. Women and providers often ask what a healthy diet for a pregnant woman should look like. The message should be "eat better, not more." This can be achieved by basing diet on a variety of nutrient-dense, whole foods, including fruits, vegetables, legumes, whole grains, healthy fats with omega-3 fatty acids that include nuts and seeds, and fish, in place of poorer quality highly processed foods. Such a diet embodies nutritional density and is less likely to be accompanied by excessive energy intake than the standard American diet consisting of increased intakes of processed foods, fatty red meat, and sweetened foods and beverages. Women who report "prudent" or "health-conscious" eating patterns before and/or during pregnancy may have fewer pregnancy complications and adverse child health outcomes. Comprehensive nutritional supplementation (multiple micronutrients plus balanced protein energy) among women with inadequate nutrition has been associated with improved birth outcomes, including decreased rates of low birthweight. A diet that severely restricts any macronutrient class should be avoided, specifically the ketogenic diet that lacks carbohydrates, the Paleo diet because of dairy restriction, and any diet characterized by excess saturated fats. User-friendly tools to facilitate a quick evaluation of dietary patterns with clear guidance on how to address dietary inadequacies and embedded support from trained healthcare providers are urgently needed. Recent evidence has shown that although excessive gestational weight gain predicts adverse perinatal outcomes among women with normal weight, the degree of prepregnancy obesity predicts adverse perinatal outcomes to a greater degree than gestational weight gain among women with obesity. Furthermore, low body mass index and insufficient gestational weight gain are associated with poor perinatal outcomes. Observational data have shown that first-trimester gain is the strongest predictor of adverse outcomes. Interventions beginning in early pregnancy or preconception are needed to prevent downstream complications for mothers and their children. For neonates, human milk provides personalized nutrition and is associated with short- and long-term health benefits for infants and mothers. Eating a healthy diet is a way for lactating mothers to support optimal health for themselves and their infants.

Elevated Anthropometric and Metabolic Indicators among Young Adult Offspring of Mothers with Pregestational Diabetes: Early Results from the Transgenerational Effect on Adult Morbidity Study (the TEAM Study).

Exposure to maternal diabetes in utero increases the risk in the offspring for a range of metabolic disturbances. However, the timing and variability of in utero hyperglycemic exposure necessary to cause impairment have not been elucidated. The TEAM Study was initiated to evaluate young adult offspring of mothers with pregestational diabetes mellitus. This paper outlines the unique enrollment challenges of the TEAM Study and preliminary analysis of the association between exposure to diabetes in pregnancy and adverse metabolic outcomes. The TEAM Study enrolls offspring of women who participated in a Diabetes in Pregnancy (DiP) Program Project Grant between 1978 and 1995. The DiP Study collected medical and obstetric data across pregnancy. The first 96 eligible offspring of women with pregestational diabetes were age-, sex-, and race-matched to adults from the National Health and Nutrition Examination Survey (NHANES) 2015-2016 with an OGTT. Descriptive and regression analyses were employed to compare TEAM participants to NHANES participants. Among a subset of TEAM participants, we compared the metabolic outcomes across maternal glucose profiles using a longitudinal data clustering technique that characterizes level and variability, in maternal glucose across pregnancy. By comparing categories of BMI, TEAM Study participants had over 2.0 times the odds of being obese compared to matched NHANES participants (for class III obesity, OR = 2.81; 95% confidence interval (CI): 1.15, 6.87). Increasing levels of two-hour glucose were also associated with in utero exposure to pregestational diabetes in matched analyses. Exposure to pregestational diabetes in utero may be associated with an increased risk of metabolic impairment in the offspring with clinical implications.

Pregnancy and weaning regulate human maternal liver size and function.

During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.