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 (HDP) and gestational diabetes mellitus (GDM), influence maternal cardiovascular heath (CVH) long after pregnancy, but their relationship to offspring CVH following in utero exposure remains uncertain. OBJECTIVE: To examine associations of HDP or GDM with offspring CVH in early adolescence. STUDY DESIGN: This analysis used data from the prospective Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study from 2000 to 2006 and the HAPO Follow-Up Study from 2013 to 2016. This analysis included 3,317 mother-child dyads from 10 field centers, comprising 70.8% of HAPO Follow-Up Study participants. Those with pregestational diabetes and chronic hypertension were excluded. The exposures were having any HDP or GDM compared with not having HDP or GDM, respectively (reference). The outcome was offspring CVH at ages 10 to 14 years, based on four 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 outcome was primarily defined as having at least one CVH metric that was non-ideal versus all ideal (reference), and secondarily as the number of non-ideal CVH metrics: at least one intermediate metric, one poor metric, or at least two poor metrics versus 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 3,317 maternal-child dyads, the median (IQR) 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 HDP and 14.6% developed GDM. At follow-up, 55.5% of offspring had at least one non-ideal CVH metric. In adjusted models, having HDP (aRR 1.14; 95% CI 1.04, 1.25) or having GDM (aRR 1.10; 95% CI 1.02, 1.19) was associated with greater risk that offspring developed less-than-ideal CVH at ages 10 to 14 years. The above associations strengthened in magnitude as the severity of adverse CVH metrics increased (i.e., 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. CONCLUSONS: In this multi-national prospective cohort, pregnant individuals who experienced either HDP and GDM were at significantly increased risk of having offspring with worse CVH 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.

Leptin and adiposity measures from birth to later childhood: Findings from the Hyperglycemia and Adverse Pregnancy Outcomes Follow-Up Study.

BACKGROUND: Cord blood (CB) leptin is positively associated with adiposity at birth, but the association with child adiposity is unclear. OBJECTIVES: We hypothesized that CB leptin is positively associated with adiposity in peripubertal children and with childhood leptin. METHODS: Leptin was measured in 986 CB and 931 childhood stored samples from a prospective birth cohort. Adiposity measures were collected at birth and mean age 11.5 years. Linear and logistic regression analyses were used to evaluate associations between log-transformed CB leptin and neonatal and childhood adiposity measures as continuous and categorical variables, respectively. RESULTS: CB leptin was positively associated with neonatal and childhood adiposity. Childhood associations were attenuated when adjusted for maternal body mass index (BMI) and glucose, but remained statistically significant for childhood body fat percentage (ß = 1.15%, confidence interval [CI] = 0.46-1.84), body fat mass (ß = 0.69 kg, 95% CI = 0.16-1.23), sum of skin-folds (ß = 1.77 mm, 95% CI = 0.31-3.24), log-transformed child serum leptin (ß = 0.13, 95% CI = 0.06-0.20), overweight/obesity (OR = 1.21, 95% CI = 1.03-1.42), obesity (OR = 1.31, 95% CI = 1.04-1.66) and body fat percentage >85th percentile (OR = 1.38, 95% CI = 1.12-1.73). Positive associations between newborn adiposity measures and CB leptin confirmed previous reports. CONCLUSION: CB leptin is positively associated with neonatal and childhood adiposity and child leptin levels, independent of maternal BMI and maternal hyperglycemia. CB leptin may be a biomarker of future adiposity risk.

One children's hospital planning and development process to adhere to the FDA recommendation that babies and young children undergo thyroid function testing after receiving an injection of iodine-containing contrast media for medical imaging.

The United States (US) Food and Drug Administration (FDA) has issued multiple statements and guidelines since 2015 on the topic of thyroid function testing in babies and children through 3 years old after receiving iodinated contrast media for medical imaging exams. In April 2023, the FDA adjusted this recommendation to target babies and young children younger than 4 years of age who have a history of prematurity, very low birth weight, or underlying conditions which affect thyroid gland function, largely in response to solid arguments from expert statements from the American College of Radiology (ACR) which is endorsed by the Society for Pediatric Radiology (SPR), Pediatric Endocrinology Society (PES), and the Society for Cardiovascular Angiography & Intervention (SCAI). Herein we describe our approach and development of a clinical care guideline along with the steps necessary for implementation of the plan including alterations in ordering exams requiring iodinated contrast media, automatic triggering of lab orders, reporting, and follow-up, to address the 2022 FDA guidance statement to monitor thyroid function in children after receiving iodinated contrast media. The newly implemented clinical care guideline at Ann and Robert H. Lurie Children's Hospital of Chicago remains applicable following the 2023 updated recommendation from the FDA. We will track patients less than 3 months of age who undergo thyroid function testing following computed tomography (CT), interventional radiology, and cardiac catheterization exams for which an iodinated contrast media is administered as a clinical care quality initiative.

Total Thyroidectomy and Subsequent Weight Gain in Pediatric Populations.

OBJECTIVE: To evaluate weight gain in children post-thyroidectomy and identify predictors. METHODS: Charts from patients at a tertiary health care facility who underwent total thyroidectomy from 2014 to 2020 were reviewed for Body Mass Index z-scores (BMIz) at the time of thyroidectomy and at 1 and 2-year post-operation intervals. Patient demographic information, comorbidities, pre- and postoperative thyroid stimulating hormone, and postoperative free T4 levels were also extracted. Patients with other known endocrine abnormalities, chronic kidney disease, or without sufficient follow-up were excluded. RESULTS: A total of 56 patients (ages 3-17 years old) met the inclusion criteria (n = 17 Graves' disease; n = 39 presumed cancer). Over the first year, average BMIz significantly increased in patients with Graves' disease (∆BMIz = 0.45 ± 0.77, p = 0.03), Hispanic ethnicity (∆BMIz = 0.43 ± 0.68, p = 0.004), Medicaid/no insurance coverage (∆BMIz = 0.33 ± 0.74, p = 0.038), age <13 years at thyroidectomy (∆BMIz = 0.35 ± 0.68, p = 0.016), and persistent postoperative hypothyroidism (∆BMIz = 0.41 ± 0.41, p = 0.012). These changes remained significant after the second year. Age at thyroidectomy correlated negatively with ∆BMIz only after the first year (r = -0.40, p = 0.002). Regression analysis, controlling for Graves' status, persistent postoperative hypothyroidism, and insurance coverage, identified age at thyroidectomy as a significant predictor of ∆BMIz after the first year (b = -0.06, p = 0.004) and Hispanic ethnicity as a significant predictor after the second year (b = 0.60, p = 0.003). CONCLUSION: A small increase in BMIz post-thyroidectomy was observed across several patient subgroups. Younger age at thyroidectomy and Hispanic ethnicity were associated with increased BMIz in the first 2 years post-thyroidectomy. LEVEL OF EVIDENCE: Level 4 - Historically controlled cohort Laryngoscope, 133:1518-1523, 2023.

Short-Term Complications After Total Thyroidectomy in Children.

INTRODUCTION: Total thyroidectomy for benign disease is becoming more common among children. The purpose of this study was to evaluate 30-day outcomes in children undergoing total thyroidectomy and determine if the short-term outcomes are different in those with a malignant versus benign indication for surgery. METHODS: This retrospective cohort study used the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-Pediatric) to identify all children who underwent total thyroidectomy from 2015 to 2019. Fisher's exact test was used to compare postoperative outcomes between benign and malignant indications for thyroidectomy. RESULTS: Among 1595 total thyroidectomy patients, 1091 (68.4%) had a benign indication and 504 (31.6%) had a malignant indication. There were 1234 (77.4%) females, and the median age was 14.9 y (interquartile range [IQR] 12.5, 16.6). Average length of stay (LOS) was similar between cohorts (1.7 d for benign and 1.9 d for malignant, P = 0.30). Parathyroid auto-transplantation was performed in 71 (6.5%) patients in the benign cohort and 43 (8.6%) in the malignant cohort (P = 0.15). The most common complications were readmissions (23 [2.1%] benign and 15 [3.0%] malignant, P = 0.29) and reoperations (7 [0.6%] benign and 5 [1.0%] malignant, P = 0.54). Complication profiles were similar between benign and malignant cohorts (2.8% and 4.6%, respectively [P = 0.10]). CONCLUSIONS: Children undergoing total thyroidectomy for benign and malignant indications have low rates of 30-d postoperative complications, suggesting that total thyroidectomy is a safe option for children with benign disease. Evaluation of long-term outcomes is needed.

The 2015 American Thyroid Association guidelines and trends in hemithyroidectomy utilization for pediatric thyroid cancer.

BACKGROUND: In 2015, the American Thyroid Association (ATA) released its inaugural recommendations for the management of thyroid cancer in children. We aim to evaluate whether there has been a change in hemithyroidectomy utilization for pediatric differentiated thyroid cancer, and the association between those changes and the release of the ATA guidelines. METHODS: The National Cancer Database was queried and identified 4776 patients ≤18 years old with differentiated thyroid cancer. Causal impact time-series analysis and logistic analysis were utilized to assess factors associated with use of hemithyroidectomy. RESULTS: Post-2015 hemithyroidectomy rate was greater than predicted based on preguideline trends (predicted: 8.4%, actual: 12.6%, p = 0.001). In logistic analysis of factors associated with hemithyroidectomy use, we find that Papillary histology, tumor size >1 cm, nodal examination, and positive nodes were associated with lower rate of hemithyroidectomy (OR: 0.23, 0.51, 0.62, and 0.18, respectively). CONCLUSION: There has been a significant increase in hemithyroidectomy utilization for pediatric differentiated thyroid cancer.

Neurofibromatosis Type 1 Has a Wide Spectrum of Growth Hormone Excess.

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.

A Mini-Review of Pediatric Anthropometrics as Predictors of Future Insulin Resistance.

The impact of rising rates of childhood obesity is far reaching. Metabolic syndrome in children is increasing, yet for most children the consequences of excess adiposity will manifest in adulthood. Excess early fat accrual is a risk factor for future insulin resistance. However, certain types of fat and patterns of fat distribution are more relevant than others to metabolic risk. Therefore, adiposity measures are important. The link between childhood obesity and future insulin resistance was initially established with body mass index (BMI), but BMI is an in imperfect measure of adiposity. It is worthwhile to evaluate other anthropometrics as they may more accurately capture metabolic risk. While measures such as waist to height ratio are established as superior screening measures in adulthood - the findings are not as robust in pediatrics. Emerging evidence suggests that alternative anthropometrics may be slightly superior to BMI in identifying those youth most at risk of developing insulin resistance, but the clinical significance of that superiority appears limited. Increasing study is needed in longitudinal and varied cohorts to identify which pediatric anthropometric best predicts adult insulin resistance. We review alternative anthropometrics as predictors of future insulin resistance and identify current gaps in knowledge and potential future directions of inquiry.

Effect of surgeon volume on pediatric thyroid surgery outcomes: A systematic review.

BACKGROUND: Pediatric thyroidectomy has been identified as a surgical procedure that may benefit from concentrating cases to high-volume surgeons. This systematic review aimed to address the definition of "high-volume surgeon" for pediatric thyroidectomy and to examine the relationship between surgeon volume and outcomes. METHODS: PubMed, Embase, Cochrane Library, Scopus, Web of Science, ClinicalTrials.gov, and OpenGrey databases were searched for through February 2020 for studies which reported on pediatric thyroidectomy and specified surgeon volume and surgical outcomes. RESULTS: Ten studies, encompassing 6430 patients, were included in the review. Five single-center retrospective studies reported only on high-volume surgeons, one single center retrospective study reported on only low-volume surgeons, and four national database studies (2 cross sectional, 2 retrospective reviews) reported outcomes for both high-volume and low-volume surgeons. Majority of patients underwent total thyroidectomy (54.9%); common indications for surgery were malignancy (41.7%) and hyperthyroidism/thyroiditis (40.5%). Rates of transient hypocalcemia (11.4% - 74.2%), transient recurrent laryngeal nerve injury (0% - 9.7%), and bleeding (0.5% - 4.3%) varied across studies. Definitions for high-volume pediatric thyroid surgeons ranged from ≥9 annual pediatric thyroid operations to >200 annual thyroid operations (with >30 pediatric cases). Four studies reported significantly better outcomes, including lower post-operative complications and shorter length of hospital stay, for patients treated by high-volume surgeons. CONCLUSIONS: Despite significant variation in caseloads to define volume, pediatric thyroid patients have generally better outcomes when operated on by higher volume surgeons. Concentration thyroidectomy cases to a smaller cohort of surgeons within pediatric practices may confer improved outcomes. LEVEL OF EVIDENCE: Systematic Reviews and Meta-Analyses; Level IV.

Surgeon perceptions of volume threshold and essential practices for pediatric thyroidectomy✰.

INTRODUCTION: The topics of sub-specialization and regionalization of care have garnered increased attention among pediatric surgeons. Thyroid surgeries are one such sub-specialty and are commonly concentrated within practices. A national survey was conducted examining current surgeon practices and beliefs surrounding pediatric thyroid surgery. METHODS: Non-resident members of the American Pediatric Surgical Association (APSA) were surveyed in October 2020. Respondents were stratified based on self-reported thyroid surgical experience. Those who performed thyroid surgery were asked about surgical technique and operative practices; those who did not were asked about referral patterns. All respondents were asked about perceptions surrounding the volume-outcome relationship for pediatric thyroid surgery. RESULTS: Among 1015 APSA members, 405 (40%) responded, with 79% (317/400) practicing at academic hospitals, 58% (232/401) practicing in major metropolitan area, and 41% (161/392) with over 10 years of attending pediatric surgery experience. Most respondents (88%, n = 356) agreed that thyroid surgery volume affects outcome, though wide variation was reported in the annual case threshold for "high volume" surgery. Eighty-four respondents (21%) reported performing ≥ 1 pediatric thyroid surgery in the past year. Of these, 82% routinely use recurrent laryngeal nerve monitoring, 32% routinely send hemithyroidectomy patients home the same day, and there was little consensus surrounding postoperative hypocalcemia management. The majority of respondents endorse performing thyroid procedures with a colleague. CONCLUSIONS: Pediatric thyroid surgery appears to be performed by a subset of active pediatric surgeons, most of whom endorse the use of a dual operating team. More evidence is needed to build consensus around additional perioperative practices.

Long-term follow-up of children with in utero exposure to sulfonylurea medications.

BACKGROUND: Offspring born to mothers with gestational diabetes mellitus (GDM) are more likely to have negative neurodevelopmental health outcomes, early obesity, type 2 diabetes, and metabolic syndrome in childhood, adolescence, and adulthood. Standard of care management for GDM and type 2 diabetes mellitus during pregnancy is insulin, but oral sulfonylurea use is increasing, and these medications cross the placenta. Literature on treatment with sulfonylureas for maternal GDM has focused on maternal glycemic control and neonatal outcomes. Studies that have evaluated the long-term outcomes of children exposed to sulfonylureas in utero are limited. OBJECTIVE: This study evaluated anthropometric and neurodevelopmental outcomes of 55 children (ages 5-10) born to mothers with diabetes during pregnancy treated with sulfonylurea or insulin. METHODS AND RESULTS: A group of 25 sulfonylurea-exposed and 30 insulin-exposed participants were age- and sex-matched between groups. No significant differences were identified in z-scores for body mass index (BMI), waist circumference, skinfold measurements, and body fat or rates of overweight/obese BMI between groups. On performance-based cognitive assessment, the sulfonylurea-exposed group had significantly lower scores on inhibition (p = 0.043). CONCLUSION: In summary, children with in utero sulfonylurea exposure had similar physical measurements compared to children with insulin exposure and lower performance on a measure of executive function (inhibition), which is associated with adverse health outcomes.

Newborn Adiposity and Cord Blood C-Peptide as Mediators of the Maternal Metabolic Environment and Childhood Adiposity.

OBJECTIVE: Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity. RESEARCH DESIGN AND METHODS: Data on mother/offspring pairs (N = 4,832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow-up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes. RESULTS: In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, P value) BMI (0.26, 0.12-0.39, <0.001), BMI z-score (0.072, 0.033-0.11, <0.001), fat mass (kg) (0.51, 0.26-0.76, <0.001), percentage of body fat (0.61, 0.27-0.95, <0.001), and sum of skinfolds (mm) (1.14, 0.43-1.86, 0.0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2.5% and 1%, respectively), fat mass (3.1%, 1.2%), percentage of body fat (3.6%, 1.8%), and sum of skinfolds (2.9%, 1.8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22.0% and 21.0%, respectively), percentage of body fat (15.0%, 18.0%), and sum of skinfolds (15.0%, 20.0%). CONCLUSIONS: Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity.

Hypocalcemia prevention and management after thyroidectomy in children: A systematic review.

INTRODUCTION: Hypocalcemia is the most common complication following thyroidectomy in children. Guidelines to manage post-thyroidectomy hypocalcemia are available for adults, but not children. The objective of this review was to identify practices related to hypocalcemia prevention and management in pediatric patients. METHODS: We identified studies examining the prevention and management of hypocalcemia in pediatric patients post-thyroidectomy within PubMed, EMBASE, Web of Science and Cochrane databases. Three independent reviewers screened citations and reviewed full-text papers. RESULTS: A total of 15 studies were included, representing 1552 patients. The overall study quality was weak with lack of randomization and inconsistent outcome reporting. The pooled incidence of hypocalcemia from the 15 studies was 35.5% for transient hypocalcemia and 4.2% for permanent hypocalcemia. All studies discussed post-operative hypocalcemia treatment, with most patients requiring admission for intra-venous calcium therapy. One study described a protocol discharging asymptomatic patients on calcitriol and calcium. Three studies discussed preoperative calcium supplementation in patients at risk of hypocalcemia. No studies examined routine use of calcium and/or vitamin D supplementation to prevent post-operative hypocalcemia. CONCLUSION: A significant number of children undergoing thyroidectomy develop hypocalcemia. Despite this high incidence, our systematic review demonstrates significant practice variation surrounding post-thyroidectomy hypocalcemia prevention and management in children. LEVEL OF EVIDENCE: III (systematic review of studies of which some were case-control studies (III) and some were case series (IV)).

Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study: newborn anthropometrics and childhood glucose metabolism.

AIMS/HYPOTHESIS: We aimed to examine associations of newborn anthropometric measures with childhood glucose metabolism with the hypothesis that greater newborn birthweight, adiposity and cord C-peptide are associated with higher childhood glucose levels and lower insulin sensitivity. METHODS: Data from the international, multi-ethnic, population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study were used. The analytic cohort included 4155 children (mean age [SD], 11.4 [1.2] years; 51.0% male). Multiple linear regression was used to examine associations of primary predictors, birthweight, newborn sum of skinfolds (SSF) and cord C-peptide, from HAPO with continuous child glucose outcomes from the HAPO Follow-Up Study. RESULTS: In an initial model that included family history of diabetes and maternal BMI during pregnancy, birthweight and SSF demonstrated a significant, inverse association with 30 min and 1 h plasma glucose levels. In the primary model, which included further adjustment for maternal sum of glucose z scores from an oral glucose tolerance test during pregnancy, the associations were strengthened, and birthweight and SSF were inversely associated with fasting, 30 min, 1 h and 2 h plasma glucose levels. Birthweight and SSF were also associated with higher insulin sensitivity (Matsuda index) (ß = 1.388; 95% CI 0.870, 1.906; p < 0.001; ß = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (ß = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (ß = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model. CONCLUSIONS/INTERPRETATION: This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.

The Joint Associations of Maternal BMI and Glycemia with Childhood Adiposity.

CONTEXT: An obesogenic perinatal environment contributes to adverse offspring metabolic health. Previous studies have been limited by lack of direct adiposity measurements and failure to account for potential confounders. OBJECTIVE: Examine the joint associations of maternal midpregnancy body mass index (BMI) and glycemia with direct adiposity measures in 10-14 year old offspring. DESIGN AND SETTING: International, epidemiological study: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and HAPO Follow-up Study, conducted between 2000-2006 and 2013-2016, respectively. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 4832 children, adiposity measures for body mass index (BMI), body fat with air displacement plethysmography, skinfold thickness, and waist circumference were obtained at mean age 11.4 years. RESULTS: Maternal BMI and glucose, as continuous and categorical variables, were the primary predictors. In fully adjusted models controlling for child age, sex, field center, and maternal characteristics, maternal BMI had significant, positive associations with all childhood adiposity outcomes, while maternal glycemia had significant, positive associations with childhood adiposity outcomes except BMI. In joint analyses, and compared with a nonobese, nongestational diabetes mellitus (GDM) reference group, maternal obesity and GDM were associated with higher odds (maternal obesity odds ratio; OR [95% confidence interval; CI], GDM OR [95% CI]; combined OR [95% CI]) of childhood overweight/obese BMI (3.00 [2.42-3.74], 1.39 [1.14-1.71], 3.55 [2.49-5.05]), obese BMI (3.54 [2.70-4.64], 1.73 [1.29-2.30], 6.10 [4.14-8.99]), percent body fat >85th percentile (2.15 [1.68-2.75], 1.33 [1.03-1.72], 3.88 [2.72-5.55]), sum of skinfolds >85th percentile (2.35 [1.83-3.00], 1.75 [1.37-2.24], 3.66 [2.55-5.27]), and waist circumference >85th percentile (2.52 [1.99-3.21], 1.39 [1.07-1.80], 4.18 [2.93-5.96]). CONCLUSIONS: Midpregnancy maternal BMI and glycemia are independently and additively associated with direct adiposity measures in 10-14 year old children. The combination of maternal obesity and GDM is associated with the highest odds of childhood adiposity.

One-year postpartum anthropometric outcomes in mothers and children in the LIFE-Moms lifestyle intervention clinical trials.

BACKGROUND/OBJECTIVES: Excess gestational weight gain (GWG) is a risk factor for maternal postpartum weight retention and excessive neonatal adiposity, especially in women with overweight or obesity. Whether lifestyle interventions to reduce excess GWG also reduce 12-month maternal postpartum weight retention and infant weight-for-length z score is unknown. Randomized controlled trials from the LIFE-Moms consortium investigated lifestyle interventions that began in pregnancy and tested whether there was benefit through 12 months on maternal postpartum weight retention (i.e., the difference in weight from early pregnancy to 12 months) and infant-weight-for-length z scores. SUBJECTS/METHODS: In LIFE-Moms, women (N = 1150; 14.1 weeks gestation at enrollment) with overweight or obesity were randomized within each of seven trials to lifestyle intervention or standard care. Individual participant data were combined and analyzed using generalized linear mixed models with trial entered as a random effect. The 12-month assessment was completed by 83% (959/1150) of women and 84% (961/1150) of infants. RESULTS: Compared with standard care, lifestyle intervention reduced postpartum weight retention (2.2 ± 7.0 vs. 0.7 ± 6.2 kg, respectively; difference of -1.6 kg (95% CI -2.5, -0.7; p = 0.0003); the intervention effect was mediated by reduction in excess GWG, which explained 22% of the effect on postpartum weight retention. Lifestyle intervention also significantly increased the odds (OR = 1.68 (95% CI, 1.26, 2.24)) and percentage of mothers (48.2% vs. 36.2%) at or below baseline weight at 12 months postpartum (yes/no) compared with standard care. There was no statistically significant treatment group effect on infant anthropometric outcomes at 12 months. CONCLUSIONS: Compared with standard care, lifestyle interventions initiated in pregnancy and focused on healthy eating, increased physical activity, and other behavioral strategies resulted in significantly less weight retention but similar infant anthropometric outcomes at 12 months postpartum in a large, diverse US population of women with overweight and obesity.

Association of cord blood methylation with neonatal leptin: An epigenome wide association study.

BACKGROUND: Neonatal adiposity is a risk factor for childhood obesity. Investigating contributors to neonatal adiposity is important for understanding early life obesity risk. Epigenetic changes of metabolic genes in cord blood may contribute to excessive neonatal adiposity and subsequent childhood obesity. This study aims to evaluate the association of cord blood DNA methylation patterns with anthropometric measures and cord blood leptin, a biomarker of neonatal adiposity. METHODS: A cross-sectional study was performed on a multiethnic cohort of 114 full term neonates born to mothers without gestational diabetes at a university hospital. Cord blood was assayed for leptin and for epigenome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariable linear regression was used to analyze associations between individual CpG sites as well as differentially methylated regions in cord blood DNA with measures of newborn adiposity including anthropometrics (birth weight, fat mass and percent body fat) and cord blood leptin. False discovery rate was estimated to account for multiple comparisons. RESULTS: 247 CpG sites as well as 18 differentially methylated gene regions were associated with cord blood leptin but no epigenetic changes were associated with birth weight, fat mass or percent body fat. Genes of interest identified in this study are DNAJA4, TFR2, SMAD3, PLAG1, FGF1, and HNF4A. CONCLUSION: Epigenetic changes in cord blood DNA are associated with cord blood leptin levels, a measure of neonatal adiposity.

Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes.

PURPOSE OF REVIEW: This review will focus on the long-term outcomes in offspring exposed to in utero hyperglycemia and gestational diabetes (GDM), including obesity, adiposity, glucose metabolism, hypertension, hyperlipidemia, nonalcoholic fatty liver disease, and puberty. RECENT FINDINGS: There is evidence, mostly from observational studies, that offspring of GDM mothers have increased risk of obesity, increased adiposity, disorders of glucose metabolism (insulin resistance and type 2 diabetes), and hypertension. In contrast, evidence from the two intervention studies of treatment of mild GDM and childhood measures of BMI, adiposity, and glucose tolerance do not demonstrate that GDM treatment significantly reduces adverse childhood metabolic outcomes. Thus, more evidence is needed to understand the impact of maternal GDM on offspring's adiposity, glucose metabolism, lipid metabolism, risk of fatty liver disease, and pubertal onset. Offspring of GDM mothers may have increased risk for metabolic and cardiovascular complications. Targeting this group for intervention studies to prevent obesity and disorders of glucose metabolism is one potential strategy to prevent adverse metabolic health outcomes.