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Obesity is one of the biggest challenges facing global reproductive health. Women in the UK and USA are today more likely to be obese or overweight at booking than normal weight, and many low-and middle-income countries (LMICs) seem destined to follow suit (Poston et al. Lancet Diabetes Endocrinol 2016;4:1025-36). Understanding how, and to what extent, maternal body mass index (BMI) and weight gain during pregnancy contribute to adverse outcomes for mothers and their offspring is therefore vital to informing future health policy.In an individual participant data meta-analysis of over 265 000 births, Santos et al. (BJOG 2019;126:984-95) confirm strong correlations between pre-pregnancy maternal BMI and the risks of gestational hypertension, preeclampsia and gestational diabetes. Over one-third of such complications in the study population were considered attributable to maternal overweight and obesity. The risk of large size for gestational age (LGA) at birth increased similarly across all categories of pre-pregnancy BMI and gestational weight gain, although these data should be interpreted in the context of a continuing debate regarding the customisation of fetal growth charts. It remains uncertain how maternal height and weight influence fetal growth potential, and whether LGA babies born to mothers who are obese or mothers with excessive weight gain carry the same short-and long-term health risks as LGA babies born to mothers who are normal weight. Preterm birth was also more common among women who are obese and past literature has suggested that this association is strongest for extremely preterm delivery (Cnattingius et al. JAMA 2013;309:2362-70), whether spontaneous or iatrogenic.Whereas women who are obese or have high weight gain are consistently shown to be at greatest risk, there is clear evidence of a continuum of risk across the full BMI range, which is emphasised by the authors' use of population attributable risk (PAR). Notably, the overall burden of pregnancy complications is similar in overweight and obese groups (PAR 11.4 and 12.5%, respectively). This calls into question traditional models of care targeting women with a booking BMI above 30 kg/m 2 or even higher thresholds. Minimising gestational weight gain in these women ameliorates but does not remove the excess risk, and ultimately may have less impact on outcomes at a population level than previously hoped.The authors acknowledge that the data were derived from cohorts who were largely white; however, comparable findings have been reported in LMICs with varied ethnic populations (Rahman et al. Obes Rev 2015;16:758-70).Being healthy entails more than just not being obese, and the study also draws important attention to the risks of small size for gestational age and preterm birth, particularly amongst underweight women with inadequate weight gain during pregnancy. These findings strengthen the argument for novel public health approaches to optimise maternal health with a shift in focus towards pre-conception and interpregnancy intervent...

OBJECTIVETo characterize physiologic subtypes of gestational diabetes mellitus (GDM).RESEARCH DESIGN AND METHODSInsulin sensitivity and secretion were estimated in 809 women at 24–30 weeks' gestation, using oral glucose tolerance test–based indices. In women with GDM (8.3%), defects in insulin sensitivity or secretion were defined below the 25th percentile in women with normal glucose tolerance (NGT). GDM subtypes were defined based on the defect(s) present.RESULTSRelative to women with NGT, women with predominant insulin sensitivity defects (51% of GDM) had higher BMI and fasting glucose, larger infants (birth weight z score 0.57 [−0.01 to 1.37] vs. 0.03 [−0.53 to 0.52], P = 0.001), and greater risk of GDM-associated adverse outcomes (57.6 vs. 28.2%, P = 0.003); differences were independent of BMI. Women with predominant insulin secretion defects (30% of GDM) had BMI, fasting glucose, infant birth weights, and risk of adverse outcomes similar to those in women with NGT.CONCLUSIONSHeterogeneity of physiologic processes underlying hyperglycemia exists among women with GDM. GDM with impaired insulin sensitivity confers a greater risk of adverse outcomes.

IMPORTANCE Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges. OBJECTIVES To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories. DESIGN, SETTING, AND PARTICIPANTS Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015. EXPOSURES Gestational weight gain. MAIN OUTCOMES AND MEASURES The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth. RESULTS Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI <18.5); 133 788 (68.0%), normal weight (BMI, 18.5-24.9); 38 828 (19.7%), overweight (BMI, 25.0-29.9); 11 992 (6.1%), obesity grade 1 (BMI, 30.0-34.9); 3284 (1.7%), obesity grade 2 (BMI, 35.0-39.9); and 969 (0.5%), obesity grade 3 (BMI, Ն40.0). Overall, any adverse outcome occurred in 37.2% (n = 73 161) of women, ranging from 34.7% (2706 of 7809) among women categorized as underweight to 61.1% (592 of 969) among women categorized as obesity grade 3. Optimal gestational weight gain ranges were 14.0 kg to less than 16.0 kg for women categorized as underweight; 10.0 kg to less than 18.0 kg for normal weight; 2.0 kg to less than 16.0 kg for overweight; 2.0 kg to less than 6.0 kg for obesity grade 1; weight loss or gain of 0 kg to less than 4.0 kg for obesity grade 2; and weight gain of 0 kg to less than 6.0 kg for obesity grade 3. These gestational weight gain ranges were associated with low to moderate discrimination between those with and those without adverse outcomes (range for area under the receiver operating characteristic curve, 0.55-0.76). Results for discriminative performance in the validation sample were similar to the corresponding results in the main study sample (range for area under the receiver operating characteristic curve, 0.51-0.79). CONCLUSIONS AND RELEVANCE In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational wei...

The progressive increase of insulin resistance observed in pregnancy contributes to the pathophysiology of gestational diabetes mellitus (GDM). There is controversy whether vitamin D deficiency contributes to abnormal glycemic regulation in pregnancy. We tested the associations between first trimester 25-hydroxyvitamin D (25OHD) levels and: 1) the risk of developing GDM; 2) insulin resistance/sensitivity, beta cell function and compensation indices in a large population-based prospective cohort of pregnant women. Participants (n = 655) were seen at first (6-13 weeks) and second (24-28 weeks) trimesters for blood samples. At first trimester, 25OHD levels were measured. At second trimester, glucose and insulin were measured 3 times during the oral glucose tolerance test to estimate insulin resistance (HOMA-IR), beta cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUCins/gluc) and beta cell compensation (ISSI-2). Based on IADPSG criteria, 54 participants (8.2 %) developed GDM. Lower first trimester 25OHD levels were associated with higher risk of developing GDM even after adjustment for vitamin D confounding factors and GDM risk factors (OR = 1.48 per decrease of one SD in 25OHD levels; P = 0.04). Lower first trimester 25OHD levels were associated with higher HOMA-IR (r = - 0.08; P = 0.03), lower Matsuda index (r = 0.13; P = 0.001) and lower ISSI-2 (r = 0.08; P = 0.04). After adjustment for confounders, we found no significant association with HOMA-B and AUCins/gluc. Our results suggest that low levels of 25OHD at first trimester are (1) an independent risk factor for developing GDM and (2) associated with insulin resistance at second trimester.

OBJECTIVETo evaluate the associations between adiponectin levels and 1) the risk of developing gestational diabetes mellitus (GDM), and 2) insulin resistance/sensitivity, β-cell function, and compensation indices in a prospective cohort representative of the general population of pregnant women.RESEARCH DESIGN AND METHODSWe performed anthropometric measurements and collected blood samples at 1st (6–13 weeks) and 2nd (24–28 weeks) trimesters. Diagnosis of GDM was made at 2nd trimester based on a 75-g oral glucose tolerance test (International Association of the Diabetes and Pregnancy Study Groups criteria). Insulin was measured (ELISA; Luminex) to estimate homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUCinsulin/glucose), and β-cell compensation (insulin secretion sensitivity index-2). Adiponectin was measured by radioimmunoassay.RESULTSAmong the 445 participants included in this study, 38 women developed GDM. Women who developed GDM had lower 1st-trimester adiponectin levels (9.67 ± 3.84 vs. 11.92 ± 4.59 µg/mL in women with normal glucose tolerance). Lower adiponectin levels were associated with higher risk of developing GDM (OR, 1.12 per 1 µg/mL decrease of adiponectin levels; P = 0.02, adjusted for BMI and HbA1c at 1st trimester). Adiponectin levels at 1st and 2nd trimesters were associated with HOMA-IR (both: r = −0.22, P < 0.0001) and Matsuda index (r = 0.28, P < 0.0001, and r = 0.29, P < 0.0001). After adjustment for confounding factors, we found no significant association with HOMA-B and AUCinsulin/glucose.CONCLUSIONSPregnant women with lower adiponectin levels at 1st trimester have higher levels of insulin resistance and are more likely to develop GDM independently of adiposity or glycemic measurements.

BackgroundGestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies.MethodsWe used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape.ResultsWe observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4–17.4) for underweight women, 14.5 kg (11.5–17.7) for normal weight women, 13.9 kg (10.1–17.9) for overweight women, and 11.2 kg (7.0–15.7), 8.7 kg (4.3–13.4) and 6.3 kg (1.9–11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications.ConclusionsGestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1189-1) contains supplementary material, which is available to authorized users.

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS 10 ) and showed it was an adequate instrumental variable (b D 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE D 0.007; P D 7.8 £ 10 ¡11 ; N D 467). A higher GRS 10 was associated with lower methylation levels at cg12083122 located near LEP (b D ¡0.072 unit per additional risk allele; SE D 0.04; P D 0.05; N D 166). Direction and effect size of association between the instrumental variable GRS 10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (b D ¡0.17 log of cord blood leptin per unit; SE D 0.07; P D 0.01; N D 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.