Parental Height and Weight Influence Offspring Adiposity at 2 Years; Findings from the ROLO Kids Birth Cohort Study

Objective The perinatal period and in utero environment are important for fetal growth, development, and fetal programming. This study aimed to determine the effect of parental anthropometry and the maternal metabolic milieu on offspring adiposity at 2 years of age. Study Design This longitudinal birth cohort includes analysis of maternal (n = 337) and paternal (n = 219) anthropometry and maternal and fetal metabolic markers (n = 337), including glucose, homeostatic model of assessment (HOMA), C-peptide, and leptin from participants of the ROLO (the Randomized Control Trial of Low) pregnancy study, and their partners, to determine an association with offspring anthropometry at two years of age. Results Linear regression, when adjusted for confounders, indicated maternal and paternal anthropometry and was associated with offspring weight and length at 2 years of age. Maternal height was negatively associated with general adiposity in the total cohort of children (p = 0.002) and in female children (p = 0.006) and central adiposity in the total child cohort (p < 0.001). Paternal height was also negatively associated with general adiposity in all children (p = 0.002) and central adiposity in total (p = 0.023) and female children (p = 0.008). Maternal glucose, insulin resistance, and fetal C-peptide positively correlated with anthropometry in total, male, and female children. Conclusion Parental anthropometry in the perinatal period has a long-lasting effect on offspring anthropometry beyond the neonatal period. Maternal and fetal metabolic factors influence adiposity, and this extends beyond the perinatal period. Parental adiposity may play a significant role in early childhood adiposity and may be a target for interventions to decrease the risk of early childhood obesity. Key Points

Maternal Carbohydrate Intake During Pregnancy is Associated with Child Peripubertal Markers of Metabolic Health but not Adiposity

Objective: Examine the associations of trimester-specific maternal prenatal carbohydrate (CHO) intake with offspring adiposity and metabolic health during the peripuberty. Design: Prospective cohort study in which maternal dietary intake was collected via validated food frequency questionnaire (FFQ) during each trimester. Offspring adiposity and metabolic biomarkers were evaluated at age 8-14y. We used multivariable linear regression to examine associations between total-energy adjusted maternal CHO intake and offspring Body Mass Index z-score (BMIz), skinfold thickness, and metabolic syndrome risk z-score (MetRiskz) calculated as the average of waist circumference, fasting glucose, fasting C-peptide, triglyceride:HDL, and systolic blood pressure + diastolic blood pressure/2. Setting: Mexico City, Mexico Subjects: N=237 mother-child pairs in the ELEMENT cohort. Results: We found non-linear associations of maternal CHO intake during pregnancy with offspring metabolic health during peripuberty. After adjusting for maternal age, and child age, sex, and pubertal status, children whose mothers were in the 4th vs 1st quartile of total CHO intake during the 3rd trimester had 0.42 (95% CI: −0.01, 0.08) ng/mL lower C-peptide and 0.10 (95% CI: −0.02, 0.22) units lower CP-IR. We found similar magnitude and direction of association with respect to net CHO intake during the 1st trimester and offspring C-peptide and CP-IR. Maternal CHO intake during pregnancy was not associated with offspring adiposity. Conclusions: In this study of mother-child pairs in Mexico City, children born to women in the highest quartile of CHO intake during pregnancy had lowest C-peptide and CP-IR during peripuberty. Additional research is warranted to replicate and identify mechanisms.

A Role for the Pregravid Maternal Milieu in the Intergenerational Transmission of Obesity

Objectives Maternal obesity increases the risk for adverse pregnancy and offspring outcomes; however, with large heterogeneity. We hypothesize that in mothers with obesity, the heterogeneity of offspring adiposity is due to prolonged exposure to excess maternal substrates, namely glucose and triglycerides, which promote fetal fat accretion. The aims of this prospective observational study were to 1) examine the maternal metabolic milieu in pregnant women with metabolically unhealthy obesity, MUO and metabolically healthy obesity, MHO; and 2) identify if these maternal metabolic phenotypes in women with obesity influence infant adiposity. Methods During early pregnancy, 51 women with obesity were classified to have MUO (n = 9) or MHO (n = 13) based on the presence of zero (MHO) or ≥ 2 (MUO) risk factors for metabolic syndrome (SBP &gt; 130 or DBP &gt; 85, HDL &lt; 50 mg/dL, LDL ≥ 100 mg/dL, triglycerides ≥ 150 mg/dL, and glucose ≥ 100 mg/dL). Area under the pregnancy concentration curve (AUC) for glucose and triglycerides, gestational weight gain (GWG), fat accretion, and energy intake and expenditure from early (13–16 wks), mid (24–27 wks) to late (35–37 wks) pregnancy and infant fat mass were compared between groups. Results Compared to women with MHO, women with MUO were not different with respect to maternal BMI, GWG, fat accretion, energy and macronutrient intake, and energy expenditure. In both groups, maternal substrates changed similarly from ∼13 to ∼37 weeks of pregnancy, however MUO resulted in greater pregnancy AUC for glucose (+2169.7 ± 381.5 p &lt; 0.001 mg/dL · day) and triglycerides (+12,210.5 ± 3916.1 mg/dL · day, p &lt; 0.001). The offspring of women with MHO had significantly lower birth weight (−620.8 ± 204.6 g, p = 0.01), body fat percentage (−5.8 ± 2.1%, p = 0.02), and total fat mass (−268.8 ± 88.4 g, p = 0.01). Conclusions Differing obesity phenotypes in pregnancy may explain the heterogeneity of offspring adiposity. Metabolically unhealthy obesity resulted in a more prolonged exposure of fetal fat promoting substrates and increased adiposity at birth. This study identifies a population of women with obesity most in need of prenatal interventions and suggests that obesity phenotypes need to be considered when evaluating intervention effect on offspring outcomes. Funding Sources R01DK099175.

Maternal nutrition and its intergenerational links to non-communicable disease metabolic risk factors: a systematic review and narrative synthesis

Background Non-communicable diseases (NCDs) are the leading cause of death and disability globally, while malnutrition presents a major global burden. An increasing body of evidence suggests that poor maternal nutrition is related to the development of NCDs and their risk factors in adult offspring. However, there has been no systematic evaluation of this evidence. Methods We searched eight electronic databases and reference lists for primary research published between 1 January 1996 and 31 May 2016 for studies presenting data on various dimensions of maternal nutritional status (including maternal exposure to famine, maternal gestational weight gain (GWG), maternal weight and/or body mass index (BMI), and maternal dietary intake) during pregnancy or lactation, and measures of at least one of three NCD metabolic risk factors (blood pressure, blood lipids and blood glucose) in the study population of offspring aged 18 years or over. Owing to high heterogeneity across exposures and outcomes, we employed a narrative approach for data synthesis (PROSPERO= CRD42016039244, CRD42016039247). Results Twenty-seven studies from 10 countries with 62,607 participants in total met our inclusion criteria. The review revealed considerable heterogeneity in findings across studies. There was evidence of a link between maternal exposure to famine during pregnancy with adverse blood pressure, blood lipid, and glucose metabolism outcomes in adult offspring in some contexts, with some tentative support for an influence of adult offspring adiposity in this relationship. However, the evidence base for maternal BMI, GWG, and dietary intake of specific nutrients during pregnancy was more limited and revealed no consistent support for a link between these exposures and adult offspring NCD metabolic risk factors. Conclusion The links identified between maternal exposure to famine and offspring NCD risk factors in some contexts, and the tentative support for the role of adult offspring adiposity in influencing this relationship, suggest the need for increased collaboration between maternal nutrition and NCD sectors. However, in view of the current scant evidence base for other aspects of maternal nutrition, and the overall heterogeneity of findings, ongoing monitoring and evaluation using large prospective studies and linked data sets is a major priority.

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomization using polygenic risk scores

BackgroundIt has been hypothesised that greater maternal adiposity before or during pregnancy causes greater offspring adiposity in childhood and adulthood, via causal intrauterine or periconceptional mechanisms. Previous Mendelian randomization (MR) estimates were imprecise, with wide confidence intervals that included potentially important protective or adverse effects, and may have been biased by collider effects or imperfect adjustment for genetic inheritance. Here we use an improved MR approach to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal, or are instead due to confounding.Methods and findingsWe undertook confounder adjusted multivariable (MV) regression and Mendelian randomization (MR) using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB the outcomes were birthweight (BW; N = 9339) and BMI at age 1 (N = 8659) and 4 years (N = 7575), and in ALSPAC only we investigated BMI at 10 (N = 4476) and 15 years (N = 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10– 18 years (N = 2659 to 3855). We compared MR results from several polygenic risk scores (PRS), calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). MV and MR showed a consistent positive association of maternal BMI with BW, but for adiposity at most older ages MR estimates were weaker than MV estimates. In MV regression a one standard deviation (SD) higher maternal BMI was associated with a 0.13 (95% confidence interval [CI]: 0.10, 0.16) SD increase in offspring BW. The corresponding MR estimate from the strongest PRS (including up to 80,939 SNPs) was 0.14 (95% CI: 0.05, 0.23), with no difference between the two estimates (Pdifference = 0.84). For 15 year BMI the MV and MR estimates (80,939 SNPs) were 0.32 (95% CI: 0.29, 0.36) and 0.13 (95% CI: 0.01, 0.24) respectively (Pdifference = 1.0e-3). Results for FMI were similar to those for adolescent BMI. As the number of SNPs included in the PRS increased, the MR confidence intervals narrowed and the effect estimates for adolescent adiposity became closer to the MV estimates. Sensitivity analyses suggested the stronger effects with more SNPs were explained by horizontal pleiotropic bias away from zero. Consequently, the unbiased difference between the MV and MR estimates is probably greater than shown in our main analyses. Furthermore, MR estimates from IVs with fewer SNPs provided no strong evidence for a causal effect on adolescent adiposity.ConclusionsOur results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.

Neonatal amygdala microstructure mediates the relationship between gestational glycemia and offspring adiposity

IntroductionTo determine if variations in the neonatal amygdala mediate the association between maternal antenatal glycemia and offspring adiposity in early childhood.Research design and methods123 non-obese pregnant women with no pregnancy complications aside from gestational diabetes underwent a 75 g 2-hour oral glucose tolerance test at 26–28 weeks’ gestation. Volume and fractional anisotropy (FA) of the neonatal amygdala (5–17 days old) were measured by MRI. The Body Mass Index (BMI) z-scores and sum of skinfold thickness (subscapular and triceps) of these children were tracked up to 60 months of age (18, 24, 36, 48, 54 and 60 months).ResultsMaternal fasting glucose levels were positively associated with the offspring’s sum of skinfold thickness at age 48 months (β=3.12, 95% CI 0.18 to 6.06 mm) and 60 months (β=4.14, 95% CI 0.46 to 7.82 mm) and BMI z-scores at 48 months (β=0.94, 95% CI 0.03 to 1.85), 54 months (β=0.74, 95% CI 0.12 to 1.36) and 60 months (β=0.74, 95% CI 0.08 to 1.39). Maternal fasting glucose was negatively associated with the offspring’s FA of the right amygdala (β=−0.019, 95% CI −0.036 to −0.003). Right amygdala FA was negatively associated with the sum of skinfold thickness in the offspring at age 48 months (β=−56.95, 95% CI −98.43 to −15.47 mm), 54 months (β=−46.18, 95% CI −88.57 to −3.78 mm), and 60 months (β=−53.69, 95% CI −105.74 to −1.64 mm). The effect sizes mediated by right amygdala FA between fasting glucose and sum of skinfolds were estimated at β=5.14 (95% CI 0.74 to 9.53) mm (p=0.022), β=4.40 (95% CI 0.08 to 8.72) (p=0.049) mm and β=4.56 (95% CI −0.17 to 9.29) mm (p=0.059) at 48, 54 and 60 months, respectively.ConclusionsIn the offspring of non-obese mothers, gestational fasting glucose concentration is negatively associated with neonatal right amygdala FA and positively associated with childhood adiposity. Neonatal right amygdala FA may be a potential mediator between maternal glycemia and childhood adiposity.

Macronutrient intake during pregnancy in women with a history of obesity or gestational diabetes and offspring adiposity at 5 years of age

Background/objectives The impact of maternal macronutrient intake during pregnancy on offspring childhood adiposity is unclear. We assessed the associations between maternal macronutrient intake during and after pregnancy with offspring adiposity at 5 years of age. Additionally, we investigated whether gestational diabetes (GDM), BMI, or breastfeeding modified these associations. Subjects/methods Altogether, 301 mother–child dyads with maternal prepregnancy BMI ≥ 30 and/or previous GDM participated in the Finnish Gestational Diabetes Prevention Study (RADIEL) and its 5 years follow-up. Macronutrient intakes (E%) were calculated from 3-day food records collected at 5–18 weeks’ gestation, in the third trimester, and at 12 months and 5 years after pregnancy. Offspring body fat mass (BFM) and fat percentage (BF%) at 5 years were measured by bioimpedance. Statistical analyses were multivariate linear regression. Results Mean (SD) prepregnancy BMI was 33(4) kg/m2. GDM was diagnosed in 47%. In normoglycemic women, higher first half of pregnancy n-3 PUFA intake was associated with lower offspring BFM (g) (ß −0.90; 95% CI −1.62, −0.18) and BF% (ß −3.45; 95% CI −6.17, −0.72). In women with GDM, higher first half of pregnancy n-3 PUFA intake was associated with higher offspring BFM (ß 0.94; 95% CI 0.14, 1.75) and BF% (ß 3.21; 95% CI 0.43, 5.99). Higher SFA intake in the third trimester and cumulative intake across pregnancy (mean of the first half and late pregnancy) was associated with higher BFM and BF% (across pregnancy: ß 0.12; 95% CI 0.03, 0.20 and ß 0.44; 95% CI 0.15, 0.73, respectively). Higher carbohydrate intake across pregnancy was associated with lower BFM (ß −0.044; 95% CI −0.086, −0.003), and borderline associated with BF% (ß −0.15; 95% CI −0.31, 0.00). Conclusions The macronutrient composition of maternal diet during pregnancy is associated with offspring BFM and BF% at 5 years. GDM modifies the association between prenatal n-3 PUFA intake and offspring anthropometrics.