UC Berkeley

Although the obesity epidemic in the United States appears to be leveling off, over half of all reproductive aged women in the U.S. are overweight [defined as body mass index (BMI) ≥25 kg/m²] or obesity [defined as body mass index (BMI) ≥30 kg/m²]. Overweight and obese women are more likely to suffer from a variety of reproductive complications, including adverse perinatal outcomes; overweight and obesity are also well-established risk factors for gestational diabetes and type 2 diabetes. Gestational diabetes mellitus (GDM), defined as carbohydrate intolerance leading to hyperglycemia with first onset or recognition during pregnancy, complicates 7% to 10% of pregnancies in the U.S. Type 2 diabetes mellitus (T2DM) is emerging as a leading cause of death and disability in the U.S. and currently straining the health care system.

This goal of this dissertation is to investigate the effects of periconceptual and prenatal maternal glucose levels on immediate and longer-term offspring outcomes. Three studies were undertaken, comprising three chapters, to complete this dissertation; all utilize a cohort study design, with data obtained from several sources. The study described in the first chapter examines the association between periconceptual maternal glycaemia and newborn sex ratio in a large data set from Kaiser Permanente Northern California. Women were categorized into the following groups: overt pregravid diabetes, gestational diabetes, mild pregnancy hyperglycemia and normoglycemic pregnancies. It has long been hypothesized that natural selection would favor a reproductive strategy biased towards females under adverse circumstances and males under favorable conditions in order to maximize the number of surviving grandchildren. Thus, I hypothesized that women with overt pregravid diabetes would exhibit the lowest newborn sex ratio (ratio of males to females at birth, i.e. more girls) due to the unfavorable state of chronic disease and women with gestational diabetes would exhibit the highest sex ratio (i.e. more boys) due to the presence of excessive fuel substrates early in pregnancy.

The study described in the second chapter explores programming for childhood obesity by maternal pregnancy glucose levels in women without recognized diabetes or gestational diabetes; the study comprising the third chapter considers the association between pregnancy glucose levels in these same women and cardiometabolic risk factors in their children at 7 years of age. Data for chapters 2 and 3 come from the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) longitudinal birth cohort. Several studies have demonstrated an increased risk for childhood obesity and adverse cardiometabolic profiles among children exposed to maternal diabetes or gestational diabetes in utero. Yet no study has considered the risk of childhood obesity across several ages or examined the childhood growth trajectory associated with increasing maternal glucose levels among children who were not exposed to maternal diabetes or gestational diabetes in utero. Likewise, little is known regarding the association between increasing maternal glucose levels and childhood cardiometabolic risk factors among children who were not exposed to maternal diabetes or gestational diabetes in utero. There appears to be a continuous association between increasing maternal glucose levels and the risk of several perinatal complications in infants born to women whose pregnancies were not complicated by diabetes, thus it is plausible that increasing pregnancy glucose levels below those diagnostic of disease could also be associated with longer-term adverse outcomes in the offspring.

In the first study, examination of the crude sex ratio across categories of maternal glycemia suggested a trend consistent with my hypothesis, but the odds ratio estimates did not attain statistical significance. The second study found a significant association between maternal pregnancy glucose levels in women without recognized diabetes or gestational diabetes and increased BMI z-score at 7 years of age in their children. The third study discovered that maternal pregnancy glucose levels in the same population were significantly associated with increased cardiometabolic risk in the children, specifically increased blood pressure and waist circumference. The results of studies two and three extend upon research in women with overt, recognized diabetes or gestational diabetes during pregnancy and lend additional support to the developmental origins of disease hypothesis. The findings of this dissertation indeed suggest that periconceptual and prenatal maternal glucose levels effect immediate and longer-term offspring outcomes. Of particular concern are the findings of studies two and three, which suggest programming for adverse childhood outcomes in women without recognized, overt disease. Given the epidemic of obesity in the U.S. and the relationship between obesity and increased levels of glycemia, these findings suggest the need for lifestyle interventions targeting maternal pregravid obesity and mildly increased levels of pregnancy glycemia in order to improve the health of the next generation.