Sneha B. Sridhar

Racial/Ethnic Disparities in the Prevalence of Gestational Diabetes Mellitus by BMI

OBJECTIVE To examine whether the association between gestational diabetes mellitus (GDM) and BMI category varies by racial/ethnic group. RESEARCH DESIGN AND METHODS In a cohort of 123,040 women without recognized pregravid diabetes who delivered babies between 1995 and 2006 at Kaiser Permanente of Northern California, we examined racial/ethnic disparities in the prevalence of GDM by BMI category and the population-attributable risk (PAR) associated with overweight/obesity. RESULTS Among all racial/ethnic groups, the age-adjusted prevalence of GDM increased with increasing BMI (kg/m2) category. However, Asian and Filipina women had a prevalence of GDM of 9.9 and 8.5%, respectively, at a BMI of 22.0–24.9 kg/m2, whereas in Hispanic, non-Hispanic white, and African American women, the prevalence of GDM was >8.0% at a higher BMI, such as 28–30, 34–36, and ≥37 kg/m2, respectively. The estimated PARs suggest that the percentage of GDM that could be prevented if all pregnant women were of normal weight (BMI <25.0 kg/m2) ranging from 65% for African American women to only 23% among Asian women. CONCLUSIONS Clinicians should be aware that the BMI thresholds for increased risk of GDM varies by racial/ethnic group and that the risk is high even at relatively low BMI cutoffs in Asian and Filipina women. Asian women may benefit from different prevention strategies in addition to weight management.

Maternal gestational weight gain and offspring risk for childhood overweight or obesity

OBJECTIVE The objective of the study was to evaluate the association between gestational weight gain, per the 2009 Institute of Medicine (IOM) recommendations, and offspring overweight/obesity at 2-5 years of age. STUDY DESIGN This was a prospective cohort study of 4145 women who completed a health survey (2007-2009) and subsequently delivered a singleton at Kaiser Permanente Northern California (2007-2010). Childhood overweight/obesity was defined as a body mass index (BMI) z-score of the 85th percentile or greater of the Centers for Disease Control and Prevention child growth standards. Gestational weight gain was categorized according to the 2009 IOM recommendations. Logistic regression was used; meeting the IOM recommendations was the referent. RESULTS Exceeding the IOM recommendations was associated with a 46% increase in odds of having an overweight/obese child (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.17-1.83), after adjusting for maternal prepregnancy BMI, race/ethnicity, age at delivery, education, child age, birthweight, gestational age at delivery, gestational diabetes, parity, infant sex, total metabolic equivalents, and dietary pattern. The OR (95% CI) for childhood overweight/obesity among women gaining below the IOM recommendations was 1.23 (0.88-1.71). The associations between gaining outside the IOM recommendations and childhood obesity were stronger among women with a normal prepregnancy BMI (OR, 1.63; 95% CI, 1.03-2.57) (below); OR, 1.79; 95% CI, 1.32-2.43) (exceeded). CONCLUSION Gestational weight gain outside the IOM recommendations is associated with increased odds of childhood overweight/obesity, independent of several potential confounders and mediators. Gestational weight gain had a greater impact on childhood overweight/obesity among normal-weight women, suggesting that the effect may be independent of genetic predictors of obesity.

Low Prepregnancy Adiponectin Concentrations Are Associated With a Marked Increase in Risk for Development of Gestational Diabetes Mellitus

OBJECTIVE To examine whether circulating total and high–molecular weight (HMW) adiponectin concentrations, measured before pregnancy, are associated with subsequent risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up exam (1984–1996) with a serum sample obtained and who had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case subjects were the 256 women who developed GDM. Two control subjects were selected for each case and matched for year of blood draw, age at exam, age at pregnancy, and number of intervening pregnancies. RESULTS Compared with the highest quartile of adiponectin, the risk of GDM increased with decreasing quartile (odds ratio [OR] 1.5 [95% CI 0.7–2.9], 3.7 [1.9–7.2], and 5.2 [2.6–10.1]; Ptrend <0.001) after adjustment for family history of diabetes, BMI, parity, race/ethnicity, cigarette smoking, and glucose and insulin concentrations. Similar estimates were observed for HMW (Ptrend <0.001). The combined effects of having total adiponectin levels below the median (<10.29 mg/mL) and being overweight or obese (BMI ≥25.0 kg/m2) were associated with a sevenfold increased risk of GDM compared with normal-weight women with adiponectin levels above the median (OR 6.7 [95% CI 3.6–12.5]). CONCLUSIONS Prepregnancy low adiponectin concentrations, a marker of decreased insulin sensitivity and altered adipocyte endocrine function, is associated with reduced glucose tolerance during pregnancy and may identify women at high risk for GDM to target for early intervention.

Risk of large-for-gestational-age newborns in women with gestational diabetes by race and ethnicity and body mass index categories.

OBJECTIVE: To compare the prevalence of large-for-gestational-age (LGA) newborns across categories of body mass index (BMI) in five racial and ethnic groups. METHODS: This cohort study examined 7,468 women with gestational diabetes mellitus (GDM) who delivered a live newborn between 1995 and 2006 at Kaiser Permanente Northern California. The racial and ethnic groups were non-Hispanic white, African American, Hispanic, Asian, and Filipina. The BMI was classified using the World Health Organization International guidelines (normal, 18.50–24.99; overweight, 25.00–29.99; obese, 30.00–34.99; obese class II, 35.00 or higher). Having an LGA newborn was defined as birth weight more than 90th percentile for the study populations race or ethnicity and gestational age--specific birth weight distribution. Logistic regression was used to estimate odds of having an LGA newborn by BMI and race and ethnicity. RESULTS: Overall prevalence of LGA newborns was highest in African American women (25.1%), lowest in Asians (13.9%), and intermediate among Hispanic (17.3%), white (16.4%), and Filipina women (15.3%). The highest increased risk of LGA newborns was observed among women with class II obesity in most racial and ethnic groups, and African American and Asian women with class II obesity had a four-fold increased risk of LGA newborns compared with women of normal weight in the same racial and ethnic group. CONCLUSIONS: African American women with GDM have a greater risk of LGA newborns at a lower BMI than other racial and ethnic groups. Clinicians should be aware that among women with GDM, there may be significant racial and ethnic differences in the risk of LGA newborns by BMI threshold. LEVEL OF EVIDENCE: II

Pregravid Liver Enzyme Levels and Risk of Gestational Diabetes Mellitus During a Subsequent Pregnancy

OBJECTIVE Liver enzymes are independent predictors of type 2 diabetes. Although liver fat content correlates with features of insulin resistance, a risk factor for developing gestational diabetes mellitus (GDM), the relationship between liver enzymes and GDM is unclear. The objective of this study was to assess whether pregravid liver enzyme levels are associated with subsequent risk of GDM. RESEARCH DESIGN AND METHODS A nested case-control study was conducted among women who participated in the Kaiser Permanente Northern California multiphasic health checkup (1984–1996) and had a subsequent pregnancy (1984–2009). Case patients were 256 women who developed GDM. Two control subjects were selected for each case patient and matched for year of blood draw, age at examination, age at pregnancy, and number of intervening pregnancies. RESULTS Being in the highest quartile versus the lowest quartile of γ-glutamyl transferase (GGT) levels was associated with a twofold increased risk of subsequent GDM (odds ratio 1.97 [95% CI 1.14–3.42]), after adjusting for race/ethnicity, prepregnancy BMI, family history of diabetes, and alcohol use. This result was attenuated after adjusting for homeostasis model assessment of insulin resistance (HOMA-IR), fasting status, and rate of gestational weight gain. There was significant interaction between GGT and HOMA-IR; the association with GGT was found among women in the highest tertile of HOMA-IR. Aspartate aminotransferase and alanine aminotransferase were not associated with increased GDM risk. CONCLUSIONS Pregravid GGT level, but not alanine aminotransferase or aspartate aminotransferase level, predicted the subsequent risk of GDM. Markers of liver fat accumulation, such as GGT level, are present years before pregnancy and may help to identify women at increased risk for subsequent GDM.

Prepregnancy cardiometabolic and inflammatory risk factors and subsequent risk of hypertensive disorders of pregnancy

OBJECTIVE The purpose of this study was to examine prepregnancy cardiometabolic and inflammatory markers and the subsequent risk of hypertensive disorders of pregnancy. STUDY DESIGN This was a retrospective cohort study of 3380 women who took part in a comprehensive multiphasic health checkup (MHC) examination between 1984 and 1996 and who subsequently delivered at Kaiser Permanente Northern California. RESULTS Two hundred five women were diagnosed with a hypertensive disorder of pregnancy. Prepregnancy measurements of overweight/obesity (body mass index, ≥25.0 kg/m(2)), prehypertension, and inflammation (leukocytes, ≥7.2 10(3)/μL) were associated independently with hypertensive disorder of pregnancy risk (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2-2.3; OR, 2.1; 95% CI, 1.5-2.8; and OR, 1.6; 95% CI, 1.1-2.3, respectively). Being overweight/obese and having prehypertension before pregnancy was associated with a 3.5-fold increased risk of hypertensive disorder of pregnancy compared with women with normal levels of both risk factors. CONCLUSION A prepregnancy cardiometabolic and inflammation risk profile may help clinicians identify high-risk women to target for early intervention or management of hypertensive disorder of pregnancy.

Prepregnancy SHBG concentrations and risk for subsequently developing gestational diabetes mellitus.

OBJECTIVE Lower levels of sex hormone–binding globulin (SHBG) have been associated with increased risk of diabetes among postmenopausal women; however, it is unclear whether they are associated with glucose intolerance in younger women. We examined whether SHBG concentrations, measured before pregnancy, are associated with risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up examination (1984–1996) and had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case patients were 256 women in whom GDM developed. Two control subjects were selected for each case patient and were matched for year of blood draw, age at examination, age at pregnancy, and number of intervening pregnancies. RESULTS Compared with the highest quartile of SHBG concentrations, the odds of GDM increased with decreasing quartile (odds ratio 1.06 [95% CI 0.44–2.52]; 2.33 [1.07–5.09]; 4.06 [1.90–8.65]; P for trend < 0.001), after adjusting for family history of diabetes, prepregnancy BMI, race/ethnicity, alcohol use, prepregnancy weight changes, and homeostasis model assessment of insulin resistance. Having SHBG levels below the median (<64.5 nmol/L) and a BMI ≥25.0 kg/m2 was associated with fivefold increased odds of GDM compared with normal-weight women with SHBG levels at or above the median (5.34 [3.00–9.49]). CONCLUSIONS Low prepregnancy SHBG concentrations were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies.

Prepregnancy Adverse Lipid Profile and Subsequent Risk of Gestational Diabetes

CONTEXT Lower low-density lipoprotein (LDL) peak diameter and a predominance of small, dense LDL are associated with type 2 diabetes, but it is unclear whether they are a risk factor for gestational diabetes mellitus (GDM). OBJECTIVE To evaluate whether prepregnancy lipid profile predicts the development of GDM during pregnancy. DESIGN A nested case-control study among women who participated in a multiphasic health exam, where blood was collected and stored between 1984 and 1996, and who then had a subsequent pregnancy between 1984 and 2009. SETTING Kaiser Permanente Northern California. PARTICIPANTS Cases were 254 women who developed GDM. Two controls were selected for each case and matched for year of blood draw, age at baseline, age at pregnancy, and number of intervening pregnancies. MAIN OUTCOME MEASURES Prepregnancy LDL peak diameter and prepregnancy lipid subfraction concentrations grouped according to size, and the odds of developing GDM. RESULTS Women in the lowest quartiles of LDL peak diameter and high-density lipoprotein had increased odds of GDM compared with women in the highest quartiles (odds ratio [95% CI], 2.60 [1.37-4.94] and 1.98 [1.01-3.86], respectively), in multivariable adjusted models. Being in the highest quartile of small and very small LDL subfractions also increased the odds of GDM (2.61 [1.35-5.03] and 2.44 [1.22-4.85], respectively). CONCLUSIONS Lower LDL peak diameter size and high-density lipoprotein levels and higher levels of small and very small LDL subfraction groups were present years before pregnancy in women who developed GDM. A prepregnancy atherogenic lipid profile may help identify women at risk of GDM to target for prevention.

Trimester-Specific Gestational Weight Gain and Infant Size for Gestational Age.

Gestational weight gain is known to influence fetal growth. However, it is unclear whether the associations between gestational weight gain and fetal growth vary by trimester. In a diverse cohort of 8,977 women who delivered a singleton between 2011 and 2013, we evaluated the associations between trimester-specific gestational weight gain and infant size for gestational age. Gestational weight gain was categorized per the 2009 Institute of Medicine (IOM) recommendations; meeting the recommendations was the referent. Large for gestational age and small for gestational age were defined as birthweight > 90th percentile or <10th percentile, respectively, based on a national reference standard birthweight distribution. Logistic regression models estimated the odds of having a large or small for gestational age versus an appropriate for gestational age infant. Only gestational weight gain exceeding the IOM recommendations in the 2nd and 3rd trimesters independently increased the odds of delivering a large for gestational age infant (Odds Ratio (95% Confidence Interval): 1st: 1.17 [0.94, 1.44], 2nd: 1.47 [1.13, 1.92], 3rd: 1.70 [1.30, 2.22]). Gestational weight gain below the IOM recommendations increased the likelihood of having a small for gestational age infant in the 2nd trimester only (1.76 [1.23, 2.52]). There was effect modification, and gestational weight gain below the IOM recommendations increased the likelihood of having a small for gestational age infant in the 2nd trimester and only among women with a pre-pregnancy body mass index from 18.5–24.9 kg/m2 (2.06 [1.35, 3.15]). These findings indicate that gestational weight gain during the 2nd and 3rd trimesters is more strongly associated with infant growth. Interventions to achieve appropriate gestational weight gain may optimize infant size at birth.

A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin

One‐third of type‐2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long‐term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long‐term response. In all, 1,056 patients contributed their genetic, demographic, and long‐term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one‐third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long‐term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.