John T. Brinton

Associations of maternal BMI and gestational weight gain with neonatal adiposity in the Healthy Start study

BACKGROUND Maternal obesity and weight gain during pregnancy are risk factors for child obesity. Associations may be attributable to causal effects of the intrauterine environment or genetic and postnatal environmental factors. OBJECTIVE We estimated associations of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) overall and in early pregnancy, midpregnancy, and late pregnancy with neonatal adiposity. DESIGN Participants were 826 women enrolled in a Colorado prebirth cohort who delivered term infants (2010-2013). GWG to 39 wk of gestation was predicted by using mixed models, and early pregnancy, midpregnancy, and late pregnancy rates of GWG (0-17, 17-27, and 27 wk to delivery) were calculated from repeated weight measures. Neonatal body composition was measured by using air-displacement plethysmography ≤3 d after birth. RESULTS Each1-kg/m(2) increase in maternal BMI was associated with increased neonatal fat mass (5.2 g; 95% CI: 3.5, 6.9 g), fat-free mass (7.7 g; 95% CI: 4.5, 10.9 g), and percentage of body fat (0.12%; 95% CI: 0.08%, 0.16%). Each 0.1-kg/wk increase in predicted GWG was associated with increased fat mass (24.0 g; 95% CI: 17.4, 30.5 g), fat-free mass (34.0 g; 95% CI: 21.4, 46.6 g), and percentage of body fat (0.55%; 95% CI: 0.37%, 0.72%). No interaction was detected between BMI and GWG in their effects on neonatal body composition. Early pregnancy, midpregnancy, and late pregnancy rates of GWG were independently associated with fat mass and percentage of body fat. Midpregnancy and late pregnancy GWGs were associated with fat-free mass. An observed GWG that exceeded recommendations was associated with higher neonatal fat mass and fat-free mass but not percentage of body fat relative to adequate GWG. CONCLUSIONS Maternal prepregnancy BMI and GWG, including period-specific GWG, were positively and independently associated with neonatal adiposity. Associations of early and midpregnancy weight gain with neonatal adiposity support the hypothesis that greater maternal weight gain during pregnancy, regardless of prepregnancy BMI, is directly related to offspring adiposity at birth. The Healthy Start study was registered as an observational study at clinicaltrials.gov as NCT02273297.

Maternal obesity, gestational weight gain, and offspring adiposity: the exploring perinatal outcomes among children study.

OBJECTIVE To determine whether adequate vs excessive gestational weight gain (GWG) attenuated the association between maternal obesity and offspring outcomes. STUDY DESIGN Data from 313 mother-child pairs participating in the Exploring Perinatal Outcomes among Children study were used to test this hypothesis. Maternal prepregnancy body mass index (BMI) and weight measures throughout pregnancy were abstracted from electronic medical records. GWG was categorized according to the 2009 Institute of Medicine criteria as adequate or excessive. Offspring outcomes were obtained at a research visit (average age 10.4 years) and included BMI, waist circumference (WC), subcutaneous adipose tissue (SAT) and visceral adipose tissue, high-density lipoprotein cholesterol, and triglyceride levels. RESULTS More overweight/obese mothers exceeded the Institute of Medicine GWG recommendations (68%) compared with normal-weight women (50%) (P < .01). Maternal prepregnancy BMI was associated with worse childhood outcomes, particularly among offspring of mothers with excessive GWG (increased BMI [20.34 vs 17.80 kg/m(2)], WC [69.23 vs 62.83 cm], SAT [149.30 vs 90.47 cm(2)], visceral adipose tissue [24.11 vs 17.55 cm(2)], and homeostatic model assessment [52.52 vs 36.69], all P < .001). The effect of maternal prepregnancy BMI on several childhood outcomes was attenuated for offspring of mothers with adequate vs excessive GWG (P < .05 for the interaction between maternal BMI and GWG status on childhood BMI, WC, SAT, and high-density lipoprotein cholesterol). CONCLUSION Our findings lend support for pregnancy interventions aiming at controlling GWG to prevent childhood obesity.

Physical activity in pregnancy and neonatal body composition: the Healthy Start study.

OBJECTIVE: To examine associations between pregnancy physical activity and neonatal fat mass and fat-free mass, birth weight, and small for gestational age (SGA). METHODS: We analyzed 826 mother–neonate pairs (term births) participating in the longitudinal Healthy Start study. The Pregnancy Physical Activity Questionnaire was used to assess total energy expenditure and meeting American College of Obstetricians and Gynecologists (College) guidelines for physical activity during early pregnancy, midpregnancy, and late pregnancy. Models were adjusted for maternal and neonatal characteristics. RESULTS: Neonates had mean fat mass of 292.9 g, fat-free mass of 2,849.8 g, and birth weight of 3,290.7 g. We observed 107 (12.9%) SGA and 30 (3.6%) large-for-gestational age neonates. A significant inverse linear trend between total energy expenditure during late pregnancy and neonatal fat mass (Ptrend=.04) was detected. Neonates of mothers in the highest compared with the lowest quartile of total energy expenditure during late pregnancy had 41.1 g less fat mass (249.4 compared with 290.5 g; P=.03). No significant trend was found with total energy expenditure and neonatal fat-free mass or birth weight. Early-pregnancy and midpregnancy total energy expenditure were not associated with neonatal outcomes. No significant trend was observed between late-pregnancy total energy expenditure and SGA (Ptrend=.07), but neonates of mothers in the highest compared with the lowest quartile had a 3.0 (95% confidence interval 1.4–6.7) higher likelihood of SGA. Meeting the College’s physical activity guidelines during pregnancy was not associated with differences in neonatal outcomes. CONCLUSION: Increasing levels of late-pregnancy total energy expenditure are associated with decreased neonatal adiposity without significantly reduced neonatal fat-free mass. LEVEL OF EVIDENCE: II

Maternal Fuels and Metabolic Measures During Pregnancy and Neonatal Body Composition: The Healthy Start Study

CONTEXT The impact of specific maternal fuels and metabolic measures during early and late gestation on neonatal body composition is not well defined. OBJECTIVE To determine how circulating maternal glucose, lipids, and insulin resistance in the first and second halves of pregnancy influence neonatal body composition. DESIGN A prospective pre-birth cohort enrolling pregnant women, the Healthy Start Study, was conducted, in which fasting maternal serum samples were collected twice during pregnancy to measure glucose, insulin, hemoglobin A1c, triglyceride, total cholesterol, high-density lipoprotein, and free fatty acids. Neonatal body composition was measured with air displacement plethysmography. SETTING An observational epidemiology study of pregnant women attending obstetric clinics at the University of Colorado, Anschutz Medical Center. PARTICIPANTS This analysis includes 804 maternal-neonate pairs. RESULTS A strong positive linear relationship between maternal estimated insulin resistance (homeostasis model of assessment for insulin resistance) in the first half of pregnancy and neonatal fat mass (FM) and FM percentage (FM%) was detected, independent of prepregnancy body mass index (BMI). In the second half of pregnancy, positive linear relationships between maternal glucose levels and offspring FM and FM% were observed, independent of prepregnancy BMI. An inverse relationship was detected between high-density lipoprotein in the first half of pregnancy and FM, independent of prepregnancy BMI. Free fatty acid levels in the second half of pregnancy were positively associated with higher birth weight, independent of prepregnancy BMI. CONCLUSION Maternal insulin resistance in the first half of pregnancy is highly predictive of neonatal FM%, whereas maternal glycemia, even within the normal range, is an important driver of neonatal adiposity in later pregnancy, independent of prepregnancy BMI. Our data provide additional insights on potential maternal factors responsible for fetal fat accretion and early development of adiposity.

Breast cancer risk assessment in 64,659 women at a single high-volume mammography clinic.

RATIONALE AND OBJECTIVES In 2007, the American Cancer Society (ACS) recommended that women at elevated risk of breast cancer be screened with breast magnetic resonance imaging (MRI) as an adjunct to mammography. This study estimates the proportion of women presenting for screening mammography who are at elevated lifetime risk of breast cancer as determined by the Gail model. This study provides preliminary information for a proposed follow-up study, including the proportion of women who completed the recommended MRI at the same clinic that had conducted the risk assessment. MATERIALS AND METHODS This study is an observational prospective cohort of 64,659 women presenting for mammographic screening at a single high-volume clinic. If a woman reported a first-degree maternal relative with breast cancer and had at least 20% lifetime risk on the Gail model, the radiologists report included a recommendation that the primary care physician refer the woman for breast MRI screening. Records were examined to determine if women completed the recommended MRI at the clinic within one year of the initial risk assessment. RESULTS Of 64,659 women, 1,246 (1.9%) had a lifetime risk of breast cancer of 20% or greater, and 436 (0.7 %) had a lifetime risk of breast cancer 25% or greater. Of the women at elevated risk, 173 (13.9%) completed the recommended breast MRI screening at the clinic within a year. CONCLUSION The effectiveness of matching screening intensity to risk on cancer detection, biopsy rate, and cost should be evaluated by studying multiple clinics and multiple risk assessment tools.

Testing the fuel-mediated hypothesis: maternal insulin resistance and glucose mediate the association between maternal and neonatal adiposity, the Healthy Start study

Aims/hypothesisIn women who are overweight or obese before or during pregnancy there is an associated risk of increased fetal growth and higher birthweight. The metabolic phenotype of the overweight/obese pregnant woman, characterised by higher than normal insulin resistance (IR) and increased circulating fuels, suggests a mechanism resulting in fetal overnutrition and subsequent increased adiposity. We tested the fuel-mediated hypothesis in an observational pre-birth cohort of 951 mother–offspring pairs, the Healthy Start study.MethodsWe conducted a path analysis to estimate the simultaneous effects of maternal IR and maternal fuels (fasting glucose, triacylglycerol [TG] and NEFA levels) in late pregnancy in mediating the relationship between maternal pre-pregnancy BMI and neonatal adiposity (per cent fat mass [%FM]).ResultsThe total effect of maternal BMI on neonatal %FM was significant (total effect 0.16, 95% CI 0.08, 0.22, p < 0.001). The mediated path including maternal IR and glucose levels together accounted for 21% (p < 0.01) of the total effect of maternal BMI on neonatal %FM while the mediating effects of all other fuels were non-significant.Conclusions/interpretationUsing a novel application of path analysis our data implicate maternal IR and glucose levels as important mediators of the association between maternal and infant adiposity.

Severe gastric dilatation due to superior mesenteric artery syndrome in anorexia nervosa

Forty-seven year old female, with a history of anorexia nervosa, was admitted to a medical stabilization unit (ACUTE) complaining of abdominal pain exacerbated by oral intake, associated with nausea, and relieved by emesis. Admission body mass index was 10.6. Labs were notable for hepatitis and hypoglycemia. On her progressive oral refeeding plan, she suddenly developed severe abdominal pain. Computed tomography (CT) revealed gastric dilatation and superior mesenteric artery (SMA) syndrome. SMA syndrome is a rare complication of severe malnutrition resulting from compression of the duodenum between the aorta and the SMA. It is diagnosed by an upper gastrointestinal series or an abdominal CT. Gastric dilatation, in turn, is a rare complication of SMA syndrome to be included in the differential diagnoses of abdominal pain in severely malnourished patients as it is potentially life-threatening. The patient was switched to an oral liquid diet, began weight restoring, and had resolution of symptoms.

Associations of maternal weight status prior and during pregnancy with neonatal cardiometabolic markers at birth: the Healthy Start study

Background:Maternal obesity increases adult offspring risk for cardiovascular disease; however, the role of offspring adiposity in mediating this association remains poorly characterized.Objective:To investigate the associations of maternal pre-pregnant body mass index (maternal BMI) and gestational weight gain (GWG) with neonatal cardiometabolic markers independent of fetal growth and neonatal adiposity.Methods:A total of 753 maternal–infant pairs from the Healthy Start study, a large multiethnic pre-birth observational cohort were used. Neonatal cardiometabolic markers included cord blood glucose, insulin, glucose-to-insulin ratio (Glu/Ins), total and high-density lipoprotein cholesterol (HDL-c), triglycerides, free fatty acids and leptin. Maternal BMI was abstracted from medical records or self-reported. GWG was calculated as the difference between the first pre-pregnant weight and the last weight measurement before delivery. Neonatal adiposity (percent fat mass) was measured within 72 h of delivery using whole-body air-displacement plethysmography.Results:In covariate adjusted models, maternal BMI was positively associated with cord blood insulin (P=0.01) and leptin (P<0.001) levels, and inversely associated with cord blood HDL-c (P=0.05) and Glu/Ins (P=0.003). Adjustment for fetal growth or neonatal adiposity attenuated the effect of maternal BMI on neonatal insulin, rendering the association nonsignificant. However, maternal BMI remained associated with higher leptin (P<0.0011), lower HDL-c (P=0.02) and Glu/Ins (P=0.05), independent of neonatal adiposity. GWG was positively associated with neonatal insulin (P=0.02), glucose (P=0.03) and leptin levels (P<0.001) and negatively associated with Glu/Ins (P=0.006). After adjusting for neonatal adiposity, GWG remained associated with higher neonatal glucose (P=0.02) and leptin levels (P=0.02) and lower Glu/Ins (P=0.048).Conclusions:Maternal weight prior and/or during pregnancy is associated with neonatal cardiometabolic makers including leptin, glucose and HDL-c at delivery, independent of neonatal adiposity. Our results suggest that intrauterine exposure to maternal obesity influences metabolic processes beyond fetal growth and fat accretion.

Leptin levels at birth and infant growth: the EPOCH study.

OBJECTIVE To examine the association of cord blood leptin with body mass index (BMI) growth velocity from birth to 12 months of age among infants exposed and not exposed to over-nutrition in utero (defined as maternal overweight/obesity or presence of gestational diabetes). METHODS 185 infants enrolled in the Exploring Perinatal Outcomes among Children study (76 exposed and 109 not exposed) had leptin and insulin measured in cord blood. Longitudinal weight and length measures in the first 12 months of life (average 4 per participant) obtained from medical records were used to compute BMI growth rates. Mixed models were used to examine associations of cord blood leptin with growth. RESULTS Compared with unexposed infants, those exposed had significantly higher cord blood insulin (8.64 v. 6.97 uU/ml, P<0.01) and leptin levels (8.89 v. 5.92 ng/ml, P=0.05) as well as increased birth weights (3438.04 v. 3306.89 g, P=0.04). There was an inverse relationship between cord leptin levels and BMI growth from birth to 12 months of age (P=0.005); however, exposure to over-nutrition in utero did not significantly modify this association (P=0.59). CONCLUSION We provide support of a possible operational feedback mechanism by which lower cord blood leptin levels are associated with faster infant growth in the first year of life. Our data do not tend to support the hypothesis that this mechanism is altered in infants exposed to over-nutrition in utero; however our sample is too small to provide sufficient evidence. Larger epidemiological studies are needed to elucidate the mechanisms responsible for increased propensity for obesity in exposed offspring.

Bias in estimating accuracy of a binary screening test with differential disease verification

Sensitivity, specificity, positive and negative predictive value are typically used to quantify the accuracy of a binary screening test. In some studies, it may not be ethical or feasible to obtain definitive disease ascertainment for all subjects using a gold standard test. When a gold standard test cannot be used, an imperfect reference test that is less than 100 per cent sensitive and specific may be used instead. In breast cancer screening, for example, follow-up for cancer diagnosis is used as an imperfect reference test for women where it is not possible to obtain gold standard results. This incomplete ascertainment of true disease, or differential disease verification, can result in biased estimates of accuracy. In this paper, we derive the apparent accuracy values for studies subject to differential verification. We determine how the bias is affected by the accuracy of the imperfect reference test, the percent who receive the imperfect reference standard test not receiving the gold standard, the prevalence of the disease, and the correlation between the results for the screening test and the imperfect reference test. It is shown that designs with differential disease verification can yield biased estimates of accuracy. Estimates of sensitivity in cancer screening trials may be substantially biased. However, careful design decisions, including selection of the imperfect reference test, can help to minimize bias. A hypothetical breast cancer screening study is used to illustrate the problem.