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To prospectively determine the risk of gestational diabetes (GDM) in association with life-course weight characteristics and adult abdominal adiposity.
We investigated the joint and independent impact of birth weight, childhood size by somatotypes, adolescent and adult body mass index (BMI) and abdominal adiposity on GDM risk among 21,647 women in the Nurses’ Health Study II who reported a singleton pregnancy between 1989 and 2001. 1,386 incident GDM cases were reported. Relative risk (RR) was estimated by pooled logistic regression adjusting for age, prematurity, race, smoking status, parental history of diabetes, age of first birth, parity, and physical activity.
Birth weight was inversely associated with GDM risk (P-trend 0.02). Childhood somatotypes at ages 5 and 10 years were not associated with risk. U-shaped associations were found for BMI at age 18 and somatotype at age 20 years. Weight gain between adolescence and adulthood, pre-gravid BMI and abdominal adiposity were positively associated with risk (p-trends all<0.01). Multivariate adjusted RR for GDM from lowest to highest quintile of waist-to-hip ratio were 1.00, 1.50, 1.51, 2.03, 2.12 (P-trend 0.0003). Lower birth weight (<7 pounds) without adulthood overweight (BMI>25 kg/m2) was associated with 20% increased risk (95% CI: 1.02–1.41). However, adulthood overweight alone was related to 2.36 times greater GDM risk (95% CI: 2.12–3.77).
Although lower birth weight is an independent risk factor for GDM, weight gain since early adulthood, and overall and central obesity in adulthood were more strongly associated with elevated GDM risk independent of other known risk factors.
Gestational diabetes (GDM) is glucose intolerance with first recognition during pregnancy, and stems from the failure to adapt to the increased metabolic demands of pregnancy.(1) GDM complicates approximately 7% of all pregnancies in the U.S, and is associated with substantially increased future risk of type 2 diabetes in the mothers. Furthermore, it confers increased risks of obesity and other metabolic syndrome conditions for the offspring that could last into adulthood.(2)
Although pre-gravid obesity is a recognised risk factor for GDM, very few studies have comprehensively examined weight characteristics over the life-course. Low birth weight has been associated with an increased risk of GDM.(3) However, data assessing whether this association is independent of important confounders have been limited. Larger childhood body shape has been associated with lower levels of IGF-1,(4) which, in turn, is associated with decreased insulin secretion and increased risk of type 2 diabetes;(5) however, data on the relationship between childhood adiposity and GDM risk are lacking. Adolescent(6) and pre-gravid adulthood obesity(7) have been associated with GDM risk. In addition, although abdominal obesity is a strong risk factor for type 2 diabetes among non-pregnant individuals,(8) its association with GDM risk has not been well studied.
Longitudinal changes in weight, or crossing of weight categories was suggested being as or more important for development of insulin resistance and type 2 diabetes than measures of weight at one point in the life course.(9) In an earlier report from the Nurses’ Health Study II,(10) excessive weight gain from adolescence to adulthood was a strong risk factor of GDM.(11) Only a few studies either among pregnant or non-pregnant individuals, however, have examined weight characteristics from birth to adulthood and these have provided conflicting findings on whether there are additional influences of their interactions on insulin resistance and glucose intolerance.(12–16) Therefore, we investigated associations of life course weight and adult abdominal adiposity with the development of GDM in a prospective cohort of women from the Nurses’ Health Study II (NHSII).
The NHSII is an ongoing prospective study which originally recruited 116,608 US female nurses between the ages of 25 to 42 years in 1989. Follow-up is conducted using biennial questionnaires on lifestyle and health information. Among the cohort, 27,863 women reported a pregnancy lasting at least 6 months between 1989 and 2001. 21,647 participants remained after exclusion for women who reported a multiple gestation (i.e. twins) or a diagnosis of diabetes, cancer, cardiovascular disease, or GDM at baseline, or diabetes prior to GDM, and those who were missing information on birth weight, childhood body shape, adolescent BMI, adult BMI, or dates of diagnosis for diabetes or death. In 1993, 64% of the participants reported their waist and hip circumferences. For the analysis of abdominal adiposity and GDM, only women (N=4,981) who reported a singleton pregnancy after 1993 and who provided information on waist and hip circumferences were included. This study was approved by the institutional review board of the Partners Health Care System (Boston, Massachusetts). Implied informed consent was assumed by each participant’s return of her completed questionnaire.
Figure 1 shows the time of data collection for the primary exposures of interest. At baseline, body fatness at ages 5, 10 and 20 years was assessed by asking participants to report their shape at each age using a nine-level set of figures called somatotypes originally developed by Stunkard et al(17) (category 1 being most lean to category 9 being most heavy). Recalled somatotypes such as the ones used in the present study have been validated in both older (mean age 73 years) and younger (mean age 21 years) women by comparison with childhood records of weight and height and calculated BMI.(18,19) Somatotypes at ages 5, 10, and 20 years correlated fairly well with records (r=0.60, 0.65, and 0.66, respectively).(20) Weight at age 18 and adult height and weight were self-reported at baseline. BMI was calculated as weight in kilograms divided by height in metres squared. Weight gain was the difference between baseline adult weight and weight at age 18.
In 1991, participants were asked to report their birth weight by 5 categories: <5.5, 5.5–6.9, 7.0–8.4, 8.5–9.9, or ≥ 10 pounds (<2.49, 2.49-<3.13, 3.18-<3.86, ≥ 3.86 kg). They were also asked whether they were born premature or of a multiple gestational birth. Due to the small number of GDM cases (N= 12) among those in the birth weight category of ≥ 10 lb, categories 8.5–9.9 lb, and ≥ 10 lb were combined as ≥ 8.5 pounds. In a previous validation study involving 220 women, a strong correlation was found between self-reported birth weight and that recorded on birth certificates (Spearman r=0.74).(21)
Waist and hip circumferences were reported to the nearest quarter inch in 1993 among a subset of participants. In the NHSII, the correlation between recalled weight at age 18 and documented weight from college or nursing school records was 0.84.(22) Correlations between self-report and technician conducted measurements were 0.96 for weight, 0.89 for waist circumference, 0.84 for hip circumference, and 0.70 for waist to hip ratio (WHR).(23,24)
GDM was ascertained by self-report. A previous validation study of 114 women in NHSII showed that 94% of women self-reporting GDM had a physician diagnosis on record;(25) all women with confirmed diagnosis had abnormal glucose homeostasis and most physicians followed the National Diabetes Data Group diagnostic criteria. Moreover, among 100 women in NHSII who reported a pregnancy uncomplicated by GDM and were sent supplementary questionnaires to assess surveillance, 83% reported having a glucose loading test indicating a high degree of surveillance in this cohort.(26)
Age was calculated as months from the reported birth date to date of questionnaire return. Race, smoking status, age of menarche, being breastfed, and family history of diabetes were reported at baseline in 1989. Parity and age at first birth were measured biennially. Alcohol consumption was reported on semi-quantitative food frequency questionnaires in years 1991 and 1995. Physical activity, in metabolic equivalent (MET) units derived from the average time spent in certain activities (e.g. jogging, running, bicycling), was assessed in 1989, 1991, and 1997.
Differences in baseline characteristics by birth weight categories were compared using chi-square for categorical variables and linear regression for continuous variables. The analyses of the majority life-course weight characteristics (birth weight, childhood and adolescent weight characteristics, and BMI) were conducted within the full cohort of women who experienced a pregnancy between 1989 and 2001 (n=21,647). As central adiposity variables were collected in 1993, analyses for the association of these variables with GDM risk were conducted among women who experienced a pregnancy between 1993 and 2001 (n=4981).
Pooled logistic regression was used to estimate the relative risk of incident GDM for each weight characteristic, which included birth weight (<5.5, 5.5–6.9, 7.0–8.4, ≥ 8.5 lbs); somatotype at ages 5, 10 and 20 years (1 to ≥ 5), BMI at age 18 years (<18, 18.0–19.9, 20.0–21.9, 22.0–24.9, 25–29.9, ≥ 30 kg/m2), height (quintiles), adulthood BMI (<20, 20.0–21.9, 22.0–24.9, 25.0–29.9, ≥ 30 kg/m2), and abdominal adiposity measures of waist circumference, waist to hip ratio, hip girth, and waist to height ratio (quintiles). Analyses were adjusted for age (5 categories), race (white, black, other), smoking status (current, former, never), age at first birth (<24 years, ≥ 24 years), parity (number of pregnancies lasting >6 months), family history of diabetes (mother, father, both) and physical activity (quintiles of METs). Information on adult BMI, physical activity, parity, and age at first birth were updated in subsequent questionnaires. These updated measures were used in adjusted analyses by inclusion of the most recent data for each 2-year follow-up interval. For instance, if GDM was reported in 2001, BMI reported in 1999 was used. Analyses of birth weight additionally adjusted for prematurity. To test for significant trends over the weight characteristic categories, linear models were fitted using the median values of each category of exposure. (e.g. Birth weight was tested using values of 5.00, 6.25, 7.75, and 9.75 lbs).
We used “centile crossing” methods as previously described(27) to analyze the joint effect between birth weight and adult BMI at baseline. Four centiles of BMI at baseline were created to correspond to the four centiles of birth weight (<7th, 7–37th, 37–86th and >86th percentile). For example, ~7% of the cohort reported a birth weight less than 5.5 lbs, thus the first BMI centile category consisted of women who reported an adult BMI below the 7th centile based on the distribution of the cohort. The centiles of BMI were then cross-tabulated with birth weight categories to result in 16 categories for assessing joint effects. Adjusted relative risk estimates were determined using the reference group of women who had a normal birth weight (7–8.4 lbs) and remained in the same centile of BMI (37–86th) as adults. An interaction term was created between centiles of BMI and birth weight categories to test for interaction.
We also investigated the joint effect of lower birth weight (<7 lbs), adolescent overweight (BMI at age 18 >25 kg/m2) and adult overweight (BMI at baseline >25 kg/m2) on GDM risk by creating an eight category variable with the reference being women born at 7 lbs or heavier and were lean in adolescence and adulthood.
In sensitivity analyses, we repeated the main analyses using both incident cases of GDM and prevalent cases at baseline; these analyses included women reporting a singleton birth prior to the start of the study. We also repeated analyses with only women born full-term, excluding on prematurity. All analyses were conducted using SAS v.8.2. (SAS Institute Inc, Cary, North Carolina). All statistical tests were 2-sided, and significance determined at p<0.05. EHY had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
At baseline, the mean age of the cohort was 30 years, 96% were white, 6.6% had low birth weight (<5.5 lbs) and 14.6% had high birth weight (≥8.5 lbs). Birth weight was positively associated with somatotypes at ages 5 to 20 years, and adulthood weight and height (Table 1), whereas it was not significantly associated with BMI in adolescence (p=0.09) or in adulthood (p=0.38), or with measures of abdominal adiposity (p>0.15). Maternal history of diabetes was more frequent among those with high birth weight whereas paternal history was more frequent among those with low birth weight. Low birth weight was also associated with a slightly higher prevalence of current smoking.
1386 women developed incident GDM over the 12 years of follow-up. Weight characteristics at different time points were significantly associated with the risk of GDM. (Table 2) Women who reported low (<5.5 lbs) or below average (5.5–6.9 lbs) birth weight were more likely to have GDM than women who reported normal birth weight (7.0–8.4 lbs); the linear association remained significant (p=0.02) after adjusting for age, race, prematurity, parity, family history, physical activity and adult BMI. In addition, overweight at age 10 years (somatotype ≥ 5) was significantly related to GDM risk in age-adjusted analyses, although the association was marginally significant after adjusting for other factors. There was a U-shaped association between risk of GDM and adolescent size by BMI at age 18 and somatotype at age 20 years. The significant association with thinness did not persist after adjustment for weight gain in adulthood (RR 1.12; 95%CI: 0.92–1.36 for BMI<18 kg/m2 compared to BMI of 18-<20 at age 18), although the association with large body size remained significant (RR 1.91; 95%CI: 1.37–2.65 for BMI of ≥ 30 at age 18). Both adult BMI and weight gain since adolescence were significantly and positively associated with GDM (adjusted P for linear trend <0.001 for both). GDM risk was increased significantly even among women within the normal BMI range (22–25 kg/m2) as compared to the very lean (<20 kg/m2) (RR 1.49; 95% CI: 1.21–1.83). Taller height was significantly associated with decreased risk of GDM (p-trend <0.001).
Among women (n=4,981) who measured their waist and hip circumferences, pre-gravid waist circumference, WHR, and waist-to-height ratio were all significantly and positively associated with GDM risk (adjusted P for linear trend all <0.001). (Figure 2) Although risks were attenuated after adjustment for continuous BMI, the associations remained statistically significant. For instance, the relative risk from lowest to highest quintile of WHR after adjusting for continuous BMI and confounders were 1.00, 1.50, 1.51, 2.03, 2.12 (95% CI: 1.38–3.27) (P-trend <0.001). In comparison to women belonging to the lowest quintile of waist-to-height ratio, those in the highest quintile had 2.75 (95%CI: 1.62–4.66) times greater risk of GDM. Hip circumference was not associated with risk of GDM after adjusting for BMI. Since height has an inverse association with GDM, the waist-to-height ratio may be difficult to interpret. Sensitivity analyses were conducted with the residuals of waist adjusted for height. The associations with GDM using these residuals were slightly stronger than using waist alone but less than with waist to height ratio with the RR of the highest to lowest quintile comparison being 2.26 (95%CI: 1.35–3.78).
We further investigated the independent and joint effects of birth weight and adult BMI on GDM risk (Table 3). The association between birth weight and GDM risk did not differ by adult BMI. Even among women who were lean in adulthood (centile 7–37th), birth weight was inversely associated with GDM risk; the RR per birth weight category increase was 0.94 (95%CI: 0.85–1.04). Similarly, regardless of birth weight category, each unit of BMI increase conferred 7–9% increased risk of GDM. (p-interaction=0.37)
To further understand the risk of GDM from cumulative exposure of overweight from adolescence to adulthood combined with lower birth weight, we examined models with the addition of adolescent BMI. Women who reported all three conditions (i.e. birth weight <7 lbs and overweight by BMI>25 both at age 18 years and at adulthood) had 2.83 times increased risk of GDM (95% CI: 2.12–3.77) compared to those who reported none of these conditions. (Figure 2) Lower birth weight independently increased risk of GDM by 20% (95% CI: 1.03–1.41). However, adult overweight had a much stronger effect, increasing GDM risk by 2-fold (RR 2.36: 2.00–2.79).
In sensitivity analyses, we explored whether the results differed if we included prevalent cases of GDM from baseline. Similar associations were observed for birth weight and prevalent cases of GDM (n=3,939) although the magnitude of the associations increased slightly. Multivariate adjusted RR (95% CI) across birth weight groups, using 7.0–8.4 lbs as reference and without combining the highest two categories, were 1.47 (1.33–1.62) for birth weight <5.5 lbs, 1.18 (1.11–1.25) for 5.5–6.9 lbs, 1.06 (1.01–1.10) for 8.5–9.9 lbs, and, 1.06 (0.95–1.19) for ≥ 10 lbs. (P-trend <0.001) All results were similar in analyses among women who were born full-term. (data not shown)
In this large prospective cohort of women, lower birth weight, greater adolescent BMI, and greater adult BMI and abdominal adiposity, were all significantly associated with an elevated risk of incident GDM independent of other known risk factors such as age, family history and physical activity. Childhood adiposity alone (at ages 5 and 10 years), however, was not significantly associated with GDM. Lower birth weight combined with a high BMI in both adolescence and adulthood was associated with particularly increased risk.
United States birth data indicates high rates of low birth weight.(28) Almost one in twelve babies (8.2%) born in 2007 had a birth weight of less than 2500g (or 5lbs 8oz).(29) Low birth weight has previously been linked with increased risk for metabolic dysfunction in child-and adulthood; the mechanism of which has been suggested to be fetal programming in response to maternal malnutrition.(30) In studies of malnutrition in youth, such as that occurring in famine conditions, low birth weight has been found to be associated with significant risks of cardiovascular disease and type 2 diabetes.(31) One hypothesized pathway that this could occur is through epigenetic changes such as DNA methylation that alter expressions of growth or other metabolic factors in utero to compensate for nutritional insufficiencies that later in life leads to metabolic risk due to exposure to over-nutrition.(32) This evidence has primarily been based on animal models as it remains difficult to study in epidemiologic settings.(33) Another possible mechanism is shared genetic risk factors of low birth weight and defects in insulin secretion.(34) Prior studies have generally shown either a linear inverse or a U-shaped association of GDM risk with birth weight.(35) Our ability to detect a U-shaped association may have been compromised by our inclusion in the highest birth weight category of all women reporting a birth weight of 8.5 or greater due to the relatively small number of cases with birth weight over 10 lbs. In our sensitivity analysis including prevalent cases of GDM to increase sample size, we did observe that a birth weight over 10 lbs was associated with increased risk of GDM in age-adjusted analysis. However, this association became statistically insignificant after controlling for other risk factors, suggesting that it is possible that the increase in GDM risk associated with higher birth weight in other studies could be attributable to uncontrolled confounders.
There were no significant associations between GDM and childhood somatotypes at ages 5 or 10 years, despite previous findings in this cohort that childhood somatotypes are associated with adult levels of insulin growth factors.(36) In other studies, pediatric overweight has been associated with increased metabolic dysfunction including hyperglycaemia during childhood which persists into adulthood.(37) Our null finding may be due to misclassification by the use of recalled somatotypes as a measure of childhood adiposity, although this measure does have proven validity when compared against childhood records of size.(38,39) Another possible explanation could be that the women who had low birth weight or were premature had caught up by 5 or 10 years of age as indicated by low variability in birth weight by childhood somatotype. Studies in type 2 diabetes literature have demonstrated that early age of adiposity rebound is an independent determinant of metabolic risk.(40) Our reports of childhood size did not capture this aspect of growth and remains to be explored in future studies.
On the other hand, we found a U-shaped relationship between GDM risk and somatotypes at age 20 years, which was similar to results using BMI at age 18 years. The increased GDM risk we observed in underweight individuals appeared to be explained by the greater subsequent weight gain in women who were leaner at age 18. The increased risk of GDM associated with adolescent overweight (BMI>25kg/m2) is in agreement with findings from studies of adolescent overweight and insulin resistance and type 2 diabetes.(41)
Previous reports, including this cohort,(42) have indicated increased risk for GDM associated with increased pre-gravid BMI, with risk in overweight women twice that in normal weight women and that in morbidly obese women increased 5–6 fold.(43) Adult overweight was the strongest risk factor for GDM with lower birth weight and adolescent overweight having minor effects when the three risk factors were assessed in combination. That adult overweight had stronger associations than early life risk factors is not surprising, as it is more proximal to events and may already represent underlying metabolic dysregulation. Our finding of increased GDM risk even among women with BMI 22–25 kg/m2, as compared with leaner women, indicates that even BMIs in the “normal” range may confer increased risk in pregnancy.
Added information for abdominal obesity rather than reliance on BMI alone could be one way to distinguish those at risk in the lower BMI categories. Prior studies of the association of central adiposity with incident GDM risk are scarce and have been limited by their cross-sectional design and/or small number of GDM cases.(44,45) Our report is among the largest studies on abdominal adiposity and GDM risk. Consistent with findings from the present study, a cross-sectional study of pregnant women in Brazil (n=1113) demonstrated significant and positive associations between glucose levels on oral glucose tolerance testing and waist and WHR.(46) Our findings also concord with evidence from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study, which demonstrated that increased pre-pregnancy waist, hip, and WHR were significantly associated with increased risk of GDM.(47) We additionally looked at waist to height ratio and found stronger protective effects, possibly due to taller height being inversely associated with GDM as demonstrated here and as previously reported.(48) Our results, together with these findings support that visceral adiposity contributes to GDM risk beyond the risk associated with increased total body adiposity.
We found that lower birth weight was associated with increased GDM risk across a wide range of BMI in adulthood. In contrast, a previous study utilizing birth certificates reported that low birth weight was associated with increased GDM risk only among women with BMIs less than 25 kg/m2. (49) Our finding of no qualitative interaction between adult BMI and birth weight in association with GDM risk, is consistent with findings in studies of type 2 diabetes(50) and insulin resistance.(51)
There were limitations to our study. Recall of weight characteristics is subject to misclassification but previous validation studies have supported consistency with medical records or clinical measures.(52,53) Misclassification may have led to underestimates of the true associations but the prospective study design avoids bias in reporting related to subsequent disease status. We did not have information on gestational age nor other measures such as ponderal index at birth that may provide more accurate measures of fetal growth and assessment of intra-uterine growth restriction. Because of the observational nature of our study, we cannot prove the causality of the observed association and rule out the impact of residual confounding, although we controlled for most known risk factors of GDM. Birth weight information was not available for 14% of the eligible women; however, distributions of major characteristics (e.g. age, BMI, incidence of GDM, etc.) were similar among individuals who were missing birth weight information compared to those who reported it. We also acknowledge that we use the term “pre-gravid” for any measures prior to pregnancy despite the length of time prior to pregnancy that they may have been collected. For BMI which was updated every two years, the interval of time was short but for waist or hip measurements with median of three years prior before index pregnancy. However, it remains a strength to have information prior to pregnancy. Lastly, GDM was ascertained by self-report which is dependent upon screening. Where universal screening was not practiced, any misclassification of case status may not have been random as obesity is a recognised indicator for screening. However, previous validation of this measure in this cohort suggests the large majority of the participants underwent glucose screening during their pregnancy.(54) The validationstudy also indicated a high degree of accuracy of self-reportedGDM compared with medical record review.25
Strengths of our report include the large sample size, which allowed us to explore interactions and provide precise estimates of GDM risk. In addition, NHSII collected detailed information on important risk factors such as parental diabetes history, physical activity, and anthropometry which spanned the life course.
In conclusion, lower birth weight, increased adiposity in adolescence, and greater overall body and abdominal adiposity in adulthood were all significantly associated with an elevated risk of incident GDM independent of other known risk factors. Women who were born smaller than the average and who subsequently became overweight in both adolescence and adulthood were at the highest risk of GDM whereas women born small but who remained lean only had slightly increased risk. That low birth weight and adult overweight are independently associated with GDM risk suggests that they may operate through different pathways. From a public health standpoint, however, overweight and obesity are associated with much larger absolute risks of GDM than low birth weight. Therefore, weight loss prior to pregnancy then, remains the most important strategy that women can implement to prevent GDM.
This study was funded by research grants CA50385 and DK58845from the National Institutes of Health. Drs Yeung, Buck Louis, Schisterman and Zhang were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health.
Duality of interest: none declared.