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
) 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
) 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
) 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
) 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.