Our study yielded three key findings. First, the strongest determinant of infant birth weight and of having a large-for-gestational-age infant was maternal adiposity, with BMI before pregnancy and weight gain during pregnancy emerging as the strongest predictors for both outcomes in the fully adjusted analyses. This finding is consistent with those of previous studies, which suggests the central role of maternal weight as a determinant of birth weight.17–19
Although the underlying mechanisms remain unclear, shared genetic factors may be relevant to both maternal adiposity and fetal growth.
Obesity is associated with pathologic sequelae, including chronic inflammation (increased C-reactive protein level) and adipocyte dysregulation (increased leptin and low adiponectin levels).20
In this context, the second key observation of our study pertains to the relative contributions of these obesity-related circulating factors. Specifically, we found leptin to be a significant negative predictor of both birth weight and large-for-gestational-age infant after adjustment for covariates, including BMI before pregnancy and weight gain during pregnancy. An inverse relation between leptin level and infant birth weight has been observed in some, though not all, previous studies.21–24
Of note, Verhaeghe and colleagues found that, compared with glucose, insulin, adiponectin and tumour necrosis factor-α, leptin was the mediator that was most strongly (and negatively) associated with birth weight.23
Placental dysfunction has been suggested as a unifying mechanism underlying both fetal growth restriction and elevated maternal leptin levels (through increased placental production of leptin), although this model remains speculative.24
Like leptin, C-reactive protein also emerged as a negative determinant of infant birth weight in our multiple linear regression analysis. In the Hyperglycemia and Adverse Pregnancy Outcome Study, an inverse relation between C-reactive protein level and birth weight was seen after adjustment for covariates, including maternal BMI.25
The negative associations of leptin and C-reactive protein with birth weight became apparent in our study only after adjustment for covariates, including BMI before pregnancy. Thus, despite the elevated circulating levels of leptin and C-reactive protein in the setting of obesity (which itself is the primary determinant of increased birth weight), both of these proteins were found to be independently associated with decreased birth weight. Although the mechanisms are unclear, our data suggest that these factors may play a role in attenuating the pro-macrosomia effects of maternal adiposity. Overall, coupled with the inverse relation between total adiponectin level and birth weight, these data suggest a model in which fetal growth is influenced both positively and negatively by complex interplay between maternal adiposity and its associated circulating factors.
The third key finding from our study is that, although gestational impaired glucose tolerance was an independent predictor of birth weight in the multiple linear regression analysis, its impact was relatively modest compared with that of BMI before pregnancy, weight gain during pregnancy up to the time the oral glucose tolerance test and the leptin level. Moreover, unlike the latter three factors, gestational impaired glucose tolerance was not a significant independent predictor of having a large-for-gestational-age infant. Similarly, none of the lipid measures was independently associated with birth weight or large-for-gestational-age infant. These data suggest that maternal weight and its associated circulating factors have a greater impact on infant birth weight than do mild glucose intolerance and lipid levels in women without gestational diabetes.
This concept is consistent with findings from two recent studies addressing the relative effects of maternal obesity and glycemia on fetal growth. In a re-analysis of data from the Hyperglycemia and Adverse Pregnancy Outcome Study, Ryan recently showed that maternal BMI had a greater impact on the odds of having a large-for-gestational-age infant than did maternal glucose in all but the highest category of glycemia.26
In addition, in a study involving Spanish women, Ricart and colleagues found that BMI before pregnancy commanded a much higher population-attributable risk for macrosomia than did gestational hyperglycemia.17
Our study further extends this discussion by showing that both BMI before pregnancy and weight gain during pregnancy had a greater independent impact on the risk of excessive fetal growth than did glycemia in women without gestational diabetes.
This emerging concept regarding the relative importance of maternal obesity versus glycemia may hold implications for the current debate regarding the lowering of diagnostic thresholds for gestational diabetes on antepartum glucose tolerance testing.26,27
Specifically, among the additional women who will be identified as having gestational diabetes owing to this change, their mild glucose intolerance may play a comparatively modest role in determining risk of macrosomia. In this context, it may instead be more prudent to target maternal obesity, the prevalence of which has risen dramatically in recent years.10
Strengths and limitations
A major strength of our analysis is that it evaluated simultaneously the effect of several maternal metabolic factors, including glucose tolerance, adiposity, and fasting levels of insulin, lipids, adipokines and inflammatory proteins. This approach enabled the assessment of the factors’ independent associations with infant birth weight after adjustment for one another.
One limitation of our study is that we did not evaluate the high-molecular-weight form of adiponectin. Although total and high-molecular-weight adiponectin are generally highly correlated, the high-molecular-weight form may be the specific maternal mediator affecting fetal growth.28
Another limitation is that weight before pregnancy was determined by patient recall and hence may have been subject to bias. In addition, weight gain during pregnancy was determined only up to the time of the oral glucose tolerance test and not across the total length of gestation. However, the impact of this limitation should be modest, because changes in maternal weight in the first and second trimesters have been shown to have a much greater influence on birth weight than changes in the third trimester.29
Among women without gestational diabetes, the strongest metabolic determinant of macrosomia was maternal adiposity, as reflected by BMI before pregnancy and weight gain during pregnancy up to the time of the oral glucose tolerance test. Furthermore, after adjustment for these attributes, weight-related circulating factors (particularly leptin) emerged as negative independent predictors of having a large-for-gestational-age infant. In contrast, glucose intolerance and lipid levels had a modest effect in this cohort.
In the context of the current obesity epidemic, these data support the importance of targeting healthy body weight in young women as a strategy for reducing the risk of excessive fetal growth and infant macrosomia. Furthermore, these findings suggest that, in the care of overweight or obese women in pregnancy, closer monitoring of weight gain during pregnancy may be warranted.