The results of previous reports from the HAPO Study have shown significant independent associations of higher maternal glucose concentrations (4
) and maternal obesity (5
) with adverse pregnancy outcomes. This study adds to the previous reports by examining the impact of GDM and obesity alone as well as their combined impact on adverse pregnancy outcomes. The combination of these factors shows a greater risk of adverse pregnancy outcomes than either GDM or obesity alone.
In the U.S., ~7% or 200,000 pregnant women are currently diagnosed with GDM (16
). Using the IADPSG criteria will increase the number of women diagnosed with GDM (10
). Much of this potential increase in the frequency of GDM in the U.S. and other developed countries can be attributed to the increase in obesity in women of reproductive age (17
). Approximately 60% of women of reproductive age are overweight or obese in the U.S. and other developed countries (17
). Obesity is an increasing problem in other areas of the world, where many of the HAPO field centers were located. Although we defined obesity in pregnancy corresponding to WHO criteria (11
), lower BMI in many developing populations, particularly in Asia, may correlate better with the BMI of ≥30 in Western countries because of the relative increase in visceral adiposity (18
). However, a WHO consultation concluded that available data do not necessarily indicate a clear BMI cutoff point for all Asians for overweight or obesity and that the WHO BMI cutoff points should be retained as international classifications (19
GDM and maternal obesity alone and in combination are independently associated with adverse pregnancy outcomes, and it is tempting to compare the Model II associations among subgroups. We have a number of concerns about using this approach. First, among the several outcomes summarized in , there is no consistent pattern regarding Model II OR for GDM without obesity compared with obesity without GDM. Furthermore, when BMI of the participants was classified from estimated prepregnancy weight the ORs were more variable and associations with obesity without GDM tended to be weaker. What is most striking is that the combination of GDM and obesity is most strongly associated with each outcome. In addition, clearly illustrates the strong association of a combination of overweight and intermediate levels of maternal glucose with outcomes. Finally, GDM and obesity seem to influence a number of the outcomes through similar mechanisms.
The HAPO Study supports the Pedersen hypothesis that increased maternal glucose concentration shows a strong continuous relationship with fetal growth as does the strong association between cord C-peptide and fetal adiposity (20
). As indicated in and published reports (5
), obesity is also independently associated with fetal hyperinsulinemia, birth weight, and newborn adiposity. In a recent study that used continuous glucose monitoring, Harmon et al. (22
) found that obese women with normal glucose tolerance have higher daytime and nocturnal glucose profiles compared with normal weight women. There is also evidence that circulating levels of other nutrients such as lipids and amino acids, which are influenced by insulin and insulin resistance, are increased in both GDM (23
) and obesity (24
) and may contribute to hyperinsulinemia, fetal growth, and adiposity. The pathways for fatty acid esterification in fetal adipose tissue are not well described. However, emerging data on the characterization of fatty acid binding proteins, lipid transporters, and enzymes for fatty acid esterification in the human placenta have now improved our understanding of how maternal lipids may contribute to increased fetal fat accretion (25
Maternal obesity has a strong independent relationship with adverse perinatal outcomes (8
), and the pathophysiology of some of the associations may have similarities with GDM as described above. Other associations may have different mechanisms. For example, we found a higher risk of preeclampsia in obese non-GDM women (OR 3.91, Model II; ) than in nonobese GDM (OR 1.74, Model II). Obese women are more insulin resistant as compared with normal weight women (8
); hence increased insulin resistance may be relevant to the development of preeclampsia in obese women and women developing GDM. However, obesity in addition to GDM was associated with a greater risk of preeclampsia than either factor alone (OR 5.98, Model II; ), thereby implicating other potential mechanisms such as inflammation in the development of preeclampsia in this high-risk group.
The utility of the HAPO Study is that it provides objective evidence upon which to base future strategies to improve perinatal health. The randomized controlled trials of Crowther et al. (26
) and Landon et al. (27
) for the treatment of mild GDM, using current management protocols, in which only 8–20% of mild GDMs required insulin therapy, reported improved outcomes including decreased risks of birth weight >90th percentile and preeclampsia. Maternal weight gain was decreased in the treated GDM as compared with the control group in both studies. Avoidance of excessive gestational weight gain in obese women may improve perinatal outcomes such as birth weight >90th percentile. Because 50–60% of overweight and obese women gain more weight during pregnancy than that recommended in the 2009 Institute of Medicine guidelines (28
), avoidance of excessive gestational weight gain should result in decreased postpartum weight retention for future pregnancies, thereby decreasing the vicious cycle of obesity affecting obese pregnant women and their offspring. However, further research is needed to determine which lifestyle treatment options best improve perinatal outcomes in obese women.
In summary, both maternal GDM and obesity are independently associated with adverse pregnancy outcomes. The combination of the two, however, has a greater impact than either one alone. Although management of GDM requires strict glucose control, it results in lower frequencies of adverse outcomes. Optimal management of maternal obesity per se has yet to be defined. Until the results of ongoing research studies are available, avoidance of excessive gestational weight gain, moderate exercise, and a prudent diet are reasonable recommendations for obese pregnant women.