Letter by Harder et al Regarding Article, “Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth”
To the Editor:
We read with interest the work by Pfab et al1 that concludes, from a moderate inverse correlation (r=0.07) between total fetal glycosylated hemoglobin and absolute birth weight, that insulin resistance is preprogrammed in utero in newborns with low birth weight. Although this is an interesting hypothesis, we are concerned about this general conclusion for the following reasons:
1. To the best of our knowledge, total glycosylated hemoglobin (TGH) is not an appropriate, reproducible indicator of insulin resistance—in neither fetal nor later life.
2. As Figure 2A suggests,1 no infants with low birth weight (<2500 g) seemed to have TGH in the upper tertile of the distribution.
3. It would have been more convincing to use parameters of weight relative to length rather than absolute weight for analyses. Relative weight much more closely reflects estimates of insulin resistance.
4. Because maternal TGH was causally linked to fetal TGH (as one would expect),1 both parameters cannot be estimated together in a regression model without bias.2 Therefore, conclusions on the relative impact of maternal and child TGH on birth weight might be incorrect.
5. A positive correlation between maternal and fetal TGH, and a negative correlation of the latter with birth weight, implies a negative relation between maternal TGH (indicating fetal glucose supply) and birth weight in a considerable number of cases. This, however, contradicts the basal physiology of fetal growth. The only established condition potentially leading to this paradox (but not necessarily to macrosomia) is untreated or inadequately treated maternal hyperglycemia, which is known to program diabetic disposition in utero. Notably, the prevalence of gestational diabetes during the recruitment period was up to 14%,3 but it was only 2.8% in the presented cohort.1 This might indicate underestimation of gestational diabetes, which, however, could not be considered in the statistical models.
6. Finally, the analyses seem to contradict at least 7 other studies on this topic so far which, unfortunately, were not considered in this article.
Although this is an interesting study on an important subject, we would suggest a more cautious interpretation of the rather marginally significant observations before drawing far-ranging conclusions.
Pfab T, Slowinski T, Godes M, Halle H, Priem F, Hocher B. Low birth weight, a risk factor for cardiovascular diseases in later life, is already associated with elevated fetal glycosylated hemoglobin at birth. Circulation. 2006; 114: 1687–1692.
Kleinwechter H. The government sponsored model project gestational diabetes (GDM). Schleswig-Holstein: prevalence and foetal outcome in unselected pregnant women following the successful implementation of screening for GDM. Diabetologia. 2000; 43 Suppl 1: A56.