In our last post, we discussed the preconceptional evaluation of the woman with pregestational diabetes – this evaluation pertains to women with eithertype 1 or type 2 diabetes. As part of the evaluation, we mentioned screening for ‘hemoglobin A1c’ and one of my local readers asked me to explain that in more detail. She is, herself, a nurse, and I appreciate her reminding me that sometimes I get ahead of myself without providing adequate explanations to our readers, even those who are medical professionals themselves. I confess this is a common fault of our profession, so let me see what I can do to offer an explanation of what it is and why we suggest including it in the evaluation of diabetic women…
Hemoglobin is contained in red blood cells and is the oxygen-carrying component of red blood cells and, because of its iron content, it is that which makes blood appear red. In individuals without genetic abnormalities of their hemoglobin, hemoglobin A (which stands for ‘Adult’), is the predominant type of hemoglobin found in the red blood cells. In normal (nondiabetic) individuals, more than 92% of the hemoglobin A is simply hemoglobin A. However, a small percentage of the hemoglobin A molecules have sugar (glucose) that is attached to them. These ‘glycosylated’ hemoglobin molecules are called ‘hemoglobin A1c’.
The percentage of hemoglobin A that actually becomes hemoglobin A1c depends on the blood glucose levels over the long-term, generally six to eight weeks (although some believe that 3-4 weeks is more accurate). The higher the average blood glucose levels, the higher the percentage of hemoglobin A1c. Once a hemoglobin molecule becomes ‘glycosylated’, it stays that way for the life of the red blood cell (about 120 days) (Bunn, et al., Biochem Biophys Res Commu. 1975;67:103–9). Short-term fluctuations of blood sugar, such as those associated with meals, do not have much effect on the concentrations of hemoglobin A1c, unless of course, they are abnormal and contribute to an unusually high range overall. For these reasons, levels of hemoglobin A1c are a direct reflection of blood glucose control over time.
In healthy individuals, hemoglobin A1c comprises less than 7% of the total hemoglobin that is present. Conditions that can falsely elevate levels of hemoglobin A1c include kidney failure, hypertriglyceridemia, and folate and vitamin B12 deficiencies that are accompanied by slower rates of red blood cell turnover. Conditions that cause more rapid turnover of red blood cells, such as blood loss, sickle cell disease, or glucose-6-phosphate dehydrogenase (G6PD) deficiency, can falsely decrease levels.
Rahbar and colleagues (Biochem Biophys Res Commun 1969; 36: 838–43) first identified the presence of elevated levels of hemoglobin A1c in diabetics and others have correlated the levels with degree of blood glucose control (Koenig, et al., N Eng. J Med 1976; 295: 417-20). To give some perspective on this, average blood sugars of 90 mg/dL are associated with hemoglobin A1c concentrations of about 5%, blood sugars of 120 mg/dL with 6%, 150 mg/dL with 75, 180 mg/dL with 8%, and so on. The International Diabetes Federation and American College of Endocrinology suggest that ‘normal’ levels of hemoglobin A1c be considered values below 6.5%.
As pointed out in our previous post, poor diabetic control, as reflected in elevated levels of hemoglobin A1c during the time of embryogenesis, is associated with both early pregnancy loss and congenital anomalies. For example, as shown by Miller and colleagues (New Engl Med J 1981;304:1331-1334) a hemoglobin A1c level >8.5% confers a risk of birth defects of approximately 22% versus 3.4% in women with A1c levels <8.5%. On the flip side, normal hemoglobin A1c levels during this critical time in fetal development, even in long-term diabetics with other complications, are generally accompanied by a risk for birth defects close to that of the nondiabetic population.
It is important to note, however, that it is not the hemoglobin A1c level that causes the birth defects, it is the poor diabetic control (high maternal blood sugars). In other words, if a diabetic comes in for preconceptional counseling and has a hemoglobin A1c of 11.5% (very bad), quickly normalizes her blood sugar control according to our strict standards, then gets pregnant a week later and continues good control of her blood sugars during the period of her baby’s embryogenesis, the hemoglobin A1c level may be high, but the baby’s risk should be minimal. On the other hand, if she says “I have normal blood sugars” and she gets to 14 weeks and her hemoglobin A1c is 11.5%, check her glucometer and be on the look out for major congenital malformations!