HbA1c is a measure of average glucose values in past 3–4 months. In pregnant women, the utility of HbA1c was earlier challenged due to the relatively faster erythrocyte turnover and hemodilution. Later as normative values for HbA1c for different trimesters became available, the guidelines have adopted trimester specific cutoffs for pregnant women. Although HbA1c level may not be reflective of the glycemic levels of last 3–4 months in pregnant women, it is certainly useful to assess the glycemic status of the last 1–2 months. (10) This physiological change may be useful in pregnancy because the follow up visits in pregnancy especially in those with diabetes are much more frequent than a non-pregnant patient and it becomes a more accurate indicator of glycemia in the near past without the confounding effect of remote hyperglycemia of 3 to 4 months back making it more relevant in the context of pregnancy where there can be relatively faster changes in the level of glycemia.
HbA1c measured at term pregnancy reflects the average blood glucose values experienced by the mother and fetus after the 28–32 week of gestation. The importance of such a measurement in a patient not diagnosed to have diabetes till third trimester is to assess the glycemic exposure of the mother and the fetus in the last trimester. It may also help in determining the risk of future diabetes in the mother. In pregnant patients diagnosed to have diabetes, the HbA1c level can help in assessment of adequacy of glycemic control and of risk of maternal and fetal complications.
Maternal hyperglycemia can occur any time during a pregnancy, the risk being higher in the later part of it. It has been shown that peripheral insulin sensitivity (defined as the ability of insulin to increase glucose uptake in skeletal muscle and adipose tissue) decreases by approximately 50% by late gestation and in women with normal glucose tolerance, there is a 2–3-fold increase in insulin secretion in response to the decreased insulin sensitivity that maintains euglycemia. (11, 12) Despite this higher risk the screening programs do not assess for hyperglycemia after the 28th week of gestation (13).
The current multicentric study was done to find the normative value of HbA1c at term pregnancy in healthy pregnant women admitted for safe confinement. The study determined the mean HbA1c value at delivery in previously normal women, admitted for safe confinement without any maternal or fetal complications to be 5.0 (± 0.38) %. As HbA1c levels decrease during pregnancy, in order to ensure optimal glycaemic control in pregnant woman with diabetes, it is necessary to use HbA1c reference values specific for each trimester (14). With the current study normal value of HbA1c at the end of third trimester has been defined for the first time. Previously reference ranges have been studied for the 3rd trimester of pregnancy but the HbA1c estimation was done for different patients at different times during the third trimester ranging from 28th to 36th week of gestation. (15, 16)
Some investigation has previously been done on HbA1c at the time of delivery with pregnancy outcomes especially caesarean delivery, but again normal values in non-diabetic pregnant women has not been defined. (17)
The current study finds that the upper limit of reference interval for HbA1c at full term pregnancy is 5.9%. It is in consistence with the American Diabetes association target for HbA1c which recommend a level of < 6% to be optimal during pregnancy if it can be achieved without hypoglycemic episodes (18). In the 2nd and 3rd trimesters, HbA1c < 6% has been proposed to have lowest risk of large for gestational age infants, preterm delivery, and preeclampsia (19). It is also recommended that HbA1c should be monitored more frequently i.e., monthly, during pregnancy (19).
Regarding the determinants of HbA1c at full term gestation, the current study found that 2nd trimester GTT, 2 hour glucose value, FPG and PPG of first trimester, Pre-pregnancy BMI, Systolic BP, Diastolic BP, and Maternal age have significant correlation with HbA1c levels at term. As only women with normal BMI, without GDM or overt diabetes and those without any fetal and maternal complications were included in the analysis the relation between HbA1c and the birthweight and fetal insulin levels may have been masked as those with high BMI, diagnosed GDM or overt diabetes. Pre-pregnancy BMI exerts its influence on HbA1c even in the third trimester of pregnancy highlighting the importance of adiposity in the pathogenesis of GDM. This association has been consistently observed in many previous studies on HbA1c in all trimesters of pregnancy. This highlights the importance of normalizing BMI, prior to conception for possible prevention of GDM. 2nd trimester OGTT 2 Hour glucose value association with HbA1c is important as it may be evaluated as a sensitive predictor of hyperglycemia in the third trimester of pregnancy.
Intrauterine hyperglycaemia through its effects on fetal β-cells and adipose tissue can lead to late development of metabolic complications in the offspring. In a follow- up study (20) from Denmark, offspring’s (18–27 years of age) of women with GDM, 21% of the offspring had pre- diabetes or diabetes accounting for an eight-fold increased risk compared with the background population. Furthermore, the risk of overweight and the metabolic syndrome was higher (twofold and fourfold, respectively) and insulin sensitivity and secretion were reduced. The ‘HAPO- Follow up study’ confirmed these findings but suggests that although maternal adiposity is a strong risk factor for offspring obesity, GDM remains a significant risk factor, even after adjustment for maternal BMI (21). Further studies correlating the effects of sustained third trimester hyperglycaemia (as reflected by HbA1c at term) in offspring are needed.
The current study had a strength of multicentric data collection and a large sample size. The study had the novelty of defining HbA1c levels at term in normal pregnant women for the first time. The limitations of the study included lack of fetal C peptide level estimation which would have been a better marker for fetal endogenous insulin secretion.