Conclusions
In our study we observed that increased HbA1c ≥5.7 measured during early pregnancy reflects impairments in beta-cell function and glucose disposal that are characteristic of GDM. Further, HbA1c at early pregnancy may be useful as an indicator of disturbed beta-cell function even independent of BMI. As far as we know, this is the first study providing data of simultaneously performed 75 g OGTT including insulin and C-peptide measurements in addition to HbA1c during early pregnancy. In our population, increased maternal HbA1c was associated with higher glucose levels during OGTT as well as alterations in dynamics. Moreover, analysis of OGTT-derived indices showed impaired beta-cell function and differences in disposition index in women with increased HbA1c which were independent of early pregnancy BMI or pregestational BMI status.
Characteristic of GDM is the insufficient compensation of increasing insulin requirements during pregnancy primarily due to defective beta-cell function.1 15 Concomitant to changes in the insulin signaling cascade, the growing placenta produces hormones with insulin-desensitizing effects that increase insulin resistance—here maternal adiposity gains relevance as an antecedent risk factor during early pregnancy that defines level of basal insulin sensitivity.1 16 To sum up, maintenance of euglycemia during gestation depends mainly on the plasticity of maternal beta-cell function to sufficiently compensate insulin resistance, which aggravates depending on additional metabolic risk factors during pregnancy—otherwise it is a matter of time that GDM becomes evident.1 15 However, measures indicating beta-cell function or the disposition index require too extensive and precise procedures including multiple blood samples and thus are inconvenient for first trimester screening. HbA1c during early pregnancy may give an estimate of the maternal glucose metabolism at baseline before significant hormonal pregnancy-related changes develop—thus it offers an opportunity to identify those women who could benefit of tighter glycemic control at very early stage of gestation. In our study, we could demonstrate that HbA1c >5.7% is associated with lower levels of disposition index, which reflects compensatory effectiveness of beta-cell function in answer to insulin resistance. We further observed that HbA1c is related to later insulin requirement, which is another corroborating aspect for the predictive value of early measured HbA1c.
Since HbA1c is already broadly applied during first routine antenatal visit for detection of pregestational diabetes, implementation of HbA1c in GDM risk stratification becomes an attractive option. Several studies already reported that women with elevated HbA1c during early pregnancy have a higher risk for GDM and/or adverse pregnancy outcomes. In a retrospective analysis Osmundson et al showed that risk for GDM was increased by 50% (adjusted RR, 1.48; 95% CI 1.15 to 1.89) in women with first trimester HbA1c of 5.7%–6.4% compared with women with an HbA1c in normal range.17 Other studies concluded similarly that HbA1c levels referred for pre-diabetes outside of pregnancy are associated with GDM manifestation and hereby supported the prognostic applicability of HbA1c in GDM risk prediction.6 7 18 Of interest, in a very recent retrospective cohort study pregravid HbA1c measured at median 1.4 years before pregnancy was shown to be a robust predictor of GDM. For each 0.1% elevation of pregravid HbA1c the odds of GDM in a subsequent pregnancy was increased by 22%—however, the authors could not define a threshold for pregravid HbA1c that is implementable to reduce the burden of OGTT screening during pregnancy.19
Similar to our findings, several previous studies concluded an overall limited predictive ability of HbA1c at prediabetic level.6 7 17–19 After reviewing indicated test characteristics of former studies we could detect limitations in comparability of these to our results mainly due to the differences in study design. Our observations of a relatively high specificity but low sensitivity at an HbA1c cut-off of 5.7% for GDM development are very similar to the findings of the retrospective study by Osmundson et al, who equally used the IADPSG criteria for GDM diagnosis and applied the same threshold for their analysis.17 As far as applicable, we could further extract similar test characteristics (ie, specificity and sensitivity) for a cut-point of 5.7% from studies, which differ regarding to diagnosis criteria (ie, the two-step screening by Carpenter and Coustan criteria with preceding challenge test) and the primary choice of a lower threshold.7 20 21 Further, it has to be considered that HbA1c changes throughout pregnancy7 which may explain why only moderate correlations are detectable between early HbA1c and glucose examinations in third trimester. However, we are now confronted with the challenge that during an outbreak of pandemic disease measures for containment of virulent infection are required, which limit indications for time-consuming OGTTs—here simple algorithms comprising rapidly obtainable parameters would facilitate preparation of temporary guidelines that adequately balance their benefits versus burden in disease management during special conditions. Thus, the actual COVID-19 pandemic shows that it is worth to direct attention towards large-scale studies comparing different approaches for use in exceptional situations.
Moreover, we observed that elevated maternal HbA1c at early pregnancy is associated with a higher risk for delivering LGA infants even after adjustment for GDM status. Hughes et al as well found a higher rate of LGA newborns based on population-adjusted percentiles6 whereas others reported no significant difference in birth weight.17 21 However, available data are not powered to identify neonatal differences. The use of HbA1c during early pregnancy represents average glucose level over the prior 3 months and thus might be a better predictor of very early influences on fetal development that are not covered by mid-pregnancy to late pregnancy glucose-based testing. Of further interest is if any early intervention based on maternal HbA1c brings a benefit for pregnancy and/or neonatal outcome—but this aspect is so far not sufficiently addressed in randomized trials. In a study with small sample size it was shown that early treatment for women with HbA1c in prediabetic range did not significantly reduce overall rate of GDM diagnosis in 24th–28th GWs but in a subgroup analysis of non-obese women, GDM risk was decreased by 50%.22 Recently, Roeder et al aimed to examine the effects of early treatment on neonatal hyperinsulinemia and fat mass in women with HbA1c ≥5.7% and/or fasting glucose ≤92 mg/dL. The study stopped early because of low enrollment but presented data showed so far no significant benefit.23 In another study, investigators randomized obese women to compare early screening prior to 20th week to routine screening, whereby women with HbA1c between 6.2% and 6.5% at initial contact were provided with early screening regardless of randomization arm. Altogether, they found no reduction of composite perinatal outcome between in those who received early screening.24
Current recommendations mostly fail to consider women with pre-existing deteriorations in glucose hemostasis who enter pregnancy with glucose elevations below the threshold used for overt diabetes. Further, lack of agreement on uniform screening standards during early pregnancy additionally hardens comparability of studies aiming to characterize high-risk pregnancies. In summary, our data show that early HbA1c ≥5.7% but below overt diabetes reflects impairments in beta-cell function and glucose disposal that are indicative for underlying defects in compensation mechanisms and risk for early GDM. These associations on pathophysiological level argue for the utility of HbA1c as early predictor for pregnancies at glucometabolic risk that warrant further research.