Association Between Serum Glycated Hemoglobin Levels at Early Gestation and the Risk of Subsequent Pregnancy Loss in Pregnant Women Without Diabetes Mellitus: Prospective Cohort Study (Preprint)

Abstract

BACKGROUND As one of serious pregnancy morbidities, the etiology of spontaneous pregnancy loss (SPL) remains largely unknown. HbA1c levels in diabetic pregnant women are established risk factor for SPL, but little is known about whether there is an association among non-diabetic women when glycemic control levels are within the normal range. OBJECTIVE This study aimed to quantify the associations of maternal HbA1c levels in early pregnancy with subsequent SPL risk in a cohort of non-diabetic pregnant women. METHODS This was a prospective cohort study involving 10773 non-diabetic pregnant women with HbA1c examined in early pregnancy enrolled between March 2016 and December 2018. Pregnant women with diabetes before or during pregnancy were excluded. SPL defined as fetal death occurring before 28 gestational weeks was derived and confirmed based on the medical records. Generalized linear models were used to quantify the associations of maternal HbA1c levels with the SPL risk, reported as risk ratios (RRs) and 95% confidence intervals (CIs) after adjustment for covariates. RESULTS A total of 273 (2.5%) SPL occurred. Maternal HbA1c levels were linearly associated an 23% increase in SPL risk (adjusted RR [aRR] per .5% increase in HbA1c, 1.23; 95% CI, 1.01-1.50). Additional analyses using HbA1c of 5.6% and 5.9% as the cutoffs showed an 60% (aRR, 1.60; 95% CI, 1.01-2.54) and 67% (aRR, 1.67; 95% CI, .67-3.67) higher risk of SPL, respectively. Sensitivity analyses showed similar results when including the participants with missing medical records or missing HbA1c data. The significant associations were observed even in the pregnant women without overweight, alcohol drinking, family history of diabetes and abnormal pregnancy history exposures. CONCLUSIONS Higher HbA1c levels in early pregnancy of among non-diabetic women were associated with increased SPL risk in a dose-response manner. Our findings support the necessity to monitor HbA1c levels for identifying high-risk of subsequent SPL in general pregnant women, and expand on the growing literature linking overall metabolic health to reproductive and pregnancy health among otherwise healthy women. CLINICALTRIAL NCT02737644