Prepregnancy Habitual Intakes of Total, Supplemental, and Food Folate and Risk of Gestational Diabetes Mellitus: A Prospective Cohort Study

Abstract

Objective: To identify novel modifiable risk factors of gestational diabetes mellitus (GDM) by examining the association between prepregnancy habitual folate intake and GDM risk.

Research design and methods: The study included 14,553 women in the Nurses' Health Study II who reported at least one singleton pregnancy between the 1991 and 2001 questionnaires. Prepregnancy intakes of total folate, supplemental folate, and food folate were assessed using a food frequency questionnaire administered every 4 years. Incident GDM was ascertained from a self-reported physician diagnosis. Relative risks (RRs) of GDM were estimated using log-binomial models, with adjustment for demographic, lifestyle, and dietary factors.

Results: Over the study follow-up, 824 incident GDM cases were reported among 20,199 pregnancies. Women with adequate total folate intake (≥400 μg/day) had an RR of GDM of 0.83 (95% CI 0.72, 0,95, P = 0.007) compared with women with inadequate intake (<400 μg/day). This association was entirely driven by supplemental folate intake. The RRs of GDM for 1-399, 400-599, and ≥600 μg/day of supplemental folate intake were 0.83, 0.77, and 0.70, respectively, compared with no supplemental folate intake (P _trend = 0.002). The association between supplemental folate intake and GDM risk largely persisted after additional adjustment for intake of multivitamins and other micronutrients, as well as among women who likely planned for the pregnancy.

Conclusions: Higher habitual intakes of supplemental folate before pregnancy were significantly associated with lower GDM risk. If confirmed, these findings indicate that prepregnancy folic acid supplementation could offer a novel and low-cost avenue to reduce GDM risk.

Figure 1

OR and 95% CI of GDM according to supplemental folate intake. The model was estimated using restricted cubic spline logistic regression models with three knots, taking account of age (months), race (white, African American, Hispanic, Asian, others), parity (0, 1, 2, ≥3), family history of diabetes (yes, no), physical activity (quartiles), prepregnancy BMI (<21.0, 21.0‒22.9, 23.0‒24.9, 25.0‒26.9, 27.0‒28.9, 29.0‒30.9, 31.0‒32.9, 33.0‒34.9, ≥35.0 kg/m²), cigarette smoking (never, past, current), alcohol use (0, 0.1‒5.0, 5.1‒9.9, ≥10 g/day), and quartiles of dietary intakes of total energy, glycemic load, saturated fat, total fiber, and heme iron.

Figure 2

RRs and 95% CI of GDM according to prepregnancy supplemental (A) and food folate (B) intake by MTHFR C677T genotypes among white women. The CC/CT and TT groups included 1,136 and 177 pregnancies, respectively. Models adjusted for age (months), nulliparity (yes, no), family history of diabetes (yes, no), physical activity (MET h/week), prepregnancy BMI (<25.0, 25.0‒29.9, and >30.0 kg/m²), current smoking (yes, no), alcohol use (yes, no), and dietary intakes of total energy (kcal/day), glycemic load (unit), saturated fat (% energy), total fiber (g/day), and heme iron (mg/day). Three categories of supplemental folate intake were used instead of four to avoid small numbers in some categories. Q, quartile.