Maternal serum folate species in early pregnancy and risk of preterm birth123

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Background: Poor maternal folate status has been associated with an increased risk of preterm birth. However, major gaps remain in our understanding of how individual folate species relate to preterm birth.

Objective: Our objective was to assess the association between maternal folate status as measured by 5-methyltetrahydrofolate (5MeTHF), 5-formyltetrahydrofolate (5FoTHF), and folic acid concentrations, which are the 3 primary folate species in serum, and the risk of preterm birth and spontaneous preterm birth (sPTB).

Design: A cohort of 313 pregnant women who received care at resident antepartum clinics at Magee-Womens Hospital (Pittsburgh, PA) (2003–2007) was enrolled at <16 wk gestation. We analyzed nonfasting blood samples that were drawn from subjects at enrollment for the 3 folate species by using HPLC–tandem mass spectrometry.

Results: Serum 5MeTHF and 5FoTHF concentrations comprised 65% and 33% of total folate concentrations, respectively. In confounder-adjusted, multivariable, log-binomial regression models, 1-SD increases in serum total folate and serum 5MeTHF concentrations were associated with significant reductions in the risk of sPTB (P < 0.05). There was a significant interaction between serum 5MeTHF and 5FoTHF concentrations and risk of preterm birth (P = 0.01). When serum 5MeTHF concentrations were low, there was a positive linear relation between 5FoTHF and risk of preterm birth. When 5MeTHF concentrations were high, there was a strong negative relation between 5FoTHF and preterm birth.

Conclusions: Our results imply that the relative concentrations of folate species may be more critical than total folate in preventing preterm birth. An improved understanding of folate metabolism during pregnancy may lead to targeted intervention strategies that decrease the rate of preterm birth.

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1

From the Department of Epidemiology, Graduate School of Public Health (LMB, J-YC, RWE, and JLM); the Departments of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine (KPH and HNS); the Department of Pharmaceutical Sciences, School of Pharmacy (RV); and the Department of Pathology, School of Pharmacy (RV), University of Pittsburgh, Pittsburgh, PA, and the Magee-Womens Research Institute, Pittsburgh, PA (LMB, KPH, and HNS).

2

Supported by National Institutes of Health grants R01 HD041663 and R01 HD052732 (HNS) and K01 MH074092 and R01 HD056999 (LMB).

3

Address correspondence to LM Bodnar, Department of Epidemiology, University of Pittsburgh, A742 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261. E-mail: [email protected]