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Maternal Prepregnancy Folate Intake and Risk of Spontaneous Abortion and Stillbirth

Gaskins, Audrey J. ScD; Rich-Edwards, Janet W. ScD; Hauser, Russ MD, ScD; Williams, Paige L. PhD; Gillman, Matthew W. MD, SM; Ginsburg, Elizabeth S. MD; Missmer, Stacey A. ScD; Chavarro, Jorge E. MD, ScD

doi: 10.1097/AOG.0000000000000343
Contents: Original Research

OBJECTIVE: To evaluate prospectively the relationship between prepregnancy folate intake and risk of spontaneous abortion and stillbirth.

METHODS: Women in the Nurses' Health Study II who self-reported a pregnancy between 1992 and 2009 were included in this analysis. Dietary folate and supplement use was assessed every 4 years, starting in 1991, by a food frequency questionnaire. Pregnancies were self-reported with case pregnancies lost spontaneously (spontaneous abortion less than 20 weeks of gestation and stillbirth 20+ weeks of gestation) and comparison pregnancies ending in ectopic pregnancy, induced abortion, or live birth.

RESULTS: Among the 11,072 women, 15,950 pregnancies were reported of which 2,756 (17.3%) ended in spontaneous abortion and 120 (0.8%) ended in stillbirth. Compared with women in the lowest quintile of prepregnancy folate intake (less than 285 micrograms/d), those in the highest quintile (greater than 851 micrograms/d) had a relative risk of spontaneous abortion of 0.91 (95% confidence interval [CI] 0.82–1.02) after multivariable adjustment (P trend=.04). This association was primarily attributable to intake of folate from supplements. Compared with women without supplemental folate intake (0 micrograms/d), those in the highest category (greater than 730 micrograms/d) had a relative risk of spontaneous abortion of 0.80 (95% CI 0.71–0.90) after multivariable adjustment (P trend <.001). The association of prepregnancy supplemental folate with risk of spontaneous abortion was consistent across gestational period of loss. A similar inverse trend was observed with the risk of stillbirth, which fell short of conventional significance (P trend=.06).

CONCLUSIONS: Higher intake of folate from supplements was associated with reduced risk of spontaneous abortion. Women at risk of pregnancy should use supplemental folate for neural tube defect prevention and because it may decrease the risk of spontaneous abortion.


A higher intake of folate from supplements is associated with a reduced risk of spontaneous abortion.Supplemental Digital Content is Available in the Text.

Departments of Nutrition, Epidemiology, Environmental Health, and Biostatistics, Harvard School of Public Health, the Department of Population Medicine, Harvard Medical School/Harvard Pilgrim Health Care Institute, and the Department of Obstetrics, Gynecology and Reproductive Biology, the Channing Division of Network Medicine, and the Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Corresponding author: Audrey J. Gaskins, BSE, Harvard School of Public Health, Building II, 3rd Floor, 655 Huntington Avenue, Boston, MA 02115; e-mail:

Supported by National Institutes of Health grants T32DK007703-16, T32HD060454, and UM1 CA176726.

Presented at the annual meeting for the Society of Pediatric and Perinatal Epidemiology, June 17–18, 2013, Boston, Massachusetts.

Financial Disclosure The authors did not report any potential conflicts of interest.

© 2014 by The American College of Obstetricians and Gynecologists.