Folic Acid Antagonists Increase Birth Defect Risk

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Folic Acid Antagonists Increase Birth Defect Risk

Matok I, Gorodischer R, Koren G, et al. Exposure To Folic Acid Antagonists During The First Trimester of Pregnancy and the Risk of Major Malformations.

doi: 10.1111/1365-2125.2009.03544.x


Exposure To Folic Acid Antagonists During The First Trimester of Pregnancy and the Risk of Major Malformations
I. Matok, MSc Pharm 1 , R. Gorodischer, MD 2,4,5,7 , G. Koren, MD 6,7 , D. Landau, MD 2,4,5 , A. Wiznitzer, MD 3,4 , and A. Levy, PhD 1,7
Departments of 1Epidemiology, 2 Pediatrics and 3 Obstetrics and Gynecology, Faculty of Health Sciences, Ben Gurion University of the Negev, 4 Soroka Medical Center, 5 Clalit Health Services (Southern District), Beer-Sheva, Israel and 6 The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada, 7 BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration).
Correspondence to Professor Gideon Koren, MD, FRCPC, FACMT
Division of Clinical Pharmacology
The Hospital for Sick Children
555 University Avenue
Toronto, Ontario, Canada
Tel: +416- 813.5780
Fax: +416- 813.7562
This is an Accepted Article that has been peer-reviewed and approved for publication in the British Journal of Clinical Pharmacology, but has yet to undergo copy-editing and proof correction. Please cite this article as an "Accepted Article"; doi: 10.1111/1365-2125.2009.03544.x

folic acid antagonists • congenital malformations • pregnancy outcomes • drug safety
What is already known about this subject:
Previous studies suggested tendency of antifolate drugs to be associated with higher rates of neural tube defects. What this paper adds
This paper makes use of the data on abortuses, which is missed in many other studies. In this case-the abortion data was critical.
The study documents that clinicians should avoid, as much as possible, the use of folic acid antagonists during the first trimester of pregnancy, when embryogenesis takes place.

Aim: Investigate the safety of folic acid antagonists during the first trimester of pregnancy in a large cohort.
Methods: Computerized databases for medications dispensed from 1998 to 2007 to women registered in "Clalit" HMO, Israel southern district, was linked with maternal and infant hospitalization records, and to therapeutics abortions data. The risk for adverse pregnancy outcomes of folic acid antagonists exposure was assessed by adjusting for known confounders.
Results: 84,823 infants were born and 998 therapeutic abortions took place; 571 fetuses and infants were exposed to 1 or more folic acid antagonists in the first trimester of pregnancy. Exposure was associated with an overall increased risk of congenital malformations (OR = 2.43, 95% CI: 1.92 – 3.08), due mainly to increased risk for neural tube (adjusted OR 6.5, 95% CI: 4.34-9.15) and cardiovascular defects (OR 1.76, CI: 1.05-2.95).
Conclusion: First trimester exposure to folic acid antagonists is associated with increased risk of congenital malformations.

Accepted for publication 12 September 2009

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