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Maternal Hyperthermia and the Risk for Neural Tube Defects in Offspring: Systematic Review and Meta-Analysis

Moretti, Myla E.*; Bar-Oz, Benjamin; Fried, Shawn*; Koren, Gideon*

doi: 10.1097/01.ede.0000152903.55579.15
Original Article

Background: In animals, excessive core body temperatures have been documented to cause malformations; neural tube defects (NTDs) are among the most frequently reported. In humans, data are inconclusive and often conflicting. The objective of our report is to determine the risk for neural tube defects associated with maternal hyperthermia in early pregnancy

Methods: We conducted a systematic review and meta-analysis to evaluate available evidence on this topic in humans. MEDLINE, EMBASE, references from published reports, and biologic abstracts from meetings were searched for relevant studies. Reviewers evaluated all the retrieved articles and extracted the relevant data. Individual and summary odds ratios and relative risks were calculated using the Mantel–Haenszel method.

Results: Fifteen studies, reporting on 1,719 cases and 37,898 noncases, were included in the meta-analysis. The overall odds ratio for neural tube defects associated with maternal hyperthermia was 1.92 (95% confidence interval = 1.61–2.29). When analyzed separately, the 9 case-control studies had an odds ratio of 1.93 (1.53–2.42). The summary relative risk for the 6 cohort studies was 1.95 (1.30–2.92).

Conclusions: Maternal hyperthermia in early pregnancy is associated with increased risk for neural tube defects and may be a human teratogen.

Supplemental Digital Content is Available in the Text.

From the *The Motherisk Program, The Hospital for Sick Children, Toronto, Canada; †Department of Neonatology, Hadassah Medical Center, Jerusalem, Israel.

Submitted 21 October 2003; final version accepted 22 November 2004.

B.B.O. received a Research Fellowship Award from The Hospital for Sick Children's Research Institute

G.K. is a Senior Scientist of the Canadian Institutes for Health Research.

Supplemental material for this article is available with the online version of the journal at

Correspondence: Myla Moretti, Assistant Director, Motherisk Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. E-mail:

© 2005 Lippincott Williams & Wilkins, Inc.