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*
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 www.epidem.com
Correspondence: Myla Moretti, Assistant Director, Motherisk Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. E-mail: email@example.com.
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.
Click on the links below to access all the ArticlePlus for this article.
Please note that ArticlePlus files may launch a viewer application outside of your web browser.
Nearly 100 years ago, scientists discovered that malformations could be induced in various animal species by exposing the mother to high core body temperatures during critical periods of gestation.1 Although a number of teratologic outcomes were produced, including fetal loss and various malformations, the brain was particularly sensitive.2,3 In humans, an elevated core body temperature can occur with fever caused by viral or bacterial illnesses. In addition, extreme exercise, saunas, hot tubs, heated beds, and electric blankets may all lead to increased body temperatures. Presently, there is no consensus as to the role of hyperthermia during pregnancy in causing malformations in humans. Many of the available studies are inconclusive due to insufficient sample size.
A fever can be of varying duration, as with exposure to other potential teratogens. A fever may be recognized and treated with antipyretics or it may remain unidentified or untreated. Serious illnesses accompanied by fevers (eg, malaria) may be associated with poor nutritional intake by the mother, which itself may be associated with poor pregnancy outcome. The infectious agent itself may be teratogenic (such as rubella, varicella or cytomegalovirus). The literature on the effects of maternal hyperthermia has investigated various outcomes, including pregnancy loss and specific malformations. Our objective was to investigate the association between maternal hyperthermia in early pregnancy and the risk for risk for neural tube defects (NTDs). We chose this outcome because there are a substantial number of published studies on this association, and because it is an outcome for which animal data lend biologic plausibility.
We searched MEDLINE and EMBASE to locate articles in any language in 1966 through August 2003. In addition, the reference sections from articles retrieved from the original database searches were inspected for additional publications. Published meeting abstracts and proceedings were also searched between 1980 and February 2003 for studies in progress or studies not published in the peer reviewed literature. The keywords “pregnancy,” “pregnancy outcome,” “birth defect,” “teratogen,” and “congenital abnormalities” were searched. The intersection of this search with articles retrieved by using the keyword “hyperthermia” generated the final set of articles retrieved for evaluation.
Two investigators familiar with clinical study design acted as reviewers, selecting studies for inclusion in the meta-analysis based on preset inclusion criteria and following a standardized checklist (Appendix 1, available with the electronic version of this article). Reviewers received only the Methods sections; they were unaware of the authors’ and journal names, and year of publication. Studies were excluded if they were not performed in humans, did not report pregnancy outcome, did not specifically extract information on neural tube defects, reported on fewer than 5 subjects, did not have a control group, were not cohort or case–control studies, or did not report hyperthermia exposure occurring in the first trimester. Hyperthermia or fever was included if it was either internal (such as maternal fever caused by illness) or external (exposures to hot tubs, heated beds, saunas or electric blankets). Each reviewer listed the reason for exclusion.
The reviewers were then given the Results section of each of the included papers, with identifying information removed. Reviewers extracted the relevant data from the text and tables, and entered these numbers into 2 × 2 tables. The following neural tube defects were included: anencephaly, spina bifida, encephalocele, myelomeningocele, exencephaly, myeloschisis, iniencephaly, and craniorachischisis. Studies were included if they reported the total number of NTDs, even if the numbers of specific NTDs were not specified. Internal hyperthermia was defined as documented maternal fever (either receiving treatment or not) or documentation of maternal illnesses know to be associated with fever (“febrile illnesses”) in the first trimester of pregnancy. External hyperthermia was defined as exposure to at least 15 minutes of high temperature exposure via hot tub, sauna, electric blanket or heated waterbed in the first trimester of pregnancy.
Each reviewer extracted the data independently. For studies about which there was disagreement on inclusion or data extraction, the reviewers discussed the rationale for their choices and came to consensus. The extracted data were entered into Cochrane's Review Manager (version 4.1, Oxford: Cochrane Collaboration). For summaries that included case-control studies, we calculated individual and summary odds ratios (ORs) and 95% confidence intervals (CIs) by the Mantel-Haenszel method. For cohort studies we used the relative risk (RR) and 95% CI. Included studies were tested for heterogeneity using the χ2 test. Publication bias was assessed by visual examination of the funnel plot (effect size versus log study size) and by the trim-and-fill method of Duval and Tweedie.4,5
Initially, 42 studies were identified and presented to the reviewers for possible inclusion. Of these, we subsequently excluded 24 articles because they did not meet the inclusion criteria or because the Methods and Results sections did not provide sufficient information. For example, a study from a Japanese group6 was excluded because it described a retrospective cohort with no control group. Another study7 reported sauna use in all cases and all controls and focused on comparing habits of sauna use in the 2 groups. One study8 was excluded because the report did not give the total number of prospectively collected subjects but rather described only the affected cases in detail. An additional 3 studies were excluded because they were publication of duplicate data.9–11 A full list of excluded articles is available from the authors (Appendix 2, available with the electronic version of this article).
Details regarding the 15 included studies are shown in Table 1. 12–26 There were 9 case–control studies, with a total of 1601 NTD cases and 5149 controls. The overall OR was 1.93 (95% CI = 1.53–2.42) for NTDs associated with maternal hyperthermia exposure (Fig. 1). There were 6 prospective cohort studies reporting on 8,798 exposed infants and 24,069 unexposed infants, yielding an overall RR of 1.95 (CI = 1.30–2.92) (Fig. 2). When combined, the overall OR of all 15 studies was 1.92 (CI = 1.61-2.29). The χ2 test for heterogeneity was 13.14 (df = 13; P = 0.44), with no statistical evidence for heterogeneity. One cohort study24 did not contribute to the summary rates because there were no NTDs detected, and thus the individual RR/OR could not be estimated. Findings did not vary by year of publication. Some publications reported on other potential sources for variation in findings (eg, maternal characteristics, degree of fever and folate intake). However, there were not sufficient data to conduct secondary analysis on these parameters. A funnel plot arrangement of the results was asymmetric, suggesting the presence of publication bias. The adjusted odds ratio (using the trim-and-fill method) was 1.86 (95% CI = 1.54–2.24).
Hyperthermia was the first environmental teratogen identified by scientists in animal models. Even so, there has not been a consensus about its effect in humans. In animals, one can deliver precise amount of hyperthermia in terms of timing, length, and degree. Evaluation of exposure in humans has been substantially more complicated. In humans, hyperthermia is often associated with an infectious disease that may pose a risk to the fetus both in terms of the pathogen itself and through other changes in maternal well being and nutritional status.
We focused on NTDs because this was the endpoint of most human studies on pregnancy outcomes after exposure to hyperthermia. Most studies were conducted before the association between risk for NTD and low folate intake was established and, therefore, data on daily folate or blood levels of this vitamin were not included. Four studies made note of maternal use of multivitamins or folic acid specifically.18–20,25 In 2 of these publications,18,19 elevated risks for NTD persisted even after adjusting for maternal multivitamin use; in the more recent article by Shaw et al,20 the ORs for the association of hyperthermia with NTDs were somewhat lower among vitamin users but still elevated. In contrast, Milunsky et al25 showed that only hot tub use affected NTD risk after controlling for folic acid, while the risks for NTD following maternal fever, sauna or electric blanket use in pregnancy were minimal.
In the analysis reported here, the heat source for most studies was influenza or other febrile illnesses. However, a similar increased risk was found in studies where hyperthermia was due to exposure to external heat sources (eg, Milunsky et al25). These studies suggest that, as in the animal data, it is core body temperature and not confounding effects of viral infections that cause NTDs. Of note, Lynberg et al18 reported that influenza was associated with an increased risk for NTDs, whereas other febrile illnesses did not appear to increase the NTD risk after adjusting for confounders. Only 3 studies reported on outcome after both internal fever and external hyperthermia13,14,25; however, the sample size was very small in 2 of these studies,13,14 and in the third,25 internal and external heat sources were not separated.
There was some indication of a dose response. Milunsky et al25 reported that risks were higher among women who had exposure to more than one heat source, and Chambers et al26 found all cases of NTDs were in the high-fever group. Even so, given the limited data addressing specific details of magnitude and duration of the exposures, it remains unclear whether the hyperthermia itself or the maternal illness was the cause of the teratogenic outcomes.
Several studies explicitly reported the pharmacologic treatment of the maternal fevers,14,16,18,19,26 although data were rarely presented in a way we could include in our analysis. Lynberg et al18 found that ORs for NTDs were increased if medications were taken, whereas Shaw et al19 reported that use of medications decreased risks for NTD. We found very similar effects in case–control and cohort studies, lending further credibility to the observed association. The studies were statistically homogeneous, suggesting that pooling the data is appropriate.
One of the concerns regarding meta-analysis is the combination of studies with a range of quality. As suggested originally by Glass27,28 and confirmed by us,29 the quality of the study does not appear to affect the directional of the results. However, there are too few empiric observations to support such generalizations.
Publication bias also was a concern in meta-analysis. Arranging the results in a funnel plot should produce an inverted funnel if publication bias is not present. In this case the funnel plot was not symmetrical, with the lower left quadrant absent, suggesting a deficit of smaller negative studies. Among the methods for quantifying the degree of asymmetry (and thus publication bias) the most widely used is the trim–and-fill method proposed by Duval and Tweedie.4,5 In this analysis the assessment did not change the direction or significance of the results, suggesting that publication bias is not an important factor in these results.
In the studies reviewed here, hyperthermia met many of the criteria for a human teratogen as established by Shepard.30 The exposures occurred at a critical time in prenatal development; only studies that defined exposures in the first trimester were included in our meta-analysis. The findings were consistent across epidemiologic studies of high quality. Despite the fact that some of the studies did not control for confounders or biases, all studies showed the same directional of risk. Finally, as described earlier, similar consistent findings have been shown in animals, which lends biologic plausibility to teratogenic causality. To strengthen the evidence for causality, future studies should attempt to define exposures with more detail and precision, while incorporating measures of folate intake to correct for this potential effect modifier.
1. Warkany J. Teratogen update: hyperthermia. Teratology
2. Edwards MJ. Congenital defects in guinea pigs: prenatal retardation of brain growth of guinea pigs following hyperthermia during gestation. Teratology
3. Edwards MJ. Congenital defects in guinea pigs: fetal resorptions, abortions, and malformations following induced hyperthermia during early gestation. Teratology
4. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics
5. Duval S, Tweedie R. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Stat Assoc
6. Hirayama Y, Suzuki H, Arima M. Maternal hyperthermia during pregnancy in severely multi-disabled children [Japanese]. No To Hattatsu
7. Saxen L, Holmberg PC, Nurminen M, Kuosma E. Sauna and congenital defects. Teratology
8. Smith DW, Clarren SK, Harvey MA. Hyperthermia as a possible teratogenic agent. J Pediatr
9. Layde PM, Edmonds LD, Erickson JD. Maternal fever and neural tube defects. Teratology
10. Erickson JD. Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study. Teratology
11. Botto LD, Erickson JD, Mulinare J, Lynberg MC, Liu Y. Maternal fever, multivitamin use, and selected birth defects: evidence of interaction? Epidemiology
12. Chance PF, Smith DW. Hyperthermia and meningomyelocele and anencephaly (letter). Lancet
13. Halperin LR, Wilroy RS Jr. Maternal hyperthermia and neural-tube defects (letter). Lancet
14. Miller P, Smith DW, Shepard TH. Maternal hyperthermia as a possible cause of anencephaly. Lancet
15. Fisher NL, Smith DW. Occipital encephalocele and early gestational hyperthermia. Pediatrics
16. Shiota K. Neural tube defects and maternal hyperthermia in early pregnancy: epidemiology in a human embryo population. Am J Med Genet
17. Dlugosz L, Vena J, Byers T, Sever L, Bracken M, Marshall E. Congenital defects and electric bed heating in New York State: a register-based case-control study. Am J Epidemiol
18. Lynberg MC, Khoury MJ, Lu X, Cocian T. Maternal flu, fever, and the risk of neural tube defects: a population- based case-control study. Am J Epidemiol
19. Shaw GM, Todoroff K, Velie EM, Lammer EJ. Maternal illness, including fever and medication use as risk factors for neural tube defects. Teratology
20. Shaw GM, Nelson V, Carmichael SL, Lammer EJ, Finnell RH, Rosenquist TH. Maternal periconceptional vitamins: interactions with selected factors and congenital anomalies? Epidemiology
21. Coffey VP, Jessop WJE. Maternal influenza and congenital deformities: A prospective study. Lancet
22. McDonald AD. Maternal health in early pregnancy and congenital defect. Br J Prev Soc Med
23. Kleinebrecht J, Michaelis H, Michaelis J, Koller S. Fever in pregnancy and congenital anomalies (letter). Lancet
24. Little BB, Ghali FE, Snell LM, Knoll KA, Johnston W, Gilstrap LC III. Is hyperthermia teratogenic in the human? Am J Perinatol
25. Milunsky A, Ulcickas M, Rothman KJ, Willett W, Jick SS, Jick H. Maternal heat exposure and neural tube defects. JAMA
26. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Maternal fever and birth outcome: a prospective study. Teratology
27. Glass GV. Primary, secondary, and meta-analysis of research. Educ Res
28. Glass GV. Integrating findings: the meta-analysis of research. Rev Res Educ
29. Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol
30. Shepard. TH. Catalog of Teratogenic Agents
. 10th ed. Baltimore: Johns Hopkins University Press; 2001.
This article has been cited 48 time(s).
Childs Nervous SystemSprengel's deformity and spinal dysraphism: connecting the shoulder and the spineChilds Nervous System
Birth Defects Research Part C-Embryo Today-ReviewsArrhenius thermodynamics and birth defects: Chemical teratogen synergy. Untested, testable, and projected relevanceBirth Defects Research Part C-Embryo Today-Reviews
Journal of Maternal-Fetal & Neonatal MedicineSelective uptake of influenza vaccine and pregnancy outcomesJournal of Maternal-Fetal & Neonatal Medicine
American Journal of Preventive MedicineMinimization of Heatwave Morbidity and MortalityAmerican Journal of Preventive Medicine
Lancet NeurologyNeural tube defects: recent advances, unsolved questions, and controversiesLancet Neurology
Clinical GeneticsNeurodevelopmental consequences of maternal distress: what do we really know?Clinical Genetics
Journal of Autism and Developmental DisordersIs Maternal Influenza or Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) StudyJournal of Autism and Developmental Disorders
Taiwanese Journal of Obstetrics & Gynecology
Syndromes, Disorders and Maternal Risk Factors Associated With Neural Tube Defects (II)
Taiwanese Journal of Obstetrics & Gynecology, 47(1):
Birth Defects Research Part B-Developmental and Reproductive ToxicologyThe Roles of p53 and p21 in Normal Development and Hyperthermia-Induced MalformationsBirth Defects Research Part B-Developmental and Reproductive Toxicology
Scandinavian Journal of Work Environment & Health
Pregnancy outcomes among daycare employees in Finland
Scandinavian Journal of Work Environment & Health, 36(3):
International Journal of Morphology
Relation Between Levels of Folic acid, Vitamin B12 and Maternal Homocysteine with Neural Tube Defects and Cleft Lip
International Journal of Morphology, 26(4):
Novel H1N1 Virus Infection and Pregnancy
Postgraduate Medicine, 121(6):
Experimental Brain ResearchMitochondrial dysmorphology in the neuroepithelium of rat embryos following a single dose of maternal hyperthermia during gestationExperimental Brain Research
British Journal of AnaesthesiaPandemic (H1N1) 2009 influenzaBritish Journal of Anaesthesia
Birth Defects Research Part A-Clinical and Molecular TeratologyInducible 70 kDa Heat Shock Proteins Protect Embryos from Teratogen-Induced Exencephaly: Analysis Using Hspa1a/a1b Knockout MiceBirth Defects Research Part A-Clinical and Molecular Teratology
Birth Defects Research Part A-Clinical and Molecular TeratologyReview: Hyperthermia and fever during pregnancyBirth Defects Research Part A-Clinical and Molecular Teratology
Maternal and Child Health JournalMaternal exposures to cigarette smoke, alcohol, and street drugs and neural tube defect occurrence in offspringMaternal and Child Health Journal
M S-Medecine Sciences
Pregnancy: a high risk factor in influenza infection
M S-Medecine Sciences, 26(1):
Fetal Diagnosis and TherapyFetal spina bifida repair - Current trends and prospects of intrauterine neurosurgeryFetal Diagnosis and Therapy
Childs Nervous SystemThe changing incidence of myelomeningocele and its impact on pediatric neurosurgery: a review from the Children's Memorial HospitalChilds Nervous System
Birth Defects Research Part A-Clinical and Molecular TeratologyPrevalence of Self-reported Infection during Pregnancy among Control Mothers in the National Birth Defects Prevention StudyBirth Defects Research Part A-Clinical and Molecular Teratology
Plos GeneticsHsp90 selectively modulates phenotype in vertebrate developmentPlos Genetics
Journal of the American Academy of Orthopaedic Surgeons
Exercise and Pregnancy
Journal of the American Academy of Orthopaedic Surgeons, 17(8):
Journal of PathologyGenetics and development of neural tube defectsJournal of Pathology
Infectious Disease Clinics of North AmericaEmerging and Zoonotic Infections in WomenInfectious Disease Clinics of North America
Schizophrenia BulletinSchizophrenia and neural tube defects: Comparisons from an epidemiological perspectiveSchizophrenia Bulletin
Birth Defects Research Part A-Clinical and Molecular TeratologyPediatric perspective on prenatal counseling for myelomeningoceleBirth Defects Research Part A-Clinical and Molecular Teratology
Canadian Medical Association JournalSafety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding womenCanadian Medical Association Journal
Pediatric NeurosurgeryStudy on the Pathomorphology of MyelodysplasiaPediatric Neurosurgery
LancetH1N1 2009 influenza virus infection during pregnancy in the USALancet
Obstetrics and Gynecology Clinics of North AmericaSelected Viral Infections in PregnancyObstetrics and Gynecology Clinics of North America
Journal of the Neurological SciencesManagement of neural tube defects in a Sub-Saharan African country: The situation in Yaounde, CameroonJournal of the Neurological Sciences
Journal of the Neurological SciencesRole of Npm1 in proliferation, apoptosis and differentiation of neural stem cellsJournal of the Neurological Sciences
Paediatric and Perinatal EpidemiologyEffect of folic acid fortification on the incidence of neural tube defectsPaediatric and Perinatal Epidemiology
Birth Defects Research Part A-Clinical and Molecular TeratologySpina Bifida Research Resource: Study Design and Participant CharacteristicsBirth Defects Research Part A-Clinical and Molecular Teratology
American Journal of Medical Genetics Part AEmerging infections and pregnancy: Assessing the impact on the embryo or fetusAmerican Journal of Medical Genetics Part A
Revista De Saude Publica
Effects of folic acid fortification on the prevalence of neural tube defects
Revista De Saude Publica, 43(4):
Fetal Diagnosis and TherapyAcoustic Output as Measured by Thermal and Mechanical Indices during Fetal Nuchal Translucency Ultrasound ExaminationsFetal Diagnosis and Therapy
Journal of the Neurological SciencesNeural tube defects are rare among black Americans but not in sub-Saharan black Africans: The case of Yaounde - CameroonJournal of the Neurological Sciences
American Journal of Public HealthPandemic Influenza and Pregnant Women: Summary of a Meeting of ExpertsAmerican Journal of Public Health
Prenatal DiagnosisThe safety of obstetrical ultrasound: a reviewPrenatal Diagnosis
Developmental Disabilities Research ReviewsEpidemiologic and Genetic Aspects of Spina Bifida and Other Neural Tube DefectsDevelopmental Disabilities Research Reviews
Emerging Infectious Diseases
Pandemic influenza and pregnant women
Emerging Infectious Diseases, 14(1):
Jognn-Journal of Obstetric Gynecologic and Neonatal Nursing
Current resources for evidence-based practice, January/February 2006
Jognn-Journal of Obstetric Gynecologic and Neonatal Nursing, 35(1):
American Journal of PerinatologyManagement of Influenza in PregnancyAmerican Journal of Perinatology
Neurourology and UrodynamicsDifferences in urodynamic study variables in adult patients with neurogenic bladder and myelomeningocele before and after augmentation enterocystoplastyNeurourology and Urodynamics
Future VirologyInfluenza infection during pregnancy: virology, pathogenesis and clinical challengesFuture Virology
Does maternal Helicobacter pylori infection increase the risk of occurrence of neural tube defects in newborns in Northern Iran?
Supplemental Digital Content
© 2005 Lippincott Williams & Wilkins, Inc.