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Congenital heart defects after maternal fever Lorenzo D. Botto, MD; Janice D. Panichello, PhD; Marilyn L. Browne, PhD; Sergey Krikov, MS; Marcia L. Feldkamp, PhD; Edward Lammer, MD; Gary M. Shaw, DrPH; and the National Birth Defects Prevention Study OBJECTIVE: The purpose of this study was to evaluate whether

maternal febrile illnesses in early pregnancy are associated with increased risk for congenital heart defects in the offspring and whether such risk is mitigated by multivitamin supplement use. STUDY DESIGN: From a multistate population-based case-control

study (National Birth Defects Prevention Study), we compared maternal reports of first-trimester febrile illness from 7020 subjects with heart defects and 6746 unaffected control subjects who were born from 1997 through 2005. Relative risks were computed with no fever or infection during the first trimester as reference group and were adjusted for potential confounders.

RESULTS: First-trimester febrile illness was reported by 7.4% of control mothers (1 in 13). Febrile genitourinary infections were associated with selected heart defects, particularly right-sided obstructive defects (odds ratios, >3) and possibly others, whereas common respiratory illnesses were associated with low-to-negligible risks for most heart defects. When risk estimates were elevated, they tended to be mitigated when multivitamin supplements had been taken in the periconceptional period. CONCLUSION: The source of fever and the use of supplements appear to influence the risk for heart defects. This information can be helpful in counseling and research, in particular with regard to primary prevention.

Key words: congenital heart defect, fever, infection, prevention

Cite this article as: Botto LD, Panichello JD, Browne ML, et al. Congenital heart defects after maternal fever. Am J Obstet Gynecol 2013;210:.


ebrile illnesses in early pregnancy are common. Their frequency likely varies by season, geography, and immunization status; on average, studies estimate that 5-10% of women report a fever in early pregnancy.1-7 If accurate, these estimates would translate into as many as 10 million fever-exposed pregnancies every year worldwide. The full range of fetal effects of maternal febrile illnesses is unclear. Among structural malformations, robust evidence supports an association with an increased risk for neural tube defects, and possibly,

although less conclusively, for other birth defects.5,8-15 For congenital heart defects, moderately increased risks have been reported for ventricular septal defects, conotruncal defects, and right-sided obstructive defects.4,7,16,17 However, these associations are not consistent across studies. Because febrile illnesses in pregnancy are so common and congenital heart defects are so frequent (1 in 110 births),18-20 even modest teratogenic risks could result in a substantial burden of disease. Better quantification and qualification of these

From the Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT (Drs Botto, Panichello, and Feldkamp and Mr Krikov); Bureau of Environmental and Occupational Epidemiology, New York State Department of Health, Albany, NY (Dr Browne); and Children’s Hospital Oakland Research Institute, Oakland Children’s Hospital, Oakland (Dr Lammer), and Department of Pediatrics, Stanford University School of Medicine, Stanford (Dr Shaw), CA. Received May 29, 2013; revised Sept. 16, 2013; accepted Oct. 29, 2013. Supported by the Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities (U50/CCU913241 [G.S. and E.L], U50/CCU223184 [M.B], and U50/ CCU822097 [L.B., M.F., J.P., and S.K.]). The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention or of the California Department of Public Health. The authors report no conflict of interest. Reprints: Lorenzo Botto, MD, Division of Medical Genetics, University of Utah, 2C412 SOM, 50 North Medical Dr., Salt Lake City Utah 84132. [email protected] 0002-9378/$36.00  ª 2013 Mosby, Inc. All rights reserved.

risks could provide not only research insights into mechanisms of teratogenicity but also could be helpful in clinical counseling of exposed women and primary prevention. Such investigations, however, are challenging. Febrile illness is an inherently complex exposure (Figure 1). In theory, there might be a role for the fever itself (ie, the elevation of body temperature), the type and severity of the underlying infection or inflammation (ie, the cause of fever), or some combination of these. Additional modifiers such as folic acid supplement use could mitigate such effects6,16; a finding that, if confirmed, could provide opportunities for prevention. This report used data from the National Birth Defects Prevention Study (NBDPS) to investigate some of these questions and focused, in particular, on describing if and how risks varied by type of heart defects, source of fever, and multivitamin supplement use.




The NBDPS is a large ongoing casecontrol study of 30 major structural malformations in the United States. The NBDPS is an approved activity of the institutional review boards of participating centers and the Centers for Disease Control and Prevention. For all

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Febrile illness and heart defects: possible causal relations and modifiers

d-TGA, d-transposition of the great arteries. Botto. Maternal fever and congenital heart defects. Am J Obstet Gynecol 2013.

subjects, informed consent was provided. Detailed study methods have been published.21,22 Briefly, data originate from the following sites, each of which is based on a population-based birth defect registry with active case ascertainment: Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah. Every year each participating site enrolls eligible cases of major malformations among liveborn infants, stillbirths, and pregnancy terminations, excluding cases of chromosomal or single-gene conditions. Control subjects without major malformations are selected randomly from birth certificates or birth hospital records from the same underlying population. Eligible families are approached; after informed consent is obtained, mothers

are interviewed by telephone with the use of a structured, computer-assisted questionnaire. Buccal samples are requested from baby, mother, and father.21,22

Case selection, review, and classification Diagnosis of congenital heart defects is confirmed by echocardiography, catheterization, surgery, or autopsy. Most diagnoses occurred in the first year of life, and all occurred by the second year of life (by protocol, maternal interviews are conducted by the child’s second birthday). A central team of clinicians with expertise in pediatric cardiology and genetics reviewed, coded, and classified the phenotypes, using a structured and published process.23 Briefly, each congenital heart defect was classified as simple, association, or complex. Simple

1.e2 American Journal of Obstetrics & Gynecology MONTH 2013

defects are single, well-defined heart defects with a unifying diagnosis. Examples include isolated ventricular septal defects or tetralogy of Fallot. Associations are the combination of typically 2 heart defects that usually occur in isolation and do not constitute a well-defined single entity (for this reason, tetralogy of Fallot is considered simple and not an association). An example of association is the combination of perimembranous ventricular septal defect with secundum atrial septal defect. The complex category includes a small group of phenotypes with multiple structural cardiac findings that can occur in heterotaxy or certain single ventricle phenotypes.23 To improve case homogeneity, this analysis focused on those congenital heart defects that were classified as simple, in addition to selected associations and heterotaxy. Association phenotypes included (1) left ventricular outflow tract obstruction associations (coarctation of the aorta plus either aortic stenosis, ventricular septal defect or atrial septal defect), (2) right ventricular outflow tract obstruction association (pulmonary valve stenosis plus ventricular septal defect or atrial septal defect), and (3) septal association (ventricular septal defect plus atrial septal defect). Septal defects in these associations do not include primum atrial septal defects and inlet or supracristal ventricular septal defects because these are considered part of other groups: primum atrial septal defects and inlet ventricular septal defects are included with atrioventricular septal defects and supracristal ventricular septal defects are included with outflow tract/conotruncal malformations. Finally, each case was also classified as isolated or nonisolated, depending on the presence of major unrelated extracardiac malformations. Because of the high prevalence of muscular ventricular septal defects and ventricular septal defects “not otherwise specified,” these defects were eligible only in the initial years of the study (California, Georgia, Iowa, Massachusetts, New York, and Texas before Oct. 1, 1998; Arkansas and New Jersey before Jan. 1, 1999).

Obstetrics Exposure assessment Overall participation in the interview in NBDPS was 69% among case mothers and 66% among control mothers. Maternal interviews, in English or Spanish, were performed by telephone with a standardized, computer-based questionnaire, no earlier than 6 weeks and not later than 24 months after the infant’s estimated date of delivery. For febrile illnesses, variables were based on several questions on type of illnesses (respiratory illnesses, pelvic inflammatory disease, urinary tract infections, and others) and their timing, duration, presence of fever (fever duration and peak value), and associated use of medication. When the exposure was uncertain (eg, mothers reported a febrile illness but was unsure of the month or reported a respiratory illness but was unsure of fever), these data were excluded from the analysis to minimize exposure misclassification. Exclusions and inclusions We included deliveries with estimated due dates from 1997-2005. Interviews were completed with 8134 mothers of babies with a major eligible congenital heart defect and 6807 control mothers on average by 12 months from the date of delivery for case mothers and 9 months for control mothers. We excluded all case and control mothers with reported type 1 or type 2 pregestational diabetes mellitus (231) because of the strong teratogenic risk of this condition. The final analysis included data from 7020 case mothers and 6746 control mothers. Statistical methods Effect estimates were generated by logistic modeling (SAS Corporation, Cary, NC) and are presented as odds ratio (OR) with 95% confidence intervals (CIs). CIs are presented in preference to probability values because confidence intervals convey more information. We used as reference the stratum with no reported fever or infection during the first trimester; estimates were produced separately for first-trimester illnesses with fever and without fever (2 mutually exclusive groups) to investigate the relative contribution of fever and the underlying illnesses to overall disease



Distribution of congenital heart defects, by type, National Birth Defects Prevention Study, 1997-2005 Type of heart defect

Total, n



Conotruncal defects


Isolated, n (%)a 0 1036 (84.4)

Tetralogy of Fallot


529 (79.8)

d-Transposition of the great arteries


357 (94.9)

Atrioventricular septal defect


94 (86.2)

Total anomalous pulmonary venous return


145 (92.9)

Left ventricular outflow tract obstructions


1055 (88.8)

Hypoplastic left heart


322 (92.0)

Coarctation of the aorta


314 (86.7)

Aortic stenosis


178 (94.7)

Left ventricular outflow tract obstruction associations, all


230 (83.6)


990 (92.1)

Pulmonary atresia


96 (94.1)

Pulmonic valve stenosis


593 (95.3)

Right ventricular outflow tract obstruction association


197 (84.5)


2553 (83.3)


893 (88.3)

Ventricular septal defect, muscular


147 (89.6)

Atrial septal defect, secundum


780 (80.1)

Atrial septal defect, not otherwise specified


275 (82.3)

Septal associations


426 (79.3)


5873 (83.7)

Right ventricular outflow tract obstructions

Septal defects Ventricular septal defect, perimembranous

Total a

Without major extracardiac malformations.

Botto. Maternal fever and congenital heart defects. Am J Obstet Gynecol 2013.

risk. Covariates in the logistic model were selected based on case-control differences and evidence from the published literature regarding risk factors for congenital heart defects. The same covariate set was used throughout the analyses. Covariates that were retained in final models included maternal age (single year as a continuous variable); maternal race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, other); maternal cigarette smoking during the first trimester (yes, no); maternal alcohol consumption during the first trimester (yes, no); maternal education (12 years, >12 years); prepregnancy body mass index (continuous); history of seizures (yes, no); time to interview

(1 year, >1 year); and family history of a first-degree relative with a major congenital heart defect (yes, no). Parity and gestational diabetes mellitus did not modify the risk estimates appreciably and were not included. Periconceptional multivitamin use was defined as regular use (at least 3 times weekly) from 1 month before conception through the end of the first trimester. This variable was used as a stratification variable to investigate its role as an effect modifier. To do so, we constructed 3 strata: (1) vitamin users, without reported fever or illness (the common reference group); (2) vitamin nonusers, with reported febrile illness; and (3) vitamin users, with reported febrile illness. ORs were

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Maternal and infant characteristics among infants with heart defects and infants without birth defects, National Birth Defects Prevention Study, 1997-2005 Cases, n (%)a,b

Control subjects, n (%)a,c

12 y)

3905 (56)

3889 (58)

Non-Hispanic white

4102 (58)

3993 (59)

Non-Hispanic black

807 (12)

765 (11)

1577 (22)

1489 (22)

517 (7)

470 (7)


5674 (81)

5548 (82)


1242 (18)

1110 (16)


5403 (77)

5098 (76)


1480 (21)

1529 (23)

952 (14)

852 (13)

5875 (84)

5733 (85)

369 (5)

360 (5)

Normal weight (18.5

Congenital heart defects after maternal fever.

The purpose of this study was to evaluate whether maternal febrile illnesses in early pregnancy are associated with increased risk for congenital hear...
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