congenital heart defects after maternal fever

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OBSTETRICS

Congenital heart defects after maternal feverLorenzo 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 RESULTS: First-trimester febrile illness was reported by 7.4% of control
maternal febrile illnesses in early pregnancy are associated withincreased risk for congenital heart defects in the offspring and whethersuch risk is mitigated by multivitamin supplement use.
STUDY DESIGN: From a multistate population-based case-controlstudy (National Birth Defects Prevention Study), we comparedmaternal reports of first-trimester febrile illness from 7020subjects with heart defects and 6746 unaffected control sub-jects who were born from 1997 through 2005. Relative riskswere computed with no fever or infection during the firsttrimester as reference group and were adjusted for potentialconfounders.

From the Division of Medical Genetics, Department of Pediatrics, University oMedicine, Salt Lake City, UT (Drs Botto, Panichello, and Feldkamp and Mr KEnvironmental and Occupational Epidemiology, New York State Department(Dr Browne); and Children’s Hospital Oakland Research Institute, Oakland COakland (Dr Lammer), and Department of Pediatrics, Stanford University SchStanford (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 CenteDevelopmental Disabilities (U50/CCU913241 [G.S. and E.L], U50/CCU2231CCU822097 [L.B., M.F., J.P., and S.K.]).

The findings and conclusions in this report are those of the author(s) and do nothe views of the Centers for Disease Control and Prevention or of the CaliforniHealth.

The authors report no conflict of interest.

Reprints: LorenzoBotto, MD, Division of Medical Genetics, University of Utah,Medical Dr., Salt Lake City Utah 84132. [email protected].

0002-9378/$36.00 � ª 2013 Mosby, Inc. All rights reserved. � http://dx.doi.org/10.1

mothers (1 in 13). Febrile genitourinary infections were associated withselected heart defects, particularly right-sided obstructive defects (oddsratios, >3) and possibly others, whereas common respiratory illnesseswere associated with low-to-negligible risks for most heart defects.When risk estimates were elevated, they tended to be mitigated whenmultivitamin supplements had been taken in the periconceptional period.

CONCLUSION: The source of fever and the use of supplements appearto influence the risk for heart defects. This information can be helpful incounseling 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
F are common. Their frequency likelyvaries by season, geography, and im-munization status; on average, studiesestimate that 5-10% of women report afever in early pregnancy.1-7 If accurate,these estimates would translate into asmany as 10 million fever-exposed preg-nancies every year worldwide. The fullrange of fetal effects of maternal febrileillnesses is unclear. Among structuralmalformations, robust evidence supportsan association with an increased risk forneural tube defects, and possibly,
although less conclusively, for other birthdefects.5,8-15 For congenital heart defects,moderately increased risks have beenreported for ventricular septal defects,conotruncal defects, and right-sided ob-structive defects.4,7,16,17 However, theseassociations are not consistent acrossstudies.Because febrile illnesses in pregnancy

are so common and congenital heart de-fects are so frequent (1 in 110 births),18-20

evenmodest teratogenic risks could resultin a substantial burden of disease. Betterquantification and qualification of these

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risks could provide not only research in-sights into mechanisms of teratogenicitybut also could be helpful in clinicalcounseling of exposed women and pri-mary prevention. Such investigations,however, are challenging. Febrile illnessis an inherently complex exposure(Figure 1). In theory, theremight be a rolefor the fever itself (ie, the elevation ofbody temperature), the type and severityof the underlying infection or inflam-mation (ie, the cause of fever), or somecombination of these. Additional modi-fiers such as folic acid supplement usecould mitigate such effects6,16; a findingthat, if confirmed, could provide oppor-tunities for prevention. This report useddata from the National Birth DefectsPrevention Study (NBDPS) to investigatesome of these questions and focused, inparticular, on describing if and how risksvaried by type of heart defects, source offever, and multivitamin supplement use.

MATERIALS AND METHODS

The NBDPS is a large ongoing case-control study of 30 major structuralmalformations in the United States. TheNBDPS is an approved activity of theinstitutional review boards of partici-pating centers and the Centers for Dis-ease Control and Prevention. For all

erican Journal of Obstetrics & Gynecology 1.e1

mailto:[email protected]

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FIGURE 1Febrile 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.

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subjects, informed consent was pro-vided. Detailed study methods have beenpublished.21,22 Briefly, data originatefrom the following sites, each of which isbased on a population-based birth defectregistry with active case ascertainment:Arkansas, California, Georgia, Iowa,Massachusetts, New Jersey, New York,North Carolina, Texas, and Utah. Everyyear each participating site enrollseligible cases of major malformationsamong liveborn infants, stillbirths, andpregnancy terminations, excluding casesof chromosomal or single-gene condi-tions. Control subjects without majormalformations are selected randomlyfrom birth certificates or birth hospitalrecords from the same underlyingpopulation.

Eligible families are approached; afterinformed consent is obtained, mothers

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are interviewed by telephone with the useof a structured, computer-assisted ques-tionnaire. Buccal samples are requestedfrom baby, mother, and father.21,22

Case selection, review, andclassificationDiagnosis of congenital heart defects isconfirmed by echocardiography, cathe-terization, surgery, or autopsy. Most di-agnoses occurred in the first year of life,and all occurred by the second year of life(by protocol, maternal interviews areconducted by the child’s secondbirthday). A central team of clinicianswith expertise in pediatric cardiologyand genetics reviewed, coded, and clas-sified the phenotypes, using a structuredand published process.23 Briefly, eachcongenital heart defect was classified assimple, association, or complex. Simple

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defects are single, well-defined heartdefects with a unifying diagnosis. Ex-amples include isolated ventricularseptal defects or tetralogy of Fallot.Associations are the combination oftypically 2 heart defects that usuallyoccur in isolation and do not constitutea well-defined single entity (for thisreason, tetralogy of Fallot is consideredsimple and not an association). Anexample of association is the combina-tion of perimembranous ventricularseptal defect with secundum atrial septaldefect. The complex category includes asmall group of phenotypes with multiplestructural cardiac findings that can occurin heterotaxy or certain single ventriclephenotypes.23

To improve case homogeneity, thisanalysis focused on those congenitalheart defects that were classified as sim-ple, in addition to selected associationsand heterotaxy. Association phenotypesincluded (1) left ventricular outflowtract obstruction associations (coarcta-tion of the aorta plus either aortic ste-nosis, ventricular septal defect or atrialseptal defect), (2) right ventricularoutflow tract obstruction association(pulmonary valve stenosis plus ventric-ular septal defect or atrial septal defect),and (3) septal association (ventricularseptal defect plus atrial septal defect).Septal defects in these associations donot include primum atrial septal defectsand inlet or supracristal ventricularseptal defects because these are consid-ered part of other groups: primum atrialseptal defects and inlet ventricular septaldefects are included with atrioventric-ular septal defects and supracristalventricular septal defects are includedwith outflow tract/conotruncal malfor-mations. Finally, each case was alsoclassified as isolated or nonisolated,depending on the presence of majorunrelated extracardiac malformations.Because of the high prevalence ofmuscular ventricular septal defects andventricular septal defects “not otherwisespecified,” these defects were eligibleonly in the initial years of the study(California, Georgia, Iowa, Massachu-setts, New York, and Texas before Oct. 1,1998; Arkansas and New Jersey beforeJan. 1, 1999).

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TABLE 1Distribution of congenital heart defects, by type, National Birth DefectsPrevention Study, 1997-2005Type of heart defect Total, n Isolated, n (%)a

Heterotaxy 200 0

Conotruncal defects 1227 1036 (84.4)

Tetralogy of Fallot 663 529 (79.8)

d-Transposition of the great arteries 376 357 (94.9)

Atrioventricular septal defect 109 94 (86.2)

Total anomalous pulmonary venous return 156 145 (92.9)

Left ventricular outflow tract obstructions 1188 1055 (88.8)

Hypoplastic left heart 350 322 (92.0)

Coarctation of the aorta 362 314 (86.7)

Aortic stenosis 188 178 (94.7)

Left ventricular outflow tract obstruction associations, all 275 230 (83.6)

Right ventricular outflow tract obstructions 1075 990 (92.1)

Pulmonary atresia 102 96 (94.1)

Pulmonic valve stenosis 622 593 (95.3)

Right ventricular outflow tract obstruction association 233 197 (84.5)

Septal defects 3065 2553 (83.3)

Ventricular septal defect, perimembranous 1011 893 (88.3)

Ventricular septal defect, muscular 164 147 (89.6)

Atrial septal defect, secundum 974 780 (80.1)

Atrial septal defect, not otherwise specified 334 275 (82.3)

Septal associations 537 426 (79.3)

Total 7020 5873 (83.7)a Without major extracardiac malformations.


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Exposure assessmentOverall participation in the interview inNBDPS was 69% among case mothersand 66% among control mothers.Maternal interviews, in English or Span-ish, were performed by telephone with astandardized, computer-based question-naire, no earlier than 6 weeks and notlater than 24 months after the infant’sestimated date of delivery. For febrile ill-nesses, variables were based on severalquestions on type of illnesses (respiratoryillnesses, pelvic inflammatory disease,urinary tract infections, and others) andtheir timing, duration, presence of fever(fever duration and peak value), andassociated use of medication. When theexposure was uncertain (eg, mothers re-ported a febrile illness but was unsure ofthe month or reported a respiratoryillness but was unsure of fever), these datawere excluded from the analysis tominimize exposure misclassification.

Exclusions and inclusionsWe included deliveries with estimateddue dates from 1997-2005. Interviewswere completed with 8134 mothers ofbabies with a major eligible congenitalheart defect and 6807 controlmothers onaverage by 12 months from the date ofdelivery for case mothers and 9 monthsfor control mothers. We excluded all caseand controlmothers with reported type 1or type 2 pregestational diabetes mellitus(231) because of the strong teratogenicrisk of this condition. The final analysisincluded data from 7020 case mothersand 6746 control mothers.

Statistical methodsEffect estimates were generated by lo-gistic modeling (SAS Corporation, Cary,NC) and are presented as odds ratio(OR) with 95% confidence intervals(CIs). CIs are presented in preference toprobability values because confidenceintervals convey more information. Weused as reference the stratum with noreported fever or infection during thefirst trimester; estimates were producedseparately for first-trimester illnesseswith fever and without fever (2 mutuallyexclusive groups) to investigate therelative contribution of fever and theunderlying illnesses to overall disease

risk. Covariates in the logistic modelwere selected based on case-control dif-ferences and evidence from the pub-lished literature regarding risk factors forcongenital heart defects. The same co-variate set was used throughout the an-alyses. Covariates that were retainedin final models included maternal age(single year as a continuous variable);maternal race/ethnicity (non-Hispanicwhite, non-Hispanic black, Hispanic,other); maternal cigarette smoking dur-ing the first trimester (yes, no); maternalalcohol consumption during the firsttrimester (yes, no); maternal education(�12 years, >12 years); prepregnancybody mass index (continuous); historyof seizures (yes, no); time to interview

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(�1 year,>1 year); and family history ofa first-degree relative with a majorcongenital heart defect (yes, no). Parityand gestational diabetes mellitus did notmodify the risk estimates appreciablyand were not included. Periconceptionalmultivitamin use was defined as regularuse (at least 3 times weekly) from 1month before conception through theend of the first trimester. This variablewas used as a stratification variable toinvestigate its role as an effect modifier.To do so, we constructed 3 strata: (1)vitamin users, without reported fever orillness (the common reference group);(2) vitamin nonusers, with reportedfebrile illness; and (3) vitamin users,with reported febrile illness. ORs were


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TABLE 2Maternal and infant characteristics among infants with heart defectsand infants without birth defects, National Birth Defects PreventionStudy, 1997-2005Characteristic Cases, n (%)a,b Control subjects, n (%)a,c

Maternal education, y

<High school (<12 y) 1202 (17) 1114 (17)

High school (12 y) 1792 (26) 1635 (24)

>High school (>12 y) 3905 (56) 3889 (58)

Race/ethnicity

Non-Hispanic white 4102 (58) 3993 (59)

Non-Hispanic black 807 (12) 765 (11)

Hispanic 1577 (22) 1489 (22)

Other 517 (7) 470 (7)

Maternal smoking, first trimester

No 5674 (81) 5548 (82)

Yes 1242 (18) 1110 (16)

Maternal alcohol use, first trimester

No 5403 (77) 5098 (76)

Yes 1480 (21) 1529 (23)

Folic acid supplement use, first trimester

No 952 (14) 852 (13)

Yes 5875 (84) 5733 (85)

Body mass index, kg/m2

Underweight (<18.5) 369 (5) 360 (5)

Normal weight (18.5�<25) 3460 (49) 3620 (54)

Overweight (25�<30) 1593 (23) 1447 (21)

Obesity (�30) 1292 (18) 1036 (15)

Family history of heart defects

Yes 239 (3) 83 (1)

No 6781 (97) 6683 (98)

a Percentages may not add to 100% because of rounding and missing values; b n ¼ 7020; c n ¼ 6746.



then generated by contrasting group 2 vsgroup 1, and group 3 vs group 1. In theanalysis by fever severity, we definedhigh fevers as fever �102�F and feversof long duration as reported to havelasted �24 hours. In the analysis by useof antipyretics, we evaluated the use ofnonsteroidal antiinflammatory drugs,which included paracetamol, acetylsali-cylic acid, and paracetamol during thefirst trimester. Because of the analytic


structure of the data, the use of antipy-retics could be established for the timeperiod of interest but not directly linkedto the individual episode of febrileillness.

RESULTS

The study (Table 1) included 7020mothers of babies with major congenitalheart defects (cases) and 6746 mothersof babies without birth defects (control

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subjects). Overall, the heart defect wasisolated (ie, without additional extrac-ardiac defects) in 84% of cases, but withsome variability between heart defecttypes (eg, between conotruncal defects).Case and control mothers were similarin many characteristics, although case-mothers were slightly more likely to beoverweight or obese and to report first-trimester smoking and a family historyof heart defects (Table 2).

A first-trimester febrile illness was re-ported by 7.4% (1 in 13) control mothersand by 8.1% of case mothers (Table 3).The phenotypesmore strongly associatedoverall with febrile illness were hetero-taxy, aortic stenosis, right ventricularoutflow tract obstructions (RVOTO),and septal associations. ORs, whenelevated, were modestly so (<2) withmany confidence intervals includingunity. Further analyses identified a morecomplex pattern of associations. Febrileillnesses were associated with generallyhigher ORs compared with nonfebrileillnesses. Examples include heterotaxy(OR, 1.7 for febrile illness vs 0.8 for non-febrile illness), aortic stenosis (OR, 1.8 vs1.1), RVOTO (OR, 1.3 vs 0.9), andRVOTO associations (OR, 1.8 vs 1.0).Isolated cases seemed to drive the overallrisk estimates (Table 4). Regarding thesource of febrile illness, the strongestassociations with heart defect risk werefound for urinary tract infections andpelvic inflammatory disease (Figure 2);for these infections, 10 associations hadORs >2 compared with none for respi-ratory illnesses (Table 3). Because respi-ratory illnesses were by far the mostcommon source of fever, which accoun-ted for 91% (456/501) of all febrileillnesses among control subjects, theoverall association of fever with heartdefects was weak.

To assess for possible associations withseverity, we reanalyzed the data bymagnitude and duration of the fever.Restricting the analysis to higher fevers(�102�F) did not change the overall riskfor heart defects (OR, 1.01; 95% CI,0.81e1.26, based on 162 and 156 exposedcases and control subjects, respectively).Similarly, fevers of longer duration(�24 hours) were not associated withhigher risks (data not shown).

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TABLE 3Risk for congenital heart defects with maternal febrile and nonfebrile illnesses, National Birth Defects Prevention Study, 1997-2005

Group All, n

Febrile illnessaFebrile urinary tract infection orpelvic inflammatory disease Febrile respiratory infections Nonfebrile illnessb

Exposed,n

AdjustedOR 95% CI

Exposed,n

AdjustedOR 95% CI

Exposed,n

AdjustedOR 95% CI

Exposed,n Adjusted OR 95% CI

Control subjects 6746 501 1.0 Reference 24 1.0 Reference 456 1.0 Reference 1022 1.0 Reference

Total cases 7020 572 1.14 1.00e1.30 48 1.73 1.03e2.92 493 1.09 0.94e1.25 1039 1.05 0.95e1.16

Heterotaxy 200 24 1.71 1.07e2.74 3 2.61 0.59e11.51 20 1.66 1.00e2.74 23 0.78 0.49e1.26

Tetralogy of Fallot 663 49 1.11 0.80e1.53 6 2.55 0.94e6.92 37 0.93 0.65e1.33 102 1.15 0.90e1.45

d-Transposition of great arteries 376 31 1.23 0.83e1.81 1 0.84 0.11e6.31 28 1.23 0.81e1.85 58 1.07 0.79e1.46

Atrioventricular septal defect 109 4 0.57 0.21e1.60 0 — — 4 0.64 0.23e1.80 22 1.46 0.88e2.43

Total anomalous pulmonaryvenous return

156 22 0.72 0.34e1.49 2 3.38 0.76e15.12 6 0.60 0.26e1.40 8 0.85 0.52e1.41

Hypoplastic left heart syndrome 350 31 1.25 0.83e1.88 1 1.01 0.13e7.64 27 1.17 0.76e1.81 49 0.96 0.69e1.33

Coarctation of the aorta 362 26 0.98 0.63e1.54 3 2.94 0.84e10.2 22 0.88 0.54e1.44 53 1.10 0.80e1.51

Aortic stenosis 188 27 1.78 1.09e2.90 1 1.76 0.24e13.1 25 1.87 1.13e3.09 26 1.06 0.68e1.66

Left ventricular outflow tractobstruction associationc

275 24 1.20 0.77e1.88 2 2.49 0.57e10.9 20 1.10 0.68e1.78 36 0.84 0.58e1.24

Pulmonary atresia 102 9 1.19 0.58e2.41 0 — — 8 1.17 0.55e2.47 14 0.83 0.46e1.52

Pulmonic valve stenosis 622 56 1.3 0.95e1.78 7 4.29 1.77e10.4 47 1.18 0.84e1.66 80 0.92 0.71e1.19

Right ventricular outflow tractobstruction associationd

233 25 1.77 1.13e2.78 4 4.32 1.37e13.6 21 1.67 1.03e2.71 31 1.03 0.68e1.5

Ventricular septal defect,perimembranous

1011 82 1.16 0.90e1.51 1 0.00 0.00e0.00 80 1.26 0.97e1.65 168 1.20 0.99e1.45

Ventricular septal defect, muscular 164 12 0.78 0.40e1.54 1 1.06 0.10e11.20 10 0.71 0.34e1.46 24 0.98 0.59e1.63

Atrial septal defect, secundum 974 63 0.91 0.68e1.21 7 1.79 0.74e4.33 52 0.82 0.60e1.13 145 1.01 0.83e1.24

Atrial septal defect,not otherwise specified

334 19 0.84 0.51e1.38 2 1.76 0.40e7.82 16 0.77 0.45e1.33 58 1.20 0.87e1.65

Septal associatione 537 51 1.41 1.03e1.95 6 3.70 1.44-9.50 42 1.28 0.90e1.81 73 0.92 0.69e1.22

CI, confidence interval; OR, odds ratio.

a Respiratory, urinary tract, pelvic inflammatory, other, and multiple; b Same as “footnote a,” but without fever; c Include coarctation of the aorta þ aortic stenosis; coarctation of the aorta þ ventricular septal defect; coarctation of the aorta þ ventricular septaldefect þ atrial septal defect; d Include pulmonary valve stenosis þ ventricular septal defect and pulmonary valve stenosis þ atrial septal defect; ventricular septal defect þ atrial septal defect.


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TABLE 4Risk associated with febrile illness for isolated and nonisolated congenital heart defects, National Birth DefectsPrevention Study, 1997-2005

Group

Isolated (no extracardiac malformations)Nonisolated (with extracardiacmalformations

All, nExposed,n (%)

AdjustedOR 95% CI All, n

Exposed,n (%)

AdjustedOR 95% CI

Control subjects 6746 501 (7.4) 1.00 Reference 1.00 Reference

All heart defects combined 5873 473 (8.1) 1.13 0.99e1.31 1147 99 (8.6) 1.21 0.95e1.54

Heterotaxy — — — — 200 24 (12.0) 1.71 1.07e2.74

Conotruncal defects 1036 83 (8.0) 1.26 0.98e1.62 191 14 (7.3) 0.94 0.51e1.72

Tetralogy of Fallot 529 41 (7.8) 1.24 0.88e1.75 134 8 (6.0) 0.67 0.29e1.56

d-transposition of the great arteries 357 30 (8.4) 1.26 0.85e1.88 19 1 (5.3) 0.66 0.08e5.14

Atrioventricular septal defect 94 2 (2.1) 0.32 0.08e1.35 15 2 (13.3) 2.24 0.47e10.6

Total anomalous pulmonary venous return 145 8 (5.5) 0.77 0.37e1.61 11 0 —

Left ventricular outflow tract obstructions 1055 96 (9.1) 1.23 0.96e1.58 133 13 (9.8) 1.28 0.69e2.38

Hypoplastic left heart 322 28 (8.7) 1.24 0.81e1.91 28 3 (10.7) 1.49 0.44e5.19

Coarctation of the aorta 314 23 (7.3) 0.99 0.61e1.60 48 3 (6.3) 0.92 0.28e3.07

Aortic stenosis 178 26 (14.6) 1.91 1.18e3.17 10 1 (10.0) 0.00 0.00e0.00

Left ventricular outflow tract obstructionassociation

230 18 (7.8) 1.06 0.64e1.76 45 6 (13.3) 2.01 0.81e4.99

Right ventricular outflow tract obstructions 990 93 (9.4) 1.35 1.05e1.73 85 7 (8.2) 1.25 0.56e2.80

Pulmonary atresia 96 9 (9.4) 1.26 0.62e2.59 6 0 —

Pulmonic valve stenosis 593 56 (9.4) 1.38 1.01e1.89 29 0 —

Right ventricular outflow tract obstructionsassociation

197 19 (9.6) 1.56 0.93e2.59 36 6 (16.7) 3.21 1.19e7.98

Septal defects 2553 191 (7.5) 1.06 0.89e1.28 512 39 (7.6) 1.10 0.77e1.58

Ventricular septal defect, perimembranous 893 75 (8.4) 1.21 0.91e1.57 118 7 (5.9) 0.91 0.41e2.01

Ventricular septal defect, muscular 147 12 (8.2) 0.87 0.44e1.72 17 0 —

Atrial septal defect, secundum 780 49 (6.3) 0.88 0.64e1.22 194 14 (7.2) 0.98 0.55e1.77

Atrial septal defect, not otherwise specified 275 15 (5.5) 0.77 0.44e1.35 59 4 (6.8) 1.21 0.42e3.48

Septal association 426 37 (8.7) 1.31 0.91e1.89 111 14 (12.6) 1.83 0.99e3.38




Because of sample size, stratificationby antipyretic use during the peri-conceptional period was possible for allheart defects combined and not for in-dividual heart defect types (Table 5). Thepattern was suggestive of a possiblemitigating role of antipyretic use, whichwas driven by febrile illnesses associatedwith urinary tract infection/pelvic in-flammatory disease; however, sparsedata limited the precision of the riskestimates.


Stratification of women by whetherthey had used multivitamin supple-ments regularly in the periconceptionalperiod (Figure 3) showed the followingpattern of ORs: estimated risks tendedto be higher risks among nonusers,with little if any increased risk amongusers (Table 6). Examples include het-erotaxy (OR, 1.6 vs 3.6), d-trans-position of the great arteries (OR, 1.1 vs2.9) and RVOTO associations (OR, 1.7vs 4.0).

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COMMENT

Findings from this large population-based study highlight the considerableheterogeneity of risk patterns forcongenital heart defects that are associ-ated with maternal febrile illness duringthe first trimester of pregnancy. Theoverall risk estimate for all heart defectscombined (Table 3) was modest (OR,1.14). Arguably this finding could still beof some concern because of the potentialattributable fraction of such a common

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FIGURE 2Risk estimates by presence of fever and class of underlying illness,National Birth Defects Prevention Study, 1997-2005

PID, pelvic inflammatory disease; UTI, urinary tract infection.



exposure (7.4% in this study). However,the main finding is that such a modestaggregate risk estimate appears to hide amuch greater variation of risk by type ofheart defect, type of illness, andmaternaluse of vitamins; this variation could haveclinical as well as research implications.Specifically, risks seem to be confinedlargely to febrile illnesses that were causedby genitourinary infections (Table 3),with limited risk associated with respi-ratory illnesses. Also, risk estimates wereincreased only for selected heart defects(eg, heterotaxy and some obstructivedefects). Finally and of potential interestfor primary prevention, the increasedrisks that were associated with febrileillnesses, where present, appeared to bemitigated largely in women who werevitamin supplement users in the peri-conceptional period (Figure 3; Table 6).The use of antipyretics could possiblymitigate the risk of febrile urinary tractinfection/pelvic inflammatory diseaseevents, but the small sample size andthe limitations of the data make these

findings suggestive at best and requirereplication in larger datasets.These findings underscore several

points. From a research perspective, thefindings highlight how overall risk esti-mates for congenital heart defects as agroup can be uninformative and poten-tially misleading. The developmentaland etiologic heterogeneity of heart de-fects requires specific evaluations by typeof heart defect. Similarly, exposures suchas febrile illnesses can be complex andheterogeneous (Figure 1) and can benefitfrom the evaluation of the source offever.In interpreting these findings, it is

important to consider the study’s limi-tations and strengths. The study’s mainpotential limitations, in our view,include participation rates and the ac-curacy of maternal reports as a basis forexposure assessment. Participation ratesamong case and control mothers weresimilar, but selection bias cannot beexcluded. The accuracy of maternal re-ports likely was enhanced by the use of a

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computer-assisted interview that includedspecific questions on illness and timing.However, selective reporting or under-reporting of the occurrence, duration,and magnitude of the fever cannot beexcluded, particularly for milder febrileepisodes. This is a general challenge,in that standardized biomarkers ofexposure that can be used in retrospectivecase-control setting are not yet available.How these factors would bias thefindings is not entirely clear. If women didnot report a febrile illness and if thisoccurred equally in both case and controlmothers, disease risk generally would beunderestimated. The frequency of re-ported febrile illnesses in other publishedstudies from the United States andEurope was 5-10%,1-7 usually 6-8%,comparable with the 7.4% reported in ourcontrol population. Finally, some findingscould be due to chance; this is a consid-eration in any epidemiologic study butparticularly in studies such as this thatinclude multiple comparisons. An addi-tional limitation is the limited sample sizeof certain heart defect and exposuregroups, which decreases the precision ofrisk estimates and consequently also theability to detect effects when these arepresent. Small sample size is particularlylimiting when interactions are evaluated,such as the potential mitigating effect ofvitamin supplement use on fever risk(Figure 3), where large variations in pointestimates were associated still with over-lapping CIs. Replication with a largersample size would provide important in-formation on this potentially importantquestion.

Strengths of this study include caseascertainment, clinical classification, sam-ple size, and the systematic inquiry aboutfebrile illness. Cases were ascertainedactively through population-based pro-grams. Common case definitions andclinical review were used to improvehomogeneity of case reporting andclassification. Initial sample size was alsoconsiderable, compared with severalrecent studies, although because ofstratification by underlying illness, thepresence of fever, and the use of sup-plements, eventually cell sizes becamesmall.


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TABLE 5Risk for congenital heart defects with maternal febrile illnesses by use of antipyretic medications during thesame time period, National Birth Defects Prevention Study, 1997-2005

Fever Antipyretics

All febrile illnesses Respiratory feverUrinary tract infection/pelvicinflammatory disease fever

Cases,n

Controlsubjects,n OR (95%CI)

Cases,n

Controlsubjects,n OR (95% CI)

Cases,n

Controlsubjects,n OR (95% CI)

Yes Yes 577 515 1.06 (0.92e1.22) 447 430 0.98 (0.79e1.07) 55 40 1.30 (0.86e1.97)

Yes No 61 37 1.56 (1.03e2.36) 40 35 1.08 (0.68e1.71) 7 0 Infinitya

No Yes 4930 4815 0.97 (0.89e1.06) 4930 4815 0.97 (0.88e1.06) 4930 4815 0.97 (0.88e1.06)

No No 1253 1183 1.00 (Reference) 1253 1183 1.00 (Reference) 1253 1183 1.00

TOTALS 6821 6550 6670 6463 6245 6039


a With 1 exposed control subject (conservative adjustment), the OR is 6.61 (95% CI, 1.14e38.4).



In terms of biologic plausibility, it isnotable that both hyperthermia andunderlying infections are establishedteratogens in animal models.14,24,25 In

FIGURE 3Risk estimates for heart defects afterDefects Prevention Study, 1997-2005

Variation by whether mothers were periconception

nonusers (circles).

LVOTO, left ventricular outflow tract obstruction; NOS, not otherwise

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


humans, accumulating evidence suggeststhat first-trimester febrile or flu-likeillnesses are associated with a moder-ately increased risk for heart defects in

maternal fever, National Birth

al multivitamin supplement users (triangles) or

specified; RVOTO, right ventricular outflow tract obstructions.

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the aggregate (relative risks, generally<3), with higher relative risks for certainconditions such as tricuspid atresia,coarctation of the aorta, aortic stenosis,and perhaps ventricular septal de-fects.1,3,5-7,14,26 However, these estimatesvary between studies, both in magnitudeand specificity (type of heart defect).An association with right ventricularobstructive defects was reported in mul-tiple studies, although the general in-consistency across studies in the types ofheart defects that are associated withfebrile illnesses lessens the ability to drawfirm inferences. In our study, we notedthe association with right ventricularobstructive defects and heterotaxy, thelatter being a relatively novel finding.Nevertheless, the continuing reports ofsuch associations in studies fromdifferentperiods, geographic locations, and studyapproaches suggest that febrile illnessesshould be considered a concerning ex-posure in early pregnancy. The spectrumof associated heart defects may be relatedto the timing of exposure: defects thatoccur earlier in development (eg, heter-otaxy and d-transposition of the greatarteries) could be related to earlier expo-sures compared with obstructive defects(eg, aortic stenosis), which are thought tooccur at later stages of heart morpho-genesis. From a developmental perspec-tive, it is notable that the associationwith d-transposition of the great arterieswas not seen for tetralogy of Fallot. These

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TABLE 6Febrile illness and heart defects: variation by periconceptional use of vitamin supplements with folic acid, National Birth Defects Prevention Study,1997-2005

Group

OR (95% CI) n

Fever [ no/supplement [ yes

Fever [ yes/supplement [ no

Fever [ yes/supplement [ yes

Fever [ no/supplement [ yes

Fever [ yes/supplement [ no

Fever [ yes/supplement [ yes

Control subjects Reference 3464 50 437

Heterotaxy Reference 3.6 (1.3e 9.6) 1.6 (0.9e 2.8) 93 6 17

Conotruncal Reference 1.9 (1.1e 3.6) 1.1 (0.1e 1.4) 580 14 75

Tetralogy of Fallot Reference 1.3 (0.5e 3.4) 1.0 (0.7e 1.5) 323 5 38

d-Transposition of the great arteries Reference 2.9 (1.2e 6.9) 1.1 (0.7e 1.7) 177 6 24

Atrioventricular septal defects Reference 0 0.7 (0.2e 1.9) 49 0 4

Total anomalous pulmonary venous return Reference 0 0.8 (0.4e 1.8) 73 0 7

Left ventricular outflow tract obstructions Reference 1.2 (0.9e 1.6) 1.1 (0.5e 2.5) 597 8 99

Hypoplastic left heart syndrome Reference 1.5 (0.4e 4.9) 1.2 (0.8e 1.8) 181 3 27

Coarctation of the aorta Reference 1.0 (0.2e 4.2) 1.0 (0.6e 1.6) 177 2 24

Aortic stenosis Reference 0 1.8 (1.1e 3.1) 91 0 26

Left ventricular outflow tract associations Reference 1.8 (0.5e 6.0) 1.2 (0.7e 1.9) 140 3 21

Right ventricular outflow tract obstructions Reference 1.7 (0.9e 3.4) 1.4 (1.1e 1.8) 515 13 86

Pulmonary atresia Reference 0 1.2 (0.6e 2.5) 56 0 8

Pulmonary valve stenosis Reference 1.4 (0.5e 3.7) 1.4 (0.9e 2.0) 304 6 50

Right ventricular outflow tract associations Reference 4.0 (1.6e 10.2) 1.7 (1.0e 2.9) 104 6 19

Septal defects Reference 1.4 (0.8e 2.3) 1.0 (0.9e 1.3) 1493 26 192

Perimembranous ventricular septal defect Reference 1.5 (0.7e 3.2) 1.1 (0.9e 1.5) 482 9 69

Muscular ventricular septal defects Reference 0.4 (0.1e 3.4) 0.9 (0.4e 1.9) 80 1 10

Atrial septal defect, secundum Reference 0.6 (0.2e 1.8) 1.0 (0.7e 1.4) 475 4 58

Atrial septal defect, not otherwise specified Reference 2.6 (0.8e 8.0) 0.7 (0.4e 1.2) 167 4 14

Septal association Reference 2.5 (1.1e 5.8) 1.3 (0.9e 1.8) 265 7 39

ORs are adjusted for potential confounders (see “Methods”).



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2 conditions are often grouped instudies as “conotruncal defects,” butincreasingly they appear to be develop-mentally different and to have differentrisk factor profiles.4,23,27

The pattern of stronger associationswith febrile illnesses compared with non-febrile, if real, suggests either a potenti-ating effect of temperature elevation,beyond the effect of the infection, or aneffect that is confined to more severe in-fections. Resolving this question could beimportant for prevention because it maysuggest a role for the treatment of feverquickly in the course of the disease. Inaddition, the stronger association withgenitourinary infections rather than res-piratory illnesses raises several issuesrelated to causation and pathogenesis.Of particular interest would be furtherresearch into the interaction of anatomy,specific infectious agents (typicallydifferent in the 2 classes of infections),and the activation and role of systemicand local inflammatory response. Stan-dardized biomarkers of infection andinflammation, which are collected atcritical times, are likely to be veryhelpful in pursuing these leads.

Finally, this study showed a possiblemitigating effect on risk among womenwho use multivitamin supplements inthe periconceptional period, which isconsistent with 2 earlier studies.5,6 Thispattern simply could reflect a yet unde-termined effect of a healthier lifestyle;however, because in our analysis, casesand control subjects were both stratifiedby vitamin use, confounding by factorsthat are associated with vitamin useshould have been removed. The biologicplausibility for such an effect is not clear,although one hypothesis suggested thatit may involve a mitigation of apoptosis.Data from experimental models indicatethat fever and (viral) infection increaseapoptosis (programmed cell death),which is a process that is crucial in bothnormal and abnormal development ofthe heart.14,25,28-32 Folate deficiency alsoappears to increase apoptosis, and,conversely, excess apoptosis may bemitigated by supplementation of theexperimental systems with folate.33-40

Thus, vitamin supplementation mightact as a protective buffer to mitigate the

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biologic effects of a potential teratogensuch as fever and possibly otherexposures.5,6

In summary, in this population-basedstudy, first-trimester fever was a com-mon event that was reported in 1 in 13pregnancies. The overall, modest-to-nullassociation with all heart defects com-bined appears to mask several findings ofpotential interest for research andcounseling, which includes associationswith selected heart defects, a potentiallyconcerning role for genitourinary in-fections, and possibly a mitigating effectof periconceptional multivitamin sup-plementation. Conversely, the reassuringfindings for common respiratory ill-nesses, particularly if afebrile, can beuseful information in clinical practiceand counseling of exposed pregnantwomen.From a clinical and research perspec-

tive, the findings underscore the need toavoid simplistic groupings of complexoutcomes (such as congenital heart de-fects) and complex exposures (such asfebrile illnesses) and to pursue detailedanalyses that address, to the extentfeasible with the data at hand, the un-derlying biologic condition of theresearch question. Such detailed evalua-tion can help not only highlight riskpatterns that might be otherwise missedbut also potentially generate importantinformation for targeted research andpersonalized clinical counseling. To thisend, well-designed and large collaborativestudies are crucial. Although complexand resource intensive, such studies withdetailed exposure information and largesample size should provide increasinginsights into the true complexity of hu-man exposures in pregnancy, with theircombination of risk and mitigating fac-tors for congenital heart defects. -

ACKNOWLEDGMENT

We thank the California Department of PublicHealth Maternal Child and Adolescent HealthDivision for providing data for these analyses.

REFERENCES

1. Tikkanen J, Heinonen OP. Maternal hyper-thermia during pregnancy and cardiovascularmalformations in the offspring. Eur J Epidemiol1991;7:628-35.

gy MONTH 2013

2. Shaw GM, Malcoe LH, Swan SH,Cummins SK, Schulman J. Congenital cardiacanomalies relative to selected maternal expo-sures and conditions during early pregnancy.Eur J Epidemiol 1992;8:757-60.3. Zhang J, Cai WW. Association of the com-mon cold in the first trimester of pregnancy withbirth defects. Pediatrics 1993;92:559-63.4. Ferencz C, Loffredo CA, Correa-Villasenor A,Wilson PD. Genetic and environmental risk fac-tors of major congenital heart disease: theBaltimore-Washington Infant Study 1981-1989.Mount Kisco NY: Futura Publishing Company,Inc; 1997.5. Botto LD, Erickson JD, Mulinare J,Lynberg MC, Liu Y. Maternal fever, multivitaminuse, and selected birth defects: evidence ofinteraction? Epidemiology 2002;13:485-8.6. Shaw GM, Nelson V, Carmichael SL,Lammer EJ, Finnell RH, Rosenquist TH.Maternal periconceptional vitamins: interactionswith selected factors and congenital anomalies?Epidemiology 2002;13:625-30.7. Oster ME, Riehle-Colarusso T, Alverson CJ,Correa A. Associations between maternal Feverand influenza and congenital heart defects.J Pediatr 2011;158:990-5.8. EdwardsMJ. Review: hyperthermia and feverduring pregnancy. Birth Defects Res A Clin MolTeratol 2006;76:507-16.9. Chambers CD, Johnson KA, Dick LM,Felix RJ, Jones KL. Maternal fever and birthoutcome: a prospective study. Teratology1998;58:251-7.10. Czeizel AE, Puho EH, Acs N, Banhidy F.High fever-related maternal diseases aspossible causes of multiple congenital abnor-malities: a population-based case-controlstudy. Birth Defects Res A Clin Mol Teratol2007;79:544-51.11. Li Z, Ren A, Liu J, Pei L, Zhang L, Guo Z.Maternal flu or fever, medication use, and neuraltube defects: a population-based case-controlstudy in Northern China. Birth Defects Res AClinMol Teratol 2007;79:295-300.12. Lynberg MC, Khoury MJ, Lu X, Cocian T.Maternal flu, fever, and the risk of neural tubedefects: a population-based case-control study.Am J Epidemiol 1994;140:244-55.13. Shaw GM, Todoroff K, Velie EM,Lammer EJ. Maternal illness, including fever andmedication use as risk factors for neural tubedefects. Teratology 1998;57:1-7.14. Graham JM Jr, Edwards MJ. Teratogenupdate: gestational effects of maternal hyper-thermia due to febrile illnesses and resultantpatterns of defects in humans. Teratology1998;58:209-21.15. Moretti ME, Bar-Oz B, Fried S, Koren G.Maternal hyperthermia and the risk for neuraltube defects in offspring: systematic reviewand meta-analysis. Epidemiology 2005;16:216-9.16. Botto LD. Congenital heart defects,maternal febrile illness, and multivitamin use: apopulation-based study [see comments.].Epidemiology 2001;12:485-90.

http://refhub.elsevier.com/S0002-9378(13)01990-X/sref1

































































http://www.AJOG.org


17. Cleves MA, Malik S, Yang S, Carter TC,Hobbs CA. Maternal urinary tract infectionsand selected cardiovascular malformations.Birth Defects Res A Clin Mol Teratol 2008;82:464-73.18. Botto LD, Correa A. Decreasing the burdenof congenital heart anomalies: an epidemiologicevaluation of risk factors and survival. ProgPediatr Cardiol 2003;18:111-21.19. Hoffman JI, Kaplan S. The incidence ofcongenital heart disease. J Am Coll Cardiol2002;39:1890-900.20. Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalenceof congenital heart defects in metropolitanAtlanta, 1998-2005. J Pediatr 2008;153:807-13.21. Rasmussen SA, Olney RS, Holmes LB,Lin AE, Keppler-Noreuil KM, Moore CA.Guidelines for case classification for the Na-tional Birth Defects Prevention Study. BirthDefects Res A Clin Mol Teratol 2003;67:193-201.22. Yoon PW, Rasmussen SA, Lynberg MC,et al. The National Birth Defects PreventionStudy. Public Health Rep 2001;116(suppl 1):32-40.23. Botto LD, Lin AE, Riehle-Colarusso T,Malik S, Correa A. Seeking causes: classifyingand evaluating congenital heart defects in etio-logic studies. Birth Defects Res A Clin Mol Ter-atol 2007;79:714-27.24. Edwards MJ, Shiota K, Smith MS,Walsh DA. Hyperthermia and birth defects.Reprod Toxicol 1995;9:411-25.

25. Roulston A, Marcellus RC, Branton PE. Vi-ruses and apoptosis. Annu Rev Microbiol1999;53:577-628.26. Loffredo CA. Epidemiology of cardiovascu-lar malformations: prevalence and risk factors.Am J Med Genet 2000;97:319-25.27. Clark EB. Pathogenetic mechanisms ofcongenital cardiovascular malformations revis-ited. Semin Perinatol 1996;20:465-72.28. Mirkes PE, Little SA. Teratogen-inducedcell death in postimplantation mouse em-bryos: differential tissue sensitivity and hall-marks of apoptosis. Cell Death Differ 1998;5:592-600.29. Schaefer KS, Doughman YQ, Fisher SA,Watanabe M. Dynamic patterns of apoptosis inthe developing chicken heart. Dev Dyn2004;229:489-99.30. Rothenberg F, Fisher SA, Watanabe M.Sculpting the cardiac outflow tract. Birth DefectsRes C Embryo Today 2003;69:38-45.31. Fisher SA, Langille BL, Srivastava D.Apoptosis during cardiovascular development.Circ Res 2000;87:856-64.32. Mirkes PE. 2001 Warkany lecture: to die ornot to die, the role of apoptosis in normal andabnormal mammalian development. Teratology2002;65:228-39.33. Chern CL, Huang RF, Chen YH, Cheng JT,Liu TZ. Folate deficiency-induced oxidativestress and apoptosis are mediated viahomocysteine-dependent overproduction ofhydrogen peroxide and enhanced activation ofNF-kappaB in human Hep G2 cells. BiomedPharmacother 2001;55:434-42.

MONTH 2013 Ame

34. Huang RF, Ho YH, Lin HL, Wei JS, Liu TZ.Folate deficiency induces a cell cycle-specificapoptosis in HepG2 cells. J Nutr 1999;129:25-31.35. Huang RF, Yaong HC, Chen SC, Lu YF.In vitro folate supplementation alleviates oxida-tive stress, mitochondria-associated deathsignalling and apoptosis induced by 7-keto-cholesterol. Br J Nutr 2004;92:887-94.36. James SJ, Basnakian AG, Miller BJ. In vitrofolate deficiency induces deoxynucleotide poolimbalance, apoptosis, and mutagenesis in Chi-nese hamster ovary cells. Cancer Res 1994;54:5075-80.37. James SJ, Miller BJ, Basnakian AG,Pogribny IP, Pogribna M, Muskhelishvili L.Apoptosis and proliferation under conditions ofdeoxynucleotide pool imbalance in liver of folate/methyl deficient rats. Carcinogenesis 1997;18:287-93.38. Koury MJ, Horne DW. Apoptosis mediatesand thymidine prevents erythroblast destructionin folate deficiency anemia. Proc Natl Acad SciU S A 1994;91:4067-71.39. Koury MJ, Horne DW, Brown ZA, et al.Apoptosis of late-stage erythroblasts in mega-loblastic anemia: association with DNA damageand macrocyte production. Blood 1997;89:4617-23.40. Tang LS, Wlodarczyk BJ, Santillano DR,Miranda RC, Finnell RH. Developmental con-sequences of abnormal folate transportduring murine heart morphogenesis. BirthDefects Res A Clin Mol Teratol 2004;70:449-58.

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