Background
Low-dose fluconazole is used commonly to treat vulvovaginal candidiasis, a condition occurring frequently during pregnancy. Conflicting information exists on the association between low-dose fluconazole use among pregnant women and the risk of major birth defects.
Objective
We used data from the National Birth Defects Prevention Study to examine this association.
Study Design
The National Birth Defects Prevention Study is a multisite, population-based, case-control study that includes pregnancies with estimated delivery dates from 1997 to 2011. Information on fluconazole use in early pregnancy was collected by self-report from 31,645 mothers of birth defect cases and 11,612 mothers of unaffected controls. Adjusted odds ratios and 95% confidence intervals were estimated for birth defects with 5 or more exposed cases; crude odds ratios and exact 95% confidence intervals were estimated for birth defects with 3–4 exposed cases.
Results
Of the 43,257 mothers analyzed, 44 case mothers and 6 control mothers reported using fluconazole. Six exposed infants had cleft lip with cleft palate, 4 had an atrial septal defect, and each of the following defects had 3 exposed cases: hypospadias, tetralogy of Fallot, d-transposition of the great arteries, and pulmonary valve stenosis. Fluconazole use was associated with cleft lip with cleft palate (odds ratio = 5.53; confidence interval = 1.68–18.24) and d-transposition of the great arteries (odds ratio = 7.56; confidence interval = 1.22–35.45).
Conclusions
The associations between fluconazole and both cleft lip with cleft palate and d-transposition of the great arteries are consistent with earlier published case reports but not recent epidemiologic studies. Despite the larger sample size of the National Birth Defects Prevention Study, fluconazole use was rare. Further investigation is needed in large studies, with particular emphasis on oral clefts and conotruncal heart defects.
Fluconazole is a systemic azole antifungal drug taken orally or intravenously. Low-dose fluconazole (150 mg/day) often is prescribed for the treatment of vulvovaginal candidiasis, a common condition during pregnancy. High-dose fluconazole use (400–800 mg/day) is used to treat systemic fungal infections. Case reports have linked high-dose fluconazole use to a pattern of birth defects marked by the presence of craniofacial, skeletal, and sometimes heart defects. Studies in animals have confirmed the teratogenicity of fluconazole when given at high doses (the human equivalent of more than 800 mg per day).
Several epidemiologic studies have examined the risk of birth defects among infants whose mothers took low doses of fluconazole. The majority of these studies did not report an increased risk of birth defects, but most either were not large enough to examine individual birth defects or were focused on the presence of birth defects overall. In contrast, a recent Danish cohort study reported an association between maternal first-trimester fluconazole use and tetralogy of Fallot in offspring. A previous analysis using data from the National Birth Defects Prevention Study (NBDPS) found that use of antifungal medications (including fluconazole) in early pregnancy was associated with an increased risk of hypoplastic left heart syndrome. Thus, it remains unclear whether use of low-dose fluconazole in early pregnancy is associated with specific birth defects.
Understanding the teratogenicity of fluconazole at low doses remains important, given that pregnant women are at increased risk of vulvovaginal candidiasis. In 2002 and 2006, the US Centers for Disease Control and Prevention (CDC) recommended that pregnant women avoid the use of fluconazole, suggesting the use of topical azoles during pregnancy instead. In 2011, the US Food and Drug Administration (FDA) issued a drug safety communication regarding the possible teratogenic risks associated with long-term, high-dose fluconazole use, and changed the FDA pregnancy category for high-dose fluconazole from category C to D (evidence of human fetal risk, but the benefits may warrant use).
To investigate the potential teratogenicity of low-dose fluconazole, we examined the association between first-trimester fluconazole use and the risk of major birth defects by using data from the NBDPS.
Materials and Methods
The NBDPS is a large, multisite, population-based, case-control study of birth defects that began collecting data in 1997. Infants with 1 or more of 30 different categories of major structural birth defects (cases), excluding those attributed to a known chromosomal or single-gene abnormality, were ascertained through birth defect surveillance programs in 10 states (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah). Control infants were live births without birth defects randomly selected from hospital records or birth certificates in the same time period and geographic area as the cases. Estimated delivery dates included in this analysis were October 1, 1997, through December 31, 2011. Each study site obtained Institutional Review Board approval for the NBDPS and case and control mothers provided informed consent.
Case inclusion criteria have been described previously. Case information, including clinical information abstracted from case medical records, was obtained from birth defect surveillance programs. The clinical record of each case was reviewed by a clinical geneticist to determine eligibility before the interview. Clinical geneticists also reviewed and classified each case infant as having isolated, multiple, or complex birth defects. Congenital heart defect (CHD) cases were further categorized as simple, association, or complex. CHD cases classified as atrial septal defects (ASDs) not otherwise specified were viewed as probably ASD secundum type and were counted as such in the analysis. Starting in January 2006, the collection of ventricular septal defects (VSDs) changed; the current analysis excludes VSDs diagnosed after 2005. Certain study sites did not ascertain cases during the entire study period for pulmonary valve stenosis (PVS) (California before 2002) and muscular VSDs (after the first year for sites participating 1997–1998). When we analyzed those defects, cases and controls were excluded for the study sites and years for which case ascertainment was incomplete.
Noncardiac cases were grouped according to NBDPS standard classification criteria. Microtia included dysplastic ear pinna and stenosis or atresia of external auditory canal. Infants with intestinal atresia limited to the duodenum were grouped together and counted as duodenal atresias; other intestinal atresias (ileal, jejunal, and multiple intestinal atresias or stenosis) were counted as small intestinal atresias. Infants with esophageal or small intestine atresia that occurred as a component of a VATER/VACTERL association defects (ie, an association of birth defects including vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula/esophageal atresia, renal anomalies, and limb defects) were included and classified as having multiple defects. Only second- and third-degree hypospadias cases were included; the control group was restricted to male infants.
Trained interviewers conducted computer-assisted telephone interviews with the mothers of case and control infants between 6 weeks and 24 months after the estimated date of delivery. Demographics, pregnancy history, various health conditions, and exposures before and during pregnancy were collected. Mothers were asked about all medications taken during the period from 3 months preconception through the end of pregnancy and information was collected on timing, frequency, and duration of medication use. The Slone Epidemiology Center Drug Dictionary was used to code all reported medications. During the study period, 66.7% of eligible case mothers and 63.7% of eligible control mothers participated in the interview. In total, 44,029 mothers (32,200 case and 11,829 control mothers) completed the NBDPS interview.
Infants were classified as exposed if the mother reported any fluconazole use in the month before pregnancy through the third month of pregnancy. The first 3 months of pregnancy were chosen because this is the critical period in the development of the fetus associated with most structural birth defects. Given that it is often hard to pinpoint the exact date of conception, the month before pregnancy also was included in the exposure time frame to ensure all exposed infants were identified. Infants of mothers who were missing information on timing of fluconazole use were excluded from analysis, as were infants of mothers who did not answer all the medication questions during the interview.
Covariates included maternal age at delivery (≤24, 25–29, 30–34, ≥35 years), maternal race/ethnicity (non-Hispanic white, other), mother’s state of residence at the time of infant’s birth, cigarette smoking in the month before through the third month of pregnancy (yes/no), and gestational diabetes during the current pregnancy (yes/no). Chi-square tests were used to compare maternal characteristics between those with and without fluconazole exposure. For birth defects with 5 or more exposed cases, logistic regression models were constructed to estimate the adjusted odds ratio (ORs) and 95% confidence intervals (CIs) for the association between maternal fluconazole exposure and each type of birth defect, while we controlled for covariates. For birth defects with 3 or 4 exposed cases, crude ORs and exact CIs were estimated. ORs were not estimated for birth defects with fewer than 3 exposed cases. We examined all cases and then separately examined isolated cases within each birth defect (ie, cases with only 1 defect). Analyses were performed using SAS software, version 9.3 (SAS Corporation, Cary, NC).
Results
After we excluded 772 infants (555 cases, 217 controls) as the result of missing information on maternal fluconazole use, 43,257 infants (31,645 cases, 11,612 controls) were analyzed. The average time between the estimated delivery date and interview was 11.5 months among cases and 9.2 months among controls.
Overall, 50 (0.12%) mothers reported using fluconazole during the 1 month before pregnancy through the third month of pregnancy. Of the 50 exposed infants, 44 were cases and 6 were controls. The majority of the exposed mothers reported taking fluconazole for vulvovaginal candidiasis (36/50; 72%); the remainder did not specify why fluconazole was used. Most mothers (49/50; 98%) reported taking fluconazole for a short period of time (less than 1 week).
Mothers who reported using fluconazole were similar to mothers who did not in terms of maternal age, race, and smoking status and varied somewhat by study center and maternal gestational diabetes ( Table 1 ). Two exposed case mothers reported type 1 or 2 diabetes before the index pregnancy. Mothers were less likely to report fluconazole use after 2006; 42 (84%) of the exposed infants were born before 2006.
Used fluconazole | Did not use fluconazole | P value b | |
---|---|---|---|
n = 50 | n = 43,207 | ||
n (%) a | n (%) a | ||
Maternal age, y | |||
≤24 | 15 (30) | 14,405 (33) | |
25–29 | 11 (22) | 11,721 (27) | .324 |
30–34 | 12 (24) | 10,665 (25) | |
35+ | 12 (24) | 6416 (15) | |
Maternal race/ethnicity | |||
Non-Hispanic white | 35 (70) | 25,321 (59) | .103 |
Other | 15 (30) | 17,873 (41) | |
Study center | |||
Arkansas | 13 (26) | 5664 (13) | |
California | 5 (10) | 5163 (12) | |
Iowa | 2 (4) | 4242 (10) | |
Massachusetts | 6 (12) | 5334 (12) | |
New Jersey | 2 (4) | 2209 (5) | .326 |
New York | 5 (10) | 3124 (7) | |
Texas | 4 (8) | 4811 (11) | |
Atlanta | 4 (8) | 4776 (11) | |
North Carolina | 5 (10) | 3374 (8) | |
Utah | 4 (8) | 4510 (10) | |
Smoking c | |||
Yes | 9 (18) | 8397 (20) | .778 |
No | 41 (82) | 34,473 (80) | |
Gestational diabetes during pregnancy | |||
Yes | 5 (11) | 2156 (5) | 0.079 |
No | 40 (89) | 38,855 (95) |
a Numbers vary because of missing values
c From 1 month before pregnancy through the third month of pregnancy.
Mothers who took fluconazole also reported using other medications during pregnancy. Ninety-six percent of case mothers and 83% of control mothers reported using at least 1 other medication (excluding vitamins) during pregnancy. The most common medications reported were acetaminophen, ibuprofen, amoxicillin, and pseudoephedrine. No mother who used fluconazole also used folic-acid antagonist medications, which have been associated with specific birth defects. Two case mothers who used fluconazole also took valproic acid, an antiseizure medication associated with increased risk of specific birth defects. One infant had simple, isolated d-transposition of the great arteries (dTGA), and the other had isolated hypospadias.
Eight exposed infants had an oral cleft ( Table 2 ): 1 had a cleft palate, 6 had a cleft lip with cleft palate (CLP), and 1 had a cleft lip only. Three exposed infants had hypospadias. There were 9 exposed infants with a conotruncal defect, 3 of whom had dTGA and 3 of whom had tetralogy of Fallot. Three exposed infants had PVS, and 4 had ASDs. There were fewer than 3 exposed infants for all other birth defects. The CHDs among exposed infants were classified as simple with 4 exceptions: (1) 1 infant had dTGA with VSD, ASD, and PVS; (2) 1 infant had a double-outlet right ventricle with transposed great arteries with an ASD; (3) 1 infant had PVS and VSD; and (4) 1 infant had heterotaxy.
Exposed/unexposed | ||
---|---|---|
Birth defect | All cases a | Isolated cases |
Amniotic band sequence | 1/333 | 1/281 |
Central nervous system defects | ||
Anencephaly | 1/646 | 1/578 |
Spina bifida | 2/1275 | 2/1120 |
Encephalocele | 0/227 | 0/171 |
Holoprosencephaly | 0/173 | 0/125 |
Dandy-Walker malformation | 0/186 | 0/114 |
Hydrocephaly | 1/518 | 0/361 |
Cerebellar hypoplasia | 0/64 | 0/38 |
Eye defects | ||
Anophthalmia/microphtalmia | 0/232 | 0/139 |
Congenital cataracts | 1/383 | 1/341 |
Glaucoma | 0/186 | 0/153 |
Anotia/microtia | 1/690 | 1/475 |
Orofacial defects | ||
Cleft palate only | 1/1602 | 1/1284 |
Cleft lip only | 1/1097 | 1/1021 |
Cleft lip with palate | 6/2016 | 4/1717 |
Choanal atresia | 0/166 | 0/87 |
Gastrointestinal defects | ||
Esophageal atresia | 2/754 | 0/318 |
Duodenal atresia/stenosis | 0/237 | 0/148 |
Small intestine atresia/stenosis | 0/477 | 0/407 |
Anorectal atresia/stenosis | 2/1075 | 0/465 |
Biliary atresia | 0/199 | 0/170 |
Cloacal exstrophy | 0/100 | 0/59 |
Colonic atresia/stenosis | 0/56 | 0/50 |
Genitourinary defects | ||
Hypospadias | 3/2556 | 3/2283 |
Renal agenesis/hypoplasia | 0/190 | 0/135 |
Bladder exstrophy | 0/74 | 0/55 |
Musculoskeletal defects | ||
Transverse limb deficiency | 0/721 | 0/604 |
Longitudinal limb deficiency | 0/480 | 0/268 |
Intercalary limb deficiency | 0/67 | 0/46 |
Limb NOS | 0/24 | 0/16 |
Craniosynostosis | 1/1597 | 1/1446 |
Diaphragmatic hernia | 2/872 | 2/665 |
Omphalocele | 0/439 | 0/258 |
Gastroschisis | 0/1412 | 0/1282 |
Sacral agenesis | 0/109 | 0/12 |
Congenital heart defects | ||
Heterotaxy b | 1/344 | − |
Conotruncal defects | ||
Truncus arteriosus | 2/136 | 2/105 |
IAA type B | 0/50 | 0/35 |
IAA NOS | 0/8 | 0/7 |
Tetralogy of Fallot | 3/1207 | 1/964 |
d-TGA | 3/768 | 3/707 |
DORV-TGA | 1/191 | 1/158 |
Other DORV | 0/123 | 0/91 |
Conoventricular VSD | 0/117 | 0/95 |
Atrioventricular septal defect | 1/371 | 1/277 |
Total anomalous pulmonary venous return | 0/303 | 0/278 |
LVOTO defects | ||
Hypoplastic left heart syndrome | 1/659 | 1/600 |
IAA type A | 0/22 | 0/18 |
Coarctation of the aorta | 2/1169 | 2/1007 |
Aortic stenosis | 0/513 | 0/474 |
LVOTO association c | 0/534 | 0/441 |
RVOTO defects | ||
Pulmonary atresia | 1/264 | 0/245 |
Pulmonary valve stenosis | 3/1553 | 2/1433 |
Ebstein anomaly | 0/180 | 0/163 |
Tricuspid atresia | 1/178 | 1/157 |
RVOTO association d | 1/447 | 0/386 |
Septal defects | ||
Perimembranous VSD | 2/1443 | 1/1228 |
Muscular VSD | 0/161 | 0/145 |
VSD NOS | 0/17 | 0/13 |
Multiple VSDs | 0/69 | 0/58 |
Secundum ASD | 4/3069 | 1/2491 |
ASD OS | 0/11 | 0/6 |
Septal associations e | 0/767 | 0/600 |
Single ventricle defects b | 0/174 | − |