- Email: [email protected]
Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole
Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole Pierpaolo Mastroiacovo, MD, a Teresa Mazzone, MD," Lorenzo D. Botto, MD, a Maria Angela Serafini, MD, a Alberto Finardi, MD, b Laura Caramelli, MD, c and Danilo Fusco, PhD a Rome, Milan, a n d Florence, Italy
OBJECTIVE: Our purpose was to study prospectively the pregnancy outcome after first-trimester exposure to fluconazole, an effective antifungal agent teratogenic in animals. STUDY DESIGN: We conducted a prospective cohort study of women who contacted three Italian teratogen information services, We compared the pregnancy outcomes of 226 women exposed to fluconazole with that of 452 women exposed to nonteratogenic agents, with use of logistic regression to control for potential confounders. RESULTS" Among the 226 pregnancies exposed to fluconazole there were 22 miscarriages, 1 stillbirth, and 7 infants with congenital anomalies. The prevalence of these outcomes and of neonatal growth parameters and the rate of neonatal complications were similar to those in the reference group. Women in the fluconazole group had a fivefold increased occurrence of induced abortions. CONCLUSIONS: First-trimester exposure to fluconazole does not appear to increase the prevalence of miscarriages, congenital anomalies, and low birth weight. (Am J Obstet Gynecol 1996;175:1645-50.)
Key words: Fluconazole, birth defects, pregnancy outcomes
Fluconazole is an antifungal agent introduced in 1984 for the oral treatment of vaginal candidiasis. Clinical trials have shown that fluconazole is effective and rarely associated with side effects, primarily nausea and vomiting a, 2 Vaginal candidiasis and oropharyngeal and cutaneous candidiasis are usually treated with 150 mg of fluconazole as a single oral dose. Other therapeutic regimens are also used, including a repeat single 150 mg dose 1 week after the first dose or a daily 50 mg dose for 7 to 14 days. Fluconazole has been also used successfully to treat disseminated candidiasis and coccidioidal meningitis,s For these disorders the dosage ranges from 200 to 400 rag/day, and the duration of maintenance therapy may be 6 to 8 weeks or even longer, depending on the clinical response. Animal studies have shown that fluconazole can be teratogenic if given in very high doses. In pregnant rats doses 20 to 40 times higher than the From the Birth Defects Unit, Institute of Pediatrics, Catholic University, ~ the Institute of Obstetrics and Gynaecology, University of Milan, S Paolo Hospital, b the Toxicology Unit, Department of Preclinical and Clinical Pharmacology, University of Florence, Careggi General Hospital, C and the International Centre on Adverse Reproductive Outcomes, Associazione Italiana Studio Malformazioni. ~ Supported by the Associazione Italiana Studio Malformazioni and National Research Council contract no. 93.00736.PF41. Received for publication February 8, 1996; revised April 18, 1996; accepted June 20, 1996. Reprint requests: Pierpaolo Mastroiacovo, MD, Birth Defects Unit, Istituto di Pediatria, Policlinico Univesitario A Gemelli, Universitd Cattolica, Largo GemeUi 8, 00168, Roma, Italy. Copyright © 1996 by Mosby-Year Book, Inc. 0002-9378/96 (~5.00 ÷ 0 6/1/75935
equivalent h u m a n doses produced structural fetal abnormalities, including supernumerary or wavy ribs, dilatation of the renal pelvis, delays in ossification, cleft palate, and abnormal craniofacial ossification.4 In pregnant rabbits similar doses produced abortions but no fetal anomalies. 4 On the basis of these data, fluconazole has been classified by the manufacturer as a category C drug, which indicates that, because studies in animals have revealed adverse effects on the fetus and there are no controlled studies in humans, the drug should be given only if the potential benefitjustifies the potential risk to the fetus. 5 Very little is known about the effect of fluconazole in h u m a n pregnancy. In the only published prospective study in humans, no fetal abnormalities were observed among the 44 births (1 twin pair) of 43 women exposed to fluconazole, all but one exposed to a single 150 mg dose of fluconazole during pregnancy (one was exposed to multiple 150 mg doses). 6 However, the few patients studied and, especially, the lack of information on the gestational week of exposure limits the usefulness of this study. A recent report described three infants (two siblings) with craniofacial, skeletal, and cardiac defects born to two women who received high doses of fluconazole t h r o u g h o u t t h e first trimester of pregnancy. 7 One of the siblings was suspected to have an autosomal recessive disorder (Antley-Bixler syndrome). The two siblings were exposed to 400 rag/day fluconazole in the 1645
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first 24 weeks and in the first 4 months of gestation, respectively, because the mother was in maintenance treatment to prevent relapse of a previous coccidioidal meningitis. The third infant was exposed to 800 mg/day tluconazole during the first 7 weeks of gestation because the mother received maintenance therapy after Cocddioides immitis meningitis. However, because the most common indication by far for fluconazole treatment is vaginal candidiasis or other mucocutaneous conditions treated with low-dose and short-duration regimens, it is inevitable that in ihe daily clinical practice some women will take the drug shortly before or during the first weeks of pregnancy. Thus more detailed information is needed to assess qualitatively and quantitatively the fetal risk associated with the use of fluconazole at low dosage. To this end, we prospectively studied a cohort of 226 women exposed to low-dosage regimens of fluconazole during the first 12 weeks of pregnancy and compared them with an unexposed reference group of women. The specific objectives were to evaluate the incidence of congenital anomalies, spontaneous abortions, and other adverse outcomes of pregnancy as signals of potential teratogenic effect on the fetus. We also evaluated the incidence of induced abortions. Patients and methods This study was based on a cohort of women who contacted three Teratology Information Service centers in Italy. The characteristics of one of these centers has been described elsewhere, s All three centers use similar operating procedures for data collection and exposure assessment. Briefly, the Teratology Information Service staff physicians conduct a consultation that includes administering a structured interview with questions on demographic characteristics, previous and current obstetric history, family history of birth defects, maternal chronic diseases, and exposure to several factors, including alcoholic beverages, coffee, and cigarette smoking. The interview also includes a detailed history of prescription and nonprescription drug use that included information on the commercial preparation, dosage, indication, and time during pregnancy when the drug was taken. We selected as the study group all 228 pregnant women who were treated with fluconazole during the first 12 completed weeks of gestation and who contacted one of the three Teratology Information Service centers from January 1992 through June i994. o f the 228 women, 187 were recruited from the Roma, Catholic University Telefono Rosso, 21 from the Milano, San Paolo University Hospital, and 20 from the Firenze, Careggi University Hospital. Two women originally included in the cohort could not be traced for follow-up. At the first consultation during pregnancy, the Teratol-
December 1996 AmJ Obstet Gynecol
ogy Information Service staff physicians advised these women that the absolute risk of a congenital anomaly in the offspring after exposure to fluconazole was unknown but probably similar to that of general population, estimated to be around 5%. We selected the reference group from the group of women with a completed follow-up who had not been exposed to fluconazole and who had contacted the three centers during the same period for exposure to agents that are known not to be teratogenic or embryotoxic, such as dental X-ray studies, acetaminophen, penicillin, and hair dye. To be more conservative, we excluded from the reference group women with a family history of birth defects or with a chronic disease such as diabetes. The reference group was frequency-matched with the fluconazole-exposed group by region of residence to control for potential unmeasurable confounding related to geographic location. T o increase the power of the study, we included twice as many women in the reference group than in the fluconazole-exposed group, for a total of 452 women in the reference group. For the follow-up interview, women from both the study and reference groups were contacted by phone after the expected date of delivery. Women in the study group were contacted at a median of 6 weeks after the expected date of delivery (interquartile range 3 to 11 weeks). Women in the reference group were contacted at a median 7 weeks (interquartile range 4 to 11 weeks). The interviewing physicians were usually unaware of the exposure status of the women. Women were asked to refer to the baby's neonatal discharge summary during the interview. During the structured interview women were asked questions covering a wide range of topics, including the following: the outcome of the pregnancy, type of delivery, the length of hospital stay, birth weight, head circumference, length, physical findings, perinatal complications, and presence and type of congenital anomaly. If the mother reported a congenital anomaly, a neonatal problem, or a prolonged hospital stay, we requested additional information from the attending physician. We recorded only those congenital anomalies that warranted medical or surgical treatment. We analyzed fluconazole use during early pregnancy as the primary exposure variable. We included in the analyses several other variables as possible confounders, including gestational age at the time of first contact with the Teratology Information Service, maternal age, parity, previous miscarriages, previous infants with congenital anomalies, maternal education, smoking, and alcohol use. The primary outcomes u n d e r study were the risk of birth defects, late fetal deaths, miscarriages, and pregnancy termination. We also analyzed among the subset of nonmalformed livebirths the risk of prematurity (defined as a gestational age <37 weeks), low birth weight (LBW) (defined as <2500 gm), cesarean section, and
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Table I. Characteristics of w o m e n exposed to fluconazole and r e f e r e n c e g r o u p w o m e n (percent in parentheses) Fluconazole-exposed group (n = 226)
Gestational age at counseling <5 wk 5-8 wk 9-12 wk 13-16 wk -->17 wk Maternal age at delivery <20 yr 20-24 yr 25-29 yr 30-34 yr 35-39 yr ->40 yr Parity 0 1 ->2 Previous miscarriages 0 1 ->2 Previous induced abortions 0 1 ->2 Maternal education Low (8 yr) Medium (9-13 yr) High (university degree) Cigarette smoking during first trimester of pregnancy None 1-9 ->10 Alcohol use during first trimester of pregnancy No use Social use
increased hospital stay (defined as a hospital stay > 5 days). Pregnancy terminations after prenatal diagnosis of a congenital anomaly were considered as births with a congenital anomaly. We c o m p a r e d the distribution of the main variables between the study and the reference g r o u p with the X~ square test and analysis of variance. We used EGRET 9 to construct an u n c o n d i t i o n a l logistic regression m o d e l to calculate odds ratios and 95% confidence intervals of the p r e g n a n c y o u t c o m e s associated with exposure to fluconazole while adjusting for potential confounders. In the m o d e l we i n c l u d e d the time of first contact with the Teratology I n f o r m a t i o n Service (three strata: < 9 weeks, 9 to 12 weeks, -----13 weeks), maternal age (four strata: > 2 5 years, 25 to 29 years, 30 to 34 years, ->35 years), previous parity (two strata: 0, ->1), previous miscarriages (two strata: O, ->1), previous i n d u c e d abortions (two strata: O, -->1 ), previous infants with congenital anomalies (two strata: yes, no), maternal e d u c a t i o n level (three strata: low, <--8 years of education; m e d i u m , 9 to 13 years of education; high, any university degree), s m o k i n g (two strata: yes, no), and alcohol use (two strata: yes, no).
6 (2.7)
Reference group (n = 452)
Significance
68 (30.0) 10 (4.4) 7 (3.1)
6 159 120 89 78
(1.3) (35.2) (26.5) (19.7) (17.3)
p < 0.0001
1 28 85 75 32 5
3 32 152 196 51 18
(0.7) (7.1) (33.6) (43.3) (11.3) (4.0)
p = 0.036
125 (55:3) 65 (28.8) 36 (15.9)
242 (53.5) 160 (35.4) 5o (11.1)
p = 0.086
194 (85.8) 24 (10.6) 8 (3.5)
376 (83.2) 60 (26.5) 16 (7.1)
p = 0.612
205 (90.7) 15"(6.6) 6 (2.7)
415 (91.8) 32 (7.1) 5 (1.1)
p = 0.318
51 (22.6) 127 (56.2) 48 (21.2)
87 (19.2) 263 (58.2) 102 (22.6)
p = 0.595
175 (77.4) 24 (10.6) 27 (11.9)
402 (88.9) 38 (8.4) 12 (2.7)
p < 0.001
211 (93.4) 15 (6.6)
405 (89.6) 47 (10.4)
p = 0.109
135 (59.7)
(0.4) (12.4) (37.6) (33.2) (14.2) (2.2)
Interval categories for some potential c o n f o u n d e r s was chosen to minimize the risk of residual c o n f o u n d i n g possibly linked to the use of d i c h o t o m o u s variables.
Results We studied 226 w o m e n who took fluconazole in the first 12 weeks of gestation and c o m p a r e d t h e m with a r e f e r e n c e g r o u p of 452 women. Table I summarizes the primary characteristics of exposed w o m e n and r e f e r e n c e groups. C o m p a r e d with the reference group, w o m e n exposed to fluconazole called the Teratology Information Service earlier in p r e g n a n c y (62.4% in the study g r o u p vs 36.5% in the reference g r o u p called within the first 8 weeks), were y o u n g e r (50.4% vs 41.4% < 3 0 years old), and were m o r e likely to smoke d u r i n g p r e g n a n c y (22.5% vs 11.1%). T h e primary indication for fluconazole t r e a t m e n t was vaginal candidiasis (90.7%). T h e most f r e q u e n t dosage was 150 mg, usually as a single dose (105 women, 46.5%), which is the r e c o m m e n d e d schedule, or, less often, multiple doses of 150 m g (81 women, 35.8%). All the o t h e r w o m e n were exposed to 50 m g (single dose 3
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Table II. Pregnancy o u t c o m e s in fluconazole-exposed and reference groups Pregnancy outcome
Miscarriage Induced abortion Stillbirth Malformed subject
Fluconazole-exposed group (n = 226)
22 29 1 7
(9.7) a (12.8) a (0.6) b (4.0) b
Reference group (n = 452)
34 9 3 17
(7.5) a (2.0) a (0.7) b (4.2) b
Rates (percent) in parentheses calculated on total number of pregnancies (a) or total number of births (b). Table III. Description of congenital anomalies f o u n d a m o n g exposed newborns and type of t r e a t m e n t given to mothers Gestational week of treatment
Treatment
Congenital anomaly
0-4 1-2 2
150 mg × 4 I50 mg × 2 150 mg × 1
2-4 3-4 4
50 mg × 3 150 mg × 2 150 m g × 1
4
150 mg x 1
Trisomy 21 Left valgus clubfoot Hypertrophic pyloric stenosis Hypospadias Trisomy 21 Clubfoot and cryptorchidism Megaureter and hypothyroidism
women, multiple dose 23 w o m e n or to 100 m g (single dose 5 Women, multiple dose 9 w o m e n ) . T h e total dose exposure was in the range of 100 to 2100 mg, with a m e d i a n o f 200 m g (interquartile range 150 to 300 m g ) . N o n e of the w o m e n in the study g r o u p were exposed to o t h e r known teratogens (e.g., infectious diseases, high fever). Table II compares the primary p r e g n a n c y o u t c o m e s between the study and r e f e r e n c e groups. A m o n g the w o m e n exposed to fluconazole 22 miscarriages were reported, 19 during the first trimester and 3 after, for a miscarriage rate of 9.7% c o m p a r e d with 7.5% in the reference group. A m o n g the w o m e n exposed to fluconazole, 29 elective abortions were reported, all p e r f o r m e d during the first trimester, and n o n e for a prenatal diagnosis of fetal anomalies. T h e rate of elective abortions was 12.8% c o m p a r e d with 2.0% a m o n g the reference group. Finally, 175 c o m p l e t e d pregnancies were r e p o r t e d a m o n g the w o m e n exposed to fluconazole: 173 were singleton births (81 males and 92 females) and 2 were twin births (both male-male pairs). O f the 177 infants of the 175 pregnancies, one was stillborn, because of abruptio placentae at 37 weeks (birth weight of 2320 gm, no congenital anomalies r e c o r d e d at necropsy report); seven had a congenital anomaly (Table III). In only two of the seven infants were the congenital anomalies similar. Both infants had trisomy 21; o n e m o t h e r started the t r e a t m e n t at 2 weeks before c o n c e p t i o n and
Table IV. O d d s ratios and 95% c o n f i d e n c e intervals of adverse p r e g n a n c y o u t c o m e s associated with firsttrimester exposure to fluconazole with logistic regression to control for potential c o n f o u n d e r s
Pregnancy outcome
Odds ratio
95% Confidence interval
Induced abortions Miscarriages Stillbirths Congenital anomalies Prematurity LBW Cesarean section Long hospital stay
5.06 1.21 0.36 1.07 1.73 0.92 0.91 0.87
2.28-11.21 0.6%2.21 0.03-3.90 0.41-2.77 0.60-4.97 0.38-2.19 0.60-1.40 0.5%1.29
the o t h e r at 1 week after conception. N o n e of the five r e m a i n i n g infants had multiple congenital anomalies. A m o n g the liveborn infants no neonatal deaths were reported. A m o n g the subset of 169 liveborn infants without congenital anomalies, the prevalence of premature birth, LBW, cesarean section, p r o l o n g e d hospital stay (5 days), m e a n birth weight, h e a d circumference, and length were similar a m o n g infants of mothers exposed to fluconazole and those of the reference group. W h e n we used the logistic regression m o d e l to control for potential c o n f o u n d e r s (Table IV), we f o u n d that the only significant p r e g n a n c y o u t c o m e associated with exposure to fluconazole was i n d u c e d abortion (odds ratio 5.06, 95% c o n f i d e n c e interval 2.28 to 11.21),
Comment T h e risk of fluconazole to induce congenital malformations in the h u m a n fetus is essentially unknown. Experimental data show that fluconazole in animals crosses the placenta and is teratogenic in large doses. A case r e p o r t of three infants with craniofacial, skeletal, and cardiac defects suggest that p r o l o n g e d exposure to high doses of fluconazole can be teratogenic. Accordingly, fluconazole should be avoided in pregnancy; it has b e e n classified as a category C drug by the m a n u f a c t u r e r according to F o o d and D r u g Administration r e c o m m e n dations. A negative p r e g n a n c y test result, as in Italy, or adequate contraception, as in the U n i t e d Kingdom, is a prerequisite for prescribing fluconazole to w o m e n of childbearing age, although it's unclear to what extent this r e c o m m e n d a t i o n is actually followed. In our prospective c o h o r t study of 226 w o m e n who used fluconazole d u r i n g the first trimester of p r e g n a n c y we ascertained 7 infants with congenital anomalies a m o n g 177 infants, for a prevalence at birth of 4.0%, very similar to the 4.2% in the reference g r o u p of w o m e n exposed to known n o n t e r a t o g e n i c agents. O f the 7 infants with congenital anomalies, 2 had Down syndrome and 5 had u n r e l a t e d structural congenital anomalies. N o n e of t h e m had skeletal, cardiac, or facial anomalies.
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Neonatal growth parameters were similar to those in the reference group. Women exposed to fluconazole had a higher miscarriage rate than did women in the reference group, but this finding was attributable to the earlier gestational age at the time of entry in the study in fluconazole-exposed group. When we used a logistic regression model to take gestational age into account, the difference between the exposed and the reference groups disappeared. The only adverse pregnancy outcome more frequently found among women exposed to fluconazole was induced abortion, which was five times more likely than in the reference group. In evaluating the results of our study the potential limitations as well its strengths should be assessed. A potential limitation of our study is that the participants were essentially self-selected by calling the Teratology Information Service for counseling. We previously found that, compared with women in the general Italian population, women who call the Teratology Information Service tend to be older and have attained higher schooling. 8 These characteristics may be associated with a safer lifestyle and perhaps with a lower incidence of adverse reproductive outcomes. For this reason, we used an internal reference group, formed by women who called the Teratology Information Service for exposures that were not considered teratogenic, frequency matched by the region of residence with the group of women exposed to fluconazole. To further control for potential confounders, we used a logistic regression model that included several demographic and medical factors. As with most prospective studies, we were concerned about the validity of outcome information, the potential for differential ascertainment of the outcomes between the study and the reference groups, and the potential distortions that could be introduced in the results by the proportion of subjects lost to follow-up. We adopted several measures to minimize the impact of these factors: the staff at the follow-up interview was unaware of the exposure status of the interviewee (although sometimes the women revealed their exposure status during the interview), the time of the interview after the expected date of delivery was similar in the two groups, the completeness of follow-up was aggressively pursued (there were only two lost to follow-up in the exposed cohort), and the data on pregnancy outcome were requested from the women as written on the children's neonatal discharge report or, if any health problem was reported, from the physician providing care. The major strength of this study is that exposures and outcome were ascertained prospectively a n d that the reference group was selected within the same population of women who contacted the Teratology Information Service for counseling. We were also able to control for
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the gestational age at study entry, an important risk factor for miscarriage prevalence. The relevance of our finding for clinical practice is enhanced by the fact that our study group was composed of women taking fluconazole in the most commonly used low dosage range, with a median total dose of 200 mg (range 100 to 2100 mg) during the first 12 weeks of gestation. Our findings can be compared with only one similar study, 6 which, as ours, studied women exposed to a low-dosage regimen (mostly a single 150 mg dose) and did not report an increased prevalence of congenital anomalies after exposure to flnconazole. In that study 60 pregnancies exposed after conception to fluconazole were followed up to assess the pregnancy outcome. Among the 60 pregnancies there were 6 (10.0%) spontaneous abortions and 11 (18.3%) pregnancy terminations; among the 44 births (1 twin pair) no congenital anomalies were reported. Although our overall findings are reassuring for women exposed to low dosage regimens, we are concerned about our finding of an increased risk for induced abortions among women who used fluconazole. Although we cannot be certain from our data, we cannot exclude that contradictory information received by women before calling a Teratology Information Service and perhaps the particularly strong caution statements included in the drug information leaflet in our country could have played a role in the decision to terminate the pregnancy. Given that our data do not indicate an increased risk for congenital anomalies or other major adverse pregnancy outcomes associated with fluconazole use in early pregnancy at the usual low dosage regimens (150 to 700 mg per week), this kind of exposure is not a medical indication for pregnancy termination. We also recommend that women who have taken fluconazole in early pregnancy should be informed of these findings and should be followed up prospectively during pregnancy. On the other hand, our data cannot exclude an increased risk associated with prolonged high dosage regimens such as those used in systemic and life-threatening conditions. The three malformed infants reported by Pursley et al. 7 were exposed to a dose of 2800 to 5600 mg/week. The decision to prospectively treat a women in early pregnancy with fluconazole remains a complex one. Although it is true that available data, including ours, do not suggest an increased teratogenic risk compared with suitable controls, they cannot exclude it completely, because, to do so, the confidence intervals of the risk estimate would have to be very small and the study would have to be impossibly large. Thus we recommend that the prospective prescription of fluconazole to pregnant women be still approached with caution, balancing the
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a d v a n t a g e s o f successful t r e a t m e n t with p o t e n t i a l fetal risks. REFERENCES
1. Kutzer E, Oittner R, Leodolter S, Brammer KW. A comparison of fluconazole and ketoconazole in the oral treatment of vaginal candidiasis; report of a double-blind multicentre trial. Eur J Obstet Gynaecol Reprod Biol 1988;29:305-13. 2. Report of an International Multicentre Trial: a comparison of single-dose oral fluconazole with 3-day intravaginal clotrimazole in the treatment of vaginal candidiasis. Br J Obstet Gynaecol 1989;96:226-32. 3. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. Drug Ther 1994;330:263-72. 4. Tachibana M, Noguchi ¥, Monro AM. Toxicology of fluconazole in experimental animals. In: Fromtling RA, editor.
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5. 6.
7.
8.
9.
Recent trends in the discovery, development, and evaluation of antifungal agents. Barcelona: JR Prous, 1987:93-102. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 4th ed. Baltimore: Williams & Wilkins, 1993. Inman W, Pearce G, Wilton L. Safety of fluconazole in the treatment of vaginal candidiasis. EurJ Clin Pharmacol 1994; 46:115-8. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996;22:336-40. Mastroiacovo P, Serafini MA, Pagano M, De Santis M, Vercillo I, Celestini E: The "Telefono Rosso": a service for the prevention of birth defects and for the evaluation of teratogenic risk. Ann Ist Super Sanita 1993;29:115-20. EGRET software manual. Seattle: Statistlcs and Epidem!ology Research Corporation, 1991.
OBJECTIVE: Our purpose was to study prospectively the pregnancy outcome after first-trimester exposure to fluconazole, an effective antifungal agent teratogenic in animals. STUDY DESIGN: We conducted a prospective cohort study of women who contacted three Italian teratogen information services, We compared the pregnancy outcomes of 226 women exposed to fluconazole with that of 452 women exposed to nonteratogenic agents, with use of logistic regression to control for potential confounders. RESULTS" Among the 226 pregnancies exposed to fluconazole there were 22 miscarriages, 1 stillbirth, and 7 infants with congenital anomalies. The prevalence of these outcomes and of neonatal growth parameters and the rate of neonatal complications were similar to those in the reference group. Women in the fluconazole group had a fivefold increased occurrence of induced abortions. CONCLUSIONS: First-trimester exposure to fluconazole does not appear to increase the prevalence of miscarriages, congenital anomalies, and low birth weight. (Am J Obstet Gynecol 1996;175:1645-50.)
Key words: Fluconazole, birth defects, pregnancy outcomes
Fluconazole is an antifungal agent introduced in 1984 for the oral treatment of vaginal candidiasis. Clinical trials have shown that fluconazole is effective and rarely associated with side effects, primarily nausea and vomiting a, 2 Vaginal candidiasis and oropharyngeal and cutaneous candidiasis are usually treated with 150 mg of fluconazole as a single oral dose. Other therapeutic regimens are also used, including a repeat single 150 mg dose 1 week after the first dose or a daily 50 mg dose for 7 to 14 days. Fluconazole has been also used successfully to treat disseminated candidiasis and coccidioidal meningitis,s For these disorders the dosage ranges from 200 to 400 rag/day, and the duration of maintenance therapy may be 6 to 8 weeks or even longer, depending on the clinical response. Animal studies have shown that fluconazole can be teratogenic if given in very high doses. In pregnant rats doses 20 to 40 times higher than the From the Birth Defects Unit, Institute of Pediatrics, Catholic University, ~ the Institute of Obstetrics and Gynaecology, University of Milan, S Paolo Hospital, b the Toxicology Unit, Department of Preclinical and Clinical Pharmacology, University of Florence, Careggi General Hospital, C and the International Centre on Adverse Reproductive Outcomes, Associazione Italiana Studio Malformazioni. ~ Supported by the Associazione Italiana Studio Malformazioni and National Research Council contract no. 93.00736.PF41. Received for publication February 8, 1996; revised April 18, 1996; accepted June 20, 1996. Reprint requests: Pierpaolo Mastroiacovo, MD, Birth Defects Unit, Istituto di Pediatria, Policlinico Univesitario A Gemelli, Universitd Cattolica, Largo GemeUi 8, 00168, Roma, Italy. Copyright © 1996 by Mosby-Year Book, Inc. 0002-9378/96 (~5.00 ÷ 0 6/1/75935
equivalent h u m a n doses produced structural fetal abnormalities, including supernumerary or wavy ribs, dilatation of the renal pelvis, delays in ossification, cleft palate, and abnormal craniofacial ossification.4 In pregnant rabbits similar doses produced abortions but no fetal anomalies. 4 On the basis of these data, fluconazole has been classified by the manufacturer as a category C drug, which indicates that, because studies in animals have revealed adverse effects on the fetus and there are no controlled studies in humans, the drug should be given only if the potential benefitjustifies the potential risk to the fetus. 5 Very little is known about the effect of fluconazole in h u m a n pregnancy. In the only published prospective study in humans, no fetal abnormalities were observed among the 44 births (1 twin pair) of 43 women exposed to fluconazole, all but one exposed to a single 150 mg dose of fluconazole during pregnancy (one was exposed to multiple 150 mg doses). 6 However, the few patients studied and, especially, the lack of information on the gestational week of exposure limits the usefulness of this study. A recent report described three infants (two siblings) with craniofacial, skeletal, and cardiac defects born to two women who received high doses of fluconazole t h r o u g h o u t t h e first trimester of pregnancy. 7 One of the siblings was suspected to have an autosomal recessive disorder (Antley-Bixler syndrome). The two siblings were exposed to 400 rag/day fluconazole in the 1645
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first 24 weeks and in the first 4 months of gestation, respectively, because the mother was in maintenance treatment to prevent relapse of a previous coccidioidal meningitis. The third infant was exposed to 800 mg/day tluconazole during the first 7 weeks of gestation because the mother received maintenance therapy after Cocddioides immitis meningitis. However, because the most common indication by far for fluconazole treatment is vaginal candidiasis or other mucocutaneous conditions treated with low-dose and short-duration regimens, it is inevitable that in ihe daily clinical practice some women will take the drug shortly before or during the first weeks of pregnancy. Thus more detailed information is needed to assess qualitatively and quantitatively the fetal risk associated with the use of fluconazole at low dosage. To this end, we prospectively studied a cohort of 226 women exposed to low-dosage regimens of fluconazole during the first 12 weeks of pregnancy and compared them with an unexposed reference group of women. The specific objectives were to evaluate the incidence of congenital anomalies, spontaneous abortions, and other adverse outcomes of pregnancy as signals of potential teratogenic effect on the fetus. We also evaluated the incidence of induced abortions. Patients and methods This study was based on a cohort of women who contacted three Teratology Information Service centers in Italy. The characteristics of one of these centers has been described elsewhere, s All three centers use similar operating procedures for data collection and exposure assessment. Briefly, the Teratology Information Service staff physicians conduct a consultation that includes administering a structured interview with questions on demographic characteristics, previous and current obstetric history, family history of birth defects, maternal chronic diseases, and exposure to several factors, including alcoholic beverages, coffee, and cigarette smoking. The interview also includes a detailed history of prescription and nonprescription drug use that included information on the commercial preparation, dosage, indication, and time during pregnancy when the drug was taken. We selected as the study group all 228 pregnant women who were treated with fluconazole during the first 12 completed weeks of gestation and who contacted one of the three Teratology Information Service centers from January 1992 through June i994. o f the 228 women, 187 were recruited from the Roma, Catholic University Telefono Rosso, 21 from the Milano, San Paolo University Hospital, and 20 from the Firenze, Careggi University Hospital. Two women originally included in the cohort could not be traced for follow-up. At the first consultation during pregnancy, the Teratol-
December 1996 AmJ Obstet Gynecol
ogy Information Service staff physicians advised these women that the absolute risk of a congenital anomaly in the offspring after exposure to fluconazole was unknown but probably similar to that of general population, estimated to be around 5%. We selected the reference group from the group of women with a completed follow-up who had not been exposed to fluconazole and who had contacted the three centers during the same period for exposure to agents that are known not to be teratogenic or embryotoxic, such as dental X-ray studies, acetaminophen, penicillin, and hair dye. To be more conservative, we excluded from the reference group women with a family history of birth defects or with a chronic disease such as diabetes. The reference group was frequency-matched with the fluconazole-exposed group by region of residence to control for potential unmeasurable confounding related to geographic location. T o increase the power of the study, we included twice as many women in the reference group than in the fluconazole-exposed group, for a total of 452 women in the reference group. For the follow-up interview, women from both the study and reference groups were contacted by phone after the expected date of delivery. Women in the study group were contacted at a median of 6 weeks after the expected date of delivery (interquartile range 3 to 11 weeks). Women in the reference group were contacted at a median 7 weeks (interquartile range 4 to 11 weeks). The interviewing physicians were usually unaware of the exposure status of the women. Women were asked to refer to the baby's neonatal discharge summary during the interview. During the structured interview women were asked questions covering a wide range of topics, including the following: the outcome of the pregnancy, type of delivery, the length of hospital stay, birth weight, head circumference, length, physical findings, perinatal complications, and presence and type of congenital anomaly. If the mother reported a congenital anomaly, a neonatal problem, or a prolonged hospital stay, we requested additional information from the attending physician. We recorded only those congenital anomalies that warranted medical or surgical treatment. We analyzed fluconazole use during early pregnancy as the primary exposure variable. We included in the analyses several other variables as possible confounders, including gestational age at the time of first contact with the Teratology Information Service, maternal age, parity, previous miscarriages, previous infants with congenital anomalies, maternal education, smoking, and alcohol use. The primary outcomes u n d e r study were the risk of birth defects, late fetal deaths, miscarriages, and pregnancy termination. We also analyzed among the subset of nonmalformed livebirths the risk of prematurity (defined as a gestational age <37 weeks), low birth weight (LBW) (defined as <2500 gm), cesarean section, and
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Table I. Characteristics of w o m e n exposed to fluconazole and r e f e r e n c e g r o u p w o m e n (percent in parentheses) Fluconazole-exposed group (n = 226)
Gestational age at counseling <5 wk 5-8 wk 9-12 wk 13-16 wk -->17 wk Maternal age at delivery <20 yr 20-24 yr 25-29 yr 30-34 yr 35-39 yr ->40 yr Parity 0 1 ->2 Previous miscarriages 0 1 ->2 Previous induced abortions 0 1 ->2 Maternal education Low (8 yr) Medium (9-13 yr) High (university degree) Cigarette smoking during first trimester of pregnancy None 1-9 ->10 Alcohol use during first trimester of pregnancy No use Social use
increased hospital stay (defined as a hospital stay > 5 days). Pregnancy terminations after prenatal diagnosis of a congenital anomaly were considered as births with a congenital anomaly. We c o m p a r e d the distribution of the main variables between the study and the reference g r o u p with the X~ square test and analysis of variance. We used EGRET 9 to construct an u n c o n d i t i o n a l logistic regression m o d e l to calculate odds ratios and 95% confidence intervals of the p r e g n a n c y o u t c o m e s associated with exposure to fluconazole while adjusting for potential confounders. In the m o d e l we i n c l u d e d the time of first contact with the Teratology I n f o r m a t i o n Service (three strata: < 9 weeks, 9 to 12 weeks, -----13 weeks), maternal age (four strata: > 2 5 years, 25 to 29 years, 30 to 34 years, ->35 years), previous parity (two strata: 0, ->1), previous miscarriages (two strata: O, ->1), previous i n d u c e d abortions (two strata: O, -->1 ), previous infants with congenital anomalies (two strata: yes, no), maternal e d u c a t i o n level (three strata: low, <--8 years of education; m e d i u m , 9 to 13 years of education; high, any university degree), s m o k i n g (two strata: yes, no), and alcohol use (two strata: yes, no).
6 (2.7)
Reference group (n = 452)
Significance
68 (30.0) 10 (4.4) 7 (3.1)
6 159 120 89 78
(1.3) (35.2) (26.5) (19.7) (17.3)
p < 0.0001
1 28 85 75 32 5
3 32 152 196 51 18
(0.7) (7.1) (33.6) (43.3) (11.3) (4.0)
p = 0.036
125 (55:3) 65 (28.8) 36 (15.9)
242 (53.5) 160 (35.4) 5o (11.1)
p = 0.086
194 (85.8) 24 (10.6) 8 (3.5)
376 (83.2) 60 (26.5) 16 (7.1)
p = 0.612
205 (90.7) 15"(6.6) 6 (2.7)
415 (91.8) 32 (7.1) 5 (1.1)
p = 0.318
51 (22.6) 127 (56.2) 48 (21.2)
87 (19.2) 263 (58.2) 102 (22.6)
p = 0.595
175 (77.4) 24 (10.6) 27 (11.9)
402 (88.9) 38 (8.4) 12 (2.7)
p < 0.001
211 (93.4) 15 (6.6)
405 (89.6) 47 (10.4)
p = 0.109
135 (59.7)
(0.4) (12.4) (37.6) (33.2) (14.2) (2.2)
Interval categories for some potential c o n f o u n d e r s was chosen to minimize the risk of residual c o n f o u n d i n g possibly linked to the use of d i c h o t o m o u s variables.
Results We studied 226 w o m e n who took fluconazole in the first 12 weeks of gestation and c o m p a r e d t h e m with a r e f e r e n c e g r o u p of 452 women. Table I summarizes the primary characteristics of exposed w o m e n and r e f e r e n c e groups. C o m p a r e d with the reference group, w o m e n exposed to fluconazole called the Teratology Information Service earlier in p r e g n a n c y (62.4% in the study g r o u p vs 36.5% in the reference g r o u p called within the first 8 weeks), were y o u n g e r (50.4% vs 41.4% < 3 0 years old), and were m o r e likely to smoke d u r i n g p r e g n a n c y (22.5% vs 11.1%). T h e primary indication for fluconazole t r e a t m e n t was vaginal candidiasis (90.7%). T h e most f r e q u e n t dosage was 150 mg, usually as a single dose (105 women, 46.5%), which is the r e c o m m e n d e d schedule, or, less often, multiple doses of 150 m g (81 women, 35.8%). All the o t h e r w o m e n were exposed to 50 m g (single dose 3
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Table II. Pregnancy o u t c o m e s in fluconazole-exposed and reference groups Pregnancy outcome
Miscarriage Induced abortion Stillbirth Malformed subject
Fluconazole-exposed group (n = 226)
22 29 1 7
(9.7) a (12.8) a (0.6) b (4.0) b
Reference group (n = 452)
34 9 3 17
(7.5) a (2.0) a (0.7) b (4.2) b
Rates (percent) in parentheses calculated on total number of pregnancies (a) or total number of births (b). Table III. Description of congenital anomalies f o u n d a m o n g exposed newborns and type of t r e a t m e n t given to mothers Gestational week of treatment
Treatment
Congenital anomaly
0-4 1-2 2
150 mg × 4 I50 mg × 2 150 mg × 1
2-4 3-4 4
50 mg × 3 150 mg × 2 150 m g × 1
4
150 mg x 1
Trisomy 21 Left valgus clubfoot Hypertrophic pyloric stenosis Hypospadias Trisomy 21 Clubfoot and cryptorchidism Megaureter and hypothyroidism
women, multiple dose 23 w o m e n or to 100 m g (single dose 5 Women, multiple dose 9 w o m e n ) . T h e total dose exposure was in the range of 100 to 2100 mg, with a m e d i a n o f 200 m g (interquartile range 150 to 300 m g ) . N o n e of the w o m e n in the study g r o u p were exposed to o t h e r known teratogens (e.g., infectious diseases, high fever). Table II compares the primary p r e g n a n c y o u t c o m e s between the study and r e f e r e n c e groups. A m o n g the w o m e n exposed to fluconazole 22 miscarriages were reported, 19 during the first trimester and 3 after, for a miscarriage rate of 9.7% c o m p a r e d with 7.5% in the reference group. A m o n g the w o m e n exposed to fluconazole, 29 elective abortions were reported, all p e r f o r m e d during the first trimester, and n o n e for a prenatal diagnosis of fetal anomalies. T h e rate of elective abortions was 12.8% c o m p a r e d with 2.0% a m o n g the reference group. Finally, 175 c o m p l e t e d pregnancies were r e p o r t e d a m o n g the w o m e n exposed to fluconazole: 173 were singleton births (81 males and 92 females) and 2 were twin births (both male-male pairs). O f the 177 infants of the 175 pregnancies, one was stillborn, because of abruptio placentae at 37 weeks (birth weight of 2320 gm, no congenital anomalies r e c o r d e d at necropsy report); seven had a congenital anomaly (Table III). In only two of the seven infants were the congenital anomalies similar. Both infants had trisomy 21; o n e m o t h e r started the t r e a t m e n t at 2 weeks before c o n c e p t i o n and
Table IV. O d d s ratios and 95% c o n f i d e n c e intervals of adverse p r e g n a n c y o u t c o m e s associated with firsttrimester exposure to fluconazole with logistic regression to control for potential c o n f o u n d e r s
Pregnancy outcome
Odds ratio
95% Confidence interval
Induced abortions Miscarriages Stillbirths Congenital anomalies Prematurity LBW Cesarean section Long hospital stay
5.06 1.21 0.36 1.07 1.73 0.92 0.91 0.87
2.28-11.21 0.6%2.21 0.03-3.90 0.41-2.77 0.60-4.97 0.38-2.19 0.60-1.40 0.5%1.29
the o t h e r at 1 week after conception. N o n e of the five r e m a i n i n g infants had multiple congenital anomalies. A m o n g the liveborn infants no neonatal deaths were reported. A m o n g the subset of 169 liveborn infants without congenital anomalies, the prevalence of premature birth, LBW, cesarean section, p r o l o n g e d hospital stay (5 days), m e a n birth weight, h e a d circumference, and length were similar a m o n g infants of mothers exposed to fluconazole and those of the reference group. W h e n we used the logistic regression m o d e l to control for potential c o n f o u n d e r s (Table IV), we f o u n d that the only significant p r e g n a n c y o u t c o m e associated with exposure to fluconazole was i n d u c e d abortion (odds ratio 5.06, 95% c o n f i d e n c e interval 2.28 to 11.21),
Comment T h e risk of fluconazole to induce congenital malformations in the h u m a n fetus is essentially unknown. Experimental data show that fluconazole in animals crosses the placenta and is teratogenic in large doses. A case r e p o r t of three infants with craniofacial, skeletal, and cardiac defects suggest that p r o l o n g e d exposure to high doses of fluconazole can be teratogenic. Accordingly, fluconazole should be avoided in pregnancy; it has b e e n classified as a category C drug by the m a n u f a c t u r e r according to F o o d and D r u g Administration r e c o m m e n dations. A negative p r e g n a n c y test result, as in Italy, or adequate contraception, as in the U n i t e d Kingdom, is a prerequisite for prescribing fluconazole to w o m e n of childbearing age, although it's unclear to what extent this r e c o m m e n d a t i o n is actually followed. In our prospective c o h o r t study of 226 w o m e n who used fluconazole d u r i n g the first trimester of p r e g n a n c y we ascertained 7 infants with congenital anomalies a m o n g 177 infants, for a prevalence at birth of 4.0%, very similar to the 4.2% in the reference g r o u p of w o m e n exposed to known n o n t e r a t o g e n i c agents. O f the 7 infants with congenital anomalies, 2 had Down syndrome and 5 had u n r e l a t e d structural congenital anomalies. N o n e of t h e m had skeletal, cardiac, or facial anomalies.
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Neonatal growth parameters were similar to those in the reference group. Women exposed to fluconazole had a higher miscarriage rate than did women in the reference group, but this finding was attributable to the earlier gestational age at the time of entry in the study in fluconazole-exposed group. When we used a logistic regression model to take gestational age into account, the difference between the exposed and the reference groups disappeared. The only adverse pregnancy outcome more frequently found among women exposed to fluconazole was induced abortion, which was five times more likely than in the reference group. In evaluating the results of our study the potential limitations as well its strengths should be assessed. A potential limitation of our study is that the participants were essentially self-selected by calling the Teratology Information Service for counseling. We previously found that, compared with women in the general Italian population, women who call the Teratology Information Service tend to be older and have attained higher schooling. 8 These characteristics may be associated with a safer lifestyle and perhaps with a lower incidence of adverse reproductive outcomes. For this reason, we used an internal reference group, formed by women who called the Teratology Information Service for exposures that were not considered teratogenic, frequency matched by the region of residence with the group of women exposed to fluconazole. To further control for potential confounders, we used a logistic regression model that included several demographic and medical factors. As with most prospective studies, we were concerned about the validity of outcome information, the potential for differential ascertainment of the outcomes between the study and the reference groups, and the potential distortions that could be introduced in the results by the proportion of subjects lost to follow-up. We adopted several measures to minimize the impact of these factors: the staff at the follow-up interview was unaware of the exposure status of the interviewee (although sometimes the women revealed their exposure status during the interview), the time of the interview after the expected date of delivery was similar in the two groups, the completeness of follow-up was aggressively pursued (there were only two lost to follow-up in the exposed cohort), and the data on pregnancy outcome were requested from the women as written on the children's neonatal discharge report or, if any health problem was reported, from the physician providing care. The major strength of this study is that exposures and outcome were ascertained prospectively a n d that the reference group was selected within the same population of women who contacted the Teratology Information Service for counseling. We were also able to control for
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the gestational age at study entry, an important risk factor for miscarriage prevalence. The relevance of our finding for clinical practice is enhanced by the fact that our study group was composed of women taking fluconazole in the most commonly used low dosage range, with a median total dose of 200 mg (range 100 to 2100 mg) during the first 12 weeks of gestation. Our findings can be compared with only one similar study, 6 which, as ours, studied women exposed to a low-dosage regimen (mostly a single 150 mg dose) and did not report an increased prevalence of congenital anomalies after exposure to flnconazole. In that study 60 pregnancies exposed after conception to fluconazole were followed up to assess the pregnancy outcome. Among the 60 pregnancies there were 6 (10.0%) spontaneous abortions and 11 (18.3%) pregnancy terminations; among the 44 births (1 twin pair) no congenital anomalies were reported. Although our overall findings are reassuring for women exposed to low dosage regimens, we are concerned about our finding of an increased risk for induced abortions among women who used fluconazole. Although we cannot be certain from our data, we cannot exclude that contradictory information received by women before calling a Teratology Information Service and perhaps the particularly strong caution statements included in the drug information leaflet in our country could have played a role in the decision to terminate the pregnancy. Given that our data do not indicate an increased risk for congenital anomalies or other major adverse pregnancy outcomes associated with fluconazole use in early pregnancy at the usual low dosage regimens (150 to 700 mg per week), this kind of exposure is not a medical indication for pregnancy termination. We also recommend that women who have taken fluconazole in early pregnancy should be informed of these findings and should be followed up prospectively during pregnancy. On the other hand, our data cannot exclude an increased risk associated with prolonged high dosage regimens such as those used in systemic and life-threatening conditions. The three malformed infants reported by Pursley et al. 7 were exposed to a dose of 2800 to 5600 mg/week. The decision to prospectively treat a women in early pregnancy with fluconazole remains a complex one. Although it is true that available data, including ours, do not suggest an increased teratogenic risk compared with suitable controls, they cannot exclude it completely, because, to do so, the confidence intervals of the risk estimate would have to be very small and the study would have to be impossibly large. Thus we recommend that the prospective prescription of fluconazole to pregnant women be still approached with caution, balancing the
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a d v a n t a g e s o f successful t r e a t m e n t with p o t e n t i a l fetal risks. REFERENCES
1. Kutzer E, Oittner R, Leodolter S, Brammer KW. A comparison of fluconazole and ketoconazole in the oral treatment of vaginal candidiasis; report of a double-blind multicentre trial. Eur J Obstet Gynaecol Reprod Biol 1988;29:305-13. 2. Report of an International Multicentre Trial: a comparison of single-dose oral fluconazole with 3-day intravaginal clotrimazole in the treatment of vaginal candidiasis. Br J Obstet Gynaecol 1989;96:226-32. 3. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. Drug Ther 1994;330:263-72. 4. Tachibana M, Noguchi ¥, Monro AM. Toxicology of fluconazole in experimental animals. In: Fromtling RA, editor.
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Recent trends in the discovery, development, and evaluation of antifungal agents. Barcelona: JR Prous, 1987:93-102. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 4th ed. Baltimore: Williams & Wilkins, 1993. Inman W, Pearce G, Wilton L. Safety of fluconazole in the treatment of vaginal candidiasis. EurJ Clin Pharmacol 1994; 46:115-8. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996;22:336-40. Mastroiacovo P, Serafini MA, Pagano M, De Santis M, Vercillo I, Celestini E: The "Telefono Rosso": a service for the prevention of birth defects and for the evaluation of teratogenic risk. Ann Ist Super Sanita 1993;29:115-20. EGRET software manual. Seattle: Statistlcs and Epidem!ology Research Corporation, 1991.