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Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study.
BMJ. 2020 May 20; 369:m1494.BMJ

Abstract

OBJECTIVE

To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.

DESIGN

Population based cohort study.

SETTING

A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.

PARTICIPANTS

Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth.

INTERVENTIONS

Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.

MAIN OUTCOME MEASURES

Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined.

RESULTS

The study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.

CONCLUSIONS

Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.

Authors+Show Affiliations

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA yzhu15@bwh.harvard.edu.Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA.Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA.Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA.Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA.Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32434758

Citation

Zhu, Yanmin, et al. "Oral Fluconazole Use in the First Trimester and Risk of Congenital Malformations: Population Based Cohort Study." BMJ (Clinical Research Ed.), vol. 369, 2020, pp. m1494.
Zhu Y, Bateman BT, Gray KJ, et al. Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study. BMJ. 2020;369:m1494.
Zhu, Y., Bateman, B. T., Gray, K. J., Hernandez-Diaz, S., Mogun, H., Straub, L., & Huybrechts, K. F. (2020). Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study. BMJ (Clinical Research Ed.), 369, m1494. https://doi.org/10.1136/bmj.m1494
Zhu Y, et al. Oral Fluconazole Use in the First Trimester and Risk of Congenital Malformations: Population Based Cohort Study. BMJ. 2020 May 20;369:m1494. PubMed PMID: 32434758.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study. AU - Zhu,Yanmin, AU - Bateman,Brian T, AU - Gray,Kathryn J, AU - Hernandez-Diaz,Sonia, AU - Mogun,Helen, AU - Straub,Loreen, AU - Huybrechts,Krista F, Y1 - 2020/05/20/ PY - 2020/5/22/entrez PY - 2020/5/22/pubmed PY - 2020/6/11/medline SP - m1494 EP - m1494 JF - BMJ (Clinical research ed.) JO - BMJ VL - 369 N2 - OBJECTIVE: To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis. DESIGN: Population based cohort study. SETTING: A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14. PARTICIPANTS: Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth. INTERVENTIONS: Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy. MAIN OUTCOME MEASURES: Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined. RESULTS: The study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively. CONCLUSIONS: Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall. SN - 1756-1833 UR - https://www.unboundmedicine.com/medline/citation/32434758/Oral_fluconazole_use_in_the_first_trimester_and_risk_of_congenital_malformations:_population_based_cohort_study L2 - http://www.bmj.com/cgi/pmidlookup?view=long&pmid=32434758 DB - PRIME DP - Unbound Medicine ER -