Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study

ObjectiveTo 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.DesignPopulation based cohort study.SettingA cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.ParticipantsPregnancies 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.InterventionsUse of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.Main outcome measuresRisk 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.ResultsThe 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.ConclusionsOral 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.

Development of the outflow tracts with reference to aortopulmonary windows and aortoventricular tunnels

Although malformations involving the ventricular outflow tracts are often described as conotruncal malformations, there is no consensus as to the lesions included in, or excluded from, this category, reflecting, in part, the current lack of precise definitions of the embryonic truncus and conus. Analysis of development of the outflow tract in terms of proximal, intermediate, and distal components greatly facilitates understanding of the morphology of the aortopulmonary window and aortoventricular tunnels. The aortopulmonary windows reflect failure to close the embryonic aortopulmonary foramen, the space between the distal end of the cushions that divide the lumen of the outflow tract itself and the dorsal wall of the aortic sac. The aortopulmonary tunnels are produced subsequent to abnormal development of the cushions themselves. The distal ends of these cushions excavate to produce the sinuses and leaflets of the arterial valves. The proximal parts of the cushions muscularise to form the subpulmonary infundibulum. The middle part of the cushion mass disappears to provide a tissue plane between the infundibulum and the aortic root. Abnormal formation of this area accounts for the various types of aortoventricular tunnel. In our brief review, we show how the anatomy of these lesions correlates with development of the outflow tract.

FISH spots microdeletion in heart defects

The 22q11.2 microdeletion is found in most of DiGeorge and velocardiofacial syndromes. These individuals have a wide range of anomalies including congenital heart disease, palatal abnormalities, characteristic facial features, hypocalcaemia, immune deficiency, and learning difficulties. Congenital heart disease, particularly conotruncal malformations are associated with 29% of deletions. This syndrome may be inherited as an autosomal dominant trait, but the majority of patients (93%) have a de novo deletion. To access the presence of the microdeletion in those individuals whose phenotipic changes suggested abnormalities in chromosome 22, a study has been made in several children with congenital heart defects.