A population based cohort study 6 using the Quebec pregnancy cohort (1998-2008) included a total of 139 938 liveborn singleton alive whose mothers were covered by the "Régie de l'assurance maladie du Québec" drug plan for at least 12 months before and during pregnancy. Antibiotic exposure was assessed in the first trimester. After adjusting for potential confounders, clindamycin exposure was associated with an increased risk of major congenital malformations (MCMs) (aOR 1.34, 95% CI 1.02 to1.77, 60 exposed cases), musculoskeletal system malformations (aOR 1.67, 95% CI 1.12 to 2.48, 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81, 95% CI 1.04 to 3.16, 13 exposed cases). Doxycycline exposure increased the risk of circulatory system malformation, cardiac malformations and ventricular/atrial septal defect (aOR 2.38, 95% CI 1.21 to 4.67, 9 exposed cases; aOR 2.46, 95% CI 1.21 to 4.99, 8 exposed cases; aOR 3.19, 95% CI 1.57 to 6.48, 8 exposed cases, respectively). Additional associations were seen with quinolone (1 defect), moxifloxacin (1 defect), ofloxacin (1 defect), macrolide (1 defect), erythromycin (1 defect) and phenoxymethylpenicillin (1 defect). No link was observed with amoxicillin, cephalosporins and nitrofurantoin. Similar results were found when penicillins were used as the comparator group.
A multi-site, population-based case-control study 5 (1997 to 2011) included case infants/fetuses wih any major birth defects and live-born controls without major birth defects. Periconceptional (month before conception through the third month of pregnancy) use of nitrofurantoin, trimethoprim-sulfamethoxazole, or cephalosporins for UTIs was maternally reported. Women with penicillin use served as the comparator. Periconceptional UTIs were reported by 7.8% (2029/26 068) of case and 6.7% (686/10 198) of controls and antiobiotic use was reported by 68.2% of case and 66.6% of controls mothers. Among those reporting certain antibiotic use, compared with penicillin, nitrofurantoin use was associated with oral clefts (a OR 1.97, 95% CI 1.10 to 3.53), trimethoprim-sulfamethoxazole use with esophageal atresia (5.31; 1.39 to 20.24) and diaphragmatic hernia (5.09; 1.20 to 21.69), and cephalosporin use with anorectal atresia/stenosis (5.01; 1.34 to 18.76).
A population-based cohort study 4 using the Norwegian Prescription Database linked to data on all live births, stillbirths, and induced abortions after 12 weeks of gestation from The Medical Birth Registry of Norway included 180 120 pregnancies in 2004-2008. Outcomes of women who were dispensed nitrofurantoin were compared with the outcomes of women who were dispensed pivmecillinam (disease comparison group) and unexposed women. In all, 5 794 (3.2%) filled prescriptions for nitrofurantoin during pregnancy, 1 334 women (0.7%) in the first trimester and 979 women (0.5%) in the last 4 weeks of pregnancy. Nitrofurantoin during the first trimester was not associated with increased risk of major malformations (31 of 1 334; =2.3%) compared with disease controls (162 of 5 800; =2.8%, OR 0.79, 95% CI 0.51 to 1.23). No increased risk for secondary adverse pregnancy outcomes was observed when compared with the disease comparison group. Nitrofurantoin the last 30 days before delivery was associated with increased risk of neonatal jaundice (103 of 959; =10.8%) compared with unexposed women (10 336 of 127 507; =8.1%, OR 1.31, 95% CI 1.02 to 1.70).
A population-based retrospective cohort study 3 in Israel included a total of 105 492 pregnancies, 1 112 of which involved pregnancy terminations for medical reasons. A total of 1 329 infants and abortuses had been exposed to nitrofurantoin during the first trimester of pregnancy. Exposure to nitrofurantoin was not associated with increased risk of major malformations in general (adjusted OR 0.85, 95% CI 0.67 t0 1.08) or with specific malformations.
A population-based, multisite, case-control study 2 included women who had pregnancies affected by 1 of more than 30 eligible major birth defects identified via birth defect surveillance programs in 10 states in USA (n=13 155) and control women randomly selected regions (n=4 941). Nitrofurantoins were associated with anophthalmia or microphthalmos (adjusted OR 3.7; 95% CI 1.1 to 12.2), hypoplastic left heart syndrome (aOR 4.2; 95% CI 1.9 to 9.1), atrial septal defects (aOR 1.9; 95% CI 1.1 to 3.4), and cleft lip with cleft palate (aOR 2.1; 95% CI 1.2 to 3.9). Sulfonamides were associated with anencephaly, hypoplastic left heart syndrome, coarctation of the aorta, choanal atresia, transverse limb deficiency, and diaphragmatic hernia. Other antibacterial agents that showed associations included erythromycins (2 defects), penicillins (1 defect), cephalosporins (1 defect), and quinolones (1 defect).
A systematic review 1 including 4 cohort studies, 3 retrospective and 1 prospective, of women using or not using nitrofurantoin during the first trimester of pregnancy, was abstracted in DARE. No significant differences were found between the study and the control groups (pooled odds ratio for major foetal malformations = 1.29, 95% CI 0.25 to 6.57).
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