title: Exposure to nitrofurantoin during early pregnancy and congenital malformations: a systematic review and meta-analysis.
abstract: OBJECTIVE
  Because of an increased resistance of urinary pathogens to penicillin derivatives, nitrofurantoin is commonly used as an alternative in treating urinary tract infection because a wide range of both Gram negative and positive organisms are sensitive to it. The safety of the fetus after exposure to nitrofurantoin remains controversial.
  
  
  METHODS
  We conducted a systematic review and meta-analysis to evaluate the fetal safety of nitrofurantoin. We searched Medline, EMBASE, references from published reports, and meeting abstracts for relevant studies. Articles were included in the review if they were human studies, reported pregnancy outcomes, reported the use of nitrofurantoin in the first trimester of pregnancy, and included a comparator group of unexposed pregnancies. The primary outcome was the rate of major malformations; secondary outcomes were rates of craniosynostosis, cleft lip or palate defects, cardiovascular defects, and hypoplastic left heart syndrome.
  
  
  RESULTS
  Eight studies reporting on 91 115 exposed cases and 1 578 745 unexposed controls were included in the primary meta-analysis examining the risk of major malformation. Five cohort studies reported on 9275 exposed and 1 491 933 unexposed infants, resulting in an overall RR of 1.01 (95% CI 0.81 to 1.26); however, three case-control studies with a total of 39 268 cases of major malformations and 129 394 controls gave an overall OR of 1.22 (95% CI 1.02 to 1.45). No increased risk for cardiovascular malformations, oral cleft, or craniosynostosis was identified. For assessing risk of hypoplastic left heart syndrome, only three articles were eligible; these demonstrated an OR of 3.07 (95% CI 1.59 to 5.93).
  
  
  CONCLUSIONS
  While no association was found between fetal exposure to nitrofurantoin and major malformation in cohort studies, there was a slight but significant teratogenic risk in case-control studies, which are more sensitive to adverse effects.
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel; BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration).
authors.forename: Ori
authors.initials: O
authors.lastname: Goldberg
authors.affiliation: BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration); The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, Toronto ON, The University of Toronto, Toronto ON.
authors.forename: Myla
authors.initials: M
authors.lastname: Moretti
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel; The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, Toronto ON, The University of Toronto, Toronto ON.
authors.forename: Amalia
authors.initials: A
authors.lastname: Levy
authors.affiliation: BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration); The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, Toronto ON, The University of Toronto, Toronto ON.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000892:Anti-Infective Agents, Urinary / Q000009:adverse effects*; D005260:Female; D006801:Humans; D018811:Maternal Exposure; D009582:Nitrofurantoin / Q000009:adverse effects*; D011247:Pregnancy; D011261:Pregnancy Trimester, First
chemical_list: D000892:Anti-Infective Agents, Urinary; D009582:Nitrofurantoin
keywords: congenital malformations; meta-analysis; nitrofurantoin; pregnancy