Investigating the efficacy and safety of metronidazole during pregnancy; A systematic review and meta-analysis

OBJECTIVE: We aimed to review and analyze studies focusing on the efficacy of metronidazole in reducing the risk of preterm birth and the safety of metronidazole taking into account the different doses, duration of treatment and routes of administration. STUDY DESIGNS: Embase, Cochrane Library and PubMed were searched up to 29 July 2019 to identify studies assessing metronidazole exposure during pregnancy. Additional studies were identified from reference lists of retrieved papers. Measured outcomes were preterm births (<37 weeks of gestation) and associated delivery outcomes such as spontaneous abortions (≤ 20 weeks of gestation), stillbirths (≥20 weeks of gestation) and low birth weight (<2500 g) irrespective of the period of exposure and major malformations after first-trimester exposure. Overall effect estimates for RCTs and observational studies were calculated using the random-effects model and pooled using Risk Ratios (RR) and Odds Ratios (OR) respectively. ROB-2 and ROBINS-I tool were used to assess Risk of Bias for RCTs and observational studies, respectively. RESULTS: Twenty-four studies (17 observational studies and 7 RCTs) were selected. Pooled RR was 1.10 (95 % CI 0.78–1.55; n = 7; I(2) = 72 %) for preterm birth. Subgroup analysis found RR 1.67; 95 % CI 1.07–2.62; n = 3; I² = 32 %) for treatment duration of ≤3 days among women with a previous preterm delivery. Pooled OR for spontaneous abortion was 1.72 (95 % CI 1.40–2.12; n = 5; I(2) = 72 %) and 1.15 (95 % CI 0.98–1.34; n = 12; I(2) = 25 %) for major malformations. After exclusion of studies with critical risk of bias, pooled OR were 1.7 (1.42–2.04; n = 3; I(2) = 19 %) and 1.13 (0.93–1.36; n = 9; I(2) = 28 %) respectively. Among several specific malformations analyzed, only congenital hydrocephaly was significantly increased at 4.06 (95 % CI 1.75–9.42; n = 2; I² = 0%). CONCLUSIONS: Data do not confirm the efficacy of metronidazole in reducing the risk of preterm birth and associated delivery outcomes. Further research is required to confirm the effect of high dose and short duration of metronidazole treatment on preterm birth among the high-risk group. Regarding the increased odds of spontaneous abortion, RCTs are required to assess the role of the underlying infection. The need for further studies to confirm the risk of congenital hydrocephaly is paramount.