Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis

Mark A Klebanoff; Ewoud Schuit; Ronald F Lamont; Per-Göran Larsson; Hein J Odendaal; Austin Ugwumadu; Herbert Kiss; Ljubomir Petricevic; William W Andrews; Matthew K Hoffman; Andrew Shennan; Paul T Seed; Robert L Goldenberg; Lynda M Emel; Vinay Bhandaru; Steven Weiner; Michael D Larsen

doi:10.1111/ppe.12947

Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis

Paediatr Perinat Epidemiol. 2023 Mar;37(3):239-251. doi: 10.1111/ppe.12947. Epub 2023 Jan 18.

Authors

Mark A Klebanoff^{1

2}, Ewoud Schuit³, Ronald F Lamont^{4

5}, Per-Göran Larsson^{6

7}, Hein J Odendaal⁸, Austin Ugwumadu⁹, Herbert Kiss¹⁰, Ljubomir Petricevic¹⁰, William W Andrews¹¹, Matthew K Hoffman¹², Andrew Shennan¹³, Paul T Seed¹⁴, Robert L Goldenberg¹⁵, Lynda M Emel¹⁶, Vinay Bhandaru¹⁷, Steven Weiner¹⁷, Michael D Larsen^{17

18}

Affiliations

¹ Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
² Departments of Pediatrics and Obstetrics and Gynecology, and Division of Epidemiology, The Ohio State University, Columbus, Ohio, USA.
³ Julius Center for Health Sciences and Primary Care, and Cochrane Netherlands, both at University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
⁴ Division of Surgery, University College London, Northwick Park Institute for Medical Research Campus, London, UK.
⁵ Odense University Hospital, Department of Gynecology and Obstetrics, University of Southern Denmark, Institute of Clinical Research, Research Unit of Gynecology and Obstetrics, Odense, Denmark.
⁶ Department of Obstetrics and Gynaecology, Skaraborg Hospital, Skövde, Sweden.
⁷ Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden.
⁸ Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town, South Africa.
⁹ Department of Obstetrics and Gynecology, St. George's Hospital, University of London, London, UK.
¹⁰ Department of Obstetrics and Gynaecology, Medical University of Vienna, Wien, Austria.
¹¹ Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹² Department of Obstetrics and Gynecology, Christiana Health Services, Newark, Delaware, USA.
¹³ Department of Women and Children's Health, School of Life Course Sciences, FoLSM, King's College, London, UK.
¹⁴ Division of Women's Health, King's College, London, UK.
¹⁵ Department of Obstetrics and Gynecology, Columbia University, New York City, New York, USA.
¹⁶ Biostatistics, Bioinformatics, and Epidemiology/VIDD, Fred Hutchinson Cancer Center Seattle, Seattle, Washington, USA.
¹⁷ The Biostatistics Center, Milken School of Public Health, The George Washington University, Washington, District of Columbia, USA.
¹⁸ Department of Mathematics and Statistics, St. Michael's College, Colchester, Vermont, USA.

Abstract

Background: Bacterial vaginosis (BV) increases preterm delivery (PTD) risk, but treatment trials showed mixed results in preventing PTD.

Objectives: Determine, using individual participant data (IPD), whether BV treatment during pregnancy reduced PTD or prolonged time-to-delivery.

Data sources: Cochrane Systematic Review (2013), MEDLINE, EMBASE, journal searches, and searches (January 2013-September 2022) ("bacterial vaginosis AND pregnancy") of (i) clinicaltrials.gov; (ii) Cochrane Central Register of Controlled Trials; (iii) World Health Organization International Clinical Trials Registry Platform Portal; and (iv) Web of Science ("bacterial vaginosis").

Study selection and data extraction: Studies randomising asymptomatic pregnant individuals with BV to antibiotics or control, measuring delivery gestation. Extraction was from original data files. Bias risk was assessed using the Cochrane tool. Analysis used "one-step" logistic and Cox random effect models, adjusting gestation at randomisation and PTD history; heterogeneity by I² . Subgroup analysis tested interactions with treatment. In sensitivity analyses, studies not providing IPD were incorporated by "multiple random-donor hot-deck" imputation, using IPD studies as donors.

Results: There were 121 references (96 studies) with 23 eligible trials (11,979 participants); 13 studies (6915 participants) provided IPD; 12 (6115) were incorporated. Results from 9 (4887 participants) not providing IPD were imputed. Odds ratios for PTD for metronidazole and clindamycin versus placebo were 1.00 (95% CI 0.84, 1.17), I² = 62%, and 0.59 (95% CI 0.42, 0.82), I² = 0 before; and 0.95 (95% CI 0.81, 1.11), I² = 59%, and 0.90 (95% CI: 0.72, 1.12), I² = 0, after imputation. Time-to-delivery did not differ from null with either treatment. Including imputed IPD, there was no evidence that either drug was more effective when administered earlier, or among those with a PTD history.

Conclusions: Clindamycin, but not metronidazole, was beneficial in studies providing IPD, but after imputing data from missing IPD studies, treatment of BV during pregnancy did not reduce PTD, nor prolong pregnancy, in any subgroup or when started earlier in gestation.

Keywords: bacterial vaginosis; clindamycin; individual participant data; meta-analysis; metronidazole; preterm delivery; systematic review.

Publication types

Meta-Analysis
Systematic Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / therapeutic use
Clindamycin / therapeutic use
Female
Humans
Infant, Newborn
Metronidazole / therapeutic use
Pregnancy
Premature Birth* / epidemiology
Premature Birth* / prevention & control
Vaginosis, Bacterial* / drug therapy
Vaginosis, Bacterial* / prevention & control

Substances

Anti-Bacterial Agents
Clindamycin
Metronidazole

Abstract

Publication types

MeSH terms

Substances

Grants and funding