Use of antibiotics to reduce preterm birth
Authors: Elizabeth M McClure, Robert L Goldenberg
Journal: The Lancet Global Health (2018)

In this issue of The Lancet Global Health, Ann Lee and colleagues report the results of a cluster-randomised trial to screen for and treat maternal abnormal vaginal flora and asymptomatic urinary tract infection during the first half of pregnancy to reduce risk of preterm birth in a low-income region in Bangladesh.1Lee AC Mullany LC Quaiyum M et al.Effect of population-based antenatal screening and treatment of genitourinary tract infections on birth outcomes in Sylhet, Bangladesh (MIST): a cluster-randomised clinical trial.Lancet Glob Health. 2019; 7: e148-e159Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar In the intervention group, the prevalence of abnormal vaginal flora was 16·3% (95% CI 15·1–17·6) and that of urinary tract infection was 8·6% (7·7–9·5). Despite treatment of abnormal vaginal flora with clindamycin and of asymptomatic urinary tract infections with cefixime or nitrofurantoin before 20 weeks' gestation in roughly 85% of women who tested positive for these conditions, and retreatment of many who remained positive at rescreening, the incidence of preterm birth in the intervention group did not differ significantly from that in the control group, who received basic home-based antenatal care from community health workers (21·8% vs 20·6%; relative risk 1·07 [95% CI 0·91–1·24]). No significant differences between groups were noted for improvements in any other pregnancy outcome. Increased risk of preterm birth has long been associated with maternal infections, including the two conditions in this trial.2Goldenberg RL Culhane JF Iams JD Romero R Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Summary Full Text Full Text PDF PubMed Scopus (4853) Google Scholar Numerous studies have been done of attempts to reduce the risk of preterm birth through treatment of suspected maternal infections.3Goldenberg RL Mwatha A Read JS et al.The HPTN 024 study: the efficacy of antibiotics to prevent chorioamnionitis and preterm birth.Am J Obstet Gynecol. 2006; 194: 650-661Summary Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 4Bellad MB Hoffman MK Mallapur AA et al.Clindamycin to reduce preterm birth in a low resource setting: a randomised placebo-controlled clinical trial.BJOG. 2018; 125: 1601-1609Crossref PubMed Scopus (10) Google Scholar However, the use of antibiotics to treat maternal infection has not generally been shown to reduce the incidence of preterm birth.5Lamont RF Nhan-Chang CL Sobel JD Workowski K Conde-Agudelo A Romero R Treatment of abnormal vaginal flora in early pregnancy with clindamycin for the prevention of spontaneous preterm birth: a systematic review and metaanalysis.Am J Obstet Gynecol. 2011; 205: 177-190Summary Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 6Smaill FM Vazquez JC Antibiotics for asymptomatic bacteriuria in pregnancy.Cochrane Database Syst Rev. 2015; 8 (CD000490.)Google Scholar, 7Schneeberger C Geerlings SE Middleton P Crowther CA Interventions for preventing recurrent urinary tract infection during pregnancy.Cochrane Database Syst Rev. 2015; 7 (CD009279.)Google Scholar The pooled results from UK studies of abnormal vaginal flora, which were used to estimate the potential effect and to calculate the sample size of Lee and colleagues' trial, were outliers among this large body of work. Routine screening and treatment of abnormal vaginal flora was not associated with reduced risk of preterm birth in numerous trials included in a Cochrane meta-analysis.6Smaill FM Vazquez JC Antibiotics for asymptomatic bacteriuria in pregnancy.Cochrane Database Syst Rev. 2015; 8 (CD000490.)Google Scholar Similar mixed results have been noted for attempts to reduce preterm birth through screening and treatment of asymptomatic urinary tract infections. Variations of the strategies to treat abnormal vaginal flora, including the use of different antibiotics and dosages and initiation of treatment earlier in pregnancy, have largely not had any effect. Clinical trials of clindamycin specifically have been done in people with abnormal vaginal flora, and showed moderate or no benefits.6Smaill FM Vazquez JC Antibiotics for asymptomatic bacteriuria in pregnancy.Cochrane Database Syst Rev. 2015; 8 (CD000490.)Google Scholar Similar mixed results emerged from trials to reduce preterm birth through screening and treatment of asymptomatic urinary tract infections.7Schneeberger C Geerlings SE Middleton P Crowther CA Interventions for preventing recurrent urinary tract infection during pregnancy.Cochrane Database Syst Rev. 2015; 7 (CD009279.)Google Scholar However, data suggest that in low-income settings where women have poor access to prenatal care where infections can be effectively diagnosed and treated, the risks of adverse outcomes associated with maternal infection and risks of preterm birth are increased.8Blencowe H Cousens S Oestergaard MZ et al.National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.Lancet. 2012; 379: 2162-2172Summary Full Text Full Text PDF PubMed Scopus (2901) Google Scholar So far, Lee and colleagues' trial is one of the few studies6Smaill FM Vazquez JC Antibiotics for asymptomatic bacteriuria in pregnancy.Cochrane Database Syst Rev. 2015; 8 (CD000490.)Google Scholar, 7Schneeberger C Geerlings SE Middleton P Crowther CA Interventions for preventing recurrent urinary tract infection during pregnancy.Cochrane Database Syst Rev. 2015; 7 (CD009279.)Google Scholar to test a prenatal screening and treatment strategy to reduce preterm birth in women with infection in low-income settings. Lee and colleagues attributed the intervention's lack of efficacy to the low rates of effective treatment (ie, completion of the full treatment course without further evidence of infection) for both infections (58% for abnormal vaginal flora and 70% for urinary tract infection), the potential variation in the microbial composition of abnormal vaginal flora, and the host immune responses in their population. Our interpretation is that the lack of efficacy in this study is largely unknown. The fact that trials of antibiotics to treat genitourinary tract infections have generally not reduced the incidence of preterm birth or other important adverse pregnancy outcomes raises important questions. Many investigators have assumed that the strong evidence supporting increased risk of preterm birth associated with various infections implies causation. Whether that assumption is true is unknown. For example, the presence of organisms or a positive screen for abnormal vaginal flora or urinary tract infection might simply be markers for other risk factors. As pointed out by Lee and colleagues and others, abnormal vaginal flora is polymicrobial, without a single causative agent, and little is known about the organisms involved, their virulence, where they reside within the genital tract, their susceptibility to various antibiotics, and the extent of antimicrobial resistance. Additionally, of the many organisms identified so far, whether any of them cause preterm birth, and if so, the mechanisms by which they do so, remain unknown. Whether conditions in some genitourinary sites, such as the development of mucoid biofilms that protect the organisms from antibiotics, could have a role in the frequent failure of antibiotics to reduce the incidence of preterm birth is unknown.9Romero R Schaudinn C Kusanovic JP et al.Detection of a microbial biofilm in intraamniotic infection.Am J Obstet Gynecol. 2008; 198: 135Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar More randomised trials of antibiotics in women with genitourinary tract infections are unlikely to clarify these issues. Instead, we believe that it is time to refocus on more basic science investigations to address the microbiology of these infections and to answer some of the questions raised. By using advanced techniques—including multiplex quantitative PCR testing10Cox C McKenna JP Watt AP Coyle PV New assay for Gardnerella vaginalis loads correlates with Nugent scores and has potential in the diagnosis of bacterial vaginosis.J Med Microbiol. 2015; 64: 978-984Crossref PubMed Scopus (18) Google Scholar for identification and quantification of specific organisms, microbiome assessment for organism identification, and various tests for antimicrobial resistance—better identification and quantification of the pathogens, assessment of their causal relations with preterm birth, and, as applicable, establishment of which treatment strategies might be beneficial could be possible. Increasingly, these techniques are being successfully used in low-income settings where the need to reduce preterm birth is greatest. A better understanding of factors related to maternal infection risk is also crucial. Together, these advances should help to identify appropriate methods to diagnose and treat infections with improved clinical efficacy, and to develop alternative strategies to prevent preterm birth. We declare no competing interests. Effect of population-based antenatal screening and treatment of genitourinary tract infections on birth outcomes in Sylhet, Bangladesh (MIST): a cluster-randomised clinical trialA population-based antenatal screening and treatment programme for genitourinary tract infections did not reduce the incidence of preterm birth in Bangladesh. Full-Text PDF Open Access