Maternal Genitourinary Infections and Adverse Perinatal Outcomes
Condition: Maternal Infection Affecting Newborn
MeSH terms: Infections; Communicable Diseases
Study type: Interventional

Summary: 
      The primary aim of this study is to determine the impact of community-based screening and
      treatment of abnormal vaginal flora and urinary tract infections in early pregnancy (13-19
      weeks) on preterm live birth in Sylhet district, Bangladesh.

      Hypothesis 1: Community-based screening and treatment of abnormal vaginal flora (Nugent score
      >4) and urinary tract infections in early pregnancy (13-19 weeks) will reduce the population
      rate of preterm live birth by at least 15%.

      The secondary aims of this study are:

        -  To determine the impact of community-based screening and treatment of abnormal vaginal
           flora and urinary tract infections on the:

             -  proportion of pregnancies with outcomes occurring prior to 37 weeks (late
                miscarriage, preterm still birth and preterm live birth); and

             -  proportion of babies with early onset neonatal sepsis.

        -  To determine the prevalence of abnormal vaginal flora and urinary tract infections,
           including asymptomatic bactiuria, among pregnant women in Sylhet district, Bangladesh.

        -  To evaluate the accuracy of simple, low-cost, point of care diagnostic tests for
           detecting bacterial vaginosis and urinary tract infections by community health workers
           in a rural, developing country setting.
    

Detailed description: 
      Burden of Maternal Genitourinary Tract Infections: Genital and urinary tract (GU) infections
      may be due to endogenous or sexually transmitted pathogens, and are estimated to affect up to
      41% of women of reproductive age globally, although there is wide regional, country, and
      population specific variation (Table 1). These estimates, however, may underestimate the
      burden in developing countries, as 60-80% of GU infections are asymptomatic in pregnant women
      [1], and furthermore many women never receive appropriate medical care in resource poor
      settings.

      Several epidemiologic studies have been conducted in Bangladesh reporting the prevalence of
      GU infections in different populations [2-15]. Genital tract infections, particularly
      sexually transmitted infections are common among urban and high risk populations, i.e.
      commercial sex workers. In rural Bangladesh, the burden of diseases associated with bacterial
      vaginosis (BV) (5.9-18.9%) [3, 4] and asymptomatic bactiuria (12%) are high [12]. In urban
      areas, mostly Dhaka, the prevalence of BV is higher; one study reported a prevalence of 28%
      [8]. There is no known data on the prevalence of intermediate vaginal flora in Bangladesh.
      The prevalence of sexually transmitted infections including Gonorrhea, Chlamydia, Trichomonas
      and Syphilis are high among high risk urban populations of Bangladesh but generally low in
      rural areas. Given these prevalence data, we postulate that among pregnant women of rural
      Sylhet district in Bangladesh, BV and UTI are the most prevalent GU infections.

      Rationale for screening and treating asymptomatic women The rationale for treating
      asymptomatic bacterial vaginosis (Nugent score 7-10) and asymptomatic intermediate flora
      (Nugent score 4-6) is based on data: 1) showing their association with adverse pregnancy
      outcomes[38], and 2) several promising trials showing that treatment may reduce preterm
      birth[39, 40]. Up to 84% of bacterial vaginosis cases are asymptomatic [23]. In a
      meta-analysis of 32 studies in developed and developing countries by Leitich et al,
      asymptomatic BV (Nugent score 7-10) was associated with a 6.32 times elevated risk of late
      miscarriage (95% CI 3.65-10.94) and 2.16 times (95% CI 1.56-3.00) increased risk of preterm
      birth. The association with preterm birth was higher when BV was detected in early pregnancy
      (<16 weeks, OR 2.97, 95% CI 1.48-5.98)[38]. Among women with a prior history of preterm
      birth, Hauth and colleagues found that screening and treatment of asymptomatic BV (Nugent
      score 7-10) with metronidazole and erythromycin at 22 weeks gestation significantly reduced
      the incidence of preterm birth from 46% in the placebo group to 31% in the treatment group
      [41]. In the multi-center NICHD BV trial, 1953 women with asymptomatic BV between 16-24 weeks
      of gestation were randomized to receive two doses of metronidazole (2g) or placebo; however,
      treatment did not significantly affect preterm delivery or other adverse perinatal outcomes
      [42].

      Intermediate vaginal flora (Nugent score 4-6) is a heterogeneous condition which has been
      also associated with elevated risk of preterm birth and neonatal infections [43-46].
      Intermediate vaginal flora comprises 15% of all abnormal vaginal flora (Nugent score >=4)
      [39]. In a recent trial, Ugwumadu et al reported that early (12-22 weeks of gestation)
      screening and treatment for abnormal vaginal flora (Nugent score >4) with 5 days of oral
      clindamycin resulted in a significant reduction in spontaneous preterm birth rate (12% in
      placebo vs. 5% in treatment group) and late miscarriage (13-24 weeks; 4% in placebo vs. 1% in
      treatment group) [39]. Similarly, Lamont et al reported that early (13-20 week) treatment of
      abnormal vaginal flora (Nugent score >4) with intravaginal clindamycin reduced the incidence
      of preterm birth by 60% [40]. Potential explanations for the treatment effect in the 2 later
      trials may include: 1) the earlier timing of treatment, prior to the amniotic membranes
      sealing the uterus at 20 weeks [47], which may thus prevent early ascension of bacteria into
      the intrauterine cavity; 2) antibiotic choice: 5-7 day course of clindamycin, which has
      greater activity against Mobiluncus and atypical Mycoplasma species vs. 2 days of
      metronidazole [26]; and 3) treatment of abnormal vaginal flora in Ugwumadu et al and Lamont
      et al, vs. treatment of BV only in the NICHD trial. A Cochrane meta-analysis concluded that
      the risk of preterm birth was significantly reduced by treatment of abnormal vaginal flora
      (Nugent score >4) (2 trials, 894 women; OR 0.51, 95% CI 0.32-0.81). Thus, in low-resource
      settings such as in rural Bangladesh, where both BV and preterm birth are prevalent,
      treatment of abnormal vaginal flora in early pregnancy may hold promise in reducing the
      incidence of preterm birth, and an evaluation in well-conducted community-based randomized
      trials is needed.
    

Intervention name(s): Screening treatment and referral
Intervention type(s): Other
Intervention description(s): Women who are symptomatic at any study visit will be immediately referred to the sub-district hospital for full evaluation and treatment and will be visited on the following day to follow clinical status and ensure referral compliance. Referral will be reinforced by arranging transportation to the sub-district hospital and payment of hospital fees if the family is unable to afford out-of-pocket expenses. CHWs will conduct a home visit to women with positive test results within 24 hours of receiving the results to initiate treatment. All asymptomatic women will be treated for positive test results. For symptomatic women, the CHW will confirm the woman's clinical and treatment status, and provide treatment to those women who have not already received the appropriate treatment at the sub-district hospital for their infection.
Antibiotic Treatment Regimens AVF: Oral clindamycin 300 mg per oral (po) twice daily (bid) for 5 days.UTI: Macrobid/Nitrofurantoin 100 mg po bid x 7 days.
Other intervention name(s): Screening and Treatment of Abnormal Vaginal Flora; Screening and Treatment of Urinary Tract Infections
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Adverse Perinatal Outcomes; Treatment of abnormal vaginal flora