Strengths and Limitations
A strength of this study was the prospective design that allowed us to compare STI screening and treatment results with birth outcomes. The majority of previous observational studies that compared C. trachomatis or N. gonorrhoeae infections during pregnancy with birth outcomes were unable to determine receipt of treatment.(7, 20) Further, this study enrolled a unique cohort of pregnant women that would have been missed by the syndromic approach for management of STIs. While the World Health Organization recommends countries enhance syndromic management by gradually scaling-up laboratory screening;(21) the guidelines for management of asymptomatic C. trachomatis orN. gonorrhoeae infections are currently being developed and more research is needed. Finally, because low and middle income countries rely on syndromic management during pregnancy(9), there is a lack of data on the prevalence and impact of asymptomatic, curable STIs.
Our study is subject to several limitations. First, neither participants nor clinics were randomized and thus unmeasured confounding between intervention assignment and birth outcomes is likely. We attempted to address threats to internal validity through the cross-over design, controlling for imbalanced participant characteristics, and estimating a fixed effects model that purges clinic-level unobserved variables. Second, birth outcome data were missing not at random. If those missing data in the standard-of-care arm were more likely to have an adverse outcome, then our study results were attenuated. However, we made every effort to contact participants with missing data and determined that almost half were missing because they had moved away from Gaborone. Third, estimates of gestational age and birth weight were subject to mismeasurement. Birth weight measurement procedures and scale accuracy were not validated by the study. Although gestational age was not measured by the study, a sub-sample of women with a study ultrasound received estimates similar to the clinic recorded results, and 70% of participants had access to routine ultrasound prior to their third trimester visit. Finally, the sample size for this study was determined to find a difference in post-delivery prevalence and vertical transmission of C. trachomatis and N. gonorrhoeae and thus was underpowered to find a difference in preterm birth or low birth weight frequency.
Interpretation 
Our finding that STI screening and treatment could reduce adverse birth outcomes compared to syndromic management adds some support to previous systematic reviews and meta-analyses. Adachi et al., found eight studies that evaluated the effect of screening on adverse pregnancy outcomes. (8) Five studies found that treatment with erythromycin reduced adverse birth outcomes.(24-28) Two systematic reviews and meta-analyses assessed the relationship between antenatal infection and adverse birth outcomes. One review found 107 relevant observational studies reporting on 12 pregnancy and fertility-related outcomes, (20) and the meta-analysis results concluded that C. trachomatis was associated with preterm labor (unadjusted OR =1·29; 95% CI 1·11–1·50) and low birth weight (unadjusted OR = 1·80; 95% CI 1·20–2·71). However, that review found substantial heterogeneity across studies and only two studies reported whether women had received treatment. Another systematic review and meta-analysis assessing N. gonorrhoeae found that women with N. gonorrhoeae were more likely to experience preterm birth (OR 1·55, 95% CI 1·21 to 1·99, n=18 studies) and low birth weight (OR 1·66, 95% CI 1·12 to 2·48, n=8). (7) Included studies were all observational, most did not control for confounding, and most women with N. gonorrhoeae had received treatment.
A recent study investigated the relationship between C. trachomatis, N. gonorrhoeae , and Trichomonas (T.) vaginalis screening and treatment among pregnant women living with HIV in South Africa(29) and found no association between screening and preterm birth or low birth weight. However, this study was limited to women living with HIV, did not exclude symptomatic participants, found the testing group was less likely to be on anti-retroviral therapy, and treated participants for T. vaginalis . Further, participants in that study had high levels of persistent infections as 27% were positive forC. trachomatis at repeat testing.(30) No participants in the current study were positive at test-of-cure.(31)
Given the equipoise around the impact of STI screening on adverse pregnancy outcomes, future research may consider individual randomization or other methods for addressing confounding, measurement bias, and lack of power. As discussed by Low in a recent commentary,(32) observational studies face major threats to internal validity as many factors are associated with both STIs and pregnancy outcomes. Case-control and cohort studies are subject to measurement bias when receipt of treatment is not recorded because treatment likely reduces the risk of the outcome.(32) Cluster trials, such as the current study and the upcoming WANTAIM Trial(33) seek to reduce confounding and measurement bias; however, confounding can still occur through unmeasured baseline imbalance and clustering has a negative impact on the power to detect an effect and thus cluster designs typically require larger sample sizes.(34)