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)