Sexually transmitted infections in pregnancy and adverse pregnancy outcomes: A retrospective cohort study

There is a high prevalence and incidence rate of asymptomatic sexually transmitted infections (STIs) during pregnancy in adolescent girls and young women in Africa. The association between STIs and pregnancy outcomes in a hyperepidemic HIV setting has not been well described.


| INTRODUC TI ON
Over 6 million births to 15-19-year-old adolescents occurred in sub-Saharan Africa (SSA) in 1 year alone (2021). 1 In South Africa, births among very young adolescents (10-14 year olds) have increased by 48% while in 15-19 year olds the pregnancy rate has increased by 18%. 2 Lack of education, poor knowledge of reproductive rights, substance abuse, and sexual violence are all contributory factors to the increased rates of teenage pregnancies. 3Babies born to mothers under 20 years of age are reportedly at a higher risk of low birth weight, prematurity, and severe neonatal morbidity and mortality. 4cioeconomic disadvantages, behavioral factors (including smoking, alcohol, and substance abuse), suboptimal antenatal care, infections, and biological immaturity predispose adolescents to adverse pregnancy outcomes in SSA. 4 We recently reported a high prevalence (26.7%) and incidence (23.9/100 person years) of asymptomatic etiologically confirmed sexually transmitted infections (STIs) among pregnant adolescents which was similar to adult pregnant women ≥20 years of age. 5 We concluded that adolescents and young women are at high risk of asymptomatic incident STIs in the third trimester of pregnancy and may be missed if aetiological screening for STIs is not repeated.
While several studies have described some association between prevalent STIs and adverse pregnancy outcomes [6][7][8][9][10] ; studies exploring an association between incident STIs in pregnancy and adverse pregnancy outcomes are sparse.
In this retrospective cohort study, we first compared the prevalence and incidence of STIs and adverse pregnancy outcomes between adolescents and adult pregnant women and further explored an association between STIs and adverse pregnancy outcomes in the total study population.

| MATERIAL S AND ME THODS
Details of the CAPRISA 088 cohort study of HIV-negative young mothers conducted at three, public sector primary healthcare clinics in Umlazi, a periurban township in Durban, KwaZulu-Natal have been previously described. 5Briefly, consenting, HIV-negative pregnant women <28 weeks of gestation and planning to deliver their Participants were requested to return for their subsequent antenatal study visit prior to delivery and a postpartum study visit within 6 weeks of delivery.All participants who missed their second antenatal visit and/or if they had not returned within 6 weeks of their expected date of delivery were contacted by study staff.
On receiving confirmation of birth at the local regional hospital (PMMH), a research assistant retrieved Maternity Case Records (MCR) from the hospital registry for extraction of pregnancy outcome data.Pregnancy outcome data extracted from the MCR included pregnancy outcomes (miscarriage, stillbirth or live birth) and newborn outcomes (gestational age at birth and birth weight).A miscarriage was defined as fetal demise before 22 weeks' gestation, stillbirth as fetal demise from 22 weeks' gestation, preterm birth as a livebirth <37 weeks' gestation, and low birth weight as live-born birth weight <2500 g.In our analysis we included a composite pregnancy outcome that would include any of the above outcomes.
To compare sociodemographic characteristics, STI detection and pregnancy outcome (preterm birth, low birth weight, composite adverse pregnancy outcome, mode of delivery, and pregnancy complications) between pregnant adolescents (15-19 years) and adult pregnant women (>20 years) we used binary logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) and a P value of less than 0.05 was considered statistically significant.
The association between preterm delivery, low birth weight and composite adverse pregnancy outcome and STIs at baseline and at a repeat antenatal visit was assessed using a Pearson χ 2 test.
Multivariable adjusted logistic regression models were developed to assess the association of adverse pregnancy outcomes and STIs in adverse pregnancy outcomes, pregnancy, repeat screening, sexually transmitted infections the presence of maternal age and treatment received for symptomatic STIs.

| RE SULTS
A total of 752 pregnant women comprising 180 (23.9%) adolescents (15-19 years) and 572 (76.1%) young women (>20 years) were enrolled in the CAPRISA 088 HIV incidence study.For this secondary analysis, we included 90 adolescents and 313 adults who had STI test results at baseline and at a later antenatal visit and had records of pregnancy outcomes.
Adolescents and adult women were comparable for marital status, socioeconomic status, gravidity and gestational age at first booking for antenatal care (Table 1).Adolescents did not differ significantly from adult pregnant women in STI detection at baseline and repeat antenatal visits (Table 1).

| Preterm births (<37 weeks) and genital tract infections
After adjusting for age and empirical treatment, none of the STIs (N.gonorrhoeae, T. vaginalis, C. trachomatis, M. genitalium or HSV-2) detected at baseline were associated with preterm births (Table 2).
A positive HSV-2 test at the repeat visit was also more likely associated with preterm birth but these findings were not statistically significant (OR 3.39; 95% CI: 0.86-13.30).

| Any adverse pregnancy outcome and genital tract infections
Overall, having any adverse pregnancy outcome was not associated with testing positive for the STIs (N.gonorrhoeae, T. vaginalis, C. trachomatis, M. genitalium or HSV-2) at baseline (Table 4).Testing positive for T. vaginalis at the repeat visit was significantly associated with having any adverse pregnancy outcome (OR 2.11; 95% CI: 1.09-4.08).Testing positive for HSV-2 at the repeat visit was likely associated with any adverse pregnancy outcome (OR 3.16; 95% CI: 0.90-11.13);however, this was not statistically significant.

| DISCUSS ION
In this retrospective cohort study, the proportion of adolescents with largely asymptomatic and untreated STIs during pregnancy was comparable to their adult counterparts.Pregnancy outcomes were also not significantly different between adolescents and adult women.Among all women tested for STIs at the first visit, testing positive for M. genitalium was significantly associated with low birth weight babies.On retesting at a subsequent antenatal visit, T. vaginalis was significantly associated with preterm birth, low birth weight and a composite adverse pregnancy outcome.
In our study population of adolescents and adult pregnant women, preterm births <37 weeks were the most frequent adverse pregnancy outcome and while none of the STIs at baseline were associated with preterm births, pregnant women with detected T. vaginalis at repeat screening at a later visit were at two-fold higher risk of a preterm birth.Consistent with our findings, a meta-analysis concluded that there was a 41% increased risk in preterm births associated with T. vaginalis. 12Although other studies reported a strong association between C. trachomatis and N. gonorrhoeae and preterm births, 9,10 we did not find an association between these treatable STIs including T. vaginalis at the baseline visit and an adverse pregnancy outcome, despite the high prevalence of these pathogens at the baseline visit.This can be explained by the difference in the proportion of symptomatic infections that would have been treated at baseline (1 in 3) versus the subsequent visit in later pregnancy (1 in 10).Symptomatic women in our study would have received prompt treatment consisting of a single dose of azithromycin (1 g oral dose), ceftriaxone (250 mg intramuscular injection), and metronidazole (2 g oral dose).Women with STIs at the later antenatal visit were largely asymptomatic and were therefore not treated.
Preterm births were also likely to be associated with HSV-2 detected at the repeat visit in later pregnancy but this association was not statistically significant due to the low prevalence of HSV-2 infections (10 of 403 pregnancies; 2.5%).Ascending cervical HSV-2 infections have been associated with premature ripening of the cervix and subsequent preterm birth. 13In a previous study, we concluded that genital HSV-2 shedding did not appear to alter pregnancy outcomes; however, it must be noted that testing was only conducted once in pregnancy at an average gestation of 24 weeks. 14n our study, testing positive for M. genitalium at baseline was significantly associated with low-birth-weight babies.M. genitalium has been rarely investigated in association with adverse pregnancy outcomes in low-and middle-income countries.In a study of 281 American pregnant women, 18% were diagnosed with M. genitalium which was independently associated with low birthweight babies. 15Although the prevalence of M. genitalium in our population was much lower (4%), our findings are consistent TA B L E 1 Sociodemographic characteristics, sexually transmitted infections and pregnancy outcomes by maternal age.

TA B L E 2
Sexually transmitted infections at baseline and at subsequent antenatal visits that may influence preterm births.

TA B L E 3
Sexually transmitted infections at baseline and subsequent antenatal visits that may influence low birth weight.with the American study.Furthermore, in our study it appears that low birth weight was not associated with M. genitalium (5%) detected at the later pregnancy visit.The lack of persistent association cannot be explained.Having any STI in pregnancy in a Brazilian cohort of pregnant women demonstrated the strongest association with low-birth-weight babies, a finding consistent with our study. 16T. vaginalis in later pregnancy in our study was also associated with low birth weight babies in addition to preterm births, consistent with the findings of Cotch et al. for the Vaginal Infections and Prematurity Study Group, although we did not distinguish between preterm low birth weight from term low birth weight. 17erall, testing positive for any curable STI at baseline was not associated with an adverse pregnancy outcome; however, testing positive for T. vaginalis on repeat testing at a later antenatal visit was significantly associated with an adverse pregnancy outcome.In addition, a positive HSV-2 result at a later antenatal visit was also likely but not significantly associated with an adverse pregnancy outcome.
Most studies reporting the effect of STIs on adverse pregnancy outcomes have only included baseline testing of STIs in investigating any relationship with adverse pregnancy outcomes and may have missed incident or recurrent and predominantly asymptomatic STIs in the later stage of pregnancy. 5,18 conclusion, we provide further evidence that underscores the need for etiological screening for STIs throughout pregnancy and further studies are warranted to explore the effect of targeted treatment in association with repeat etiological screening to improve pregnancy outcomes. 19 babies at the Prince Mshyeni Memorial Hospital were enrolled in the CAPRISA 088 HIV incidence study at their first antenatal visit between February 2017 and March 2018.Written informed consent for participation in the CAP 088 study and for storage of biological specimens for future research was obtained from all women prior to enrolment.The CAP 088 study was approved by the University of KwaZulu-Natal Biomedical Research Ethics Committee (BE 194/18).At enrolment (first antenatal visit) research nurses collected three vaginal swabs from the posterior fornixes and lateral vaginal walls for STI testing.The swabs were eluted in 1 mL phosphate buffered saline and stored at -70°C until use.These specimen collection procedures were repeated after 34 weeks' gestation.At the end of the CAP 088 study, a stored vaginal swab was tested for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Trichomonas vaginalis using the Roche Light Cycler 480 and Roche STI kits (Roche Diagnostics, USA).A second vaginal swab was tested for herpes simplex virus-2 (HSV-2) using the Roche Light Cycler 480 and HSV-1/2 detection kit (Roche Diagnostics).During study follow-up visits, pregnant women symptomatic for STIs were treated with a single dose of azithromycin (1 g oral dose), ceftriaxone (250 mg intramuscular injection), and metronidazole (2 g oral dose) as per the National Department of Health Guidelines for STI management. 11Demographic and obstetric data collected at enrollment included maternal age, gestational age at enrolment by menstrual dating, gravidity and estimated date of delivery based on gestational age by menstrual dating.

Subsequent antenatal visit No adverse outcome Composite adverse outcome Adjusted for age and treatment No adverse outcome Composite adverse outcome Adjusted for age and treatment
Sexually transmitted infections at baseline and subsequent antenatal visits that may influence composite adverse birth outcomes.
TA B L E 4