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

OBJECTIVE: 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. METHODS: Pregnant women, HIV-1 negative and <28 weeks' gestation at three primary health clinics in KwaZulu-Natal, South Africa were enrolled from February 2017 to March 2018. Vaginal swabs collected at the first and later antenatal visits were stored and retrospectively tested for HSV-2, Trichomonas vaginalis, Chlamydia trachomatis and Neisseria gonorrhoeae at the end of the study. The association between STIs detected at first and later antenatal visits and pregnancy outcome was assessed using multivariable logistic regression models adjusted for maternal age and treatment received for symptomatic STIs. RESULTS: Testing positive Mycoplasma genitalium at the first antenatal visit was significantly associated with low birth weight (odds ratio [OR] 5.22; 95% confidence interval [CI]: 1.10-15.98). Testing positive for T. vaginalis at the repeat visit was significantly associated with preterm births (OR 2.37; 95% CI: 1.11-5.03), low birth weight (OR 2.56; 1.16-5.63) and a composite adverse pregnancy outcome (OR 2.11; 95% CI: 1.09-4.08). Testing positive for HSV-2 at the repeat visit was also likely associated with experiencing a preterm birth or any adverse pregnancy outcome (OR 3.39; 95% CI: 0.86-13.3) (P = 0.096). CONCLUSIONS: Among predominantly asymptomatic STIs, M. genitalium detected at baseline visit was significantly associated with low birth weight, while T. vaginalis detected at the repeat visit in later pregnancy was significantly associated with preterm birth. Further research is warranted to study the impact of etiological testing of STIs at more than one antenatal visit and empirical treatment on pregnancy outcomes.

Performance of Softcup® menstrual cup and vulvovaginal swab samples for detection and quantification of genital cytokines.

Cytokines are important mediators of immunity in the female genital tract, and their levels may be associated with various reproductive health outcomes. However, the measurement of cytokines and chemokines in vaginal fluid samples may be influenced by a variety of factors, each with the potential to affect the sensitivity and accuracy of the assay, including the interpretation and comparison of data. We measured and compared cytokine milieu in samples collected via Softcup® menstrual cup versus vulvovaginal swabs. One hundred and eighty vulvovaginal swabs from CAPRISA 088 and 42 Softcup supernatants from CAPRISA 016 cohorts of pregnant women were used to measure the concentrations of 28 cytokines through multiplexing. Cytokines measured in this study were detectable in each of the methods however, SoftCup supernatants showed consistently, higher detectability, expression ratios, and mean concentration of cytokines than vulvovaginal swabs. While mean concentrations differed, the majority of cytokines correlated between SoftCup supernatants and vulvovaginal swabs. Additionally, there were no significant differences in a number of participants between the two sampling methods for the classification of genital inflammation. Our findings suggest that SoftCup supernatants and vulvovaginal swab samples are suitable for the collection of genital specimens to study biological markers of genital inflammatory response. However, the Softcup menstrual cup performs better for the detection and quantification of soluble biomarkers that are found in low concentrations in cervicovaginal fluid.

Comparison of Antiretroviral Therapies in Pregnant Women Living With Human Immunodeficiency Virus and Hepatitis B Virus: A Randomized Controlled Trial.

OBJECTIVE: To describe the anti-hepatitis B virus (HBV) efficacy, HBeAg serologic changes, HBV perinatal transmission, and safety in pregnant women who are living with human immunodeficiency virus (HIV) and HBV co-infection who were randomized to various antiretroviral therapy (ART) regimens. METHODS: The PROMISE (Promoting Maternal and Infant Survival Everywhere) trial was a multicenter randomized trial for ART-naive pregnant women with HIV infection. Women with HIV and HBV co-infection at 14 or more weeks of gestation were randomized to one of three ART arms: one without HBV treatment (group 1) and two HBV treatment arms with single (group 2) or dual anti-HBV activity (group 3). The primary HBV outcome was HBV viral load antepartum change from baseline (enrollment) to 8 weeks; safety assessments included alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, and anemia (hemoglobin less than 10 g/dL). Primary comparison was for the HBV-active treatment arms. Pairwise comparisons applied t test and the Fisher exact tests. RESULTS: Of 3,543 women, 3.9% were HBsAg-positive; 42 were randomized to group 1, 48 to group 2, and 48 to group 3. Median gestational age at enrollment was 27 weeks. Among HBV-viremic women, mean antepartum HBV viral load change at week 8 was -0.26 log 10 international units/mL in group 1, -1.86 in group 2, and -1.89 in group 3. In those who were HBeAg-positive, HBeAg loss occurred in 44.4% at delivery. Two perinatal HBV transmissions occurred in group 2. During the antepartum period, one woman (2.4%) in group 1 had grade 3 or 4 ALT or AST elevations, two women (4.2%) in group 2, and three women (6.3%) in group 3. CONCLUSION: Over a short period of time, HBV DNA suppression was not different with one or two HBV-active agents. HbeAg loss occurred in a substantial proportion of participants. Perinatal transmission of HBV infection was low. Hepatitis B virus-active ART was well-tolerated in pregnancy, with few grade 3 or 4 ALT or AST elevations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT01061151.

High incidence of asymptomatic genital tract infections in pregnancy in adolescent girls and young women: need for repeat aetiological screening.

INTRODUCTION: Sexually transmitted infection (STI) prevalence and incidence estimates for pregnant adolescents are under-reported. We estimated prevalence and incidence of STIs in pregnant adolescents (15-19 years) in comparison with pregnant women 20-24 and >25 years. METHODS: Pregnant women registering at primary care clinics in Umlazi, a periurban subdistrict in KwaZulu-Natal, South Africa, were enrolled in an HIV incidence cohort study during February 2017-March 2018. Women were examined for abnormal vaginal discharge, received empirical treatment, tested for HIV-1 and had vaginal swabs taken at their first and a subsequent visit in the third trimester. Vaginal swabs were stored for STI testing at completion of study and tested for Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium using PCR. RESULTS: A total of 752 HIV-negative pregnant women were enrolled at a median gestational age of 17 weeks: 180 (23.9%), 291 (38.7%) and 281 (37.4%) in the 15-19, 20-24 and >25 years age groups. Pregnant adolescents had an STI prevalence of 26.7% at baseline, not significantly lower than the 20-24 (34.7%, OR 1.4; 95% CI 1.0 to 2.1, p=0.09) and >25 years (33.8%, OR 1.4; 95% CI 0.9 to 2.1, p=0.12) age groups. T. vaginalis (11.1%), C. trachomatis (7.8%) and N. gonorrhoeae (4.4%) were most prevalent in adolescents, a trend similar to the other age groups. Overall, 43.4% were symptomatic and treated at baseline. Overall, 40.7% (118 of 290) of women who tested negative for an STI at baseline tested positive at the repeat visit (incidence 19.5/100 person years). STI incidence in pregnant adolescents was 23.9/100 person years and comparable with older age groups (20.5/100 person years and 16.2/100 person years). At the repeat visit, 19.0% of all women with an STI were symptomatic and treated. Performance of syndromic management was poor at baseline (negative predictive value (NPV) 68.6%, positive predictive value (PPV) 34.0%) and at repeat visit (NPV 58.4%, PPV 34.3%). CONCLUSIONS: Prevalence of asymptomatic curable STIs in pregnant adolescents is high and comparable with women >20 years old. Adolescents remain at substantial risk of asymptomatic incident STIs during pregnancy.

Pregnancy and neonatal safety outcomes of timing of initiation of daily oral tenofovir disoproxil fumarate and emtricitabine pre-exposure prophylaxis for HIV prevention (CAP016): an open-label, randomised, non-inferiority trial.

BACKGROUND: The safety of tenofovir disoproxil fumarate and emtricitabine as pre-exposure prophylaxis (PrEP) in pregnant women not living with HIV is uncertain. We aimed to compare pregnancy and neonatal outcomes in women exposed and not exposed to PrEP during pregnancy. METHODS: In this single-site, open-label, randomised, non-inferiority trial in Durban, South Africa, we evaluated pregnancy and neonatal outcomes in pregnant women aged 18 years or older, not living with HIV, and at 14-28 weeks' gestation at the time of enrolment. Eligible participants were randomly assigned (1:1) using a computer-generated permuted block (block size of ten) randomisation list to immediate initiation or deferred initiation of PrEP until breastfeeding cessation. Participants in the immediate PrEP group received a monthly supply of once daily oral tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg. Participants in the deferred PrEP group received standard of care for HIV prevention. The primary outcomes were the occurrence of preterm live birth (<37 weeks gestational age) and very preterm birth (<34 weeks gestational age) determined by menstrual dating, low birthweight (<2500 g), very low birthweight (<1500 g), stillbirth (≥20 weeks gestational age), and small for gestational age (birthweight less than the tenth percentile). Post-natal safety outcomes will be reported elsewhere. We used binomial regression models to estimate risk differences and two-sided 90% CIs. Immediate PrEP was non-inferior to deferred PrEP if the upper bound of the 90% CI of the risk difference was less than the upper predefined non-inferiority margin for preterm birth (7·5%), very preterm birth (2·6%), low birthweight (5·5%), very low birthweight (1·2%), stillbirth (1·0%), and small for gestational age (3·7%). All outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT3227731. FINDINGS: Between Sept 25, 2017, and Dec 6, 2019, we screened 693 women, of whom 540 were randomly assigned to immediate PrEP (n=271) or deferred PrEP (n=269). The median gestational age was 19 weeks (IQR 15-23 for immediate PrEP and 16-23 for deferred PrEP). The risk difference between the immediate PrEP group and the deferred PrEP group for preterm birth was -4·7% (90% CI -10·7 to 1·2; immediate PrEP was non-inferior), for very preterm birth was 0·6% (-3·4 to 4·6; upper limit exceeded the non-inferiority margin), for low birthweight was 2·5% (-1·6 to 6·6; upper limit exceeded the non-inferiority margin), for very low birthweight was 0% (-1·4 to 1·4; upper limit exceeded the non-inferiority margin), for stillbirth was 1·2% (-1·5 to 3·8; upper limit exceeded the non-inferiority margin), and for small for gestational age was 0·9% (-1·2 to 2·9; immediate PrEP was non-inferior). INTERPRETATION: In our study, PrEP was not associated with preterm birth or small for gestational age infants. Our data support the use of tenofovir disoproxil fumarate and emtricitabine in pregnancy and our reassuring findings can be used to allay safety concerns among pregnant women. FUNDING: South African Medical Research Council and Gilead Sciences.

Neurodevelopmental outcomes of HIV/antiretroviral drug perinatally exposed uninfected children aged 3-6 years.

OBJECTIVE: Given the roll out of maternal antiretroviral therapy (ART) for prevention-of-perinatal-HIV-transmission, increasing numbers of children are perinatally HIV/antiretroviral exposed but uninfected (CAHEU). Some studies suggest CAHEU may be at increased risk for neurodevelopmental (ND) deficits. We aimed to assess ND performance among preschool CAHEU. DESIGN: This cross-sectional study assessed ND outcomes among 3-6-year-old CAHEU at entry into a multicountry cohort study. METHODS: We used the Mullen Scales of Early Learning (MSEL) and Kaufman Assessment Battery for Children (KABC-II) to assess ND status among 3-6-year-old CAHEU at entry into the PROMISE Ongoing Treatment Evaluation (PROMOTE) study conducted in Uganda, Malawi, Zimbabwe and South Africa. Statistical analyses (Stata 16.1) was used to generate group means for ND composite scores and subscale scores, compared to standardized test score means. We used multivariable analysis to adjust for known developmental risk factors including maternal clinical/socioeconomic variables, child sex, growth-for-age measurements, and country. RESULTS: 1647 children aged 3-6 years had baseline ND testing in PROMOTE; group-mean unadjusted Cognitive Composite scores on the MSEL were 85.8 (standard deviation [SD]: 18.2) and KABC-II were 79.5 (SD: 13.2). Composite score group-mean differences were noted by country, with South African and Zimbabwean children having higher scores. In KABC-II multivariable analyses, maternal age >40 years, lower education, male sex, and stunting were associated with lower composite scores. CONCLUSIONS: Among a large cohort of 3-6 year old CAHEU from eastern/southern Africa, group-mean composite ND scores averaged within the low-normal range; with differences noted by country, maternal clinical and socioeconomic factors.

Brief Report: Impact of Antiretroviral Regimen on Pregnancy and Infant Outcomes in Women With HIV/ HBV Coinfection.

BACKGROUND: There are limited data on the impact of antenatal antiretroviral regimens (ARV) on pregnancy and infant outcomes in HIV/HBV coinfection. We compared outcomes among 3 antenatal antiretroviral regimens for pregnant women with HIV/HBV. METHODS: The PROMISE study enrolled ARV-naive pregnant women with HIV. Women with HBV were randomized to (no anti-HBV)-zidovudine (ZDV) + intrapartum nevirapine and 1 week of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC); (3TC)-3TC + ZDV + LPV/r; or (FTC-TDF)-FTC + TDF + LPV/r. Pairwise group comparisons were performed with Fisher exact, t , or log rank tests. Adverse pregnancy outcome (APO) was a composite of low birth weight, preterm delivery, spontaneous abortion, stillbirth, or congenital anomaly. RESULTS: Of 138 women with HIV/HBV, 42, 48, and 48 were analyzed in the no anti-HBV, 3TC, and FTC-TDF arms. Median age was 27 years. APOs trended lower in the no anti-HBV (26%) vs 3TC (38%), and FTC-TDF arms (35%), P ≥ 0.25). More infant deaths occurred among the FTC-TDF [6 (13%)] vs no anti-HBV [2 (5%)] and 3TC [3 (7%)] arms. There were no differences in time-to-death, HIV-free survival, birth or one-year WHO Z-score length-for-age, and head circumference. Hepatitis B e antigen (HBeAg) was associated with an increased risk of APO, 48% vs 27% (odds ratio 2.79, 95% confidence interval: 1.19 to 6.67, post hoc ). CONCLUSION: With HBV/HIV coinfection, the risk of an APO was increased with maternal ARV compared with ZDV alone, although the differences were not statistically significant. Maternal HBeAg was associated with a significantly increased risk of APO. Infant mortality was highest with FTC + TDF + LPV/r. Early assessment of HBeAg could assist in identifying high-risk pregnancies for close monitoring.

Reliability of last menstrual period recall, an early ultrasound and a Smartphone App in predicting date of delivery and classification of preterm and post-term births.

BACKGROUND: A reliable expected date of delivery (EDD) is important for pregnant women in planning for a safe delivery and critical for management of obstetric emergencies. We compared the accuracy of LMP recall, an early ultrasound (EUS) and a Smartphone App in predicting the EDD in South African pregnant women. We further evaluated the rates of preterm and post-term births based on using the different measures. METHODS: This is a retrospective sub-study of pregnant women enrolled in a randomized controlled trial between October 2017-December 2019. EDD and gestational age (GA) at delivery were calculated from EUS, LMP and Smartphone App. Data were analysed using SPSS version 25. A Bland-Altman plot was constructed to determine the limits of agreement between LMP and EUS. RESULTS: Three hundred twenty-five pregnant women who delivered at term (≥ 37 weeks by EUS) and without pregnancy complications were included in this analysis. Women had an EUS at a mean GA of 16 weeks and 3 days). The mean difference between LMP dating and EUS is 0.8 days with the limits of agreement 31.4-30.3 days (Concordance Correlation Co-efficient 0.835; 95%CI 0.802, 0.867). The mean(SD) of the marginal time distribution of the two methods differ significantly (p = 0.00187). EDDs were < 14 days of the actual date of delivery (ADD) for 287 (88.3%;95%CI 84.4-91.4), 279 (85.9%;95%CI 81.6-89.2) and 215 (66.2%;95%CI 60.9-71.1) women for EUS, Smartphone App and LMP respectively but overall agreement between EUS and LMP was only 46.5% using a five category scale for EDD-ADD with a kappa of .22. EUS 14-24 weeks and EUS < 14 weeks predicted EDDs < 14 days of ADD in 88.1% and 79.3% of women respectively. The proportion of births classified as preterm (< 37 weeks) was 9.9% (95%CI 7.1-13.6) by LMP and 0.3% (95%CI 0.1-1.7) by Smartphone App. The proportion of post-term (> 42 weeks gestation) births was 11.4% (95%CI 8.4-15.3), 1.9% (95%CI 0.9-3.9) and 3.4% (95%CI 1.9-5.9) by LMP, EUS and Smartphone respectively. CONCLUSIONS: EUS and Smartphone App were the most accurate to estimate the EDD in pregnant women. LMP-based dating resulted in misclassification of a significantly greater number of preterm and post-term deliveries compared to EUS and the Smartphone App.