Antiretroviral therapy use during pregnancy and adverse birth outcomes in South African women

International Journal of Epidemiology, Volume 46, No. 5, Year 2017

Interpretation

Background: Studies of antiretroviral therapy (ART) use during pregnancy in HIVinfected women have suggested that ART exposure may be associated with adverse birth outcomes. However, there are few data from sub-Saharan Africa where HIV is most common, and few studies involving the World Health Organization’s (WHO’s) recommended first-line regimens. Methods: We enrolled consecutive HIV-infected pregnant women and a comparator cohort of uninfected women at a primary-level antenatal care facility in Cape Town, South Africa. Gestational assessment combined clinical history, examination and ultrasonography; outcomes included preterm (PTD), low birthweight (LBW) and small for gestational age (SGA) deliveries. In analysis we compared birth outcomes between HIVinfected and -uninfected women, and HIV-infected women who initiated ART before vs during pregnancy. Results: In 1554 women (mean age 29 years) with live singleton births at time of analysis, 82% were HIV-infected, 92% of whom received a first-line regimen of tenofovir, emtricitabine and efavirenz. Overall, higher levels of PTD [22% vs 13%; odds ratio (OR) 1.94, 95% confidence interval (CI): 1.34, 2.82] and LBW (14% vs 9%; OR 1.62, 95% CI: 1.05, 2.29) were observed in HIV-infected vs uninfected women, although SGA deliveries were similar (9% vs 11%; OR 1.06, 95% CI: 0.71, 1.61). Adjusting for demographic characteristics and HIV disease measures, HIV-infected (vs HIV-uninfected) women had persistently increased odds of PTD [adjusted odds ratio (AOR) 2.03; CI 1.33, 3.10]; associations with LBW were attenuated (AOR 1.47; CI 0.90, 2.40). Among all HIV-infected women, there appeared to be no association between the timing of ART initiation (before or during pregnancy) and adverse birth outcomes. Conclusions: These findings suggest that current WHO-recommended ART regimens appear relatively safe in pregnancy, although more data are required to understand the aetiology of preterm delivery in HIV-infected women using ART. This prospective cohort study was conducted among consecutive HIV-infected and HIV-uninfected women seeking antenatal care (ANC) at a large, community-based public sector primary care facility in Cape Town, South Africa, enrolled between April 2013 and August 2015. The facility serves a catchment population of approximately 350 000 where ANC uptake is high (95%); in 2014, the antenatal HIV seroprevalence was estimated at 30%.26 All women in this setting have gestational age estimated based on last menstrual period (LMP) and symphysis-fundal height (SFH) at the first ANC visit, as part of routine clinical care at their first ANC visit. All women without a previous HIV diagnosis underwent HIV testing, with ART eligibility based on CD4 cell count <350 cells/µl or WHO stage III/IV disease (from April to June 2013) or universal ART eligibility, regardless of CD4 cell count or disease stage (July 2013 onwards). HIV-infected women conceiving while on ART continued their current regimen throughout pregnancy; regimens included PIs (used in this setting predominantly after failure of first-line therapy) or NNRTIs such as EFV or nevirapine (NVP, used in previous first-line regimens). For women initiating ART in pregnancy, a fixed-dose combination of TDF + FTC + EFV was used throughout. Following ART initiation, clinical follow-up was through an integrated primary care service providing antenatal and HIV care. This analysis draws on data from a larger multicomponent study of antiretroviral services for HIV-infected women during pregnancy and postpartum [https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01933477","term_id":"NCT01933477"}}NCT01933477].27 HIV-uninfected women were enrolled consecutively into a separate comparator cohort with identical study procedures. The parent study was reviewed and approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee and Columbia University Medical Center Institutional Review Board. Written informed consent was obtained from all participants at their first ANC visit, and this consent included access to their clinical records for this birth outcomes analysis. Consecutive women (aged ≥ 18 years) attending their first antenatal care visit, who were identified as HIV-infected through routine rapid antibody tests, were eligible for enrolment into the HIV-infected cohort. Women not eligible for ART at their first ANC visit (receiving zidovudine prophylaxis) were excluded from this analysis. For the comparator HIV-uninfected cohort, women were eligible for enrolment based on the same criteria and a negative test on the same routine rapid antibody test. All women (HIV-infected and HIV-uninfected) completed questionnaires including demographics and obstetric and medical history. HIV-infected women provided 5 ml of blood for viral load (VL) testing using Abbot Realtime HIV-1 assay (Abbot Laboratories, Waltham, MA). At their first visit, an obstetric ultrasound (US) was performed on all women by an experienced research sonographer using a standardized assessment protocol and blinded to other clinical details. Follow-up study interviews, separate from routine clinical care, were scheduled around the second ANC visit, late third trimester and within 7 days postpartum. Obstetric outcomes, including date and mode of delivery and birthweight, were abstracted from obstetric records at delivery facilities. In analysis, gestation was based on completed weeks using the best available measure (US or combination of LMP/SFH at later gestations). HIV/ART status (the exposure of interest) was categorized as: (i) HIV-uninfected; (ii) ART initiated before pregnancy; and (iii) ART initiated during pregnancy in the (a) first trimester (<14 weeks), (b) first half of the second trimester (14–20 weeks), (c) second half of the second trimester (21–27 weeks) or (d) third trimester (≥28 weeks). Regimens were categorized as either PI or NNRTI; NNRTI regimens were either EFV-based [TDF + 3TC (lamivudine) + EFV], NVP-based (TDF + 3TC + NVP) or involving other NNRTIs. All deliveries before September 2015 were included in analysis. PTD was defined as delivery at <37 weeks’ gestation, categorized as late preterm (34–37 weeks), moderately preterm (32–34 weeks) or very preterm (<32weeks). LBW was defined as birthweight < 2500 g and very low birthweight (VLBW) as <1500 g. Using the INTERGROWTH-21st Project Standards, infants with birthweights <10th percentile for gestational age were classified SGA; those between 10th and 90th percentiles were classified appropriate for gestational age (AGA); and those >90th percentile were classified large for gestational age (LGA).28,29 Composite pregnancy loss was defined as any loss before delivery, and included: ectopic pregnancies as determined by the research sonographer; miscarriages defined as pregnancy loss <28 weeks;30 and stillbirths defined as fetal death occurring before/during labour and delivery (based on a 1-min APGAR score of 0). Statistical analyses (STATA 14.0, Stata Corporation, College Station, TX, USA) focused on three exposure comparisons: HIV-infected vs HIV-uninfected women (Comparison A); among HIV-infected women, those initiating ART before pregnancy vs those initiating during pregnancy (Comparison B); and among women initiating ART during pregnancy, comparisons across gestational ages at ART initiation (Comparison C). Pregnancy outcome analyses were restricted to live singleton births. In bivariable analyses, proportions were compared using chi-square and rank sum tests. Birth outcomes (PTD, LBW and SGA) were compared using unadjusted and adjusted logistic regression; results are presented as odds ratios (OR) with 95% confidence intervals (CI). Confounders identified a priori included age, maternal height, parity and previous PTD; and among HIV-infected women, pre-ART CD4 count and pre-ART viral load (VL). Subgroup analyses involved restrictions by EFV or PI use, and by gestation at first ANC visit. Model fit was assessed using likelihood ratio tests and Akaike’s Information Criterion; throughout, statistical tests were two-sided (alpha = 0.05).

AI Digest

Study Justification:

This study aimed to investigate the association between antiretroviral therapy (ART) use during pregnancy and adverse birth outcomes in HIV-infected women in South Africa. The justification for this study is that while previous studies have suggested a potential link between ART exposure and adverse birth outcomes, there is a lack of data from sub-Saharan Africa, where HIV is most prevalent, and few studies have focused on the World Health Organization’s recommended first-line regimens.

Highlights:

– The study enrolled consecutive HIV-infected pregnant women and a comparator cohort of uninfected women at a primary-level antenatal care facility in Cape Town, South Africa.
– The majority of HIV-infected women received a first-line ART regimen of tenofovir, emtricitabine, and efavirenz.
– The study found that HIV-infected women had higher rates of preterm delivery and low birthweight compared to uninfected women.
– Adjusting for demographic characteristics and HIV disease measures, HIV-infected women had persistently increased odds of preterm delivery.
– There appeared to be no association between the timing of ART initiation (before or during pregnancy) and adverse birth outcomes.
– These findings suggest that current WHO-recommended ART regimens appear relatively safe in pregnancy, but more data are needed to understand the causes of preterm delivery in HIV-infected women using ART.

Recommendations:

Based on the study findings, the following recommendations can be made:

1. Continued use of the current WHO-recommended first-line ART regimens during pregnancy.
2. Further research to investigate the factors contributing to preterm delivery in HIV-infected women using ART.
3. Strengthening antenatal care services to ensure early detection and management of HIV infection in pregnant women.
4. Implementation of interventions to reduce the risk of preterm delivery and low birthweight in HIV-infected women, such as nutritional support and monitoring.

Key Role Players:

To address the recommendations, the following key role players are needed:

1. Healthcare providers: Obstetricians, gynecologists, and midwives who provide antenatal care services and manage HIV-infected pregnant women.
2. Researchers: Epidemiologists, statisticians, and other researchers who can conduct further studies to investigate the factors contributing to preterm delivery in HIV-infected women using ART.
3. Policy makers: Government officials and policymakers who can implement interventions and allocate resources to improve antenatal care services and support HIV-infected pregnant women.

Cost Items:

While the actual cost of implementing the recommendations cannot be estimated without detailed planning, the following cost items should be considered in the budget:

1. Training and capacity building for healthcare providers on the management of HIV-infected pregnant women and the use of ART during pregnancy.
2. HIV testing and monitoring supplies, including rapid antibody tests and viral load testing kits.
3. Antiretroviral medications, including the first-line regimens recommended by the WHO.
4. Nutritional support programs for HIV-infected pregnant women to reduce the risk of adverse birth outcomes.
5. Research funding for further studies to investigate the causes of preterm delivery in HIV-infected women using ART.
6. Infrastructure and equipment upgrades to improve antenatal care facilities and ensure the availability of necessary resources.
Please note that the cost items provided are general considerations and may vary depending on the specific context and resources available.

Strength of Evidence

The strength of evidence for this abstract is 8 out of 10.
The evidence in the abstract is strong, but there are some areas for improvement. The study design is a prospective cohort study, which is generally considered to provide reliable evidence. The sample size is large, with 1554 women included in the analysis. The study compares birth outcomes between HIV-infected and uninfected women, as well as between HIV-infected women who initiated ART before vs during pregnancy. The findings suggest that HIV-infected women have higher odds of preterm delivery and low birthweight compared to uninfected women. However, the association between the timing of ART initiation and adverse birth outcomes is not significant. The study adjusts for demographic characteristics and HIV disease measures, which strengthens the analysis. To improve the evidence, it would be beneficial to include a control group of HIV-infected women who did not receive ART during pregnancy. Additionally, collecting data on other potential confounding factors, such as socioeconomic status and maternal nutrition, could provide a more comprehensive analysis.

Abstract

This prospective cohort study was conducted among consecutive HIV-infected and HIV-uninfected women seeking antenatal care (ANC) at a large, community-based public sector primary care facility in Cape Town, South Africa, enrolled between April 2013 and August 2015. The facility serves a catchment population of approximately 350 000 where ANC uptake is high (95%); in 2014, the antenatal HIV seroprevalence was estimated at 30%.26 All women in this setting have gestational age estimated based on last menstrual period (LMP) and symphysis-fundal height (SFH) at the first ANC visit, as part of routine clinical care at their first ANC visit. All women without a previous HIV diagnosis underwent HIV testing, with ART eligibility based on CD4 cell count <350 cells/µl or WHO stage III/IV disease (from April to June 2013) or universal ART eligibility, regardless of CD4 cell count or disease stage (July 2013 onwards). HIV-infected women conceiving while on ART continued their current regimen throughout pregnancy; regimens included PIs (used in this setting predominantly after failure of first-line therapy) or NNRTIs such as EFV or nevirapine (NVP, used in previous first-line regimens). For women initiating ART in pregnancy, a fixed-dose combination of TDF + FTC + EFV was used throughout. Following ART initiation, clinical follow-up was through an integrated primary care service providing antenatal and HIV care. This analysis draws on data from a larger multicomponent study of antiretroviral services for HIV-infected women during pregnancy and postpartum [https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01933477","term_id":"NCT01933477"}}NCT01933477].27 HIV-uninfected women were enrolled consecutively into a separate comparator cohort with identical study procedures. The parent study was reviewed and approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee and Columbia University Medical Center Institutional Review Board. Written informed consent was obtained from all participants at their first ANC visit, and this consent included access to their clinical records for this birth outcomes analysis. Consecutive women (aged ≥ 18 years) attending their first antenatal care visit, who were identified as HIV-infected through routine rapid antibody tests, were eligible for enrolment into the HIV-infected cohort. Women not eligible for ART at their first ANC visit (receiving zidovudine prophylaxis) were excluded from this analysis. For the comparator HIV-uninfected cohort, women were eligible for enrolment based on the same criteria and a negative test on the same routine rapid antibody test. All women (HIV-infected and HIV-uninfected) completed questionnaires including demographics and obstetric and medical history. HIV-infected women provided 5 ml of blood for viral load (VL) testing using Abbot Realtime HIV-1 assay (Abbot Laboratories, Waltham, MA). At their first visit, an obstetric ultrasound (US) was performed on all women by an experienced research sonographer using a standardized assessment protocol and blinded to other clinical details. Follow-up study interviews, separate from routine clinical care, were scheduled around the second ANC visit, late third trimester and within 7 days postpartum. Obstetric outcomes, including date and mode of delivery and birthweight, were abstracted from obstetric records at delivery facilities. In analysis, gestation was based on completed weeks using the best available measure (US or combination of LMP/SFH at later gestations). HIV/ART status (the exposure of interest) was categorized as: (i) HIV-uninfected; (ii) ART initiated before pregnancy; and (iii) ART initiated during pregnancy in the (a) first trimester (<14 weeks), (b) first half of the second trimester (14–20 weeks), (c) second half of the second trimester (21–27 weeks) or (d) third trimester (≥28 weeks). Regimens were categorized as either PI or NNRTI; NNRTI regimens were either EFV-based [TDF + 3TC (lamivudine) + EFV], NVP-based (TDF + 3TC + NVP) or involving other NNRTIs. All deliveries before September 2015 were included in analysis. PTD was defined as delivery at <37 weeks’ gestation, categorized as late preterm (34–37 weeks), moderately preterm (32–34 weeks) or very preterm (<32weeks). LBW was defined as birthweight < 2500 g and very low birthweight (VLBW) as <1500 g. Using the INTERGROWTH-21st Project Standards, infants with birthweights 90th percentile were classified large for gestational age (LGA).28,29 Composite pregnancy loss was defined as any loss before delivery, and included: ectopic pregnancies as determined by the research sonographer; miscarriages defined as pregnancy loss <28 weeks;30 and stillbirths defined as fetal death occurring before/during labour and delivery (based on a 1-min APGAR score of 0). Statistical analyses (STATA 14.0, Stata Corporation, College Station, TX, USA) focused on three exposure comparisons: HIV-infected vs HIV-uninfected women (Comparison A); among HIV-infected women, those initiating ART before pregnancy vs those initiating during pregnancy (Comparison B); and among women initiating ART during pregnancy, comparisons across gestational ages at ART initiation (Comparison C). Pregnancy outcome analyses were restricted to live singleton births. In bivariable analyses, proportions were compared using chi-square and rank sum tests. Birth outcomes (PTD, LBW and SGA) were compared using unadjusted and adjusted logistic regression; results are presented as odds ratios (OR) with 95% confidence intervals (CI). Confounders identified a priori included age, maternal height, parity and previous PTD; and among HIV-infected women, pre-ART CD4 count and pre-ART viral load (VL). Subgroup analyses involved restrictions by EFV or PI use, and by gestation at first ANC visit. Model fit was assessed using likelihood ratio tests and Akaike’s Information Criterion; throughout, statistical tests were two-sided (alpha = 0.05).

Materials

https://efashare.b-cdn.net/materials/5fdbaf84167fb6ddf17ea0c1e193f8db0a18f3b70cd6fa070257cad505a84d42/dyx136_ije-2016-12-1454-file007.pdf

Innovations

Based on the provided information, here are some potential innovations that could be used to improve access to maternal health:

1. Mobile Health (mHealth) Solutions: Develop mobile applications or text messaging services that provide pregnant women with information and reminders about antenatal care visits, medication adherence, and healthy behaviors during pregnancy.

2. Telemedicine: Implement telemedicine programs that allow pregnant women in remote or underserved areas to consult with healthcare providers through video conferencing or phone calls, reducing the need for travel and improving access to medical advice.

3. Community Health Workers: Train and deploy community health workers to provide education, support, and monitoring for pregnant women in their communities. These workers can help identify high-risk pregnancies, promote healthy behaviors, and facilitate access to healthcare services.

4. Integrated Antenatal Care: Establish integrated antenatal care services that combine HIV testing, antiretroviral therapy, and routine antenatal care in one location. This approach can streamline care and reduce the burden on pregnant women to visit multiple healthcare facilities.

5. Task Shifting: Train and empower nurses and midwives to provide comprehensive antenatal care, including HIV testing and antiretroviral therapy initiation. This can help alleviate the shortage of doctors and increase access to maternal health services.

6. Health Information Systems: Implement electronic health records and data management systems to improve the collection, analysis, and sharing of maternal health data. This can help identify trends, monitor outcomes, and inform evidence-based decision-making.

7. Public-Private Partnerships: Foster collaborations between public and private sectors to improve access to maternal health services. This can involve leveraging private sector resources, expertise, and infrastructure to expand healthcare delivery in underserved areas.

8. Transportation Support: Provide transportation assistance or incentives for pregnant women to attend antenatal care visits and deliver at healthcare facilities. This can help overcome geographical barriers and ensure timely access to maternal health services.

9. Maternal Health Education: Develop culturally appropriate educational materials and programs that empower pregnant women with knowledge about antenatal care, HIV prevention, and healthy pregnancy practices. This can help improve health literacy and promote informed decision-making.

10. Quality Improvement Initiatives: Implement quality improvement initiatives in healthcare facilities to enhance the delivery of maternal health services. This can involve training healthcare providers, improving infrastructure, and ensuring adherence to evidence-based guidelines.

It is important to note that the specific context and resources available in each setting will influence the feasibility and effectiveness of these innovations.

AI Innovations Description

The recommendation that can be developed into an innovation to improve access to maternal health based on the study is to ensure widespread availability and utilization of antiretroviral therapy (ART) during pregnancy for HIV-infected women. This recommendation is supported by the findings of the study, which suggest that current WHO-recommended ART regimens appear relatively safe in pregnancy.

To implement this recommendation, the following steps can be taken:

1. Strengthen healthcare systems: Ensure that healthcare facilities have the necessary infrastructure, equipment, and trained healthcare providers to offer ART services to pregnant women.

2. Increase awareness and education: Conduct targeted awareness campaigns to educate pregnant women about the importance of ART in preventing adverse birth outcomes and improving maternal and child health.

3. Improve access to ART: Ensure that ART medications are readily available and accessible to pregnant women, including in remote and underserved areas. This may involve establishing distribution centers, mobile clinics, or telemedicine services.

4. Provide comprehensive antenatal care: Integrate ART services into routine antenatal care visits to ensure that pregnant women receive regular monitoring, counseling, and support throughout their pregnancy.

5. Strengthen monitoring and evaluation: Establish systems to monitor the implementation and impact of ART services during pregnancy, including tracking birth outcomes and assessing the effectiveness of interventions.

6. Collaborate with stakeholders: Work closely with government agencies, non-governmental organizations, and community-based organizations to coordinate efforts and leverage resources for the implementation of ART services during pregnancy.

By implementing these recommendations, access to maternal health can be improved, leading to better outcomes for both HIV-infected and HIV-uninfected pregnant women.

AI Innovations Methodology

Based on the provided information, here are some potential recommendations for improving access to maternal health:

1. Strengthening ANC services: Enhance antenatal care services by ensuring that all pregnant women have access to comprehensive and high-quality care, including regular check-ups, screenings, and counseling.

2. Promoting early initiation of antiretroviral therapy (ART): Encourage HIV-infected pregnant women to start ART as early as possible, preferably before pregnancy or during the first trimester, to reduce the risk of adverse birth outcomes.

3. Improving HIV testing and counseling: Implement strategies to increase HIV testing rates among pregnant women and provide adequate counseling on the benefits of ART and its impact on maternal and fetal health.

4. Enhancing healthcare provider training: Provide training and education to healthcare providers on the latest guidelines for managing HIV-infected pregnant women, including the use of recommended ART regimens and monitoring of maternal and fetal health.

5. Strengthening referral systems: Establish effective referral systems between ANC facilities and specialized maternal health services, such as obstetric and neonatal care units, to ensure seamless and timely access to appropriate care when needed.

To simulate the impact of these recommendations on improving access to maternal health, a methodology could include the following steps:

1. Data collection: Gather data on the current state of maternal health access, including the number of pregnant women accessing ANC services, HIV testing rates, ART initiation rates, and birth outcomes.

2. Define indicators: Identify key indicators to measure the impact of the recommendations, such as the percentage of pregnant women receiving early ART initiation, the reduction in adverse birth outcomes (e.g., preterm delivery, low birthweight), and the increase in ANC coverage.

3. Develop a simulation model: Create a simulation model that incorporates the collected data and simulates the impact of the recommendations on the defined indicators. The model should consider factors such as population size, healthcare infrastructure, and resource availability.

4. Run simulations: Run multiple simulations using different scenarios, varying the implementation of the recommendations (e.g., different levels of ANC coverage, ART initiation rates) to assess their potential impact on improving access to maternal health.

5. Analyze results: Analyze the simulation results to determine the potential impact of the recommendations on the defined indicators. Compare the outcomes of different scenarios to identify the most effective strategies for improving access to maternal health.

6. Refine and validate the model: Refine the simulation model based on the analysis results and validate it using real-world data. This step ensures that the model accurately represents the impact of the recommendations and can be used for future predictions.

By following this methodology, policymakers and healthcare providers can gain insights into the potential benefits of implementing specific recommendations to improve access to maternal health and make informed decisions on resource allocation and program implementation.

Authors & Co-Authors

Statistics:

Citations: 56

Authors: 10

Identifiers:

DOI: 10.1093/ije/dyx136

ISSN: 03005771

Research Areas:

Community Interventions, Health System and Policy, Infectious Diseases, Maternal Access, Maternal and Child Health, Quality of Care, Sexual and Reproductive Health, Social Determinants, Technology and Innovations

Study Countries:

South Africa

Study Design:

Case-Control Study, Cohort Study, Cross Sectional Study

Study Approach:

Quantitative

Participants Gender:

Female