Birth outcomes in South African women receiving highly active antiretroviral therapy: A retrospective observational study

Journal of the International AIDS Society, Volume 14, No. 1, Year 2011

Interpretation

Background: Use of highly active antiretroviral therapy (HAART), a triple-drug combination, in HIV-infected pregnant women markedly reduces mother to child transmission of HIV and decreases maternal morbidity. However, there remains uncertainty about the effects of in utero exposure to HAART on foetal development. Methods. Our objectives were to investigate whether in utero exposure to HAART is associated with low birth weight and/or preterm birth in a population of South African women with advanced HIV disease. A retrospective observational study was performed on women with CD4 counts ≤250 cells/mm 3 attending antenatal antiretroviral clinics in Johannesburg between October 2004 and March 2007. Low birth weight (<2.5 kg) and preterm birth rates (<37 weeks) were compared between those exposed and unexposed to HAART during pregnancy. Effects of different HAART regimen and duration were assessed. Results: Among HAART-unexposed infants, 27% (60/224) were low birth weight compared with 23% (90/388) of early HAART-exposed (exposed ≥28 weeks gestation) and 19% (76/407) of late HAART-exposed (exposed 28 weeks) infants (p = 0.05). In the early HAART group, a higher CD4 cell count was protective against low birth weight (AOR 0.57 per 50 cells/mm3 increase, 95% CI 0.45-0.71, p < 0.001) and preterm birth (AOR 0.68 per 50 cells/mm3 increase, 95% CI 0.55-0.85, p = 0.001). HAART exposure was associated with an increased preterm birth rate (15%, or 138 of 946, versus 5%, or seven of 147, in unexposed infants, p = 0.001), with early nevirapine and efavirenz-based regimens having the strongest associations with preterm birth (AOR 5.4, 95% CI 2.1-13.7, p < 0.001, and AOR 5.6, 95% CI 2.1-15.2, p = 0.001, respectively). Conclusions: In this immunocompromised cohort, in utero HAART exposure was not associated with low birth weight. An association between NNRTI-based HAART and preterm birth was detected, but residual confounding is plausible. More advanced immunosuppression was a risk factor for low birth weight and preterm birth, highlighting the importance of earlier HAART initiation in women to optimize maternal health and improve infant outcomes. © 2011 van der Merwe et al; licensee BioMed Central Ltd. This study reports on a retrospective observational cohort of women attending integrated antenatal and antiretroviral (ANC-ARV) clinics at Rahima Moosa Mother and Child Hospital (RMH) and Charlotte Maxeke Johannesburg Academic Hospital (CMJH). Both clinics are referral centres for HIV-infected pregnant women in Johannesburg, but the latter provides care for patients with more complex medical conditions. Women attending ANC-ARV clinics at the hospitals and all mother-infant pairs at the postnatal clinic of RMH were eligible for the study if they: were HIV positive; had a singleton delivery between October 2004 and March 2007; attended an ANC-ARV clinic during pregnancy or the postnatal clinic less than two months postpartum; and had a CD4 count of ≤250 cells/mm3. CD4 cell counts were taken before HAART initiation for the HAART-exposed group, and during pregnancy or within three weeks postpartum for the HAART-unexposed group. Women attending the postnatal clinic between three weeks and two months after childbirth were included if they had a CD4 count result from during pregnancy. Most of the comparison group (HAART-unexposed women) had not received antenatal HAART because they were identified as HIV positive during labour or in the postnatal period (within three weeks of childbirth). Women gave consent for their data to be included in the clinic database and used for research purposes. The study protocol was approved by the Human Research Ethics Committee of the University of the Witwatersrand (protocol number M070438). HIV status was determined with parallel rapid HIV tests (First Response HIV Card test 1-2.0 [Kachigam, Daman, India] and Pareekshak HIV Triline card test [Bangalore, Karnataka, India]). CD4 cell count was measured using a Beckman Coulter Epics XL MCL cytometer (Fullerton, CA, United States) or Beckman Coulter TQ PREP (Fullerton, CA, United States). HIV infection status was diagnosed in infants of more than six weeks of age with a DNA polymerase chain reaction (PCR) (Amplicor HIV-1 DNA PCR version 1.5 assay; Roche Diagnostics, Inc., Alameda, CA, United States). At RMH, most pregnant women eligible for HAART initiated lopinavir/ritonavir, stavudine and lamivudine. First-line therapy at CMJH consisted of nevirapine, stavudine, and lamivudine. In both hospitals, efavirenz was initiated after the first trimester for women taking concomitant tuberculosis (TB) treatment. Women presenting in the first trimester of pregnancy who were receiving efavirenz-containing regimens were changed to lopinavir/ritonavir, while women beyond the first trimester continued efavirenz-based therapy. The HAART regimen was categorized by first regimen used in pregnancy. The primary aim of our study was to investigate the association between LBW, and HAART duration and regimen during pregnancy. LBW was defined as a birth weight below 2.5 kg and very low birth weight (VLBW) as less than 1.5 kg. For the study, early HAART was defined as initiation before 28 weeks of pregnancy and late HAART as initiation at ≥28 weeks of pregnancy. A secondary aim of the study was to examine associations between preterm birth and HAART exposure, with similar analyses of regimen type and duration. Preterm birth was defined as birth before 37 completed weeks of pregnancy and extremely preterm birth was defined at birth before 34 weeks of pregnancy. Gestational age was determined by a clinician at the first antenatal visit, using a combination of ultrasound (when available), last menstrual period and symphyseal-fundal height. In women who did not attend antenatal care, gestational age was estimated by examining the infant at birth; this estimate was recorded on the infant's clinic card. Small for gestational age was defined as a birth weight below the 10th percentile of expected weight for gestational age, birth weights above the 90th percentile as large for gestational age, and those between the 10th and 90th percentiles as appropriate for gestational age [15]. Single data entry was done in Microsoft Access and analysis performed with Intercooled Stata 8.0 (Stata Corporation, College Station, TX, United States). Characteristics of HAART-exposed and unexposed women were compared using chi-square tests for categorical exposure variables and Student's t-test for continuous variables. As we were interested in assessing the effects of drug regimen on LBW independent of the role of infant HIV infection, we initially restricted multivariate analysis of LBW to HIV-negative infants and thereafter included all infants in a similar analysis. A similar multivariate analysis was performed for variables associated with preterm birth in which we included all infants with a known gestation at birth, regardless of HIV status. Variables associated with LBW or preterm birth in univariate analysis (p < 0.1) were included in the initial multivariate model and retained if their removal markedly altered the model fit. Model fit was assessed using the likelihood ratio test and judgement about the size of changes to the model with and without the variable [16]. The model analyzed the odds of LBW or preterm birth according to regimen type: lopinavir/ritonavir-based, nevirapine-based and efavirenz-based HAART; CD4 cell categories (cells/mm3) of 0-49, 50-99, 100-149, 150-199 and 200-250; maternal age; anaemia (haemoglobin <11 g/dl); hypertension (systolic blood pressure [BP] >160 mmHg or diastolic BP >90 mmHg on two occasions four hours apart, or one diastolic BP >110 mmHg); and infant HIV status. Women in the early and late HAART groups were analyzed in separate multivariate models due to the presence of interaction: associations between the exposures (drug regimen) and outcome LBW and prematurity) varied according to the duration of HAART.

AI Digest

Study Justification:

This study aimed to investigate the effects of in utero exposure to highly active antiretroviral therapy (HAART) on birth outcomes in South African women with advanced HIV disease. The use of HAART in pregnant women with HIV has been shown to reduce mother-to-child transmission of HIV and improve maternal health. However, there is still uncertainty about the impact of HAART on fetal development. This study aimed to provide clarity on this issue.

Study Highlights:

– The study included a retrospective observational cohort of women attending antenatal and antiretroviral clinics in Johannesburg.
– The study compared birth outcomes (low birth weight and preterm birth) between infants exposed to HAART during pregnancy and those unexposed.
– Among the findings, it was observed that in utero HAART exposure was not associated with low birth weight.
– However, there was an increased risk of preterm birth associated with HAART exposure, particularly with nevirapine and efavirenz-based regimens.
– The study also highlighted the importance of earlier HAART initiation in women with advanced HIV disease to improve maternal health and infant outcomes.

Recommendations:

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

1. Encourage early initiation of HAART in pregnant women with advanced HIV disease to optimize maternal health and improve infant outcomes.
2. Further investigate the association between specific HAART regimens (such as nevirapine and efavirenz-based) and preterm birth to better understand the underlying mechanisms and potential interventions.
3. Conduct additional research to explore the long-term effects of in utero HAART exposure on child development and health.

Key Role Players:

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

1. Healthcare providers: Obstetricians, gynecologists, and HIV specialists who can ensure appropriate HAART initiation and monitoring during pregnancy.
2. Researchers: Epidemiologists and scientists who can conduct further studies to investigate the association between specific HAART regimens and preterm birth.
3. Policy makers: Government officials and policymakers who can implement guidelines and policies to promote early HAART initiation and improve maternal and infant health outcomes.

Cost Items for Planning Recommendations:

While the actual cost of implementing the recommendations will vary, the following budget items should be considered in the planning process:

1. Healthcare infrastructure: Funding for antenatal and antiretroviral clinics, including equipment, facilities, and staff.
2. Medications: Budget for providing HAART medications to pregnant women with HIV.
3. Research funding: Resources for conducting additional studies to explore the long-term effects of in utero HAART exposure.
4. Training and education: Investment in training healthcare providers on the latest guidelines and best practices for managing HIV in pregnancy.
Please note that the provided information is based on the study description and may not reflect the complete findings or recommendations of the actual study.

Strength of Evidence

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is moderately strong. The study is a retrospective observational study, which limits the ability to establish causation. However, the study includes a large sample size and analyzes various factors such as different HAART regimens and duration. To improve the strength of the evidence, a prospective study design could be considered, which would allow for better control of confounding variables and establish a stronger causal relationship.

Abstract

This study reports on a retrospective observational cohort of women attending integrated antenatal and antiretroviral (ANC-ARV) clinics at Rahima Moosa Mother and Child Hospital (RMH) and Charlotte Maxeke Johannesburg Academic Hospital (CMJH). Both clinics are referral centres for HIV-infected pregnant women in Johannesburg, but the latter provides care for patients with more complex medical conditions. Women attending ANC-ARV clinics at the hospitals and all mother-infant pairs at the postnatal clinic of RMH were eligible for the study if they: were HIV positive; had a singleton delivery between October 2004 and March 2007; attended an ANC-ARV clinic during pregnancy or the postnatal clinic less than two months postpartum; and had a CD4 count of ≤250 cells/mm3. CD4 cell counts were taken before HAART initiation for the HAART-exposed group, and during pregnancy or within three weeks postpartum for the HAART-unexposed group. Women attending the postnatal clinic between three weeks and two months after childbirth were included if they had a CD4 count result from during pregnancy. Most of the comparison group (HAART-unexposed women) had not received antenatal HAART because they were identified as HIV positive during labour or in the postnatal period (within three weeks of childbirth). Women gave consent for their data to be included in the clinic database and used for research purposes. The study protocol was approved by the Human Research Ethics Committee of the University of the Witwatersrand (protocol number M070438). HIV status was determined with parallel rapid HIV tests (First Response HIV Card test 1-2.0 [Kachigam, Daman, India] and Pareekshak HIV Triline card test [Bangalore, Karnataka, India]). CD4 cell count was measured using a Beckman Coulter Epics XL MCL cytometer (Fullerton, CA, United States) or Beckman Coulter TQ PREP (Fullerton, CA, United States). HIV infection status was diagnosed in infants of more than six weeks of age with a DNA polymerase chain reaction (PCR) (Amplicor HIV-1 DNA PCR version 1.5 assay; Roche Diagnostics, Inc., Alameda, CA, United States). At RMH, most pregnant women eligible for HAART initiated lopinavir/ritonavir, stavudine and lamivudine. First-line therapy at CMJH consisted of nevirapine, stavudine, and lamivudine. In both hospitals, efavirenz was initiated after the first trimester for women taking concomitant tuberculosis (TB) treatment. Women presenting in the first trimester of pregnancy who were receiving efavirenz-containing regimens were changed to lopinavir/ritonavir, while women beyond the first trimester continued efavirenz-based therapy. The HAART regimen was categorized by first regimen used in pregnancy. The primary aim of our study was to investigate the association between LBW, and HAART duration and regimen during pregnancy. LBW was defined as a birth weight below 2.5 kg and very low birth weight (VLBW) as less than 1.5 kg. For the study, early HAART was defined as initiation before 28 weeks of pregnancy and late HAART as initiation at ≥28 weeks of pregnancy. A secondary aim of the study was to examine associations between preterm birth and HAART exposure, with similar analyses of regimen type and duration. Preterm birth was defined as birth before 37 completed weeks of pregnancy and extremely preterm birth was defined at birth before 34 weeks of pregnancy. Gestational age was determined by a clinician at the first antenatal visit, using a combination of ultrasound (when available), last menstrual period and symphyseal-fundal height. In women who did not attend antenatal care, gestational age was estimated by examining the infant at birth; this estimate was recorded on the infant's clinic card. Small for gestational age was defined as a birth weight below the 10th percentile of expected weight for gestational age, birth weights above the 90th percentile as large for gestational age, and those between the 10th and 90th percentiles as appropriate for gestational age [15]. Single data entry was done in Microsoft Access and analysis performed with Intercooled Stata 8.0 (Stata Corporation, College Station, TX, United States). Characteristics of HAART-exposed and unexposed women were compared using chi-square tests for categorical exposure variables and Student's t-test for continuous variables. As we were interested in assessing the effects of drug regimen on LBW independent of the role of infant HIV infection, we initially restricted multivariate analysis of LBW to HIV-negative infants and thereafter included all infants in a similar analysis. A similar multivariate analysis was performed for variables associated with preterm birth in which we included all infants with a known gestation at birth, regardless of HIV status. Variables associated with LBW or preterm birth in univariate analysis (p < 0.1) were included in the initial multivariate model and retained if their removal markedly altered the model fit. Model fit was assessed using the likelihood ratio test and judgement about the size of changes to the model with and without the variable [16]. The model analyzed the odds of LBW or preterm birth according to regimen type: lopinavir/ritonavir-based, nevirapine-based and efavirenz-based HAART; CD4 cell categories (cells/mm3) of 0-49, 50-99, 100-149, 150-199 and 200-250; maternal age; anaemia (haemoglobin 160 mmHg or diastolic BP >90 mmHg on two occasions four hours apart, or one diastolic BP >110 mmHg); and infant HIV status. Women in the early and late HAART groups were analyzed in separate multivariate models due to the presence of interaction: associations between the exposures (drug regimen) and outcome LBW and prematurity) varied according to the duration of HAART.

Materials

N/A

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) applications: Develop mobile applications that provide information and resources on maternal health, including access to antenatal care, HIV testing, and highly active antiretroviral therapy (HAART). These apps can also send reminders for appointments and medication adherence.

2. Telemedicine: Implement telemedicine services to allow pregnant women in remote areas to consult with healthcare providers and receive prenatal care remotely. This can help overcome geographical barriers and improve access to specialized care.

3. Community health workers: Train and deploy community health workers who can provide education, counseling, and support to pregnant women, especially those living with HIV. These workers can help ensure that women receive appropriate care and adhere to their treatment regimens.

4. Integrated antenatal and antiretroviral clinics: Establish integrated clinics where pregnant women can receive both antenatal care and antiretroviral therapy in the same location. This can streamline the care process and improve coordination between healthcare providers.

5. Task-shifting: Train and empower nurses and midwives to provide comprehensive antenatal care, including HIV testing and HAART initiation. This can help alleviate the burden on doctors and increase access to care in resource-limited settings.

6. Health information systems: Implement robust health information systems that can track and monitor the provision of maternal health services, including HIV testing and HAART initiation. This data can help identify gaps in care and inform targeted interventions.

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, such as mobile networks or pharmaceutical companies, to expand access to care and medications.

8. Health financing mechanisms: Develop innovative financing mechanisms, such as health insurance schemes or conditional cash transfers, to ensure that pregnant women can afford the necessary maternal health services, including HIV testing and HAART.

It is important to note that the specific context and needs of the target population should be considered when implementing 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 earlier initiation of highly active antiretroviral therapy (HAART) in HIV-infected pregnant women. The study found that more advanced immunosuppression was a risk factor for low birth weight and preterm birth, highlighting the importance of earlier HAART initiation in women to optimize maternal health and improve infant outcomes.

To implement this recommendation, healthcare systems can focus on the following strategies:

1. Strengthening antenatal care services: Healthcare providers should prioritize early identification of HIV infection in pregnant women and ensure timely initiation of HAART. This can be achieved through routine HIV testing during antenatal visits and immediate access to HAART for those diagnosed with HIV.

2. Improving access to HAART: Efforts should be made to ensure that HAART medications are readily available and accessible to pregnant women. This may involve increasing the availability of HAART drugs in healthcare facilities, improving supply chain management, and reducing barriers to accessing medication, such as cost or transportation.

3. Enhancing healthcare provider training: Healthcare providers should receive training on the latest guidelines for HAART initiation in pregnant women and the management of HIV-infected pregnant women. This will ensure that they have the knowledge and skills to provide appropriate care and support to pregnant women throughout their pregnancy.

4. Promoting patient education and awareness: Pregnant women should be educated about the benefits of early HAART initiation and the importance of adhering to the prescribed treatment regimen. This can be done through counseling sessions, educational materials, and support groups.

5. Strengthening collaboration between HIV and maternal health services: Collaboration between HIV and maternal health services is crucial to ensure that pregnant women receive comprehensive care. This can be achieved through integrated antenatal and antiretroviral clinics, where pregnant women can receive both HIV testing and treatment, as well as prenatal care.

By implementing these recommendations, healthcare systems can improve access to maternal health and reduce the risk of adverse birth outcomes in HIV-infected pregnant women.

AI Innovations Methodology

To improve access to maternal health, here are some potential recommendations:

1. Strengthening healthcare infrastructure: Investing in healthcare facilities, equipment, and trained healthcare professionals in areas with limited access to maternal health services can help improve access for pregnant women.

2. Mobile health clinics: Implementing mobile health clinics that travel to remote areas or underserved communities can provide essential prenatal care, screenings, and education to pregnant women who may not have easy access to healthcare facilities.

3. Telemedicine: Utilizing telemedicine technologies can enable pregnant women to receive virtual consultations, monitoring, and support from healthcare professionals, reducing the need for physical travel and improving access to maternal health services.

4. Community health workers: Training and deploying community health workers who can provide basic prenatal care, education, and referrals in their communities can help bridge the gap in access to maternal health services, especially in rural or marginalized areas.

5. Health education and awareness campaigns: Conducting targeted health education and awareness campaigns to inform pregnant women about the importance of prenatal care, nutrition, and healthy behaviors can help increase their understanding and utilization of maternal health services.

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

1. Define the target population: Identify the specific population that would benefit from the recommended innovations, such as pregnant women in underserved areas or communities with limited access to maternal health services.

2. Collect baseline data: Gather data on the current state of access to maternal health services in the target population, including metrics such as the number of healthcare facilities, healthcare professionals, and utilization rates of prenatal care.

3. Define indicators: Determine key indicators that will be used to measure the impact of the recommendations, such as the number of pregnant women receiving prenatal care, the reduction in maternal mortality rates, or the increase in early detection of complications.

4. Simulate scenarios: Use modeling techniques to simulate different scenarios based on the implementation of the recommendations. This could involve estimating the potential increase in the number of healthcare facilities, the number of pregnant women reached through mobile health clinics, or the impact of telemedicine on reducing barriers to access.

5. Analyze results: Evaluate the simulated scenarios and compare them to the baseline data to assess the potential impact of the recommendations on improving access to maternal health. This analysis can help identify the most effective strategies and prioritize their implementation.

6. Refine and adjust: Based on the analysis of the simulated scenarios, refine the recommendations and adjust the implementation strategies as needed to maximize their impact on improving access to maternal health.

It’s important to note that the methodology for simulating the impact of recommendations may vary depending on the specific context and available data.

Author

Dima Health

Statistics:

Citations: 59

Identifiers:

DOI: 10.1186/1758-2652-14-42

Research Areas:

Genetics and Genomics, Health System and Policy, Infectious Diseases, Maternal Access, Maternal and Child Health, Noncommunicable Diseases, Sexual and Reproductive Health

Study Countries:

South Africa

Study Design:

Cohort Study, Cross Sectional Study, Quasi Experimental Study

Study Approach:

Quantitative

Participants Gender:

Female