Treatment and pregnancy outcomes of pregnant women exposed to second-line anti-tuberculosis drugs in South Africa

BMC Pregnancy and Childbirth, Volume 21, No. 1, Year 2021

Ukuhunyushwa

Background: Multi-drug resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) in pregnant women is a cause for concern globally; few data have described the safety of second-line anti-TB medications during pregnancy. We aim to describe TB treatment and pregnancy outcomes among pregnant women receiving second-line anti-tuberculosis treatment for MDR/RR-TB in Johannesburg, South Africa. Methods: We conducted a retrospective record review of pregnant women (≥ 18 years) who received treatment for MDR/RR-TB between 01/2010–08/2016 at three outpatient treatment sites in Johannesburg, South Africa. Demographic, treatment and pregnancy outcome data were collected from available medical records. Preterm birth (< 37 weeks), and miscarriage were categorized as adverse pregnancy outcomes. Results: Out of 720 women of child-bearing age who received MDR/RR-TB treatment at the three study sites, 35 (4.4%) pregnancies were identified. Overall, 68.7% (24/35) were HIV infected, 83.3% (20/24) were on antiretroviral therapy (ART). Most women, 88.6% (31/35), were pregnant at the time of MDR/RR-TB diagnosis and four women became pregnant during treatment. Pregnancy outcomes were available for 20/35 (57.1%) women, which included 15 live births (11 occurred prior to 37 weeks), 1 neonatal death, 1 miscarriage and 3 pregnancy terminations. Overall, 13/20 (65.0%) women with known pregnancy outcomes had an adverse pregnancy outcome. Of the 28 women with known TB treatment outcomes 17 (60.7%) completed treatment successfully (4 were cured and 13 completed treatment), 3 (10.7%) died and 8 (28.6%) were lost-to-follow-up. Conclusions: Pregnant women with MDR/RR-TB suffer from high rates of adverse pregnancy outcomes and about 60% achieve a successful TB treatment outcome. These vulnerable patients require close monitoring and coordinated obstetric, HIV and TB care. MDR-TB is TB that is resistant to at least isoniazid (INH) and rifampicin (RIF), the two most important anti-TB drugs in the first-line treatment regimen [15, 16]. TB that is resistant to RIF but with unidentified or awaiting sensitivities to additional drugs is referred to as rifampicin-resistant TB (RR-TB). MDR-TB with additional resistance to second-line drugs from the fluoroquinolone and injectable drug classes is defined as extensively drug-resistant TB (XDR-TB), while preXDR-TB is MDR-TB which also has resistance to either a fluoroquinolone or a second-line injectable drug. We conducted a retrospective record review of adult (18–49 years old) women diagnosed with laboratory-confirmed MDR/RR-TB, who initiated second-line anti-TB treatment (defined as a regimen containing at least two second-line agents, including at least one of a fluoroquinolone or second-line injectable agent), between 01/2010–08/2016 at three public outpatient treatment sites in Johannesburg, South Africa and had a pregnancy overlap with their TB treatment (Fig. 1). Two of the three sites are decentralized drug-resistant TB treatment sites and the third the only specialized hospital for the management of MDR-TB and XDR-TB cases in the Gauteng Province. Eligible participants were identified through each site’s respective electronic data management system and MDR/RR-TB registers. Study period alongside South Africa’s drug-resistant TB policies. DR-TB – drug-resistant tuberculosis, Km – Kanamycin, Mfx – Moxifloxacin, Eto – Ethambutol, INH – Isoniazid, Cfz – Clofazimine, Cfx – Cefozitin, BDQ – Bedaquiline, Trd –Terizidone, Z – Pyrazinamide, NTP- National TB programme, Xpert MTB/RIF – a nucleic acid amplification-based diagnostic system that detects Mycobacterium tuberculosis and rifampin (RIF) resistance in under2 hours. 1 Short course: BDQ, LZD, LFX, CFZ, Hi-INH, PZA, EMB × 9–11 months. 2 Long course: BDQ, LFX, LZD, TRD and CFZ for 18 months Clinical data on all eligible women were collected from medical records at treatment sites. This included medical, obstetric, drug-exposure histories, treatments and laboratory data for acute and chronic conditions were collected from medical records at treatment sites. Medical records were defined as all electronic or paper documentation of the patient’s medical care at the treatment facilities, including National Health Laboratory Services (NHLS) laboratory reports, prescriptions, MDR/RR-TB patient card, MDR/RR-TB clinic card, antenatal care (ANC) and delivery records and each site’s respective electronic data management system, hospital admission records, and maternal or neonatal death records where applicable. We collected the following patient sociodemographic characteristics at treatment initiation; age (18–29, ≥ 30 years), nationality (South African or non-South Africa), marital status (in a relationship/married or single, not in a relationship), highest education level (< grade 12 versus ≥ grade 12) and employment status (employed or unemployed). MDR/RR-TB related information collected include the DR-TB treatment site type (centralized or decentralized), year of MDR/RR-TB treatment initiation (2010–2011, 2012–2013 or 2014–2016), MDR/RR-TB treatment regimen and MDR/RR-TB treatment regimen changes during the course of treatment. Additionally, we collected TB drug-resistance profile (RR-TB, MDR-TB, pre-XDR-TB, XDR-TB), patient category (new, previously treated), and classification of disease (pulmonary, extra-pulmonary, pulmonary and extra-pulmonary). We categorized pregnancy onset as before or after MDR/RR-TB treatment initiation. Among those pregnant after the MDR/RR-TB treatment initiation, we calculated duration on second-line anti-TB treatment as the time (in days) from the start of MDR/RR-TB treatment to the self-reported estimated date of pregnancy onset. We categorized participants’ HIV status and antiretroviral therapy (ART) status collected from medical records as (HIV-negative, HIV-positive), (on ART, not on ART, ART status unknown) respectively, and collected ART regimens for HIV-positive participants initiated on ART. Additionally, ART initiation was categorized as before or after MDR/RR-TB treatment initiation depending on the timing of ART initiation. Adverse events during MDR/RR-TB treatment were determined from laboratory results, patient self-report or clinician documentation of adverse events on patient medical records. Loss of weight, dizziness, rash, nausea and ototoxicity and the severity grade were identified and classified as documented by the clinician. The severity of self-reported AEs was graded by clinicians using the Division of AIDS (DAIDS) adverse event’ categorization as mild (grade 1), moderate (grade 2), severe (grade 3), potentially life-threatening (grade 4), based on interference with usual functional, social, and self-care activities as detailed below [17]. Nephrotoxicity, hepatotoxicity, anaemia, hypokalaemia and neutropenia were confirmed by monitoring laboratory tests including renal function test, liver function test, haemoglobin test, serum potassium test and absolute neutrophil count, respectively. Adverse events confirmed by laboratory results were graded using the DAIDS adverse event’ categorization as either as mild, moderate, severe or life-threatening [17, 18]. MDR/RR-TB outcomes were defined using standard TB outcomes as defined in the WHO definitions and reporting framework for TB as cured, completed, died, failed, lost to follow-up (LTFU), or not evaluated [19]. Pregnancy outcomes were assigned in patient medical records according to the standard categories as live birth, miscarriage, stillbirth, and termination of pregnancy [20, 21]. Preterm birth (< 37-weeks’ gestation), stillbirth, and miscarriage were categorized as adverse pregnancy outcomes. Women were referred to other facilities for antenatal care and delivery but we did not have access to these records. We relied on documentation of antenatal, delivery and neonatal outcomes in the TB patient record. There is no infant outcome classification proposed as infant outcomes were not available in the records. We used descriptive statistics to summarize demographic, clinical characteristics, pregnancy and TB treatment outcomes. We describe the frequency and severity of adverse events occurring during MDR/RR-TB treatment. Continuous variables were described using medians and interquartile ranges (IQR) where appropriate. Categorical variables are described using frequencies and percentages. Differences by HIV status were determined using the Chi-square or Fisher’s exact tests and continuous variables by t-test or Wilcoxon sign-rank-sum test where appropriate. Statistical significance level was set at the 5% level. Analysis was conducted using STATA version 14 (Stata Corp, College Station, Texas USA).

I-AI Digest

Study Justification:

This study aimed to investigate the treatment and pregnancy outcomes of pregnant women exposed to second-line anti-tuberculosis drugs in South Africa. The justification for this study is that there is limited data on the safety of these medications during pregnancy, and pregnant women with multi-drug resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) are a vulnerable population that requires close monitoring and coordinated care.

Highlights:

– Out of 720 women of child-bearing age who received MDR/RR-TB treatment, 35 pregnancies were identified.
– Most pregnant women with MDR/RR-TB were also HIV-infected and on antiretroviral therapy.
– Adverse pregnancy outcomes were observed in 65% of women with known pregnancy outcomes.
– About 60% of women achieved a successful TB treatment outcome.

Recommendations for Lay Reader:

– Pregnant women with MDR/RR-TB should receive close monitoring and coordinated care from healthcare providers.
– It is important for pregnant women with MDR/RR-TB to adhere to their TB treatment regimen to improve treatment outcomes.
– Healthcare providers should consider the potential risks and benefits of second-line anti-TB medications when treating pregnant women with MDR/RR-TB.

Recommendations for Policy Maker:

– Develop and implement guidelines for the management of pregnant women with MDR/RR-TB, including protocols for close monitoring and coordination of care.
– Strengthen healthcare systems to ensure access to quality antenatal care, TB treatment, and HIV care for pregnant women with MDR/RR-TB.
– Conduct further research to better understand the safety and efficacy of second-line anti-TB medications during pregnancy.

Key Role Players:

– Healthcare providers (doctors, nurses, midwives) for antenatal care, TB treatment, and HIV care.
– Obstetricians and gynecologists for specialized care during pregnancy.
– Laboratory technicians for monitoring TB treatment and pregnancy outcomes.
– Policy makers and government officials responsible for developing and implementing guidelines and policies.

Cost Items for Planning Recommendations:

– Training and capacity building for healthcare providers on the management of pregnant women with MDR/RR-TB.
– Strengthening healthcare infrastructure and systems to ensure access to quality care.
– Development and dissemination of guidelines and protocols.
– Monitoring and evaluation of program implementation.
– Research funding for further studies on the safety and efficacy of second-line anti-TB medications during pregnancy.

Amandla Obufakazi

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is moderately strong, but there are some areas for improvement. The study conducted a retrospective record review of pregnant women receiving second-line anti-tuberculosis treatment for MDR/RR-TB in South Africa. The study collected data on demographic, treatment, and pregnancy outcomes. The sample size is relatively small, with only 35 pregnancies identified out of 720 women receiving MDR/RR-TB treatment. Additionally, the study relied on medical records, which may have limitations in terms of data accuracy and completeness. To improve the strength of the evidence, future studies could consider a larger sample size and prospective data collection methods. It would also be beneficial to include a comparison group of pregnant women without MDR/RR-TB to assess the relative risk of adverse pregnancy outcomes.

Abstract

MDR-TB is TB that is resistant to at least isoniazid (INH) and rifampicin (RIF), the two most important anti-TB drugs in the first-line treatment regimen [15, 16]. TB that is resistant to RIF but with unidentified or awaiting sensitivities to additional drugs is referred to as rifampicin-resistant TB (RR-TB). MDR-TB with additional resistance to second-line drugs from the fluoroquinolone and injectable drug classes is defined as extensively drug-resistant TB (XDR-TB), while preXDR-TB is MDR-TB which also has resistance to either a fluoroquinolone or a second-line injectable drug. We conducted a retrospective record review of adult (18–49 years old) women diagnosed with laboratory-confirmed MDR/RR-TB, who initiated second-line anti-TB treatment (defined as a regimen containing at least two second-line agents, including at least one of a fluoroquinolone or second-line injectable agent), between 01/2010–08/2016 at three public outpatient treatment sites in Johannesburg, South Africa and had a pregnancy overlap with their TB treatment (Fig. 1). Two of the three sites are decentralized drug-resistant TB treatment sites and the third the only specialized hospital for the management of MDR-TB and XDR-TB cases in the Gauteng Province. Eligible participants were identified through each site’s respective electronic data management system and MDR/RR-TB registers. Study period alongside South Africa’s drug-resistant TB policies. DR-TB – drug-resistant tuberculosis, Km – Kanamycin, Mfx – Moxifloxacin, Eto – Ethambutol, INH – Isoniazid, Cfz – Clofazimine, Cfx – Cefozitin, BDQ – Bedaquiline, Trd –Terizidone, Z – Pyrazinamide, NTP- National TB programme, Xpert MTB/RIF – a nucleic acid amplification-based diagnostic system that detects Mycobacterium tuberculosis and rifampin (RIF) resistance in under2 hours. 1 Short course: BDQ, LZD, LFX, CFZ, Hi-INH, PZA, EMB × 9–11 months. 2 Long course: BDQ, LFX, LZD, TRD and CFZ for 18 months Clinical data on all eligible women were collected from medical records at treatment sites. This included medical, obstetric, drug-exposure histories, treatments and laboratory data for acute and chronic conditions were collected from medical records at treatment sites. Medical records were defined as all electronic or paper documentation of the patient’s medical care at the treatment facilities, including National Health Laboratory Services (NHLS) laboratory reports, prescriptions, MDR/RR-TB patient card, MDR/RR-TB clinic card, antenatal care (ANC) and delivery records and each site’s respective electronic data management system, hospital admission records, and maternal or neonatal death records where applicable. We collected the following patient sociodemographic characteristics at treatment initiation; age (18–29, ≥ 30 years), nationality (South African or non-South Africa), marital status (in a relationship/married or single, not in a relationship), highest education level (< grade 12 versus ≥ grade 12) and employment status (employed or unemployed). MDR/RR-TB related information collected include the DR-TB treatment site type (centralized or decentralized), year of MDR/RR-TB treatment initiation (2010–2011, 2012–2013 or 2014–2016), MDR/RR-TB treatment regimen and MDR/RR-TB treatment regimen changes during the course of treatment. Additionally, we collected TB drug-resistance profile (RR-TB, MDR-TB, pre-XDR-TB, XDR-TB), patient category (new, previously treated), and classification of disease (pulmonary, extra-pulmonary, pulmonary and extra-pulmonary). We categorized pregnancy onset as before or after MDR/RR-TB treatment initiation. Among those pregnant after the MDR/RR-TB treatment initiation, we calculated duration on second-line anti-TB treatment as the time (in days) from the start of MDR/RR-TB treatment to the self-reported estimated date of pregnancy onset. We categorized participants’ HIV status and antiretroviral therapy (ART) status collected from medical records as (HIV-negative, HIV-positive), (on ART, not on ART, ART status unknown) respectively, and collected ART regimens for HIV-positive participants initiated on ART. Additionally, ART initiation was categorized as before or after MDR/RR-TB treatment initiation depending on the timing of ART initiation. Adverse events during MDR/RR-TB treatment were determined from laboratory results, patient self-report or clinician documentation of adverse events on patient medical records. Loss of weight, dizziness, rash, nausea and ototoxicity and the severity grade were identified and classified as documented by the clinician. The severity of self-reported AEs was graded by clinicians using the Division of AIDS (DAIDS) adverse event’ categorization as mild (grade 1), moderate (grade 2), severe (grade 3), potentially life-threatening (grade 4), based on interference with usual functional, social, and self-care activities as detailed below [17]. Nephrotoxicity, hepatotoxicity, anaemia, hypokalaemia and neutropenia were confirmed by monitoring laboratory tests including renal function test, liver function test, haemoglobin test, serum potassium test and absolute neutrophil count, respectively. Adverse events confirmed by laboratory results were graded using the DAIDS adverse event’ categorization as either as mild, moderate, severe or life-threatening [17, 18]. MDR/RR-TB outcomes were defined using standard TB outcomes as defined in the WHO definitions and reporting framework for TB as cured, completed, died, failed, lost to follow-up (LTFU), or not evaluated [19]. Pregnancy outcomes were assigned in patient medical records according to the standard categories as live birth, miscarriage, stillbirth, and termination of pregnancy [20, 21]. Preterm birth (< 37-weeks’ gestation), stillbirth, and miscarriage were categorized as adverse pregnancy outcomes. Women were referred to other facilities for antenatal care and delivery but we did not have access to these records. We relied on documentation of antenatal, delivery and neonatal outcomes in the TB patient record. There is no infant outcome classification proposed as infant outcomes were not available in the records. We used descriptive statistics to summarize demographic, clinical characteristics, pregnancy and TB treatment outcomes. We describe the frequency and severity of adverse events occurring during MDR/RR-TB treatment. Continuous variables were described using medians and interquartile ranges (IQR) where appropriate. Categorical variables are described using frequencies and percentages. Differences by HIV status were determined using the Chi-square or Fisher’s exact tests and continuous variables by t-test or Wilcoxon sign-rank-sum test where appropriate. Statistical significance level was set at the 5% level. Analysis was conducted using STATA version 14 (Stata Corp, College Station, Texas USA).

Izinto zokwakha

N/A

Emisha

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

1. Telemedicine: Implementing telemedicine services can allow pregnant women to receive medical consultations and check-ups remotely, reducing the need for frequent in-person visits and improving access to healthcare, especially for those in remote or underserved areas.

2. Mobile health applications: Developing mobile applications that provide pregnant women with information, reminders, and personalized care plans can empower them to take an active role in managing their health. These apps can also facilitate communication with healthcare providers and provide access to educational resources.

3. Community health workers: Training and deploying community health workers who can provide antenatal care, education, and support to pregnant women in their communities can help bridge the gap between healthcare facilities and remote areas. These workers can also assist in identifying high-risk pregnancies and referring women to appropriate healthcare facilities.

4. Integrated healthcare services: Establishing integrated healthcare services that combine maternal health services with other essential healthcare services, such as HIV/AIDS treatment and tuberculosis management, can ensure comprehensive care for pregnant women with multiple health needs. This approach can improve coordination and reduce barriers to accessing different types of care.

5. Health information systems: Implementing robust health information systems that capture and analyze data on maternal health outcomes can help identify trends, gaps, and areas for improvement. This data-driven approach can inform policy decisions and resource allocation to prioritize interventions that address specific maternal health challenges.

6. Public-private partnerships: Collaborating with private sector organizations, such as pharmaceutical companies and technology companies, can leverage their expertise, resources, and networks to develop innovative solutions for improving access to maternal health. These partnerships can lead to the development of new technologies, funding opportunities, and knowledge sharing.

It’s important to note that the specific context and needs of the target population should be considered when implementing these innovations. Additionally, continuous evaluation and adaptation of these interventions based on feedback and evidence-based practices are crucial for their effectiveness and sustainability.

AI Innovations Description

The study mentioned in the description focuses on pregnant women with multi-drug resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa. The goal of the study is to describe the treatment and pregnancy outcomes of pregnant women receiving second-line anti-tuberculosis treatment for MDR/RR-TB.

Based on the findings of the study, the following recommendations can be made to improve access to maternal health:

1. Strengthening Antenatal Care: Pregnant women with MDR/RR-TB require close monitoring and coordinated obstetric, HIV, and TB care. It is important to ensure that pregnant women have access to regular antenatal care visits where their health can be monitored, and appropriate interventions can be provided.

2. Integration of TB and Maternal Health Services: There should be a strong integration of TB and maternal health services to ensure that pregnant women with MDR/RR-TB receive comprehensive care. This can be achieved by establishing referral systems and coordination between TB treatment facilities and antenatal care clinics.

3. Access to Second-Line Anti-TB Medications: Pregnant women with MDR/RR-TB should have access to safe and effective second-line anti-TB medications. Efforts should be made to ensure the availability of these medications in healthcare facilities, especially those providing antenatal care.

4. Training and Education: Healthcare providers should be trained on the management of pregnant women with MDR/RR-TB. This includes knowledge on the safe use of second-line anti-TB medications during pregnancy, monitoring of adverse events, and coordination of care between TB and maternal health services.

5. Supportive Services: Pregnant women with MDR/RR-TB may require additional support services such as nutritional support, mental health services, and social support. These services should be integrated into the care provided to pregnant women to improve their overall well-being and pregnancy outcomes.

By implementing these recommendations, access to maternal health for pregnant women with MDR/RR-TB can be improved, leading to better pregnancy outcomes and overall health for both the mother and the baby.

AI Innovations Methodology

To improve access to maternal health in the context of pregnant women with multi-drug resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa, the following innovations and recommendations can be considered:

1. Integrated Care: Implementing a coordinated approach that integrates obstetric, HIV, and TB care to ensure comprehensive and holistic management for pregnant women with MDR/RR-TB.

2. Mobile Health (mHealth) Solutions: Utilizing mobile technologies, such as SMS reminders and telemedicine, to improve communication, adherence to treatment, and access to healthcare services for pregnant women with MDR/RR-TB.

3. Community-Based Care: Establishing community-based care models that bring healthcare services closer to pregnant women with MDR/RR-TB, reducing the need for long-distance travel and improving access to timely and appropriate care.

4. Task Shifting: Training and empowering non-specialist healthcare providers, such as nurses and community health workers, to deliver certain aspects of maternal health care, including antenatal care, under the supervision of qualified healthcare professionals.

5. Health Education and Awareness: Conducting targeted health education campaigns to raise awareness about MDR/RR-TB among pregnant women, their families, and communities, emphasizing the importance of early detection, treatment adherence, and regular antenatal care.

To simulate the impact of these recommendations on improving access to maternal health for pregnant women with MDR/RR-TB, a methodology could include the following steps:

1. Data Collection: Gather relevant data on the current access to maternal health services for pregnant women with MDR/RR-TB, including information on healthcare utilization, treatment outcomes, and pregnancy outcomes.

2. Baseline Assessment: Analyze the collected data to establish a baseline understanding of the current access to maternal health and identify any existing gaps or challenges.

3. Modeling: Develop a simulation model that incorporates the recommended innovations and recommendations. This model should consider factors such as the population size, geographical distribution, healthcare infrastructure, and available resources.

4. Parameterization: Assign appropriate values to the model parameters based on available data and expert knowledge. These parameters may include the coverage and effectiveness of the recommended interventions, as well as the potential impact on healthcare utilization and treatment outcomes.

5. Simulation Runs: Run the simulation model multiple times, varying the input parameters to assess the potential impact of different scenarios and combinations of interventions on improving access to maternal health.

6. Analysis and Evaluation: Analyze the simulation results to evaluate the effectiveness of the recommended interventions in improving access to maternal health. Assess the impact on key outcomes such as healthcare utilization, treatment adherence, pregnancy outcomes, and overall maternal health.

7. Sensitivity Analysis: Conduct sensitivity analysis to assess the robustness of the simulation results and identify the key factors that influence the outcomes. This analysis can help prioritize interventions and guide resource allocation decisions.

8. Policy Recommendations: Based on the simulation findings, develop policy recommendations and implementation strategies to improve access to maternal health for pregnant women with MDR/RR-TB. Consider factors such as feasibility, cost-effectiveness, and sustainability.

9. Monitoring and Evaluation: Implement the recommended interventions and establish a monitoring and evaluation framework to track progress, measure outcomes, and make necessary adjustments to ensure continuous improvement.

By following this methodology, policymakers and healthcare providers can gain insights into the potential impact of different innovations and recommendations on improving access to maternal health for pregnant women with MDR/RR-TB, enabling evidence-based decision-making and resource allocation.

Umbhali

Dima Health

Statistics:

Citations: 7

Identifiers:

DOI: 10.1186/s12884-021-03956-6

Research Areas:

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

Study Countries:

South Africa

Study Design:

Cohort Study, Cross Sectional Study

Study Approach:

Quantitative

Participants Gender:

Female

Yabelana ngalokhu: