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(3, 15). 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 (15, 16).
Study setting and design
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.
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, not in a relationship/widowed), highest education level (< grade 12 versus ≥ grade 12) and employment status (employed or unemployed). MDR/RR-TB related information collected include year of MDR/RR-TB treatment initiation (2010–2011, 2012–2013, 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 (days) from the start of MDR/RR-TB treatment to the self-reported estimated date of pregnancy onset.
We categorized participants’ HIV status and 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.
Maternal Adverse events
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. Nephrotoxicity, hepatotoxicity, anaemia, hypokalaemia and neutropenia were confirmed by laboratory tests. Adverse events confirmed by laboratory results were graded using the Division of AIDS (DAIDS) adverse event’ categorization (17).
Maternal MDR/RR-TB treatment outcomes
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 (16).
Pregnancy outcomes were assigned in patient medical records according to the standard categories as live birth, miscarriage, stillbirth, and termination of pregnancy (18, 19). Preterm birth (< 37-week 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).
The study was approved by the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (Wits HREC M170644). A waiver of informed consent was granted as the study was a retrospective medical record review of routinely collected data.