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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).
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