Good Outcomes in Babies With In Utero Bedaquiline Exposure Free

(See the Major Article by Loveday et al on pages 1158–68.)

The paucity of data on the use of new tuberculosis (TB) drugs in pregnant women has been recognized as a major knowledge gap, and the exclusion of pregnant women from TB treatment trials as a major challenge [1, 2]. In this issue of Clinical Infectious Diseases, the report by Loveday and colleagues on maternal and infant outcomes among pregnant women treated for drug-resistant TB in South Africa presents valuable data on the safety of second-line TB drugs used in pregnancy [3]. It uniquely documents the outcome of 58 pregnant women treated with bedaquiline-containing regimens and 49 babies exposed to bedaquiline in utero. Pregnant women treated with bedaquiline, mostly as part of an all-oral regimen for drug-resistant TB, had more favorable outcomes (71% vs 62%) and less loss to follow-up (19% vs 28%) compared to those not treated with bedaquiline, although differences were not statistically significant.

Overall, favorable treatment outcomes were reported in 67% of 108 pregnant women, which is comparable to outcomes in nonpregnant adults treated with second-line TB drugs in this setting [3]. These findings are similar to the experience in the United Kingdom where the presence or absence of pregnancy did not influence TB risk or treatment outcome with first-line TB treatment [4], although a significant increase in TB risk was observed postpartum, which has been observed in other settings as well [5]. In this study, the vast majority of pregnant women enrolled (81%) were human immunodeficiency virus (HIV) coinfected and most (83%) were on antiretroviral therapy (ART) before TB treatment was initiated, although baseline CD4 counts were low (343 cells/mm³). Nearly half of the women (48%) had an “unfavorable pregnancy outcome,” and this was increased (69%) in those with CD4 counts < 200 cells/mm³ [3]. Unfavorable pregnancy outcomes, excluding terminations of pregnancy and miscarriages, included fetal/neonatal death (9%), premature birth (28%), and low birth weight (35%).

More babies exposed to bedaquiline in utero had low birth weight (45% vs 26%, P = .034), but interestingly this was a transient effect, and at 12 months 88% of bedaquiline-exposed babies were thriving and developing normally compared to 82% of unexposed babies. This demonstrates the importance of postpartum follow-up, at least to 12 months, to accurately assess the outcome of babies exposed to TB or TB drugs in utero. Whether low birth weight may be associated with adverse consequences in the longer term remains to be determined, but differences in the median birth weight were only moderate—2690 g (interquartile range [IQR], 2380–3095 g) vs 2900 g (IQR, 2550–3270 g)—and demonstrated complete recovery by 12 months of age. Multiple factors may explain the observed difference, and the co-linearity of drug exposures and potential drug–drug interactions between second-line TB treatment and ART confounds interpretation [6]. Fetuses exposed to bedaquiline also had significantly increased exposure to clofazimine, which may increase ART levels [6], as well as levofloxacin and linezolid. The median duration of in utero bedaquiline exposure was 77 days, with only a few instances of first trimester exposure. In total, 20 (18%) women started TB treatment prior to becoming pregnant, and 19 (17%) started treatment during the first trimester, 42 (39%) during the second trimester, and 28 (26%) during the third trimester. Therefore, although no major congenital abnormalities were observed, the number of fetuses exposed during the critical first trimester was too small to provide a reliable safety assessment.

An issue that is not addressed in this article is the importance of infection control in healthcare facilities that offer maternity services. The danger of drug-resistant TB transmission posed by healthcare facilities that provide services to HIV-infected patients in Kwa-Zulu Natal, South Africa and other high-TB-incidence settings is well recognized, but this is rarely acknowledged by maternity services. Multibed “kangaroo mother care” units pose a particular risk, especially in settings with high rates of TB/HIV coinfection, resulting in premature delivery or low-birth-weight babies [7]. Since TB usually presents months after the baby has been discharged from kangaroo mother care, a connection with the hospital exposure event is rarely made [7]. Another important issue is how best to screen pregnant women for TB, especially if they are HIV infected. Community-wide active case finding studies suggest that routine Xpert MTB/RIF testing detects TB in a large percentage of patients who may be otherwise minimally symptomatic [8]. Because the Xpert MTB/RIF assay and the more sensitive Xpert Ultra assay detect both the presence of TB and rifampicin resistance, it facilitates early diagnosis and initiation of appropriate treatment for drug-resistant disease. However, its clinical utility as a routine screening test during pregnancy in high-TB-incidence areas has not been evaluated.

As this was a retrospective study describing routinely collected data, the completeness and quality of available data were suboptimal. In particular, data collection on specific drug-related adverse effects, drug–drug interactions, and reasons for changes in both drugs and drug dosages were severely limited. It is unfortunate that more data on clofazimine dosing and toxicity in pregnancy are not available, but it demonstrates the urgent need for better data collection, the inclusion of pregnant women in TB treatment trials, and the creation of prospective “TB in pregnancy” registers [1, 2]. The creation of a multicenter “TB in pregnancy” register could be a potential legacy of this important observational study. The inclusion of pregnancy status in minimal or expanded datasets reported to the World Health Organization may also help to improve data availability and clinical care in this neglected key population.

Note

Potential conflicts of interest. The author: No reported conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

References