Pregnant women are typically excluded from clinical trials of new tuberculosis medicines, leading to a lack of solid scientific evidence on how best to treat those who get TB while they are expecting.
Spotlight’s Tiyese Jeranji asked local experts about the problem, and unpacks a recent study that broke the mould by opening its doors to pregnant women.
The World Health Organisation (WHO) estimates that annually, about 200 000 pregnant women get TB. Aside from the danger this poses to their health, it is also associated with an increased risk of prematurity, low birth weight and stillbirths, among others.
TB can be cured, typically with a combination of four or so antibiotics. More difficult to treat forms of TB typically require different, less widely used antibiotics.
Unfortunately, we don’t have a clear picture of just how safe some of these antibiotics are when taken by pregnant women, because they are mostly excluded from the clinical trials in which the safety and efficacy of these medicines are established.
Risks to developing foetus
This was confirmed by Professor Keertan Dheda, a general physician, pulmonologist and critical care specialist who heads the University of Cape Town’s Division of Pulmonology and Respiratory Services at Groote Schuur Hospital.
“There are several physiological changes in pregnancy which means some drugs have to be dosed differently and so forth. In some cases, certain drugs may show changes in animal foetus studies, but whether this applies to humans may be unclear,” he said. Spotlight previously reported in detail on the impact of TB on pregnancy.)
Another reason pregnant women have been excluded is that researchers, medical doctors and people running public health systems may be concerned about potential litigation if anything goes wrong, he added.
“[If this happens] they might be blamed for inappropriately using a drug with unproven safety. However, one has to take a sensible approach. TB is the most common cause of death in pregnant women (or in the period immediately after pregnancy) in sub-Saharan Africa. Therefore, often the benefits to the mother and child outweigh the risks associated with specific drugs.”
The issue is broader than just TB though, said Dr Marian Loveday, senior scientist at the South African Medical Research Council. “Pregnant women are usually not included in any clinical trials (not only TB clinical trials) due to safety concerns for the developing foetus.
“This meant that when new drugs or regimens were shown to be effective and rolled out, pregnant women were not given access to them, as they weren’t included in the trials.”
The picture is further complicated by the fact that the evidence can sometimes be hard to interpret. Roll-out of dolutegravir, the antiretroviral widely used to treat HIV, was slowed for a few years because some early data suggested it might be linked to birth defects.
Over time, as more data accumulated, it became clear that the drug does not increase this risk.
Dr Limakatso Lebina, clinical trials unit lead at the Africa Health Research Institute, said there are also thorny ethical considerations, such as that foetuses can’t give consent to participate in research.
This is particularly relevant in studies where infants might be exposed to new medicines for which there is as yet no evidence regarding safety for the foetus.
The status quo
For reasons like the above, much data on the safety of new medicines in pregnant women have been gathered in a roundabout way.
Lebina said pregnant women have not been included in the studies evaluating new TB drugs with which she has been involved, although exceptions are sometimes made for women who fall pregnant once they are already participating in a study.
“In many clinical trials, one of the inclusion criteria is that females with childbearing potential should be on reliable hormonal contraceptives,” she says. If a participant falls pregnant while in the trial, depending on the study, they might then be given the option to continue or to withdraw from the study.
As part of study procedures, these mothers and babies, said Lebina, are then typically followed up for at least one year after delivery. Clinical outcomes for both are then used to assess the impact of the drug in question on babies and pregnant women.
An obvious drawback, though, is that there is no guarantee any women in a particular study will fall pregnant.
As a result, the data on pregnant women generated through such an approach is sparse and patchy.
Not good enough?
Some researchers and activists say this approach is not good enough. Lindsay McKenna, TB project co-director at the Treatment Action Group, a New York-based advocacy organisation, said pregnant women are often among the last groups to benefit from treatment innovations. “They get stuck with longer, more toxic, more poorly performing regimens for longer,” she said.
In a community consensus statement published in 2023, representatives of communities affected by TB said the exclusion of pregnant women from studies means that in the real world, they are deprived of the evidence they need to make decisions about their health and that of their children.
This harm, they stated, outweighs the risks associated with allowing pregnant women to participate in TB treatment studies, providing, of course, they’ve given informed consent and understand the risks.
“This status quo forces pregnant and postpartum women to make decisions in the absence of data, unacceptably shifting the burden of risk on to …women who must decide what is best for themselves, their baby and their families – without reliable information,” the statement reads.
“It is critical that everyone involved in TB research moves toward the routine inclusion of pregnant and breastfeeding women in research. Evidence-based guidelines and care practices depend on generating these data through research inclusion. Continued exclusion means they will continue to be left behind by science, absorbing unknown risks to themselves and their children.”
Breaking the mould
A recent TB clinical trial in South Africa has gained attention for specifically involving pregnant women in its study. The study, BEAT Tuberculosis, was conducted by the Isango Lethemba TB Research Unit, a subdivision of the University of the Witwatersrand’s (Wits) Clinical HIV Research Unit.
A total of 402 people with drug-resistant TB were enrolled in the study from 2019 to 2021 at Jose Pearson TB Hospital in the Eastern Cape and King Dinuzulu Hospital Complex in KwaZulu-Natal. They were randomised into two groups – one receiving a short-course treatment regimen that included a medicine called delamanid, and the other group receiving the standard public sector treatment that was provided at the time.
Dr Francesca Conradie, an infectious diseases researcher in the School of Clinical Medicine at Wits and the principal investigator, said that pregnant women were not included from the outset of the clinical trial, but about halfway through they updated the study protocol to allow women at any stage of pregnancy to participate. In the end, 10 pregnant women were enrolled – six were in the delamanid arm of the study.
“This may sound like a few,” she told Spotlight, “but it is more than any other study in the world. We had 10 healthy babies born. In addition, nine out of the 10 women were successfully treated. One woman fell pregnant while on TB treatment and most were in their second trimester [13 to 27 weeks]. In one woman, the TB came back or relapsed and this was the same [rate] as the general population.”
Asked about the rationale for including pregnant women, Conradie said: “Pregnant women can get sick with TB and women sick with TB can get pregnant.
“Aside from the potential risks for an unborn baby, pregnancy is an altered physiological state. The health of the mother is paramount for a good outcome of a pregnancy.” Delaying treatment for TB is also bad for the mother.
Part of the reasoning for including pregnant women was also that they wanted to increase the amount of evidence for the safe treatment of those who have drug-resistant TB.
“If we don’t do research in this group, the decisions on the best treatment for them rests with the treating doctor. And is not evidence-based,” she said.
Valuable data
Dheda said the study provides data that will make clinicians more comfortable with prescribing delamanid for pregnant women. However, the jury is still out on some other drug-resistant TB drugs. “At present, pretomanid (a sister drug to delamanid) is not being used in pregnancy because there are no data about the use of this drug in pregnancy, and it was associated with testicular toxicity in mice.
“There is now a greater drive to include pregnant women in research studies so that we can accumulate experience more rapidly, thus not marginalising this vulnerable group.”
Conradie says the process to update the country’s drug-resistant TB treatment guidelines, taking the study’s findings into account, has started.
“South Africa will adopt this and, in fact, it is already being done. All pregnant women with drug-resistant TB are presented to the National Clinical Advisory Committee and this is approved by this group. Globally it will take a bit longer.”
This article was first published in Spotlight
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