Why including pregnant women in a TB drug trial in South Africa was a big deal

29 Oct 2024

Pregnant women are typically excluded from clinical trials of new TB medicines. This has led to a lack of solid scientific evidence on how best to treat women who fall ill with TB while they are expecting. Spotlight asked local TB experts about the problem and puts the spotlight on a recent study that broke the mould by opening its doors to pregnant women.

The World Health Organization (WHO) estimates that every year about 200,000 pregnant women fall ill with tuberculosis (TB). On top of the danger TB poses to the health of these women, 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. That is because pregnant women are mostly excluded from the clinical trials in which the safety and efficacy of these medicines are established.

Risks to developing foetus

“Pregnant women are frequently not included in clinical trials, says 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 that 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,” Dheda tells Spotlight. (Spotlight has reported in detail on the impact of TB on pregnancy.)

Another reason pregnant women have been excluded, according to Dheda, is that researchers, medical doctors and people running public health systems may be concerned about potential litigation should anything go wrong. “[If this happens] they might be blamed for inappropriately using a drug with unproven safety in the foetus. 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, says 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.” She adds: “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. So they were excluded from new and improved drugs and regimens.”

The picture is further complicated by the fact that the evidence can sometimes be hard to interpret. Roll-out of dolutegravir, an antiretroviral widely used to treat HIV, was slowed for a few years because of some early data that suggested it might be linked to birth defects. Over time, as more data accumulated, it became clear that the drug does not increase the risk of birth defects.

Dr Limakatso Lebina, clinical trials unit lead at the Africa Health Research Institute, points out that 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 its safety for the foetus.

The status quo

For reasons such as the above, much data on the safety of new medicines in pregnant women have been gathered in a somewhat roundabout way.

Lebina explains that pregnant women have not been included in the studies evaluating new TB drugs that she has been part of, although some 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 a clinical trial, depending on the study, they might then be given the option to continue or to drop out of the study.

As part of study procedures, these mothers and babies, says Lebina, are then typically followed up for at least one year after delivery. The mother and baby’s clinical outcomes are then used to assess the impact of the drug in question on babies and pregnant women. An obvious drawback of this approach is that there is no guarantee that 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 argue that this approach is not good enough. Lindsay McKenna, TB project co-director at the Treatment Action Group, a New York-based advocacy organisation, stresses that 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 says.

In a community consensus statement published in 2023, representatives of communities affected by TB argued that the exclusion of pregnant women from studies means that pregnant women in the real world are deprived of the evidence they need to make decisions about their health and that of their children. This harm, they suggest, outweighs the risks associated with allowing pregnant women to participate in TB treatment studies, providing, of course, that they’ve given informed consent and understand the risks.

“This existing status quo forces pregnant and postpartum women and persons to make decisions in the absence of data, unacceptably shifting the burden of risk onto individual women and persons who must decide what is best for themselves, their baby and their families in the absence of reliable information,” the statement reads.

It continues: “It is critical that all those involved in TB research move toward the routine inclusion of pregnant and breastfeeding women and persons in research. Evidence-based guidelines and care practices depend on generating this data through research inclusion. Continued exclusion from research means that pregnant and postpartum women and persons 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 in the study, explains that pregnant women were not included from the outset of the clinical trial, but about halfway through they updated the study protocol to allow pregnant 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,” Conradie tells 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 in the study, Conradie says “the reason for their inclusion is that 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,” she says, adding that 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 pregnant women 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 says.

Valuable data

Dheda says the study provides data that will make clinicians more comfortable with prescribing delamanid for pregnant women. However, he stresses that 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 is no data about the use of this drug in pregnancy. Pretomanid 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 patient 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 who present 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,” she says. DM

This article was first published by Spotlight – health journalism in the public interest. Sign up to the Spotlight newsletter.

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South Africa

Risks to developing foetus

The status quo

Not good enough?

Breaking the mould

Valuable data