Why pregnant women are excluded from TB clinical trials

Pregnant women are typically excluded from clinical trials of new tuberculosis medicines, and 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.

The World Health Organisation (WHO) estimates that every year, around 200,000 pregnant women fall ill with TB. In addition to the danger TB poses to the health of these women, it is also associated with an increased risk of adverse pregnancy outcomes such as prematurity, low birth weight, and stillbirths.

Prof Keertan Dheda, a general physician, pulmonologist and critical care specialist, confirmed to Spotlight that pregnant women are frequently excluded in clinical trials as 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,” said Dheda, who heads up the University of Cape Town's Division of Pulmonology and Respiratory Services at Groote Schuur Hospital.

Another reason pregnant women have been excluded, Dheda said, was because 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,” he said.

However, according to Dr Marian Loveday, senior scientist at the South African Medical Research Council, the issue is broader than just TB.  

“Pregnant women are usually not included in any clinical trials (not only TB clinical trials) due to safety concerns for the developing foetus.”

Dr Limakatso Lebina, clinical trials unit lead at the Africa Health Research Institute, pointed out that there were also thorny ethical considerations, such as the fact 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, she said.

Due to such reason, much data on the safety of new medicines in pregnant women have been gathered in a somewhat roundabout way, she said.

“In many clinical trials, one of the inclusion criteria is that females with childbearing potential should be on reliable hormonal contraceptives,” she said. "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 are then typically followed up for at least one year post-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 draw-back 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 sparce and patchy."

However, a TB clinical trial conducted in SA has gained attention for specifically involving pregnant women in its study. Called BEAT Tuberculosis, the study was conducted by the Isango Lethemba TB Research Unit, a subdivision of Wits University's 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 Dinizulu Hospital Complex in KwaZulu-Natal.

Dr Francesca Conradie, an infectious diseases researcher in the School of Clinical Medicine at Wits and the principal investigator of the study, said pregnant women were not included from the outset of the clinical trial, but that around 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 in the study.

This may sound like a few “but it is more than any other study in the world".

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 said. – Spotlight