‘Not doing anything is causing harm’: Call to allow pregnant women to participate in clinical trials

When she became pregnant after careful planning and medical support, Angelie O’Brien was faced with a choice women’s health experts say she should not have had to make: take medication that had not been trialled in pregnant women for her chronic disease, lupus, or risk potential disaster.

“I kind of got to a point where I was obsessing about whether or not I had the right information … Some of the information on the internet is very conflicting because there’s been no research to make an informed choice,” says O’Brien.

She would have learnt that as with conditions including hypertension, epilepsy, depression, psychosis, asthma and diabetes, leaving lupus uncontrolled can be catastrophic for mother and baby, including death for either or both.

The risk of maternal death for women with the chronic autoimmune disease is more than 20-fold that of other women, and it can also cause preeclampsia, miscarriage and stillbirth, prematurity and fetal growth retardation.

But because pregnant women have been systematically excluded from clinical trials for 90 per cent of medications available worldwide, specialists must rely on what Duke University rheumatologist Megan Clowse has dubbed “best-guess treatment”.

The long-standing resistance to allowing pregnant women in clinical trials that could improve their own and their baby’s health is “protectionist”, gender-biased and harmful, an Australian-led group of 11 international researchers said in a paper published on Thursday.

On Friday, Victorian Health Minister Mary-Anne Thomas told a conference on closing the research gender gap that not allowing women, including pregnant women, to participate in such trials was discriminatory, harmed women’s health, and was a cause for women being up to 75 per cent more likely to have adverse drug side effects than men.

Associate Professor Kirsten Palmer, deputy head of the Maternal Fetal Medicine unit at Monash Medical Centre, is one of many Australian women’s health specialists calling for pregnant women to be given the option of inclusion in clinical trials.

The safety information on most drugs taken by pregnant women comes from others who have taken them, largely unsure of whether they are safe, she says. This “striking lack of data” means they and their clinicians have to make decisions on starting or continuing medicines based primarily on observational evidence.

Some stop using them or are no longer prescribed medications they need, such as antidepressants, because of unproven concerns about the risks such medications pose to developing babies.

“We’re causing harm because women are being exposed to a lack of evidence to inform their best care … not doing anything is causing harm,” said Palmer, an obstetrician and researcher.

Lack of data means pregnant women often need to use off-label drugs considered to be safe, but with worse side effects, or which are less effective than modern alternatives. Or they need to use more drugs, some of them repurposed, to manage their condition.

Such drugs can be in short supply, as is currently the case with blood pressure medications for pregnant women, because they are unattractive for makers and importers.

“Hypertension is one of those scenarios,” says Palmer. “We’ve got drugs from the ’50s and ’60s where we’ve got a lot of [observational] data, but because they’re ... old and off-patent, so there’s not much money to be made for drug manufacturers.

“Over the last several years we’ve had periods of profound shortages in access to those drugs.”

Reluctance to allow women of childbearing age onto any phase of drug trials resulted from the Thalidomide tragedy of the 1950s and early ’60s, but Palmer and other researchers said thorough background, pre-clinical and animal research coupled with close regulatory oversight and monitoring can enable development of trials in human pregnancy.

“We’re finding that pregnant women are incredibly keen to have the opportunity to be involved in research … about 30 per cent will say ‘yes’ to participating in a clinical trial, particularly when it is trial treatments for complications they are experiencing,” she said, so long as good oversight and constant assessment is in place.

“Pregnant women understand the conundrum they face; they hope it might help them but also they are hoping altruistically to make things better for the women who are going to follow them.”

‘Pregnant women are very capable of making informed decisions about whether they would like to be part of a clinical trial.’

Professor Michelle Giles, infectious diseases specialist

The United States and the United Kingdom have moved to develop regulatory frameworks for drug research including pregnant and lactating women, and Palmer says Australia risks falling behind.

Infectious disease physician Professor Michelle Giles said considering pregnant women earlier for inclusion in vaccine research, for example, could potentially save lives, especially if the disease is more severe in pregnancy.

“Pregnant women are very capable of making informed decisions about whether they would like to be part of a clinical trial or not,” said Giles, a professor in the Monash University department of obstetrics and gynaecology, and an infectious disease researcher at Melbourne University.

“They make informed decisions all the time about other investigations, tests and medicines and we need to respect the fact pregnant women can make those decisions.”

A “whole of society shift in attitude” was required, she said.

Head of rheumatology at Monash Health, Professor Eric Morand, agrees. The potentially fatal disease of lupus primarily affects women (especially those of childbearing age), but none of the revolutionary new medications for it – including the most recently TGA-registered drug, anifrolumab  – have included women on the trials.

This is despite the fact there is reason to believe it could be used safely, he said. “The risks of trials of novel therapies in pregnancy are significant because you’re in the unknown and the stakes are high … but in some case, risks could be calculated with a certain amount of confidence,” he said.

Especially for a disease which posed such grave risk to mothers and babies, Morand recommended “moving away from always saying no [to pregnant women being permitted in trials] to one where we can consider what the current benefit would be and into the future”.

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