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IT IS generally accepted that the best way to confirm that a new drug or therapeutic is both safe and actually works is to test it in clinical trials, administering it to a wide range of people in an attempt to discover any unexpected effects. But there is one group we don’t usually test: pregnant people, meaning pregnant women, pregnant trans men and anyone outside those categories who is pregnant.

Until recently, there was near unanimous agreement that exposing a fetus to a drug under study is unethical, leading to holes in what we know about the safety and use of medications in pregnancy. Now, in a seismic shift spurred on by the coronavirus pandemic, medical ethicists have said that the continued exclusion of people who are pregnant or lactating in biomedical research is wrong, given the heightened risks of severe infection and disease that many of them face.

For example, found that one-quarter of women aged 15 to 49 who were hospitalised with covid-19 between 1 March and 22 August 2020 were pregnant. Only 5 per cent of US women in this age group are pregnant at any one time, suggesting a much higher rate of hospitalisation due to covid-19.

As the US vaccination roll-out began last year, the CDC created a smartphone app to monitor recipients for any health problems. Pregnant people who received a covid-19 vaccination within the 30 days before their last menstrual period or during pregnancy could report any post-vaccination side effects.

at Cornell University, New York, says these well-intentioned efforts don’t make up for not collecting this data during the initial vaccine trials. “According to the [CDC], 100,000 pregnant women have been vaccinated against the coronavirus,” says Riley. “Those women made the decision that the risk of the vaccine was less than the risk of getting and doing very poorly from covid, which is a clear possibility.”

It didn’t have to be this way. In 2018, the US Food and Drug Administration (FDA) released saying that filling the knowledge gaps about medications during pregnancy was a “critical public health need”. When the revised US research regulations went into effect in January 2019, pregnant women were no longer designated as “potentially vulnerable to coercion or undue influence”, opening the door to including them in trials.

at the University of Pittsburgh, Pennsylvania, leads numerous investigations into the study of immunisations and therapeutics in pregnant and lactating women. He says we need to think differently about how we approach research and pregnancy.

Time for change

“In a little over a decade, we’ve had three to four disease outbreaks that were very relevant for pregnant women,” says Beigi, referring to the H1N1 swine flu pandemic in 2009, the 2013 to 2016 Ebola outbreak in West Africa, the 2015 to 2016 Zika virus epidemic in the Americas and the current coronavirus pandemic. “The best way to protect and serve pregnant women is through research.”

Evan Myers sits on the ethical review board at Duke University, North Carolina, and evaluates the justification and methods used to exclude pregnant people from research trials. He says the tide began to turn about 20 years ago, but has accelerated in the past decade because there has been a recognition that scientists and researchers probably overcorrected after the effects of thalidomide taken in pregnancy were seen in the 1960s (see “Thalidomide tragedy”).

“There are many things we don’t know because it’s very rare that a pregnant woman would have been included [in the clinical trials] and so there’s no data at all,” says Myers.

For decades, most clinical trial guidelines globally have included provisions intended to prevent pregnant participants. Oversight committees minimised the likelihood of pregnancy while trials were underway by requiring participants to agree to use contraception and take regular pregnancy tests. Those who became pregnant were removed from the trial.

The justification has always been to protect them and their fetus from harm, but Myers says this is often unnecessary.

“We keep pregnant people on medications, yet very few have actually been truly studied in pregnancy”

“These consent forms might have a whole page about the risk to a pregnancy when it’s really not applicable,” he says. “I often see this for studies for women who have heart failure. If a woman with heart failure gets pregnant, there’s a 50 per cent or higher chance that she’ll die during pregnancy. If she did get pregnant, any physician would recommend she have an abortion to save her own life.”

Instead, trials should take into consideration the likelihood of a pregnant person being a candidate for a drug, and balance that against the risk of embryonic or fetal harm based on data from animal studies, says Myers. This would help pharmaceutical firms decide at which point in their research they should gather data on pregnancy. “Lower theoretical risk of embryonic/fetal harm and high likelihood someone who has the condition might be pregnant argues for as early as possible,” says Myers.

The current overly cautious approach has led to profound knowledge gaps about the safety and efficacy of medications during pregnancy even as more people become pregnant later in life and so are more likely to have chronic conditions that require ongoing treatment. According to the FDA, in the US say they take at least one medication.

“We keep them on those medications, yet very few of them have actually been tested and truly studied in pregnancy,” says Riley. “In addition to the safety of medications, it’s not even clear that we’re using the right dose because the physiology of pregnancy is different.”

Even though there is wide agreement that pregnant people should be included in research, how to do this is less clear. A group set up to advise the US Secretary of Health and Human Services on the issue made a number of recommendations in a .

Industry buy-in

Suggestions included increased funding to allow the collection of better drug safety data before human trials begin and encouraging trials to be designed to capture long-term outcomes for pregnant people. It also recommended training more researchers to have expertise in obstetric and lactation drugs and therapies and promoting the importance of research in pregnant and lactating people.

The group also suggested incentivising pharmaceutical firms to develop products for conditions specific to pregnancy by, among other things, reducing their liability by implementing a no-fault system for injury claims. Similar litigation schemes already operate for claims about potential harms caused by vaccines in countries including the US and UK.

Getting this buy-in from the pharmaceutical industry is probably the biggest challenge. Miscarriages and congenital disabilities are fairly common, so establishing a link to a new drug would require a study with a large sample size, which is more difficult to run. “It would cost a lot to demonstrate safety and that wouldn’t completely eliminate the chances of legal claims, and the size of the potential market isn’t very big,” says Myers.

In other words, if we want pregnant people to be included in clinical trials – and we do – then someone is going to have to pay for it.

Thalidomide tragedy

Thalidomide pills are shown in this undated photo. Prescribed in the late 1950s for morning sickness and as a sedative, the drug was banned in 1962 after causing birth defects. New Jersey-based Celgene Corp. won Food and Drug Agency (FDA) approval to use the drug against a painful side-effect of leprosy known as erythema nodosum leprosum.

The exclusion of pregnant people from clinical trials is largely about avoiding another thalidomide. The drug first became available in Germany in 1956 as an anti-flu drug, and was then marketed as a sedative in 1957. By 1960, it was available in 46 countries, and used to treat nausea in early pregnancy, despite a lack of testing in pregnant people.

At the time, scientists didn’t know that drugs could cross the placenta and harm a fetus. It took five years to connect the thalidomide taken by pregnant people to the shortened or missing limbs of their babies. Researchers later found that it only had an impact in the early weeks of pregnancy – after 37 days post-conception, the drug had no effect on the fetus.

The UK government warned against the drug’s use in May 1962. The US Food and Drug Administration never approved thalidomide because of incomplete and insufficient data.

This episode led to changes in the way drugs are approved around the world. Drugs intended for human use must now be tested in humans, not just in animals, while those marketed to pregnant people must have been shown to be safe for use in pregnancy.

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