Pregnancy is a glaring, but largely unaddressed, blind-spot in our evaluation of prescription drugs. Pregnant women are almost universally excluded from clinical trials, leaving physicians with no guidance on how to manage the pre-existing conditions that so many pregnant women have. The problem, though, goes much deeper. Until recently, most women were prevented from enrolling in clinical trials, creating disparities that may persist today.
Majority Of Pregnant Women Take Prescription Drugs
Over two-thirds of women are prescribed some sort of prescription drug during pregnancy, according to Maisa Feghali, MD, an obstetrician at the University of Pittsburgh. Few of these medications, however, have been adequately-studied in pregnant women.
For obvious reasons, many women head into pregnancy with pre-existing medical conditions, including some disorders that can threaten their own health, along with the lives of their children, if left untreated. It’s critical to strike a balance here, one between adequately treating health conditions and identifying prescription drugs that can themselves be dangerous during pregnancy. But as English physician Simon Thomas argues in the British Journal of Clinical Pharmacology, medical researchers have yet to find this balance.
All too often, that leaves pregnant women, who are more likely to die from pre-existing health conditions than from pregnancy complications, at the mercy of their underlying disorders.
Pregnancy Can Have Major Effect On Drug Safety, Efficacy
The careful and well-informed prescription of drugs remains absolutely critical for many pregnant women. Staying well-informed, though, is nearly impossible. Where clinical trials are concerned, pregnant women are usually excluded as a matter of course, as researchers struggle to manage the obvious ethical implications of administering unproven drugs to mothers and their unborn children.
This leaves physicians with little information to guide their prescribing decisions.
To complicate matters, pregnancy is a complex biological process, one that initiates a host of chemical and hormonal changes. These dramatic alterations can have major implications for the way drugs act inside the body and react to the body. Due to a fundamental lack of relevant clinical data, however, we often have no way of knowing how pregnancy will affect the action of a drug until numerous pregnant women have already taken it.
Are Women Under-Represented In Drug Clinical Trials?
The real issue may be even more fundamental. Most of what we do know about prescription drugs comes to us from clinical trials that are disproportionately male. As numerous researchers have found, the problem isn’t just that drugs aren’t studied in pregnant women. It’s that women are under-represented in medical research.
Many experts argue that female patients are routinely, if not systematically, eliminated from clinical trials, studies that provide us the best evidence on how drugs work inside the human body. That’s true despite the fact that women take nearly 80% of the pharmaceuticals prescribed in America.
Take Valium as one example. The drug, commonly used to treat anxiety disorders, is taken by around 2 million women every year – but the clinical trials on which it was approved didn’t include any female patients.
Why Have Women Been Left Out Of Clinical Research?
Historically, researchers often excluded women from trials altogether, regardless of the study’s topic. Analysts at Northwestern University have shown that up to 11% of the clinical trials published by the world’s most prestigious journals in 1971 ruled out female participants explicitly in their designs.
Money & Complexity
On one level, the reason for this exclusion is pretty straightforward: men are “easier,” and cheaper, to study. Medical researchers have long-argued that the reproductive cycle, from ovulation to menstruation, complicates their trials and increases the cost of doing research unreasonably. This reasoning extends even to animal trials, in which male rats are often studied to the exclusion of female ones.
The reasoning isn’t totally false. Over the course of her menstrual period, a woman’s hormone levels will change dramatically. These changes can have a big impact on the way drugs work, but if you naively compare two women at different points in their menstrual cycle, you could miss crucial insights. The result is that many well-designed studies on women need to include more control groups to balance out the distorting statistical effects of hormonal variations. More control groups, of course, means more money, but this isn’t a particularly good argument if your focus is on health and safety.
The exclusion of women from clinical trials, though, isn’t entirely an accident of market economics. It’s very much by design, says Marianne Prout, MD, an epidemiologist at Boston University.
In 1975, Congress passed a slate of legislation intended to protect “vulnerable patients” from being mistreated by medical researchers. Among these vulnerable populations were pregnant women, but the law’s true intention was to protect fetuses, not women, from being exposed to potentially-harmful drugs in clinical trials. As Prout explains, “the most certain way to protect fetuses was to exclude all potential fetuses from research, thus excluding all women of childbearing age.” Feminists have criticized these laws for treating all women as “walking wombs.”
More recent regulatory changes have reduced the view that all women are “potential pregnancies,” and thus unfit to be clinical trial participants. As a result, explicit exclusion has been reduced in recent years. In 1991, only 3% of the clinical research published by the Journal of the American Medical Association, the Lancet and the New England Journal of Medicine included no female patients.
Researchers continue to discourage women from participating in their trials, often for pregnancy-related reasons. Even when consent documents don’t actively advise women against enrolling, the majority of clinical studies require that female patients use contraception during the study period, according to obstetricians at Penn State University. That can put a burden on women, preventing them from participating altoghether.
Awareness & Outreach
Clinical trial participants aren’t just gathered at random from the population; they are actively recruited and enrolled by researchers. In this respect, scientists are engaged in an uphill battle, especially in the United States, where scientific literacy is remarkably low.
In an intriguing survey conducted by the National Cancer Institute, government analysts discovered that as many as 40% of Americans don’t understand the idea behind a clinical trial, let alone how to ask their doctors about participating in one. This lack of understanding tilts to the disadvantage of female patients; while 38% of male respondents reported having heard about clinical trials, only 31% of female respondents did.
Do Researchers Still Study More Men Than Women?
Whether female patients are over- or under-represented in clinical studies today remains a matter of heated debate. In recent years, members of the so-called “Mens’ Rights Movement” have argued that it’s not women, but men, who are under-represented in the medical literature.
A cursory look at the evidence would seem to support the Mens’ Rights Movement’s argument. Analyzing a wide array of clinical trials conducted between 1966 and 1998, researchers at Johns Hopkins University reported that nearly 61% of all clinical trial participants were female. That number, however, only takes a relatively small sample of clinical trials into account, namely those that report the sex of participants. Far more studies, between two-thirds and three-fourths of those funded by the National Institutes of Health, do not provide sex-specific analysis.
There are many ways to parse this data, as Marianne Prout has forcefully argued. Delving deeper into the statistics, we find strong disparities in representation that persist, even as the explicit exclusion of female participants has trended downward.
Some trials are designed to look into issues of women’s health, while others are meant to investigate conditions that affect only men. These “sex-specific” clinical trials are obviously necessary, since male and female patients suffer from unique medical conditions, and can be affected in unique ways by the same medical condition. But sex-specific trials can also skew the data on who is more likely to be studied overall. Out of necessity, a sex-specific trial designed to investigate women’s health issues will include only female participants. Failing to take these sex-specific trials into account can make it look like women are actually over-represented in medical research, contributing to the false conclusion that men are the ones being excluded from clinical trials.
Overcoming The Bias Of Sex-Specific Clinical Trials
What we should study instead are those clinical trials that don’t take sex into account at all, studies designed to investigate a medical condition irrespective of a patient’s sex.
When researchers at Yale looked at clinical trials funded by the National Heart, Lung and Blood Institute from 1993 to 1998, they found that a slight majority of the participants, 54%, were female. Remove studies designed to investigate sex-specific cardiovascular problems, however, and their findings came out differently. Women accounted for only 38% of the participants in clinical trials that didn’t exclude male or female patients by design. This is a problem. Studies like the one from Yale suggest that medical researchers look at way more male than female patients, even when their studies are designed to ignore the sex of participants.
Even post-clinical studies, often mandated by the FDA to follow up on the effects of drugs with questionable safety profiles, are skewed in a distinctly-male direction. In a 2014 study, researchers from the agency’s Center for Devices and Radiological Health found that post-approval studies routinely enroll more male participants than female ones. Out of 89 studies, a full 17% included 4 male patients to every 1 female patient, despite significant, and clinically-relevant, distinctions between male and female biology. Most studies, up to 67%, represented at least some imbalance between the sexes, with fewer than 50% female participants.
Putting Dollars Behind Women’s Health
This bias in medical research has not gone unnoticed. In the wake of several major failures, including a trial on aspirin that enrolled 22,071 men and 0 women, the National Institutes of Health established its Office of Research on Women’s Health in 1990. As Londa Schiebinger, an historian at Penn State University, writes, the Office’s two primary goals are intimately intertwined:
- to support the recruitment and advancement of women in the biomedical professions
- to ensure that research supported by the National Institutes of Health adequately investigates conditions that affect women
In tackling these admirable goals, however, the Office of Research on Women’s Health was hampered by inadequate funding. In more recent years, the Office’s budget has increased by a remarkable degree. For 2003 and 2004, the National Institutes of Health devoted 13.1% of its annual budget to women’s health issues. Trials concerned with men’s health, on the other hand, received only 5.8% of the agency’s funding dollars.