As women have children later and later in life, the need to take medications during pregnancy is on the rise. Unfortunately, because very few studies have been conducted on how medications work in pregnant women, we’re really in the dark as to what kind of effects they have on both women and their fetuses. But new legislation aimed to address this lack of knowledge has finally been proposed.
Pregnant women are warned against eating or drinking many things—alcohol, caffeine, sushi, soft cheeses, to name a few—and when it comes to medication, similar precautions are taken. The problem is we actually have no idea how most medicines affect pregnant women or her fetus.
“I think it’s very important for anybody taking care of pregnant women on medication to understand that there are significant risks to not treating pregnant women,” says Maged Costantine, an Ob/Gyn and Associate Professor in the Department of Obstetrics and Gynecology at the University of Texas Medical Branch.
And women definitely take medicine while pregnant. One study reported that in 2008, more than 90 percent of pregnant women took at least one medication, prescription or over-the-counter, at some point during their pregnancy. And as the average age for first-time mothers is increasing, the need for medication is increasing both because they’re at greater risk for developing complications that need to be treated and because they’re already treating chronic age-related issues like hypertension or diabetes.
But women’s bodies change drastically during pregnancy and those changes affect the way the body responds to and breaks down medications. Blood volume and heart rate increase, movement through the gastrointestinal tract slows, the kidneys filter the blood faster, and enzymes in the liver that break down medications become more or less active depending on the enzyme. “That’s just pure, natural pregnancy,” says Maisa Feghali, an Assistant Professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences in the Magee-Women’s Hospital at the University of Pittsburgh Medical Center. “That happens to every single pregnant woman.”
“Most of these changes ultimately would affect how the body handles drugs during pregnancy,” says Costantine. The increase in blood volume can decrease the concentrations of proteins in the blood that bind to and effectively neutralize drugs. With less binding, more of the drug is available to have an effect. The slowed gastrointestinal system can give more time for medications to be absorbed into the bloodstream. And maybe most importantly, changes in kidney and liver activity can lead to medications being filtered out of the body faster.
“In other words, that means they have a very efficient elimination system for drugs and substances in their body,” says Shinya Ito, the Clinical Pharmacology and Toxicology Division Head at the Hospital for Sick Children in Toronto.
This mix of effects can have different results depending on the medication. For some drugs it might mean that they have a stronger effect even at the same dose. For others it could mean the exact opposite, at the same dose the drug is much less effective. But for most medications, we have no idea how they work in pregnant women because we’ve never studied it. And with such little information, some pregnant women choose to err on the side of caution, which could mean suffering through pain, discontinuing antidepressants, and putting themselves at risk of disease.
There are a few reasons for this. First, there’s the fear of harming the fetus. In the 1950s the drug thalidomide was prescribed to pregnant women as a way to treat morning sickness. But after thousands of babies were born with limb deformities, it became clear that medications taken by a pregnant woman posed a risk to the fetus she carried.
This was further emphasized by diethylstilbestrol, a drug once thought to prevent miscarriages and later found to cause vaginal tumors in females exposed to it in the womb. Pregnant women and even women of childbearing age were then explicitly excluded from clinical trials for some time. Once the underrepresentation of women in clinical trials was recognized as a problem and including them in trials became a priority in the 1990s, it was strongly suggested that they either use contraception or abstain from sex while taking part in trials. Currently, up to 95 percent of late-stage clinical trials still explicitly exclude pregnant women.
Other reasons are more financially-based. “The market for pregnant women is much smaller than the general market,” says Costantine. This means drug companies don’t want to take a risk on a smaller slice of the market, especially when there are no regulations in place to protect them from legal action if something went wrong.
If a woman needs a medication while pregnant or was already using one prior to pregnancy, her doctor has to anticipate and measure any potential changes in its therapeutic effect. “For some drugs you follow the concentration in the blood and adjust the doses accordingly,” says Costantine.
Alternatively, “if you don’t test the drug levels, you follow the patient clinically,” Costantine said. This means the doctor would take extra care to see if the drug was doing its job. Is the mother’s pain being managed? Is her blood pressure in check? Is her mental health being adequately treated? And if not, they could adjust their prescription accordingly, either by changing the dosage of the drug or how often it’s taken.
But we’re not entirely in the dark. In a recently published paper, Ito and his colleagues compiled all of the studies that actually looked at how medications were affected by pregnancy. And while there weren’t many, among the 121 drugs that were studied, decreased drug exposure was found across all drug classes. Meaning, even at the same dosage, less of each drug was available for action inside the body. And for the most part, this was due to the kidney and liver breaking down and filtering out the drugs more quickly.
Changes in how pregnant women’s bodies interacted with the medications were found for antibiotics, antidepressants, anxiety medications, anti-seizure medications, pain medications, anesthetics, cardiovascular treatments, antiretrovirals, and antimalarial medications.
However, many of these studies didn’t actually assess, or at least didn’t report on, if the drug break-down and filtering changes affected how the drug was actually treating the patient. None of the studies examining antibiotics, pain medications, or anesthetics reported that kind of information. But addiction management and antidepressant studies found that the reduced drug exposure also came with diminished treatment effects. Antimalarial medication studies found some mixed effects. Some reported the drug to be less effective while others reported no changes, despite reduced drug exposure.
Mixed outcomes were also reported for antiretrovirals, which are used to control HIV in infected patients. Most showed that even with reduced drug exposure, the amount of the virus that could be detected in the blood was still suppressed in pregnant women with HIV. But one study reported that for some pregnant women, the amount of detectable virus increased during pregnancy even with the standard antiretroviral dosage. In one case, the virus was detected in the woman’s child after birth. The study noted that sticking with standard dosages during pregnancy may result in unnecessary mother-to-child HIV transmission. With such compelling evidence from just a few medications, it’s clear that this is an area to focus on.
To do that, Costantine stresses that there must be a legislative push to emphasize this kind of research. “Legislation has to be an important part of this,” he says and notes that support of this kind of legislation from organizations like the Obstetric-Fetal Pharmacology Research Unit Network could help. One bill has been introduced in the House of Representatives to address this. The “Safe Medications for Moms and Babies Act of 2016” was introduced in May of last year and calls for the creation of a task force that specifically addresses the lack of knowledge surrounding medications used by pregnant and lactating women. It’s currently being reviewed by the Subcommittee on Health.
Not long ago, the drug testing industry went through a similar situation with children. Drugs tested solely in adults were being prescribed for children even though we had no data on how those drugs would or wouldn’t work in kids. And even across ages drugs would likely behave differently. A newborn and an adolescent aren’t the same. “I think first and foremost there should be a regulatory support similar to the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act,” says Feghali. These acts required drug companies to study medications in children under certain circumstances and provided incentive to do so in the form of six additional months of marketing exclusivity if they did. Costantine agrees that this is a good model to work from.
Ultimately, however we manage it, this knowledge gap is unacceptable. “We cannot tolerate this situation,” says Ito, “We don’t have good evidence or information to prescribe drugs for pregnant women. It’s getting better but we need to do more.”