Pregnancy, Medicine & Risk

Pregnant women get sick. Women with chronic illnesses get pregnant. Yet very few drugs have ever been tested for their effects on pregnant women. Understandably, there has been a long-standing ethical reluctance to test drugs that could harm a fetus, but that is changing. Having no information leaves doctors guessing when they do have to prescribe a drug. Some say the lack of testing on pregnant women puts the entire group of pregnant women and fetus’ at a much higher risk of harm because drugs are not tested on their behalf.

In December 2014 the FDA began requiring that whatever research-based information is available be listed on drug label inserts. Drugs that have been on the market for a long time have much more information for pregnant women and fertility because they’ve been used by the general population longer. Over the past several decades observational studies (after the fact) have shed some insight on safety — even though they do not meet the gold standard of research (double-blind placebo comparison), they can be very helpful. Pregnant women are being included in some studies now.

Just test which drugs can cross the placental barrier, ban those for pregnant women and we’re done, right? It’s not so simple.

Previously there was little information on the drug package insert about what safety risks are known, and not known. Doctors could check a drug classifications list, which is helpful but it holds only very general information. Drugs were identified as being in classes with “A” indicating the medication was safe during pregnancy and “D” and “X” signaling the drug was declared dangerous and never to be used in pregnancy. To find more detail doctors and patients would have to do their own research.

It doesn’t seem like research should be such a big deal — just test which drugs can cross the placental barrier, ban those for pregnant women and we’re done, right? It’s not so simple.

Pregnancy Changes Everything

The concern is broader than which drugs can reach a baby in utero. Pregnancy changes how a drug moves through the woman’s body. Higher blood volume lowers the amount of drug in her body, and her kidney processes and expels the drug out of her body very quickly, among other factors. An NIH article gives a brief, interesting explanation of why this happens.

The third affected group are women and men who have “reproductive potential” (the FDA’s choice of words, not mine!). There are drugs that if taken by either a woman or a man before a child is conceived create problems. All 3 of these issues are now required to be addressed, at least as far as they are known, on every prescription drug package insert.

If you choose to take a drug during pregnancy, you can check to see if you can join a drug registry. Registries will now have to be listed on the package insert. Pregnancy exposure registries are not managed or run by the FDA and not all drugs have a registry. Organizations or companies can sponsor them. Many, but not all, can be found here. If you are prescribed a drug and join that registry, you will be helping scientists gather information to help pregnant women in the future. And presumably by being on a registry’s list you should get a warning if harmful effects become apparent in the future.

When will the drugs already in clinical use have the new labeling? Depending on when the drug was approved, the drug company has to submit new content (pdf) 3, 4 or 5 years from now. And then the FDA has to review and approve it before it gets into the package. So don’t expect a lot of information quickly.

Another disappointment: The information is nearly incomprehensible for a layperson. I asked the FDA for a sample of a new warning and here’s what they sent on a drug that was just approved. This is just the part for pregnant women. Click here to see a pdf of the full label. Example:

Based on its mechanism of action [see Clinical Pharmacology (12.1)] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

What does that even mean?

I’m thrilled that the FDA has acknowledged that the public needs to be warned when drugs have the ability to harm a fetus in the womb and even before he or she is conceived. For too long women believed their doctors that the placental barrier would protect the fetus. Groundbreaking public service efforts in the 1960s and 1970s convinced the public that smoking and drinking does cross the barrier and harm the fetus. These campaigns were so successful that one rarely sees an obviously pregnant woman with a cigarette or a drink — and strangers feel empowered to publicly chastise her if that happens.

Yet 40 years later 70% of pregnant women are taking at least one prescription medicine during pregnancy. Yikes! But for a woman battling depression, chronic pain, epilepsy, asthma or other chronic or life-threatening conditions, taking some medicine might save both her life and that of the fetus. Not taking any medicine might not be a choice for certain women. But knowing which medicine has the fewest safety risks is a pregnant woman’s right.

Suzanne B. Robotti

Suzanne Robotti founded MedShadow Foundation in 2012. Learn more about Su and her mission.

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