It is best to avoid any new drug in women of childbearing potential or during pregnancy if an older agent with human pregnancy experience exists. However, this is not always possible, because the new drug may be a major breakthrough or is the only or most efficacious drug for the indication. So, how do you counsel the patient about a drug’s risk to the embryo or fetus when there is little or no human pregnancy data?
By Gerald G. Briggs
Fortunately, the package insert provides data for three factors that can be used to give some estimate of risk: pharmacologic class, potential to cross the placenta, and animal reproduction data. Although all of the factors are important, the animal data are often the best source for estimating human risk. The book "Drugs in Pregnancy and Lactation," which I coauthored, defines the levels of risk (low-moderate-high) that I use to evaluate the animal data.
In 2011, the Food and Drug Administration approved 30 new drugs and biologics. Because they are unlikely to be used during pregnancy or lactation, the following 10 new drugs will not be reviewed here: abiraterone (Zytiga; pregnancy risk category X) for prostate cancer; adenovirus type 4 and type 7 live virus vaccine (X), for prevention of febrile acute respiratory disease; azficel-T (LaViv; C), for nasolabial fold wrinkles; centruroides (Anascorp; C), for scorpion envenomation; Coccidioides immitis skin test antigen (Spherusol; C); gabapentin enacarbil (Horizant; C), prodrug of the antiepileptic gabapentin for restless legs syndrome; gadobutrol (Gadavist; C), a contrast agent for MRI of the central nervous system; ioflupane I123 (DaTscan; B), for single-photon emission computed tomography (SPECT) brain imaging; and two drugs for chronic obstructive pulmonary disease: indacaterol (Arcapta Neohaler; C) and roflumilast (Daliresp; C).
Of the remaining 20 drugs, only one has human pregnancy data: factor XIII concentrate human (Corifact; C). The new drugs can be categorized into 10 pharmacologic classes: 2 anticoagulants, 1 anticonvulsant, 1 antidepressant, 1 antidiabetic, 1 antihypertensive, 4 anti-infectives, 5 antineoplastics, 1 dermatologic, 2 hematologics, and 2 immunologic agents.
Rivaroxaban (Xarelto; C), a factor Xa inhibitor, is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent deep vein thrombosis in patients undergoing knee or hip replacement surgery. The drug crosses the human placenta, and the animal data suggest risk. Ticagrelor (Brilinta; C) is a platelet inhibitor indicated for reducing the rate of thrombotic events in patients with acute coronary syndrome. The animal data suggest risk, and the drug probably crosses the placenta. Although both of these agents are best avoided in pregnancy, the maternal benefit in some cases may outweigh the unknown embryo-fetal risk.
The animal data suggest risk if ezogabine (Potiga; C), an oral anticonvulsant indicated as adjunctive treatment of partial-onset seizures, is used in pregnancy. If used in pregnancy, the woman should be advised of the absence of human data. Pregnant women taking ezogabine are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
The new antidepressant is vilazodone (Viibryd; C), a selective serotonin reuptake inhibitor. As with other SSRIs, the potential developmental toxicity includes spontaneous abortion, low birth weight, preterm delivery, neonatal serotonin syndrome, neonatal withdrawal, abnormal behavior beyond the neonatal period, and persistent pulmonary hypertension of the newborn. However, the benefits of vilazodone may outweigh the risks and must be evaluated on a case by case basis.
Linagliptin (Tradjenta; B), a dipeptidyl peptidase-4 inhibitor taken orally, is indicated for type 2 diabetes. Although the animal data suggest low risk, the lack of human pregnancy data prevents an assessment of its effect in a condition requiring tight control of glucose. Insulin remains the gold standard, but other oral agents, such as glipizide, glyburide, and metformin, have been effective in selected cases.
Azilsartan (Edarbi; D) is an angiotensin II receptor blocker used for hypertension. As with all agents in this class, severe fetal toxicity, including death, is a potential complication if it is used in the second half of pregnancy.
Two of the new anti-infectives are protease inhibitors used for chronic hepatitis C infection: boceprevir (Victrelis; B) and telaprevir (Incivek; B). Although both drugs carry an FDA rating of B, they must be used in combination with ribavirin (contraindicated in pregnancy) and peginterferon alfa. Thus, they should not be used in pregnancy.
Fidaxomicin (Dificid; B) is an oral macrolide used for Clostridium difficile–associated diarrhea. Only minimal amounts are absorbed and, like other macrolides, such as erythromycin, the drug is probably compatible with pregnancy. Rilpivirine (Edurant; B) is a non-nucleoside reverse transcriptase inhibitor used in combination with other agents for HIV-1 infections. Animal data suggest low risk, but there are no human pregnancy data. However, the maternal benefit appears to outweigh embryo-fetal risk.