Commentary

The 50-year quest for better pregnancy data


 


Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.

The search for information

The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.

Female doctor giving a bottle of pills to a pregnant woman Purestock/Thinkstock
My first edition (Briggs et al., Drugs in Pregnancy and Lactation) came out in 1983 and was followed in 1993 by James L. Schardein’s book (Chemically Induced Birth Defects). In 2001, the first edition of the European book by Christof Schaefer et al. (Drugs During Pregnancy and Lactation) was released.

Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.

Gerald G. Briggs

Gerald G. Briggs

The biggest unanswered question is why so many drugs have minimal, if any, human pregnancy and breastfeeding data? In my 11th edition (in press), about 1,443 drugs are reviewed. The majority have little or no human pregnancy data. The situation is even worse for breastfeeding data. In either situation, it places the clinician in a difficult position. How do we inform the patient regarding the potential embryo, fetal, or nursing infant risk? If the maternal benefit from the drug clearly outweighs the unknown risk, then the clinician can explain this to the patient. However, such situations appear to be infrequent and, in breastfeeding, the infant can be bottle fed. In contrast, in most pregnancy cases the comparison of the maternal benefit to the potential embryo/fetal risk is unknown. So what does the clinician do?

My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).

The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Learning the lessons of the past

During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.

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