Case Example 8Assessing the Safety of Products Used During Pregnancy

DescriptionThe Antiretroviral Pregnancy Registry is the oldest ongoing pregnancy exposure registry. This multisponsor, international collaborative registry monitors prenatal exposures to all marketed antiretroviral drugs, which include several drug classes and multiple drugs in each class.
SponsorsAbbott Laboratories, Aurobindo Pharma, Barr Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb Company, Cipla, Gilead Sciences Inc, GlaxoSmithKline, Hetero USA, Merck & Co. Inc, Mylan Laboratories, Novartis Pharmaceuticals, Pfizer, Ranbaxy, Roche, and Tibotec BVBA.
Year Started1989
Year EndedOngoing
No. of SitesNot site based; open to all health care providers. More than 1,200 health care providers have enrolled patients.
No. of Patients:12,500

Challenge

Data on the teratogenic effects of pharmaceutical products is often difficult to obtain. Most clinical trials exclude pregnant women because of ethical concerns about potentially exposing the fetus to harm. While data on teratogenic risk is available from preclinical animal testing, this information is not always predictive of the effects of a drug taken during human pregnancy. As a result, data are often lacking to help patients and physicians understand the potential risks and benefits of continuing a treatment during pregnancy.

There is a great need for this information, because pregnant women may receive drugs for many reasons; for example, to treat an illness that arises during pregnancy, or to treat a chronic mental or physical illness. Women may also become pregnant while taking a drug, with the result that the fetus receives an unintended exposure. This last scenario is particularly likely, given that 50 to 60 percent of all pregnancies in the United States are unintended, and most are not recognized until late in the first trimester.

Antiretroviral treatments represent an area of particular concern, as women may need to take the drugs during pregnancy to manage their HIV infection. In addition, these drugs can reduce the risk of transmitting HIV to the infant, but this benefit must be weighed against the risk of teratogenic effects. Because of these factors, it is extremely important for clinicians and patients to understand the risks of using antiretroviral drugs during pregnancy in order to make an informed decision. However, ethical and practical concerns make a randomized trial to gather these data difficult, if not impossible.

Proposed Solution

In 1989, the first manufacturer of an antiretroviral drug voluntarily initiated a pregnancy exposure registry to track the outcomes of women who had used its product during pregnancy. The purpose of the registry is to collect information on any teratogenic effects of the product by prospectively enrolling women during the course of their pregnancy and following up with them to determine the outcome of the pregnancy. Physicians enroll a patient by providing information on the pregnancy dates, characteristics of the HIV infection, drug dosage, length of therapy, and trimester of exposure to the antiretroviral drug. Information on the pregnancy outcome is gathered through a followup form sent to the physician after the expected delivery date.

In 1993, the registry was expanded to include all antiretroviral drugs, as other manufacturers voluntarily joined the registry once their drugs were on the market. The registry is international in scope and allows any health care provider to enroll a patient who has intentional or unintentional use of an antiretroviral drug during pregnancy. The U.S. Food and Drug Administration (FDA), which has used this registry as a model for new pregnancy registries, now requires participation in the registry for all new and generic antiretroviral drugs.

Results

Since its inception 20 years ago, the registry has provided many lessons, and developed processes, on how to monitor and assess the safety of these drugs during pregnancy. To ensure both rigor and consistency, it has put in place predefined analytic methods and criteria for recognizing a potential teratogenic signal.

The monitoring system developed by the registry includes several groups, which provide different levels of monitoring. The groups include:

  • Steering Committee (comprised of representatives of all groups below).
  • Scientific Advisory Committee (comprised of experts from FDA, Centers for Disease Control and Prevention [CDC], National Institutes of Health [NIH], and academia).
  • Birth Defect Review Committee (comprised of representatives from the other groups).
  • Sponsor Committee (comprised of epidemiologists and safety experts).
  • Consultants (geneticist and pharmacoepidemiologist).
  • Coordinating Center staff (epidemiologist, project manager, and clinical research associates).

Tools for coding and classifying birth defects have been developed specifically for the registry to maximize the likelihood of identifying a teratogenic signal. This unique system groups birth defects by etiology or embryology rather than by general location or category, as does the Medical Dictionary for Regulatory Activities (MedDRA). Grouping like defects together increases the likelihood of detecting a potential signal. Another unique aspect of this registry that aids in signal detection is coding the temporal association between timing of exposure and formation of the birth defect.

Specific monitoring criteria have been developed for evaluating signals at various levels, including:

  • Individual and composite data.
  • Use of the Rule of Three—that three exposure-specific cases with the same birth defect requires immediate evaluation. This rule is based on the statistical principle that the likelihood of finding at least three of any specific defect in a cohort of 600 or fewer by chance alone is less than 5 percent.
  • Primary analysis (statistical considerations, including power/relative risk calculation and statistical probabilities associated with detecting various birth defects using internal and external comparators).
  • Complementary data, including clinical studies in pregnancy, retrospectively reported data, other registries or epidemiological studies, published studies, and case studies.

These efforts to monitor and study the teratogenic effects of antiretroviral use during pregnancy have produced many publications. Registry data have been used in 9 publications, 7 abstracts, and 22 presentations, and the registry design and operation have been the subject of many publications and presentations. The registry data and publications can help to provide clinicians and patients with information to make informed decisions regarding use of antiretroviral drugs during pregnancy.

Key Point

An observational registry can collect data to answer research questions in cases where a randomized trial is not feasible for ethical or practical reasons. For pregnancy exposure registries, the observational model allows the researchers to gather data on women and infants exposed to products during pregnancy without deliberately introducing the exposure.

For More Information

  1. Tilson H, Doi PA, Covington DL. et al. The antiretrovirals in pregnancy registry: A fifteenth anniversary celebration. Obstet Gynecol Surv. 2007;62:137–48. [PubMed: 17229330]
  2. Watts D, Covington D, Beckerman K. et al. Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy. Am J Obstet Gynecol. 2004;191:985–92. [PubMed: 15467577]
  3. Covington D, Tilson H, Elder J. et al. Assessing teratogenicity of antiretroviral drugs: monitoring and analysis plan of the Antiretroviral Pregnancy Registry. Pharmacoepidemiol Drug Saf. 2004;13:537–45. [PubMed: 15317035]
  4. Scheuerle A, Covington D. Clinical review procedures for the Antiretroviral Pregnancy Registry. Pharmacoepidemiol Drug Saf. 2004;13:529–36. [PubMed: 15317034]

From: Chapter 3, Registry Design

Cover of Registries for Evaluating Patient Outcomes: A User's Guide
Registries for Evaluating Patient Outcomes: A User's Guide. 2nd edition.
Gliklich RE, Dreyer NA, editors.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.