As indicated by this review, there is a general lack of adequately powered and well-designed studies regarding pregnancy safety for the majority of medications frequently used by women with RA during pregnancy. Furthermore, as highlighted in Tables through , there are apparent inconsistencies between the FDA Pregnancy Category and the risk assessment reflective of the human data for a number of these medications. For example, although there is extremely sparse or no human data for all six of the newer DMARDs, including leflunomide and the new biologics, pregnancy categories for medications in this group include B, C and X. Similarly, for azathioprine, chlorambucil and cyclophosphamide, the teratogenic risk based on the available human data ranges from 'unlikely', 'undetermined' to 'contra-indicated' during pregnancy, and yet all three of these medications carry an FDA Pregnancy Category D. These discrepancies are critically important for the rheumatologist and the pregnant patient as the FDA category is frequently relied upon as the primary determinant of whether or not a medication is safe to use in pregnancy.
In addition to the lack of sufficient quantity of human data for most medications, the quality of human data that is available is limited. Retrospective adverse event or case reports lack denominator information and cannot demonstrate an excess risk over baseline; survey data often suffer from poor response rates, which can threaten the validity of conclusions; uncontrolled studies with no attention to potential confounding, including confounding by maternal disease, are difficult to interpret; and information on outcomes is often incomplete without comprehensive data on the range of outcomes, including malformations, fetal growth and preterm delivery.
Yet, the demand for this information is urgent, particularly when a new drug is marketed and likely to be used by women of reproductive age. As a result, pregnancy registries have become increasingly utilized as a post-marketing tool for collecting pregnancy safety information as quickly as possible for a new drug or for a previously marketed drug that is being used for a new indication.
The common elements of 'traditional' pregnancy registry designs include enrollment on the basis of a pregnancy exposure to a specific target medication, collection of pregnancy exposure and outcome information (either retrospectively or prospectively, most commonly collected from health care providers, and outcomes usually restricted to major birth defects), and comparison of those outcomes to expected numbers (usually general population rates for major birth defects).
The 'traditional' design of pregnancy registries has led to a number of epidemiological concerns about the validity of conclusions that can be drawn from such studies. In response to this, in 2002 the FDA Center for Drug Evaluation and Research (CDER) published guidelines for the conduct of pregnancy registries aimed at setting uniform standards for these kinds of observational studies [96
]. As specified in that document, issues related to study validity include prospective recruitment of a sufficient sample size of exposed pregnant women (i.e., while still pregnant and before prenatal diagnosis), adequate detail and accuracy in exposure and outcome information, an appropriate comparison group, and minimal lost-to-follow-up.
Each of these issues presents significant challenges in the real world. One approach to meeting these challenges is that developed by OTIS, a North American network of telephone information services based in universities, hospitals and departments of health at 18 sites throughout the US and Canada. OTIS member services provide risk counseling to approximately 100,000 pregnant women and health care providers per year regarding pregnancy and breastfeeding exposures. At the same time, OTIS services collaborate to conduct pregnancy outcome studies for selected exposures [97
]. One such study is the OTIS Autoimmune Diseases in Pregnancy Project, first initiated in its present form in 2004 [98
This project represents a new effort involving the collaboration of OTIS member services, rheumatologists, pharmaceutical company sponsors, and pregnant women who are interested in contributing to better knowledge about the safety of medications used to treat RA. A prospective cohort study design is used with women recruited on the basis of having a diagnosis of RA, regardless of the medications used to treat the disease. In addition, pregnant women are recruited who do not have RA but have contacted an OTIS member service with questions about other exposures not deemed to be teratogenic. Recruitment is accomplished through referrals of spontaneous callers to OTIS member services, direct referrals through rheumatologists and other health care providers, and self-referral of women through the internet or other promotional methods.
Unique features of the OTIS study design include the following. First, the study objectives are not limited to evaluation of the safety of a single drug but rather to the evaluation of the wide variety of medications that are used to treat a specific disease during pregnancy. Second, the objectives of the study are not limited to estimation of the risk of major birth defects, but rather include a more comprehensive evaluation of the spectrum of adverse pregnancy outcomes, including spontaneous abortion, reduced birth size, preterm delivery, and postnatal growth deficiency. Third, the evaluation of each infant for birth defects is performed by one of a team of specialists who use a standard checklist to examine each child for any structural abnormalities, including both major and minor birth defects. Fourth, rather than comparing outcomes to a national population standard, the OTIS study employs disease-matched and non-diseased comparison groups recruited through the same referral mechanisms used to recruit exposed women. This allows for more appropriate comparisons regarding medications used specifically to treat RA, while at the same time controlling for the underlying disease and disease severity. Fifth, a commitment to completion of the study is made by the pregnant woman herself, so that complete outcome information is typically collected on 95% or more of all subjects. And sixth, enrollment of the pregnant woman herself allows for repeated and comprehensive collection of pregnancy exposure timing and dose information, including over-the-counter drugs, and information on potential confounding variables such as alcohol and tobacco use. This type of detailed information is usually not reliably available from secondary sources such as medical records or health care provider reports.
In addition, the OTIS Autoimmune Diseases in Pregnancy Project offers an immediate benefit to research participants as the OTIS project staff are available to provide individual counseling regarding any and all exposures that may have occurred during pregnancy.