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BY JASON G. UMANS, MD, PHD
Safety and Efficacy: These Are the Questions
It's time to resolve the lack of knowledge about optimal use of medications in pregnancy. Despite advances in drug research and policies surrounding clinical trials, we still don't know about the safety of most drugs or the full risks of untreated disease to both the mother and fetus (unborn baby). Indeed, most women and their physicians would be disappointed by how little we really know about the optimal use of medications during pregnancy.
Prior to 1993, pregnant women (or women who might conceive) were specifically not included in drug clinical trials. Thus, most of the safety data for prescribing drugs during pregnancy are either extrapolated from animal data (which can either underestimate or overestimate risk in pregnant women and their unborn babies) or from limited, often uncontrolled reports of "off-label" drug use (use for other purposes than the intended treatment) or adverse outcomes during pregnancy.
The optimal dose of a drug used during pregnancy should maximize therapeutic benefit while minimizing the risk of damage or toxicity to the mother, fetus, and placenta. Obviously, too high a dose could cause toxic effects, out of proportion to therapeutic benefits. Less obviously, too low a dose may deny women any benefits of treatment, while still exposing them to some risk.
Determining the best dose is difficult because a woman's ability to metabolize and excrete drugs, as well as her body's response to drugs, changes dramatically over the course of her pregnancy. A case in point is that most drugs are eliminated from the body either by enzymes in the liver or by excretion into the urine, and the activity of both of these processes can be increased by up to 50% in most pregnant women. This fact is rarely taken into account.
It is a basic principle of pharmacology that, when we weigh potential harms of a drug treatment, we should do so at a dose and dosing interval that maximizes potential benefit. Unfortunately, we lack this sort of dosing information for almost all drugs prescribed to pregnant women.
Most women will require one or more prescription drugs during pregnancy despite the fact that almost no commonly used drugs have been tested specifically for their use in pregnancy. Consequently, while we always have some information about fetal safety (more often in animals than in humans), we know almost nothing about maternal safety, about choosing the right dose for a pregnant woman, or about how effective the drug will be during pregnancy.
My colleagues and I continue to be amazed that in the 21st Century, in most cases, physicians have to use their best judgment to weigh risks and benefits, even though they rarely know the optimal dose of a drug that should be prescribed to their pregnant patient or the full risks of untreated disease.
A Call for Well Designed Research and Clinical Trials
It is the job of clinical trials to determine safety and efficacy, including proper dose response. Men comprise the largest proportion of subjects studied in most drug research. In most cases where there are data, research has shown that different (and, surprisingly, often higher) drug doses are required to achieve the desired drug effects in pregnant women in comparison to non-pregnant women or men. We ask, "Is the choice of not treating a woman during pregnancy better than dealing with the challenges that accompany finding the best treatments?" Surely, "yes" cannot be our answer for this would deny women the potential benefit of newer and, perhaps, safer and more effective drugs than are used currently for underlying maternal illnesses. Furthermore, we need to accelerate the development of sorely needed drugs to prevent or treat disorders unique to pregnancy such as preeclampsia, preterm birth and fetal growth restriction.
A Call for Overdue Reclassification of Drugs, Based on Accurate Risk and Clinical Considerations
Current medication labeling with respect to pregnancy is dictated by law and regulated by the US Food and Drug Administration (FDA). This labeling typically reports only on fetal safety issues with respect to the use of the medication and provides no information on changes in drug dosing or effectiveness during pregnancy. For decades, the FDA has used a system of letter categories to classify drug risks to the fetus, focusing overwhelmingly on evidence of birth defect risk, without consideration of the risks of untreated or undertreated disease and of appropriately tailored drug use in pregnancy.
US Food and Drug Administration (FDA) Drug Risk
Classifications System for Pregnant Women
The FDA system differs from grading systems in other countries by depending more heavily on animal data when human data are limited and having fewer, broader, and less specific categories. Most drugs used in pregnant women fall in FDA category C. This is anything but reassuring, as the drugs in category C have not undergone adequate and well-controlled studies in humans and have been correlated with adverse effects on the fetus in animal studies.
Several category D and X drugs are also used in pregnant women. For example, aspirin, a category D drug, is commonly used. There are cases in which category D drugs are apparently safe and crucial to the health of pregnant women and their fetuses, such as drugs used to prevent rejection of transplanted organs, despite these drugs being placed in a category defined by studies indicating risk of fetal abnormalities in humans.
An additional quirk of the FDA classification system is that drugs without proven indications in pregnancy will be classified as category X, by default, even without clear evidence of fetal risk, since they are considered to be "without benefit" and therefore must have an unacceptable risk/benefit ratio. By contrast, the "X" category in either the European or Australian fetal drug risk classification systems is reserved for drugs that have such a high risk of permanent harm to the fetus that they should absolutely not be used. This issue is important for the current classification of all statin drugs (which are classified as D, rather than X by the Australian regulators), as these have not been considered previously to have any indications for their use during pregnancy.
There are several interesting examples how research can change everything. One of the major problems with assessing fetal risk is that birth defects occur in approximately 3% of all healthy pregnancies, so we would still observe birth defects (and might suspect fetal dangers) in 3% of women who take even a perfectly-safe drug during pregnancy. Indeed, a classic example relates to the drug BendectinTM-a combination of pyridoxine and doxylamine, which was widely prescribed for "morning sickness" in the 1960s and 1970s. It was removed from the market after a flood of lawsuits blaming it for causing birth defects (without any controlled studies). It was then subjected to perhaps the largest series of studies of drug safety in pregnancy, proving its safety beyond any doubt, leading to the dismissal of all of the lawsuits, and to its classification in category A. This is why controlled studies are so important. By contrast, ACE inhibitors, a class of antihypertensive agents, were originally classified as FDA category C. The classification was only changed to D years after many reports of toxic effects on the fetal kidneys in the latter part of pregnancy. Finally, perhaps surprisingly, among the best and most thoroughly studied of all drugs in pregnancy are those for the treatment of HIV infection, many of which are now classified in category B, and used to effectively prevent the transmission of HIV from mother to fetus. We are fortunate, in a sense that everyone agreed the stakes were so high that the study of these drugs was necessary in pregnant women, rather than leaving physicians and their patients to guess at safety and the right doses to use during pregnancy.
The FDA has long recognized the current system requires a major overhaul to be more informative and useful to clinicians and patients. Over five years ago, major changes to both the pregnancy and lactation subsections of drug labels were proposed (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm) to include a narrative summary of risks, clinical considerations to support patient care decisions and counseling, and a data section with more detailed information. The proposed regulations would eliminate the current pregnancy categories A, B, C, D and X in favor of categories that more accurately and consistently convey risk and benefit. Unfortunately, we are still in limbo between the phase-out of the old letter categories, which appear in all textbooks and review articles, and the new, more informative approach, which is yet to be implemented.
Jason G. Umans, MD, PhD is Scientific Director of the Biomarker, Biochemistry, and Biorepository Core Laboratory at MedStar Health Research Institute, Director of Research Education and Training for the Georgetown-Howard Universities Center for Clinical and Translational Science, and serves as Associate Professor of both Medicine and of Obstetrics and Gynecology at Georgetown University. Dr. Umans, an internist, nephrologist, and clinical pharmacologist is also an American Society of Hypertension (ASH) Specialist in clinical hypertension who has devoted most of his efforts over the past two decades to the care of medically-complex pregnant women and to research focused on preeclampsia and on drug therapy in pregnancy. He received his MD and PhD in Pharmacology from Cornell University, and completed clinical training in Medicine and Nephrology at the University of Chicago. Prior to joining MedStar, he held faculty appointments at Cornell, Chicago, and Georgetown. He is internationally recognized as an expert in medical disorders during pregnancy, particularly hypertension and kidney disease. His research in clinical pharmacology focuses on pharmacokinetic and pharmacodynamic studies in pregnant women. Additional research interests include vascular mechanisms and risk factors for hypertension, kidney, and cardiovascular disease. He has published approximately 150 original papers on obstetric-fetal pharmacology, preeclampsia, pharmacokinetic modeling, drug assay development, neuropharmacology, vascular and renal physiology,, inflammatory mechanisms, and cardiovascular and metabolic diseases. He has written book chapters and review articles, and has spoken widely on hypertension and renal disease in pregnancy,and on pharmacotherapy in pregnancy and in renal failure.