Introduction 1 2 3 4 Preconception care provides the opportunity to optimize a woman’s use of medications in preparation for pregnancy. Such care includes identifying patterns of medication use before pregnancy occurs; adjusting those patterns to avoid the use of nonessential medications; minimizing exposure to medications known to be harmful to the embryo or fetus; and adjusting the dose, route of administration, and timing of essential treatments to optimize maternal health at each stage of pregnancy while safeguarding the embryo, fetus, and infant. In this paper, we summarize the basic principles of teratology and the current state of knowledge about the effects of medication use during pregnancy; outline basic components of preconception care that can help minimize the risk of birth defects; and provide examples of approaches to planning for the safe and effective use of medications during pregnancy through preconception care. Principles of teratology The term “teratogen” is sometimes used to describe an agent that can produce structural or functional abnormalities in a developing embryo or fetus. Although this implies that an agent is inherently either teratogenic or not, teratogenicity is actually a property of the exposure taken as whole—not only the physical and chemical nature of the agent, but also the dose, route of administration, and timing in gestation, as well as concurrent exposure to other agents and biological susceptibility of the mother and embryo or fetus. 5 1 Current state of knowledge about the effects of medication use during pregnancy Maternal effects 6 7 Changes in total body weight and body fat composition. 8 10 11 12 13 14 15 16 Unfortunately, there are relatively few studies of drug pharmacokinetics during pregnancy. The dose of medications usually prescribed during pregnancy is the same used in nonpregnant adults, but this may result in substantial under- or over-dosage during pregnancy. When blood or serum concentrations of medications can be measured and the most effective level is known, they should be monitored throughout pregnancy and appropriate dosage adjustments made as needed. Further well-designed and well-conducted pharmacokinetic and pharmacodynamic studies of medications during pregnancy are needed. Fetal effects 17 18 19 Even when available, studies addressing fetal effects of maternal medication use during pregnancy may provide conflicting results or insufficient information to assess all potential outcomes or levels of risk. The concept of safety implies the absence of risk, which is impossible to demonstrate conclusively with any kind of study. Thus, it can be difficult for women and health care providers to decide whether to use a medication during pregnancy. The balance of risk, benefit, and efficacy of treatment for both mother and fetus is not always clear and must be individualized for different women under different circumstances. Basic components of preconception care that can minimize the risk of birth defects 20 Optimize health before conception occurs. This includes counseling women to avoid smoking, use of excessive alcohol and illicit drugs, and exposure to potentially toxic environmental or occupational hazards before they are pregnant. Establish effective treatment for chronic conditions before conception occurs. Carefully manage all chronic conditions and intercurrent illnesses throughout pregnancy. Counsel women to avoid the use of nonessential medications, including prescription and over-the-counter medications and dietary or herbal supplements. Avoid the use of medications with high teratogenic risk when equally effective treatments with lower risks are available. Limit the use of essential medications to the smallest number of drugs possible that will effectively treat maternal disease without compromising the health of the woman or her fetus. Limit each essential medication to the smallest dose that can be used to effectively treat maternal disease without compromising the health of the woman or her fetus. Recommend that all women who are capable of becoming pregnant take a vitamin supplement or eat fortified foods to assure consumption of 0.4 mg (400 micrograms) of folic acid per day. Effective pregnancy management in women with chronic conditions requires careful planning, close medical supervision before and during pregnancy, and continuous communication between the pregnant woman and her health care providers. Examples of approaches to preconception planning for the use of medications during pregnancy in different clinical settings Exactly how the components of preconception planning for the use of medications during pregnancy are implemented depends on the nature of the condition requiring treatment, the known risks and safety of use of the specific drugs during pregnancy, and the woman’s individual circumstances, among other factors. In this section, we provide three examples of approaches to planning for the safe and effective use of medications in clinical settings where these factors vary Avoiding teratogenic treatments for non life-threatening maternal conditions—isotretinoin 21 22 23 24 25 26 27 Preconception care provides a unique and critical opportunity to prevent exposure to teratogens such as isotretinoin. Any woman who is considering pregnancy should be asked whether she is taking any medications including any preparation containing isotretinoin. If so, her health care provider should emphasize the risks of isotretinoin use during pregnancy, reevaluate the need for and duration of treatment, assess thoroughly the use and effectiveness of contraceptive measures, and reinforce the key elements of the iPLEDGE program. Women should be informed that conception cannot be attempted without risk of teratogenicity until one full month after the last dose of isotretinoin was taken. Educational information and materials from the iPLEDGE program can also be helpful in the setting of preconception care. Managing maternal conditions that require continuous treatment—epilepsy 28 29 30 28 31 33 34 35 28 36 38 39 40 41 33 42 Managing maternal conditions with intermittent symptoms—asthma 43 44 45 43 46 2 47 48 Managing Asthma During Pregnancy: Recommendations for Pharmaceutical Treatment—Update 2004 46 2 49 51 Conclusion Although it is always better to avoid unnecessary medical treatment during pregnancy, some women with chronic conditions may not be able to become pregnant without appropriate therapy. In many other cases, proper treatment of a chronic condition during pregnancy may be safer for both the woman and her baby than stopping this treatment. It is important that women who are planning a pregnancy talk with their health care provider before beginning a new medication or making changes in current medications for the management of acute or chronic conditions. Continuous communication between a pregnant woman and her health care providers, careful preconceptional planning, effective management of conditions prior to pregnancy, and close medical supervision during pregnancy can help assure the best possible outcome for every woman and baby. The Organization of Teratology Information Specialists (OTIS) provides medical consultation, usually by phone, to individuals and health care providers about the reproductive risks of prenatal exposures. Phone: 866-626-6847 Website: http://otispregnancy.org ® Website: www.reprotox.org The Teratogen Information System (TERIS) is a computerized database of summaries of individual agents designed to assist health care professionals in assessing the risks of exposures in pregnant women. Each summary is based on a review of the published literature and includes a risk assessment derived by consensus of an advisory board of authorities in clinical teratology. Website: http://depts.washington.edu/∼terisweb/teris Information about the results of premarketing studies of individual medications, including animal reproductive studies and human clinical trials, is usually available from the drug manufacturer. A list of many of the existing postmarketing pregnancy registries that seek to monitor exposure to specific medications during pregnancy is maintained by the Office of Women’s Health, U.S. Food and Drug Administration at www.fda.gov/womens/registries. Additional information is available from the March of Dimes at www.marchofdimes.com/pnhec/173_1453.asp.