CHAIR: Bernard Schwetz, DVM, PhD, Acting Deputy Commissioner Food and Drug Administration (FDA); Janet Woodcock, MD, Director, Center for Drug Evaluation and Research; Margaret Dotzel, JD, Acting Associate Commissioner for Policy, FDA; Joseph Levitt, JD, Director, Center for Food Safety and Applied Nutrition; Louisa Nickerson, JD, Associate Chief Counsel for Foods, Office of Chief Counsel, FDA; Michael Greene, MD, Chair, Reproductive Drugs Advisory Committee and its Pregnancy Labeling Subcommittee; Bonnie Lee, Office of Regulatory Affairs, FDA

Review of extent of medication use by pregnant women. Review of potential hazards to woman or fetus from exposure to medications and dietary supplements. Review of potential consequences to woman or fetus from delay in medical diagnosis or management of conditions during pregnancy. Additional responses to FDA questions of interest to be determined in conjunction with CDC colleagues.

In 1997, the American Herbal Products Association (AHPA) published the Botanical Safety Handbook. I was the Managing Editor of that publication. In Appendix 3 of the Handbook, we list by common name those herbs that are not to be used during pregnancy. In my presentation, I will discuss how the Handbook editors evaluated available information to reach these conclusions. In addition, I will address, on behalf of AHPA, the issues raised in the Announcement of this Public Meeting.

Overview of pregnancy-related products currently available as dietary supplements. CRN position regarding appropriate labeling of such products, including whether claims relating to morning sickness or edema of pregnancy should be permissible as structure/function statements.

The March of Dimes Birth Defects Foundation (MOD) represents more than 3 million volunteers, including scientists, health care professionals, policy makers, and others from all walks of life. They are united by a mission to improve the health of babies by preventing birth defects and infant mortality.

MOD urges FDA not to consider changes associated with pregnancy, such as "morning sickness" (nausea and vomiting of pregnancy, or NVP) and leg edema, as conditions for which claims may be made for effects of dietary supplements on bodily structure or function. MOD submits that any such claims would be, in effect, disease claims in their applicability to many women who experience such pregnancy-related changes. That is because in a small but significant percentage of pregnant women, conditions such as nausea and vomiting or leg edema are not "common conditions... that do not cause significant or permanent harm," but instead are symptoms of disease processes that can seriously endanger the women and/or their fetuses.

For example, apparent NVP can phase into hyperemesis without recognition as such by a patient, altering carbohydrate and electrolyte status in ways that impair both maternal adaptation to pregnancy and fetal development. It can produce dehydration, with increased blood viscosity that compromises placental perfusion and predisposes to pathological blood clotting. Edema can be an important sign of preeclampsia ("toxemia of pregnancy"), impending kidney failure, liver disease, or severe dietary protein deficiency. Self-medication that alleviates such symptoms can mask a disease process, delay a woman's seeking medical attention, and delay diagnosis by her physician.

FDA distinction between structure/function versus disease claims must take into account the fact that pregnancy is a unique condition, involving complex maternal adaptations that support embryonic and fetal development and that can be confused with symptoms of disease. And pregnancy is unique as a biological unit comprising two very different individuals, the smaller of which is undergoing rapid developmental changes that make it especially vulnerable to pharmacological agents or disturbances of maternal homeostasis.

If invited to participate in the 30 March public meeting, I will provide further detail, with an eye to the five points listed by FDA on pp. 9231-9232 of the Federal Register.

We are expressing concern as to how FDA's changing position may affect the status of certain existing traditional herbal products, that have a long history of human use, specifically indicated for use during pregnancy. For example, raspberry leaf and nettle leaf preparations have been, and continue to be, widely used by a significant population of women in Europe and North America to support a healthy pregnancy as a partus-preparator and/or uterine tonic preparation. We believe that responsibly formulated traditional herbal products, from companies who have produced the requisite substantiation files in support of an allowable structure/function statement and have had those files reviewed by a qualified expert, should be allowed to market their products to the women who rely on them, and to communicate the products' specific indications for use during pregnancy. We agree that there should be concerns over the safety of certain non-traditional, modern and/or novel dietary supplements marketed to pregnant women that can not demonstrate a long extent of safe use among pregnant women. With regard to safety issues, there needs to be a clear differentiation between modern, non-traditional products with no safety record from those traditional herbal products that have been used, and continue to be used, by a significant population of pregnant women for common, non-serious conditions related to supporting a healthy pregnancy. Such differentiation can easily be made by qualified individuals trained in traditional medical herbalism.

I have directed the TERIS project for 15 years. This knowledge base, which includes information on the teratogenicity of drugs and other exposures during pregnancy, is currently used at some 1500 centers throughout the world. Because of the experience I have gained through TERIS and my clinical teratology practice, I am very concerned that the final rule will have seriously adverse effects for many pregnant women.

I have two particular concerns. The first is that any dietary supplement that has a pharmacological effect has the potential of producing a teratogenic effect as well. Very little scientific information is available on the safety of most dietary supplements in pregnancy. My second concern is that the anecdotal information that exists on these supplements is often contradictory and confusing. Without a firm scientific basis and regulatory oversight, no information source can be considered authoritative. Some supplements that are recommended for use in pregnancy in one source are said to have oxytocic or abortifacent activity in other sources. Women who use a nutritional supplement during pregnancy and later read that it may be dangerous to the fetus may undergo abortion because of fear that they have harmed the fetus. Their physician cannot provide reassurance because the necessary reliable information is simply not available.

2/ Examples of currently marketed herbals/dietary supplements which contain chemicals known to have adverse effects on reproduction which are categorized in pregnancy category x as drugs.

3/ Why, in addition to excluding pregnancy-related claims from "coverage" under DSHEA, all dietary supplements/herbals should be required to carry a warning against use in pregnancy unless properly-conducted reproductive studies have shown that the chemical is safe. Such studies should be required by a certain time.

Reading statement as spokesperson for the American Academy of Pediatrics. Because of the potential for harm to the fetus, infant and child, the Academy is deeply concerned about the marketing of dietary supplements during pregnancy for structure/function claims under the Dietary Supplement Health and Education Act.

As I indicated in my Feb 7 2000 letter to Dr. Henney, the FDA's history is intimately associated with thalidomide, and it would ironic if another "thalidomide", in the form of a dietary supplement promoted for use in pregnancy, were to come about because FDA allowed such supplements to be promoted for such use without the benefit of information assuring their relative safety. Indeed, the U.S. escaped the thalidomide disaster of 40 years ago because it did not approve the drug for marketing, and when in more recent years it became clear that the drug had a unique therapeutic role, the agency again set an international standard for rigor by carefully and thoughtfully developing a unique restricted distribution program designed to minimize the risks of fetal exposure. There is virtually no data on which to currently base assessments of the fetal risks of the wide range of diet supplements, but there are recent data to suggest that, at least for some such products, there may indeed be fetal hazards. I will urge the Agency to reverse its January 6, 2000 rule and reinstate the fetal protections that the public has demanded since the thalidomide disaster.

Effects on fetus of dietary supplement and herbal medicine use.

Due to the Dietary Supplements Health and Education Act (DSHEA), dietary supplements are not regulated by the Food and Drug Administration. That means there are many unknowns. That means that there is no animal testing on the safety of the product in reproductive animals. There are no clinical trials to demonstrate the safety and efficacy of the product in humans. For dietary supplements, it means that the unknowns are what the active ingredient may be. As consumers, we do not know if there is an active ingredient and what it is. An unknown is what the other components of the product are. As consumers, we do not know what other components or contaminants may be in the products. For example, is this product contaminated with lead. An unknown is the concentration of the ingredients and how that concentration may vary from batch to batch. The manufacturing process does not have to be standardized so that there can be variability in the product with each container.

Pregnant women are a vulnerable population. Dietary supplements taken during pregnancy can affect both the mother and the fetus. Since the ingredients in dietary supplements have not been tested, we should be concerned about their potential effect and the possibility for disastrous consequences, such as in causing birth defects. I am sure that manufacturers would not want the responsibility and stigma for a harmful product. Because dietary supplements are used by a significant part of the population, it is important that there be scientific research designed to produce data that can help address questions on the safety and efficacy of these products, especially if they will be marketed to pregnant women.