NATO Advanced Research Workshop on “Drugs in Pregnancy: Consensus Conference on Teratogen Information Services”, Prague, 16–18 April 2004

Reproductive Toxicology 19 (2004) 239–260

Abstracts

NATO Advanced Research Workshop on “Drugs in Pregnancy: Consensus Conference on Teratogen Information Services”, Prague, 16–18 April 2004

I . SUMMARY OF INVITED PRESENTATIONS 1. Introductory Comments Maurizio Clementi, J. Arnon, Asher Ornoy∗ Laboratory of Teratology, Department of Anatomy and Cell Biology, Hebrew University Hadassah Medical School, Jerusalem, Israel Clinical teratology is a relatively new branch of medicine that aims to identify and evaluate human teratogens; this distinction is clinically important because results obtained in animal studies cannot automatically be applied to man. Moreover, since most teratogenic agents are not identifiable (probably due to low teratogenicity), and the mechanisms by which they produce their pathogenic effects are largely unknown, the possibility of a complete primary prevention through avoidance of hazardous prenatal exposures is unfortunately quite remote. On the other hand, maternal diseases must be treated as most are in themselves teratogenic (i.e. diabetes mellitus), and therapy may reduce the probability of fetal damage. Physicians and patients are becoming increasingly aware of the possible teratogenic risks related to exposure to environmental agents during pregnancy; however, it is evident that pertinent data are insufficient or difficult to interpret. In fact medical reports are often contradictory, limited to animal studies, or anecdotal, while media messages to the general public are alarming and misleading. On the other hand, pregnant women are particularly anxious, and they need prompt, correct information and reassurance. Every year, the pharmaceutical industry markets new drugs, whose embryo-fetal risks are unknown and whose labels warn against their use during pregnancy. As many pregnancies are not planned, women may therefore expose their em0890-6238/$ – see front matter doi:10.1016/j.reprotox.2004.08.004

bryos to environmental agents before clinical recognition of pregnancy. In North America and in Europe many Teratogen Information Services (TIS) have started a counselling activity since the 1980s. Two networks have been created: OTIS in North America and ENTIS in Europe. Although their activity has grown spontaneously, there are many NATO countries where no TIS unit is in operation. TIS units can play a specific public health role by providing information on the known reproductive risks of most environmental agents, and conducting specific research on therapies during pregnancy. Moreover, TIS units can collect prospective data on pregnancy exposure before the pregnancy outcome is known, and thus assemble large unselected cohorts of specific exposures during pregnancy over a defined period. Their activity also has many practical results such as reassuring women (as in most exposures there seems to be no risk to the developing embryo and fetus), reducing the rate of unnecessary pregnancy terminations, and counselling as to the choice of a correct drug, instead of avoiding necessary therapy in both acute and chronic illnesses. The results of prospective studies regarding new drugs or drugs for which information is poor are of interest to public health departments, obstetricians and general practitioners, as well as pharmaceutical industries. TIS units employ the most unbiased method for postmarketing surveillance of drugs with respect to their use in pregnancy because they acquire data prospectively. Collaborations with congenital malformation registries should be implemented in the future, because the results obtained by TIS units in small prospective samples could be confirmed in large retrospective “ad hoc” studies. During the workshop the following issues have been discussed: (a) the expertise and minimal requirement for starting a new TIS unit; (b) the consensus as to the safety

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of selected groups of drugs used during pregnancy and lactation; (c) the cooperation between OTIS and ENTIS; and the possibility of ENTIS to encourage the opening of new TIS units in the NATO and partner countries that presently have no such units. Keywords: European network of Teratology Information Service 2. Teratogen Information Services: European Situation Maurizio Clementi, Elena Di Gianantonio Pediatrics Department, Padova, Italy

C.E.P.I.G.—Genetica

Clinica,

Teratology is the branch of medical science that studies the contribution of the environment to abnormal prenatal growth and morphological or functional development. The evidence that rubella was responsible for a welldefined phenotype of embryopathy, and the thalidomide tragedy in the late 1950s and early 1960s demonstrated that the environment plays a significant role in determining congenital malformations. The practical consequences were an increase in basic, clinical, and epidemiological research on chemical teratogenesis and the institution of teratogen information services (TIS) in the 1980s. TIS development continued into the late 1980s and 1990s as the request for information increased. Indeed, as physicians and patients become more and more aware of the possible teratogenic risks related to exposure to environmental agents during pregnancy, it also becomes clear that pertinent data are not available or difficult to interpret. In fact medical reports are often contradictory, limited to animal studies, or anecdotal, while media messages to the general public are alarming and misleading; on the other hand, pregnant women are particularly anxious, and they need prompt, correct information and reassurance. Each year the pharmaceutical industry markets new drugs whose embryo-fetal risks are unknown and whose labels warn against their use during pregnancy. As many pregnancies are not planned, women may therefore expose their embryos to environmental agents before knowing they are pregnant. In 1990, members of 13 European programs or institutions engaged in counseling pregnancies at risk and evaluating and following up pregnancy outcome met in Milan and founded the European Network of Teratology Information Services (ENTIS). This agency is registered in The Netherlands, at the National Institute of Public Health and Environmental Protection (RIVM) in Bilthoven. At present, there are 28 active members (http://www.entis-org.com/). The main objectives and functions of ENTIS are: (a) to counsel in risk assessment in pregnancy; (b) to recognize and detect risk factors in order to prevent birth defects; and (c) to increase knowledge by stimulating the exchange of experiences and providing training in counselling. TIS units vary in staff size, population served, and methodology. Some provide information mostly to physi-

cians, others to the public; some always give a written answer in addition to telephone counseling, others counsel only over the telephone. In some units, follow-up is limited to some exposures, while others include all outcomes. All TIS units are involved in collaborative research. Candidates for membership should have practical experience in teratology information procedures and, meet specific criteria (see web site). The staffs include physicians (gynecologists, paediatricians, geneticists) and clinical scientists (pharmacists, biologists) trained in embryology and teratology as well as in complementary disciplines (toxicology, genetics, obstetrics). Specialists are consulted if required. Counseling methodology Standardized procedures for data collection are used by all the participating centers. Although each TIS unit may have specific working procedures, some common methodologies have been established among the ENTIS members. Prospective data is collected at the time of the enquiry, and includes questions on social characteristics, previous and current obstetrical history, family history of congenital malformations, and maternal chronic diseases. Information is requested regarding the commercial preparation used, its dosage, indications for use, and the time during pregnancy when it was taken as. Gestational age is calculated as the best estimate from the first day of the last menstrual period. Three to 12 months after the expected date of delivery, all women and/or their doctors are contacted by the TIS staff via mail or telephone. The information obtained includes: outcome of the pregnancy (termination, abortion or delivery); type of delivery; infant’s birth weight, head circumference and length; perinatal complications, and the presence and type of any major congenital malformation. Routine physical examination or post-mortem autopsy is not performed in cases of termination of pregnancy, or spontaneous abortion. All TIS units provide detailed counseling on the risk of congenital malformation in the exposed fetus based on literature data, and their personal database which includes all counseled cases and the follow-ups; a search in the literature databases (MEDLINE; current contents) is also performed. Since 2000, there exists a “forum” at the ENTIS web site for discussion of exposures for which present data is insufficient. 3. Organization of Teratology Information Services (OTIS): Update and Direction Christina Chambers1 , Janine Polifka2 , Julia Robertson3 , Richard K. Miller4 1 Department

of Pediatrics, University of California at San Diego, La Jolla, USA; 2 Department of Pediatrics and Family and Preventive Medicine, University of Washington, Seattle, WA, USA; 3 Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; 4 Department of Obstetrics and Gynecology, Environmental Medicine and Pathology, University of Rochester, Rochester, NY, USA

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In North America, the Organization of Teratology Information Services (OTIS) is organized exclusively to stimulate and encourage research, education, and the dissemination of knowledge in the field of Birth Defects and to improve the abilities of Teratogen Information Services (TIS’s) to provide accurate and timely information about prenatal exposures. These responsibilities have the overall objective of preventing birth defects and improving the public health. More than 100,000 telephone consults were performed by nineteen regional TIS units in North America (Canada and USA) this past year. Approximately half of the consults were from the public with the remainder from health care providers. Some of the services only provide information to health care providers, while most of the services provide information to the public as well as health care providers. Thirty-six Facts Sheets on medications and exposures relating to pregnancy are now available on the OTIS website: http://www.otispregnancy.org/. Ongoing research investigations involving all OTIS members are being conducted on Rheumatoid Arthritis medications, Asthma medications and isotretinoin. Invited testimony has been given to The Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce of the United States House of Representative in December 2002 concerning the use of isotretinion in women of reproductive age and pregnancy prevention (http://energycommerce.house.gov/107/hearings/ 12112002Hearing755/hearing.htm). The purpose of the Subcommittee Hearing was to examine safety issues related to the use of isotretinoin and the need for stricter regulations. OTIS has long been concerned about the increasing number of calls to its member services from women who had become pregnant while taking isotretinoin. As a result, OTIS has recommended that stricter regulations be added to the manufacturer’s pregnancy prevention program, including mandatory patient and physician registries. Further invited testimony was presented at the US Food and Drug Administration. Hearing on the same subject in 2004. At the FDA hearing OTIS provided interim results of an ongoing CDC-AAMC-funded study of Isotretinoin and Pregnancy Prevention. The purpose of the study is to investigate why women continue to get pregnant while taking isotretinoin despite implementation of pregnancy prevention programs by the manufacturer. Thus far the study has illustrated that errors in risk communication between the health care provider and patient as well as denial of risk by the patient account for many of the inadvertent pregnancy exposures to isotretinoin. Of greater importance is the study’s finding that in some cases the health care professionals had failed to adhere to the required components of a pregnancy prevention program, thereby removing safeguards that might have prevented these exposures. Recommendations of OTIS were adopted by the FDA panel. It has become increasingly apparent that the survival of TIS units world-wide is not dependent upon the need for such services but rather the ability to sustain such services.

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Funding for TIS’s has come from a variety of sources in the past. Only two years ago, in North America there were more than 40 services providing this unique service. Because of a dramatic decrease in regional support from State and local governments, there are now only 18 such services currently operational throughout North America. It is often all too easy for regional governments to reallocate monies based upon budgetary cuts or new directions; however, the services to the health care community and the public are now suffering. These Teratogen Information Services have dedicated professionals who have identified a critical need that has traditionally not been filled by other health care providers because of the complexity in not only interpreting information available from human and animal studies but also in determining the importance of these experimental observations for the individual patient who has an exposure during pregnancy. It is the opinion of many that funding of such TIS’s in North America should be the responsibility of the US and Canadian governments. Toward those ends, the current direction for OTIS is to assure survival of TIS’s by identifying philanthropy and National Governments that will support these critical life altering services provided by OTIS and the individual services both for the immediate future and the long term. It is envisaged that individual TIS’s will continue to seek support from regional and state governments and other sources, while OTIS will pursue a national funding perspective in Ottawa and Washington, DC. Unfortunately, time is of the essence to assure survival of the current services as well as development of new services to fill the void in provision of services in underserved areas. All involved with OTIS continue to expand the mission of research education and service. If you have questions, do contact OTIS at +1-866-626-6847 or http://www.otispregnancy.org/. 4. Teratogen Information Services—The Clinical Raison D’Etre Gideon Koren, MD, FRCPC Motherisk Program, University of Toronto, The Ivey Chair in Molecular Toxicology, University of Western Ontario, Canada Teratogen Information Services are essential in informing health professionals, women and their families on the teratogenic risks of selected drugs. As important, these services are powerful in empowering women to be treated with essential drugs that have been shown to be safe to the developing embryo. More health economic analyses are needed to corroborate these important clinical effects. In analysis conducted in 1991, we showed that in an active Teratogen Information Center counseling in clinic 600 women a year one can prevent five cases of major malformations per year, at an estimated cost of 7.5 million dollars [1]. This does not include cost savings of patients counseled over the telephone. Furthermore, a TIS can prevent numer-

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ous cases of elective pregnancy terminations due to misperception of teratogenic risk [2]. We calculated for 1991 cost savings of 336,000 dollars due to elective termination [3]. As important, is to measure levels of satisfaction by patients and health providers and in both instances we showed high levels of satisfaction [4]. We have repeatedly shown the ability of TIS to decrease unjustifiably high perception of teratogenic risk by evidence counseling [5]. Another important aspect is allowing counseled women to continue highly needed therapy. Einarson et al. documented that in many cases women with depression are told to stop “cold turkey” antidepressants, leading them to high rates of morbidity, including suicide ideations, need of hospitalization and alcohol abuse [6]). Evidence based counseling allowed two thirds of them to resume antidepressant therapy with favorable pregnancy outcome. Teratology Information Services are a relatively new type of clinical service, and are very vulnerable to termination of funding or funding shortages. It is critical to be able to show to governments, health authorities and hospitals compelling figures of the clinical savings and high levels of satisfaction associated with these services. References [1] Koren G. Teratogen information services: cost analysis. In: Koren G, editor. Maternal-fetal toxicology: a clinician’s guide. NY: Marcel Dekker; 1994. p. 747–65. [2] Koren G, Pastuszak A. Prevention of unnecessary pregnancy termination by counseling women on drugs, chemical and radiation exposure during pregnancy in the first trimester. Teratology 1999;41:657–61. [3] Koren G, Pastuszak A. Teratogen information services. In: Koren G, editor. Maternal-fetal toxicology: a clinician’s guide. 2nd ed. NY: Marcel Dekker; 1994. p. 683–706. [4] Einarson A, Park A, Koren G. How physician perceive and utilize information from a teratogen information service: The Motherisk Program, BMC Medical Education; 5 April 2004 [Pub Med]. [5] Koren G, Bologa M, Long D, Feldman Y, Shear NH. Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first trimester. Am J Obstet Gynecol 1989;160:1190–4. [6] Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counseling. J Psychiatry Neurosci 2001;26:44–8.

5. Reproductive and Genetic Risks of Preconception Exposure to Mutagenic Agents and Reproductive Toxins Robert L. Brent, MD, PhD Department of Pediatrics, A.I. duPont Hospital for Children, Thomas Jefferson University, USA There has been continued interest in the impact of environmental toxicants, drugs, and physical agents on the testes and ovary. Although the interest has been long-standing, society’s interest in environmental toxicity, radiation effects, improved work safety and the proliferation of new chemicals has more recently focused on this area. There has been a long-standing polarization of feelings among scientists with regard to the risk of preconception exposure to reproductive toxicants [1] (Table 1). A more recent issue has been the allegation that servicemen exposed to multiple agents in Iraq during Desert

Storm have fathered an increased number of children with birth defects following their return to the United States [2]. What can we say with certainty about the impact of preconception exposures on the reproductive capacity of exposed human populations? First, there are substantial data from animal experiments and epidemiological studies that indicate that ionizing radiation, drugs and chemicals can decrease male and female fertility by decreasing the number of sperm and or eggs [3,4]. These results have been observed in occupational epidemiological studies and in patient populations who have survived cancer chemotherapy or radiation therapy. In the population of male cancer survivors there is a suggestion that the males are at greater risk for infertility than the females. Thus, subfertility or infertility in men and women are proven risks from certain exposures to ionizing radiation, some chemicals and chemotherapeutic agents. But one also recognizes that these effects are threshold phenomena and therefore there are noeffect doses for these effects. Second, there is extensive mammalian animal investigations to indicate that males and females exposed to high exposures of ionizing radiation and some mutagenic chemicals have offspring with an increase in early embryonic death (dominant lethals), point mutations and chromosome abnormalities [3,4]. It is true that the maximum manifestation of some of these effects varies with the stage of sperm and egg development and the dose of these agents. But yet, in animal experiments utilizing very low exposures to mutagenic agents, experimental offspring frequently cannot be differentiated from the controls, even when the experimental conditions have been established to maximize the mutagenic effect. Third, patients who have survived therapeutic doses of radiation and chemotherapy as children or young adults may have problems with infertility, but the fertile population does not appear to have a measurably increased risk of spontaneous abortion or offspring with congenital malformations. It is true that even in the larger studies the populations are small. It is therefore possible that if there were a small risk for the induction of chromosomal aberrations and genetically caused congenital malformations that these studies would not be able to recognize them. Furthermore, patients frequently wait years following cancer treatment before having children and of course there may be two decades between childhood cancer treatment and procreation. The very low risk of transmitting induced mutations to the offspring of treated cancer survivors is a reflection of the very low risk of mutagenesis from environmental mutagens in general and the lapse in time between exposure and procreation. Fourth, the concept of “biologic filtration” is proposed to explain why mutagenic effects of ionizing radiation are readily demonstrated to be the cause of cancer in exposed animals and humans and why clinical genetic disease in the F1 generation is so difficult to demonstrate in human populations (Table 2). Fifth, low frequency EMF, microwaves and ultrasound, do not have the ability to alter DNA without affecting other

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cellular functions, they are not cytotoxic at exposures which concern us clinically and their toxic effects are deterministic (threshold effects) rather than stochastic. While some in vitro studies have suggested that these forms of radiation have mutagenic potential, the cytotoxic effects that accompanies the mutagenic effect is not present at the usual exposures of all these forms of non-ionizing radiation. Therefore, if genetic effects are to be manifested from preconception exposures to ultrasound, microwaves and low frequency EMF, the risks have to be considerably smaller than the risks from ionizing radiation, and actually there may not be any increased risks. The epidemiological studies and animal studies support this conclusion. References [1] Brent RL. Protecting the public from teratogenic and mutagenic hazards. J Clin Pharmacol 1972;12:61–70. [2] Brent RL, Beckman DA. Desert storm sequelae: are gulf war veterans fathering an increased incidence of children with congenital malformations? Pediat Res 1996;39(4, Part A):472A. [3] Brent RL. Biological factors related to male mediated reproductive and developmental toxicity. In: Olshan, AF, Mattison DR, editors. Malemediated developmental toxicity. New York: Plenum Press; 1994. p. 209–42. [4] Brent RL. Utilization of developmental basic science principles in the evaluation of reproductive risks from pre- and post conception environmental radiation exposures. Paper presented at the thirty-third annual meeting of the national council on radiation protection and measurements. The effects of pre- and postconception exposure to radiation, April 2–3, 1997, Arlington, VA. Teratology 1999;59:182–204. [5] Legator MS, Jacobson CB. Chemical mutagens as a genetic hazard. Clin Proc Child Hosp Dist Columbia. 1968 May;24(5):184–9. [6] Epstein WL, Fukuyama K, Epstein JH. Ultraviolet light, DNA repair and skin carcinogenesis in man. Fed Proc 1971 November–December;30(6):1766–71. [7] Auerbach O. Lung cancer from cigarette smoking. NY State J Med 1971 September 1;71(17):2039–40. [8] Ames BN. Mutagenesis and carcinogenesis: endogenous and exogenous factors. Environ Mol Mutagen 1989;14(Suppl 16):66–77.

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[9] Brown NA. Are offspring at risk from their father’s exposure to toxins? Nature 1985 July 11–17;316(6024):110.

6. Treatment of Thyrotoxicosis and Hypothyroidism in Pregnancy Orna Diav-Citrin, Judy Arnon, Svetlana Shechtman, Rebecka Wajnberg, Asher Ornoy The Israeli Teratogen Information Service, Israeli Ministry of Health, Jerusalem, Israel Thyrotoxicosis occurs in 0.2% of pregnancies and is caused most frequently by Graves disease. Untreated hyperthyroidism in pregnancy may adversely affect the maternal (preeclampsia, heart failure) and perinatal (prematurity, intrauterine growth restriction, stillbirth, thyrotoxicosis) outcome. Surgery is rarely indicated in pregnancy and radioactive iodine therapy should not be used during pregnancy. Antithyroid drugs (propylthiouracil (PTU), methimazole (MMZ), and carbimazole (CMZ)) are the treatment of choice for thyrotoxicosis during pregnancy. They do not represent major human teratogens. Data are insufficient to draw a definitive conclusion as to the teratogenic potential of MMZ and CMZ. There are no prospective controlled studies supporting the teratogenicity of MMZ [1]. A cluster of case reports of aplasia cutis congenita (ACC) in association with prenatal MMZ/CMZ exposure suggests a probable weak association [2–4]. A significant increase in the prevalence of ACC was found possibly associated with addition of MMZ to animal feeds as a weight enhancer [5]. A rare MMZ embryopathy has also been suggested (choanal atresia, esophageal atresia with tracheoesophageal fistula, minor facial and skin dysmorphic features, growth restriction and developmental delay) [6]. PTU has not been implicated in increasing the rate of major malformations in most studies. It may be ad-

Table 1 Controversy concerning the magnitude of the genetic risk from environmental agents “The threat of genetic damage is our number one health problem.” [5] “There is no realistic way to predict a safe human level of a substance shown to be teratogenic, carcinogenic or mutagenic in animals.” [6] “Chemical mutagenesis is certainly a very small problem as we see it at present. We view it as 1% of the very broad problem of human genetics. We do not propose setting up whatever Dr. Crow means by a monitoring system.” “If the public flatly refuses to take decisive action on the basis of the massive volumes of data linking cigarette smoking to lung cancer, how can you expect people to act vigorously on the more hazy and abstruse things like a chemical that may or may not be mutagenic in man” “I think it is absolutely essential that we do not delude ourselves about the magnitude and complexity of our task. The general public is easily scared and when they are scared, they may form pressure groups to push governmental agencies into action. These agencies are scientifically naive and have to rely on our advice. We should be very careful not to give advice that is itself naive; that is advice based on oversimplified tests and facile interpretations.” [7] “The world is full of mutagens, carcinogens and reproductive toxins, and it always has been. The important issue is the human exposure dose. Fortunately the exposure is usually minuscule”. [8] “Nature’s toxic chemicals are the major carcinogens and mutagens ingested by humans. These natural chemicals in plants are present at a level 10,000 times the prevalence of man-made pesticide residues. There is a tendency for laymen to think of chemicals as being only man-made and to characterize them as toxic”. [8] “It would be foolish to advise anything other than extreme caution over the exposure of fathers to chemical mutagens when our understanding of [9]

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Table 2 Biologic filtration: loss of genetic effects of exposure to sex cells to mutagenic agents (1) Affected germ cells may be lost during gametogenesis. (2) The mature egg or sperm may have a decreased capacity to be fertilized or to fertilize. (3) The embryos resulting from these affected eggs and sperm may result in embryonic loss during preimplantation or early organogenesis. In most cases the women may not know that they were pregnant. (4) If there is a lapse in time between the exposure to reproductive toxicants and insemination and fertilization, some of the affected gonadocytes may be lost (bridge formation, lethal mutations). (5) In many instances the mutagenic exposure to the human populations may be so low that the calculated risks would not result in a change in the incidence of genetic disease because the sample size is too small. (6) Most point mutations result in recessive genetic diseases.

vantageous over MMZ or CMZ in pregnancy due to the lack of an association between PTU and ACC or an embryopathy. Several studies have assessed the cognitive development of children after pregnancy exposure to antithyroid drugs and no effect was observed. With all antithyroid drugs, if used after the 10th gestational week, fetal toxicity should be looked for. Congenital goiter, thyroid dysfunction, or both occasionally occur. In most cases, the effect is transient, and resolves spontaneously. Prenatal ultrasonographic assessment of fetal thyroid gland is advised in women who are treated with antithyroid drugs during pregnancy. Invasive procedures should be considered in cases of significant enlargement of the thyroid gland or hydrops fetalis. Postnatal assessment of neonatal thyroid function should be performed. An estimated 2.5% of pregnant women have hypothyroidism. Levethyroxine (T4 ) is used for the treatment of hypothyroidism during pregnancy. Correction of maternal thyroid deficiency with T4 is not associated with abnormal fetal outcome or maternal complications. Thyroid requirements may increase during pregnancy, therefore, close monitoring of thyroid function is advised. Maternal hypothyroidism and severe iodine deficiency during pregnancy adversely affect the neurodevelopmental outcome of children. Decreases in performance can occur even when the pregnant woman’s hypothyroidism is mild and probably asymptomatic. Treating maternal hypothyroidism during pregnancy is beneficial for the offspring [7]. In a prospective 3-year follow-up study [8] children of women with hypothyroxinemia (fT4 below the lowest tenth percentile at 12 weeks’ gestation) had delayed mental and motor function compared to the controls. Children of treated women in whom fT4 concentration was increased at 24 and 32 weeks’ gestation had similar scores compared to the controls. TSH screening may be warranted in pregnancy. References [1] Di Gianantonio E, Schaefer C, Mastroiacovo PP, Cournot MP, Benedicenti F, Reuvers M, et al. Adverse effects of prenatal methimazole exposure. Teratology 2001;64:262–6. [2] Bihan H, Vazquez MP, Krivitky A. Aplasia cutis congenital and dysmorphic syndrome after antithyroid therapy during pregnancy. Endocrinologist 2002;12:87–91.

[3] Diav-Citrin O, Ornoy A. Teratogen update: antithyroid drugs—methimazole, carbimazole, and propylthiouracil. Teratology 2002;65:38–44. [4] Ferraris S, Valenzise M, Lerone M, Divizia MT, Rosaia L, Blaid D, et al. Malformations following methimazole exposure in utero: an open issue. Birth Defects Res Part A Clin Mol Teratol 2003;67:989–92. [5] Martinez-Frias ML, Cereijo A, Rodriguez-Pinilla E, Urioste M. Methimazole in animal feed and cutis aplasia [letter]. Lancet 1992;339:742–3. [6] Clementi M, Di Gianantonio E, Pelo E, Mammi I, Basile RT, Tenconi R. Methimazole embryopathy: delineation of the phenotype. Am J Med Genet 1999;83:43–6. [7] Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549–55. [8] Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 2003;59:282–8.

7. Major Birth Defects and Classical Anticonvulsants— How to Resume the Risk? C. Schaefer Beratungs- und Pharmakovigilanzzentrum f¨ur Embryonaltoxikologie, Berlin, Germany Among known human teratogens, classical antiepileptic drugs (AEDs; phenytoine (PHT), phenobarbital (PHB), primidone (PRM), valproic acid (VPA), carbamazepin (CBZ)) are the mostly prescribed drug group during pregnancy. In general there is a twofold risk for major birth defects anticipated for monotherapy. Conversely, it is frequently stated that there is an approximately 95% chance for having a healthy baby. One in 200 pregnant women is affected with epilepsy and/or under treatment with an AED, i.e. in Europe there are 35,000 pregnancies plus epilepsy/AED every year [1], resulting in additional 700–1400 or more major birth defects. The leading birth defects are cardiac defects (1.8%) [2], cleft lip palate (1.7%) [2], urogenital anomalies (hypospadias, etc.), musculoskeletal anomalies (limb deficiencies, clubfoot, etc.), and NTD (spina bifida with VPA and CBZ; 0.8–1.5%). Minor anomalies include midface hypoplasia (depressed broad nose bridge, short nose, anteverted nostrils, long upper lip) and

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digit hypoplasia (hypoplastic/malformed distal phalanges, coned epiphyses, shortened metacarpals). Midface hypoplasia seems to be predictive for mental developmental retardation. Recent studies have investigated many clinical endpoints of suspected teratogenic origin; however, the individual risk calculation for congenital anomalies is still complicated for several reasons, e.g. rates of major malformations under AED monotherapy vary between 3.2 and 11.3% in larger cohort studies published between 1997 and 2003. Among others the following factors contribute to these variations: (a) inclusion criteria of (major) birth defects, (b) study size (power), (c) geographical region/ethnicity (prevalence of birth defects), (d) inclusion of pregnancy loss, (e) quality of prenatal and postnatal examination, (f) quality of reporting, completeness of follow-up, and (g) age of infants at latest examination. To illustrate the variation of study design, methodology, and observed results three recently published prospective and retrospective cohort studies are presented in detail. In Holmes and coworker’s study [3] a dysmorphologist examined 316 live born infants for the presence of at least 1 of 5 features (major BD, microcephaly, IUGR, midface hypoplasia, digithypoplasia) during 1st week after birth and compared the results with two control groups: epilepsy without AEDs (n = 98), infants of healthy mothers (508). Dean et al. [4] evaluated hospital records (n = 138) over 25 years, photographs of the infants and actual interviews for major BD, facial dysmorphia, mental disorders and childhood diseases diagnosed during childhood. (Older) non-AED exposed siblings served as controls (n = 38). Kaaja et al. [5] studied live born infants (n = 740) for major BD diagnosed until hospital discharge during the 1st week after birth with infants (n = 239) of nontreated mothers with epilepsy as a control group. One of the largest, however unpublished prospective cohort studies of major BD was performed by ENTIS, enrolling over 1600 pregnant women with epilepsy/AED treatment [6]. Like in other studies the highest birth defect rate among monotherapies was found with VPA. A drug score system allowed a detection of a significant risk increase with increasing number and dose of AEDs. A unique result of this study was a significantly increased birth defect rate of 13% for a small cohort (n = 31) of non-treated mothers with epilepsy. When evaluating the risk of a particular AED exposure and applying it to an individual pregnant woman, neither consideration of only the latest published study nor limitation to meta-analysis are appropriate. Consultants should weigh the different study results against each other considering study design and methodology in relation to the individual situation of the advice-seeking (pregnant) woman. There seems to be growing evidence to support the following generalizations. Epilepsy by itself and seizures during pregnancy do not significantly contribute to birth defects [7]. VPA is the strongest teratogen among classical anticonvulsants in monotherapy and in combination with other AED. There is a dose–effect relationship indicating a higher risk associated with higher dosage and with

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polytherapy versus monotherapy; however the cut off dosage of 1000 mg/day and the cut off serum level of 70 ␮g/l for VPA (proposed by [8,9]) should be considered with caution (see results of [5]). Available data are not sufficient to define a safe AED dose for any classical AED; all classical AEDs can cause minor anomalies and none of them is safe in regard to mental effects. Recommendations If possible: (a) withdraw from AEDs before planning pregnancy (concerns approximately 50% of epileptic patients [10]); (b) do not use AEDs for non-epileptic illness; (c) prefer monotherapy; (d) try to avoid VPA, at least do not combine VPA with other AEDs, do not use VPA or CBZ with NTD in family history; (e) if there is a birth defect with AED in history change drug regimen for next pregnancy; (f) set dosage as low as possible, use sustained release preparations, 3–4 doses/day; (g) recommend 4–5 mg/day folic acid when planning pregnancy, although a protective effect against AED’s antifolate properties is not confirmed; (h) check unbound AED serum level during pregnancy monthly; (i) recommend detailed ultrasound around week 20 plus alfafetoprotein screening; (j) do not limit individual risk characterization to major BD; however communication must be careful considering long lasting maternal anxiety and expectation of a mentally retarded infant. Both could by itself threat the prenatal and postnatal development of a child. Note that gynecologists and neurologists are frequently unaware of the interactions between epilepsy, hormones, oral contraceptives, AEDs, and the required action/prevention measures, e.g. starting with the education of girls with epilepsy and their drug prescriptions. References [1] EURAP, International antiepileptic drugs and pregnancy registry: interim report. November 2003. [2] Schardein JL. Chemically induced birth defects. 3rd ed. New York: Marcel Dekker; 2000. [3] Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132–8. [4] Dean JCS, Hailey H, Moore SJ, et al. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002;39:251–9. [5] Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in offspring of women with epilepsy. Neurology 2003;60:575–9. [6] Mastroiacovo P. ENTIS-collaborative study on antiepileptic drugs and epilepsy in pregnancy. In: Presentation at the 9th annual conference of European network of teratology information services, Rome; 1998. [7] Fried S, Kozer E, Nulman I, et al. Malformation rates in children of women with untreated epilepsy. A meta-analysis. Drug Saf 2004;27:197–202. [8] Kaneko S, Battino D, Anderman E, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res 1999;33:145–58. [9] Samr´en EB, van Duijn CM, Lieve Christiaens GCM, et al. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999;46:739–46. [10] Morrow JI, Craig JI. Anti-epileptic drugs in pregnancy: current safety and other issues. Expert Opin Pharmacother 2003;4445–56.

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8. Risk for Children Exposed Prenatally to Valproic Acid E. Robert-Gnansia Institut Europ´een des G´enomutations, Lyon, France Valproic acid (VPA) is effective for different forms of epilepsy. Its anticonvulsant activity was discovered in 1963, and it was approved first for use in absence seizures in 1967 in France. Its indications have been gradually extended from epilepsy to affective disorders, and now it is tried also in exploratory indications like migraine, head trauma and even cancer. Lipophilia explains its ability to cross the blood–brain barrier and the placenta. The first reports regarding VPA teratogenicity in humans appeared in 1982. Typical for VPA is an approximate 20-fold increased risk of spina bifida, and at a lesser extent of other neural tube defects. In case of exposure between the 17th and 28th day after conception, 1–2% of the newborns may be affected [1,2]. Other malformations were recognized as associated with maternal VPA through controlled epidemiologic studies: hypospadias [3], preaxial limb defects (missing or duplicated thumb) [4,5]. The risk for cardiac defects and oral clefts is also increased, but not more than with other anticonvulsants. Typical dysmorphic features of the face and extremities in children exposed to VPA in utero are recognized as fetal valproate syndrome [6,7]. Finally, several other malformations considered as associated with maternal VPA were published as case reports or case series in the literature: craniostenoses (mainly trigonocephaly) [8], gastroschisis, septo-optic dysplasia [9], brain midline malformations [9], cerebellum midline anomalies [10], blepharoptosis [10], nasolacrimal duct obstruction [11]. The prevalence of these abnormalities in cases of in utero VPA exposure cannot be determined from case reports. Children exposed to valproate in utero also appear to be at greater risk for perinatal distress (43%) low Apgar scores (28%), postnatal growth deficiency and microcephaly [7,12]. Impact of in utero exposure to VPA on children’s behavior was first suggested in a case series published in 2000 [13]: among 46 children with typical features of fetal VPA syndrome (34 mothers were treated with monotherapy, and 12 with polytherapy), 40% had hyperactivity or poor concentration, 60% had two or more autistic features (four had a diagnosis of autism and two had Asperger’s syndrome). More than 60% of the children exposed had learning difficulties, speech delay, and/or gross motor delay. At least eight additional case reports suggest that autism and other cognitive deficits may be a consequence of in utero VPA exposure [14,15]. In a retrospective population-based study, Dean et al. [16] described 149 children exposed to antiepileptic drugs, compared with their 144 unexposed sibs. It was observed that 19% of children exposed to VPA versus 3% of non-exposed sibs (after excluding cases with a family history of speech delay) had developmental delay. Among exposed children, one had a formal diagnosis of autism, and five are said to fall in the autistic spectrum.

Very limited knowledge is available on histological anomalies associated with autism. In an autopsy of a patient exposed in utero to thalidomide and presenting features of autism, Bauman et al. [17] reported cerebellar anomalies with reductions in Purkinje cell number. Similarly, Ingram et al. [18] have shown that prenatal exposure of rats to VPA reproduces cerebellar anomalies reported by Bauman et al., namely reductions in Purkinje cell number and cerebellar volume. Genetic predisposition to teratogenic effects of VPA was shown in two strains of mice [19] where susceptibility genes were identified. A similar susceptibility in humans is supported by a study showing a 55% recurrence risk after a first affected child [13]. In rare cases neonatal liver cell necroses have been described, resulting sometimes in neonatal death. Recommendations When a pregnancy is planned, the question should be raised if anticonvulsant medication still is indicated. Because important side effects not detectable by prenatal diagnosis were shown, an absolute contra-indication in pregnancy should be envisaged for VPA. Newly marketed anticonvulsants without so far detected teratogenic effect should be tried as an alternative treatment to VPA. When epilepsy is well controlled with VPA, and if no possibility exists to replace it by one of the novel anticonvulsants, therapy may be continued when a pregnancy is planned. Monotherapy is preferred as for any anticonvulsant. Although it is unclear whether folic acid protects against embryotoxic and teratogenic effects of VPA, it should be added as a preventive measure, like for any pregnancy. A daily VPA dosage as low as possible, divided in 3 or 4 individual doses should be selected and regularly controlled with plasma concentration determination. Patients should be informed about the fetal risk. An expanded prenatal diagnosis with a detailed ultrasound testing in the 20th week should be carried out to rule out major disturbances of structural development, especially neural tube defects. References

[1] Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2:937. [2] Bjerkedal T, Czeizel A, Goujard J, K¨all´en B, Mastroiacovo P, Nevin N, et al. Valproic acid and spina bifida [letter]. Lancet 1982;2:1096. [3] Bertollini R, Kallen B, Mastroiacovo P, Robert E. Anticonvulsant drugs in monotherapy. Effect on the fetus. Eur J Epidemiol 1987;3:164–71. [4] Robert E, Jouk PS. Preaxial limb defects after valproic acid exposure during pregnancy. In: Mastroiacovo P, K¨all´en B, Castilla E, editors. Proceedings of the first international meeting of the genetic and reproductive epidemiology research society (GRERS). Ghedini Editore; Rome; 1992. p. 101–5. [5] Bron JTJ, Van DerHartenHJ, Van Geiin HP. Prenatal ultrasonographic diagnosis of radial-ray reduction malformations. Prenat Diagn 1990;10:279–88. [6] DiLiberti JH, Farndon PA, Dennis NR, Curry CJR. The fetal valproate syndrome. Am J Med Genet 1984;19:473–81.

Abstracts / Reproductive Toxicology 19 (2004) 239–260 [7] Ardinger HH, Atkin JF, Blackston RD, Elsas LJ, Clarren SK, Livingstone S, et al. Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1988;29:171–85. [8] Lajeunie E, Barcik U, Thorne JA, Ghouzzi VE, Bourgeois M, Renier D. Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg 2001;95:778–82. [9] McMahon CL, Braddock SR. Septo-optic dysplasia as a manifestation of valproic acid embryopathy. Teratology 2001;64:83–6. [10] Gigantelli JW, Braddock SR, Johnson LN. Blepharoptosis and central nervous system abnormalities in combined valproate and hydantoin embryopathy. Ophthal Plast Reconstr Surg 2000;16:52–4. [11] Hornby SJ, Welham RA. Congenital nasolacrimal duct obstruction requiring external dacryocystorhinostomies in a child with foetal valproate syndrome. Eye 2003;17:546–7. [12] Jaeger-Roman E, Deichl A, Jakob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986;108:997–1004. [13] Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, et al. A clinical study of 57 children with fetal anticonvulsant syndrome. J Med Genet 2000;37:489–97. [14] Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. Fetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 2001;43:202–6. [15] Bescoby-Chambers N, Forster P, Bates G. Foetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol 2001;43:847. [16] Dean JC, Hailey H, Moore SJ, Lloyd DJ, Turnpenny PD, Little J. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002;39:251–9. [17] Bauman ML, Kemper TL. Neuroanatomic observations in autism. In: Bauman ML, Kamper TL, editors. The neurobiology of autism. Baltimore: Johns Hopkins University Press; 1994. p. 119–45. [18] Ingram JL, Peckham SM, Tisdale B, Rodier PM. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 2000;22:319–24. [19] Bennett GD, Wlodarczyk B, Calvin JA, Craig JC, Finnell RH. Valproic acid-induced alterations in growth and neurotrophic factor gene expression in murine embryos. Reprod Toxicol 2000;14:1–11.

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9. Are New Anticonvulsants Safer than Classical? C. Schaefer Beratungs- und Pharmakovigilanzzentrum f¨ur Embryonaltoxikologie, Berlin, Germany New antiepileptic drugs (new AEDs) are Felbamat (FBM), Gabapentin (GPT), Lamotrigin (LTG), Levetiracetam (LEV), Oxcarbazepin (OXC), Tiagabin (TGB), Topiramat (TPM), Vigabatrin (VGB), and Zonisamid (ZNS). In particular LTG, GPT, and TPM are frequently prescribed drugs nowadays, also to women of reproductive age with partial and generalized seizures. General advantages of new AEDs are: (a) better tolerance and similar efficacy for partial epilepsy in monotherapy (LTG, TPM, GPT, OXC, VGB versus CBZ); (b) less (TPM, OXC) or no cytochrome P450 enzyme induction with the risk of failure of oral contraceptives; (c) no substantial antifolate properties; (d) no teratogenicity in animal experiments (apart from TPM, VBT, ZNS); (e) less effects on hormones and metabolism (adipositas, insuline resistance, Polycystic Ovary Syndrome (PCOS), etc.); and (f) low protein binding, simple pharmacokinetics. Most information on pregnancy outcome is available through sponsor’s registries [1] as well as epilepsy and pregnancy projects: EURAP [2], UK-register [3], Australian register [4], and Teratology Information Services (TIS). However, with approximately 1000 prospectively documented pregnancies under monotherapy, only the published and available unpublished data for lamotrigine (followed by gabapentin and oxcarbazepin) allow preliminary risk estimations (see Table 1). The risk for major birth defects (BD) under lamotrigine varies among registries between 2.0 [5] and 10.5% (TIS Berlin), mean 2.6%. This is neither signif-

Table 1 Experience with new AEDs Drug

Treatment indication for monotherapy

FBM

Animal teratogenicity

No. prospective pregnancies + monotherapy

Comment

No

<10

GPT

Partial seizures, neuropathic pains

No

100

No failure of oral contraceptives (OC)

LTG

Partial and generalized seizures, bipolar disorders

No

1000

No substantial antifolate properties, no failure of OC

LEV OXC

Partial and generalized seizures

TGB

No

10

No

100

No

10

No failure of OC

No substantial antifolate properties, no epoxides. Failure of OC by cyt. P450 inducing

TPM

Partial and generalized seizures

Limb and digital defects in mice, rats and rabbits

50

Failure of OC by cyt. P450 inducing

VGB

Partial seizures

Cleft defects in rabbits

50

No failure of OC

ZNS

Partial seizures

Visceral abnormalities in mice and dogs at high dose, no teratogenicity in rats

10

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icantly different from the known background prevalence in the general population nor from calculated risks under AED monotherapy shown by recent controlled cohort studies of classical AEDs except valproic acid (VPA). On the other hand, no major or minor anomaly pattern has been detected so far. Long-term follow-up for minor dysmorphic and mental effects in infants prenatally exposed to newer AEDs has not yet been evaluated; however, as recent studies support a growing concern about long term sequelae of VPA, one of today’s most frequently used classical AED, clinical teratologists should consider recommending those new AEDs, which seem to be less dangerous than VPA. This also implies reconsidering the broadly accepted recommendation not to change an effective AED regimen during (early) pregnancy or when planning a pregnancy. Comparing treatment regimens of pregnant women with epilepsy there are substantial differences between European countries [2]. In Sweden, Italy and Germany the most frequently prescribed AEDs are CBZ followed by VPA (Italy also PHB), while in Denmark LTG is leading with almost 50%. References [1] GlaxoSmithKline: lamotrigine pregnancy registry interim report 1 September 1992–30 September 2003. Issued January 2004. [2] EURAP, International antiepileptic drugs and pregnancy registry. Interim report. November 2003. [3] Morrow JI, Craig JJ, Russell AJC, et al. Which antiepileptic drugs are safest in pregnancy? Poster presented on October 13, 2003. [4] Vajda FJ, O’Brien TJ, Hitchcock A, et al. The Australian registry of anti-epileptic drugs in pregnancy: experience after 30 months. J Clin Neurosci 2003;10:543–9. [5] Sabers A, Dam M, a-Rogvi-Hansen B, et al. Epilepsy and pregnancy: lamotrigine as main drug used. Acta Neurol Scand 2004;109:9–13.

10. The Developmental Effects of Maternal Antiepileptic Drugs with Special Emphasis on Carbamazepine Asher Ornoy1,2 , Judy Arnon2 , Svetlana Shechtman2 , Orna Diav-Citrin1,2 1 Hebrew 2 Israeli

University Hadassah Medical School, Israel; Ministry of Health, Jerusalem, Israel

Intrauterine exposure to antiepileptic drugs (AED) may result in increased rate of major and minor congenital anomalies, especially if exposure occurred during the first trimester of pregnancy; however, relatively unique findings to the effects of AEDs in pregnancy are various degrees of functional damage of the developing brain, often accompanied by typical dysmorphic features, the “antiepileptic drug syndrome” (AEDS). The clinical features of AEDS differ slightly among the different antiepileptic drugs used. These injuries may be slight and clinically unnoticed, or more severe, resulting in mental retardation. Various age-related tests exist for the assessment of the cognitive, fine and gross motor abilities as well as other neurological functions. The older the child at examination, the better the prediction of the long-term outcome. In many followup studies these age appropriate tests were used, alongside

detailed questionnaires related to school placement, learning achievements, attention span and the presence of behavioral problems. Many published developmental studies are prospective in nature, while some are retrospective. While evaluating the results of such studies, the age of the children at examination, the presence of an appropriate control group and the types of tests and questionnaires used have to be considered. This is important as it may sometimes be the source of inconsistency in the literature. The drugs found to have long-term developmental consequences on the offspring were phenytoin, valproic acid, phenobarbital and carbamazepine. For most other antiepileptic drugs, there are only few studies on relatively small samples. In addition, there are several studies assessing the development of children born to epileptic mothers that were not treated during pregnancy. These studies are generally negative. The effects of in utero exposure to AED can be manifested in the newborn, as these infants are often sedated at birth and may develop hyperexcitability as a sign of withdrawal symptoms [1]. These symptoms can appear with all drugs, and do not seem to be related to the cord blood levels. Dessens et al. [2] studied 172 children exposed to different AED in comparison to 168 controls. As a rule, the children had normal cognitive function except those treated with phenobarbital in the third trimester of pregnancy, who performed poorer in comparison to the controls. In addition there were 12% of “AED children” with learning disabilities. In other studies [3] it was found that adults exposed prenatally to phenobarbital had lower intelligence scores compared to controls. Low SES and environmental deprivation further reduced their cognitive ability. Dilantin was found in several studies to reduce cognitive development. A 10.5 points reduction of cognitive ability was found in a group of 34 children exposed in utero to dilantin [4] as well as in 23 children following maternal dilantin monotherapy [5]. The combination of antiepileptic drugs is more pathogenic. Valproic acid (VPA) seems to be the most potent AED in inducing developmental disorder, although the studies are relatively scanty. Ardinger et al. [6] found that 15 of 18 exposed infants had developmental delay. Moore et al. [7] found that 46 of 57 valproic acid exposed children had developmental delay. Many of these children also suffered from behavioral problems including autistic behavioral features. Autism and Asperger syndrome have been described in several other children exposed to VPA. Another antiepileptic drug widely used not only in patients with epilepsy is Carbamazepine (CBZ). CBZ is a well-known teratogen. In a study on 210 pregnant women treated with CBZ during the first trimester of pregnancy [8] we found an increased rate of major anomalies with a Relative Risk (RR) for major anomalies of 2.24 in comparison to controls. The highest increase was in cardiac anomalies (RR 4.17) and in craniofacial defects. In a meta-analysis including 22 studies with control groups, we found that of 1255 pregnancies in women treated with CBZ from the first trimester of

Abstracts / Reproductive Toxicology 19 (2004) 239–260

pregnancy there were 6.7% of major anomalies in the CBZ offspring as opposed to 2.3% in 3756 controls [9]. The rate of anomalies following monotherapy was 5.3%, bitherapy was 8.6% and after polytherapy it was 18.8%. The developmental outcome of in utero CBZ exposed children also seems to be disturbed, but there is no consistency in the literature. In addition to several reports [7,10,11] describing developmental delay and the presence of a specific “CBZ syndrome”, there were other studies [4,12,13] that found normal development of children exposed in utero to CBZ. We also studied the development of 42 preschool age children born to mothers treated with CBZ during pregnancy in comparison to 47 control children [14]. The mental (cognitive) score, as assessed from age related psychological tests, was 100.3 in the CBZ versus 112.4 in the controls. Six of the nine children with scores below 90 exhibited the typical facial dysmorphic changes that constitute the “CBZ syndrome”. Regarding the question whether the developmental delay is related to epilepsy and not to AED, there are now studies on over 200 children born to untreated epileptic mothers indicating normal development [15]. It is important to note, however, that not all developmental studies show developmental delay in the offspring of women treated with AEDs, especially CBZ during pregnancy, and there is no consensus as to the existence of a typical “antiepileptic drug syndrome”. However, while epileptic women should receive antiepileptic (mono) therapy during pregnancy, it may be equally important to avoid treating non-epileptic women with the teratogenic AEDs as long as there are other, equally effective, neuroactive drugs that seem to have a much lower (if at all) teratogenic potential and can be used with similar effectiveness. It is however important to continue the treatment of epileptic women during pregnancy because maternal uncontrolled convulsions may be dangerous to the fetus as it may induce abruptio placentae and fetal death. References [1] Koch S, Gopfert-Geyer I, Hauser I, Hartmann A, Jakob S, JagerRoman E, et al. Neonatal behaviour disturbances in infants of epileptic women treated during pregnancy. Prog Clin Biol Res 1985;163B:453–61. [2] Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, Koppe JG, van De Poll NE, Boer K. Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatr 2000;89:533–41. [3] Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to Phenobarbital and intelligence deficit in adult men. J Am med Assoc 1995;274:1518–25. [4] Scolnik D, Nulman I, Rovet J, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. J Am Med Assoc 1994;271:767–70. [5] Koch S, Jager-Roman E, Losche G, Nau H, Rating D, Helge H. Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome. Acta Paediatr 1996;85:739– 46. [6] Ardinger HH, Atkin JF, Blackston RD, Elsas LJ, Clarren SK, Livingstone S, et al. Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1998;29:171–85.

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[7] Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. Med Genet 2000;37:489–97. [8] Diav-Citrin O, Scechtman S, Arnon J, Ornoy A. Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies. Neurology 2001;57:321–4. [9] Matalon S, Shechtman S, Ornoy A. The teratogenic effects of carbamazepine: a meta-analysis of 1255 exposures. Reprod Toxicol 2002;16:9–17. [10] Jones KL, et al. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989;320:1661–6. [11] Van Allen MI, Yerby M, Leavitt A, et al. Increased major and minor malformations in infants of epileptic mothers. Preliminary results of the pregnancy and epilepsy study. Am J Hum Gen 1998;43 (Suppl):A73. [12] van der Pol MC, Hadders-Algra M, Huisjes HJ, Touwen BCL. Antiepileptic medication in pregnancy: late effects on the children’s central nervous system development. Am J Obstet Gynecol 1991;164:121–8. [13] Wide K, Winbladh B, Tomson T, Sars-Zimmer K, Berggren E. Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study. Dev Med Child Neurol 2000;42:87–92. [14] Ornoy A, Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child 1996;75:515–20. [15] Holmes LB, Rosenberger PB, Harvey EA, Khoshbin S, Ryan L. Intelligence and physical features of children of women with epilepsy. Teratology 2000;61:196–202.

11. The Role of the Pharmaceutical Industry in Maternal–Fetal Toxicology Gideon Koren, MD, FRCPC Motherisk Program, University of Toronto, Ivey Chair in Molecular Toxicology, University of Western Ontario, Canada Due to obvious medico-legal concerns, the industry does not study and, consequently, does not label drugs for use in pregnancy. This state of affairs orphans millions of women and unborn babies from the benefits of pharmacotherapy, sometimes even in life-threatening medical conditions—a situation morally and scientifically unacceptable. In 1983 Merrel Inc. withdrew Bendectin from the market due to litigious costs. Despite this combination of doxylamine and vitamin B6 being safe to the fetus [1], and supported by repeated FDA reviews, the manufacturer could not allow the litigious costs. As a result, American women found themselves without an FDA approved drug for nausea and vomiting of pregnancy (NVP), with a resultant three-fold increase in hospitalization rate for severe forms of this condition [2]. More profoundly, this market withdrawal has sent a chilling signal to pharmaceutical houses regarding drugs and pregnancy. Twenty years later, very few drugs have been developed or studied appropriately during pregnancy, orphaning women from the benefits of modern pharmacotherapy even in life-threatening conditions. Regulatory agencies demand drug companies to report on post-marketing experi-

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ence, including drug exposure in pregnancy. Hence, all drug companies maintain databases with cases of spontaneous reporting. Yet the quality of such data is almost always poor and does not allow development of knowledge on fetal drug safety. How can we break this deadlock and move forward to ensure treatment of the mother while protecting the unborn? Ethical considerations It is evident that in the future, similar to the present situation, drug companies will not be able to initiate drug studies during the first trimester of pregnancy, exposing women and unborn babies to unknown teratogenic risks. Yet more than half of all pregnancies are unplanned and millions of pregnant women every year are exposed to medications during embryogenesis. Moreover, even after pregnancy is diagnosed, millions of women continue to take medications for depression, allergy, hypertension and scores of other conditions. Capturing this vast experience in a prospective manner, and comparing it to epidemiological-sound control groups, can create the research paradigm needed to fill this knowledge gap. Indeed, over the last two decades Teratology Information Services all over the world have reported on the apparent safety or risk of medications in pregnancy. Recently the FDA has acted on new legislation that demands drug companies to create prospective pregnancy registries for drugs that may be consumed by pregnant women [3]. Unfortunately, regulatory agencies in other countries have not followed suit. From the experience of the Organization of Teratology Information Services one has to applaud the FDA not only for setting up these new demands, but also for demanding epidemiologically—sound analysis of such data and thus, the creation of new knowledge that will assist directly women and their health professionals. While such efforts are never the work of one person, it is important to acknowledge Drs. Kwedder, Kennedy and Uhl at the FDA for moving this agenda. The labeling issue While it is understandable why drug companies have not initiated drug studies in pregnancy, their actions regarding labeling are questionable. Consider, for example, the following excerpt of pregnancy labeling for Prozac® (fluoxetine): “Safe use in pregnancy has not been established. Therefore, it should not be administered to women of childbearing age unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the child or fetus”. This text has not changed over the last 17 years! When read by a physician in a remote area, the excerpt sounds as if Prozac® is unsafe and indeed endangers the well being of the fetus. Yet, six epidemiological controlled studies, three neurobehavioral studies and at least one metaanalysis on Prozac® use in pregnancy have been published

in the last decade. This makes the statement misleading. It is difficult to imagine Ford or General Motors surviving legally such misinformation in their marketing. Whereas the FDA has developed a new system that would inform physicians on available studies in a meaningful way, this system is stalled in the American political machine. What about regulatory agencies in other countries? Neither have they have not done anything. In summary, we should expect the regulatory agencies and drug companies to be much quicker in ensuring that the most basic women and fetal rights are fulfilled in the 21st century. References

[1] Einarson T, Leeder SJ, Koren G. A method of meta-analysis of epidemiological studies. Drug Intell Clin Pharm 1988;22:813–24. [2] Neutel CI, Johansen HL. Measuring drug effectiveness by default: the case of Bendectin. Can J Public Health 1995;86:66–70. [3] Kennedy DL, Uhl K, Kweder SL. Pregnancy exposure registries. Drug Saf 2004;27:215–28.

12. Environmental and Nutritional Risk Assessment in Reproduction: Lead and Vitamins Richard K. Miller1 , Keith West2 , Parul Christian2 1 PEDECS,

Department of Obstetrics and Gynecology, Environmental Health Sciences Center, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA; 2 Bloomburg School of Public Health, Center for Human Nutrition Johns Hopkins University, Baltimore, MD, USA During the past few years on every continent, risk assessment for environmental and nutritional exposures have garnered increasing importance as related to pregnancy. The campaigns to reduce lead exposure and to increase vitamin intake (folate) are examples. Lead (Pb) In New York State, Pb screening of pregnant women has been a requirement for the past 10 years. Action levels for maternal blood lead were established at 10 mg/dl. New York was the only state in the USA to require screening of pregnant women. Specific exposures and concerns have been related to ethnic foods and spices. Among the calls received have been lead exposures via bridge painting and repair, ethnic candies in clay pots, home remodeling, urine drinking, electronics—soldering and ceramic manufacturing. Such prenatal screening not only focuses attention on the lead abatement issue but equally important sensitizes health care providers to explore more fully occupational and environmental exposures from other sources [1,2]. New York State Action Levels for Lead Poisoning in Pregnant and Postpartum Women (NYS Department of Health #2535 [1])

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Blood lead level (␮g/dL)

Action

0–9 10–19 (mildly elevated)

Provide information on sources of lead and how to avoid. Retest blood lead level to determine if lead is increasing. If increasing, seek consultation with TISa or regional resource centers. If no upward trend, repeat blood lead testing near term. Retest blood lead level to determine if lead is increasing. If increasing, seek consultation with TIS or other regional resource centers. If increasing, seek consultation for further risk reduction.

20–44 (moderately elevated) >45

a TIS:

Retest blood level; consult with a regional lead poisoning prevention center. Provide counseling on possible sources. Refer to local health agency. Consult TIS. Teratogen Information Service, see [3].

Vitamins Enhancing the intake of vitamins and micronutrients has also become popular with the concept that more vitamins will improve pregnancy outcome and reduce birth defects. Examples have been the increased use of folate (4–5 mg per day) to reduce the incidence of birth defects. While on the other hand, excessive intake of vitamin A as retinyl esters and fish oils can place an embryo at risk for birth defects. Most of the questions asked of Teratogen Information Services are related to excess exposures. It is important to note that the carotenoids (beta-carotene) is not associated with vitamin A toxicity or teratogenicity [4]. Thus, when examining intake of vitamin A, dosage, timing, duration and form of vitamin A must be determined. We know that world-wide nutritional deficiency is a leading cause of poor pregnancy outcomes that may impact on newborn development and risk of birth defects. For example, In Nepal, vitamin A supplementation (equivalent to 1000 ␮g retinol equivalents daily) has been shown to reduce maternal mortality while daily folate use (0.4 mg) has also reduced risk of infant death [5–7]. Interestingly, supplementation with a multiple micronutrient supplement did not achieve the success of vitamin A and folate alone. Thus, both excess supplementation and deficiency of micronutrients may have differential impacts during pregnancy and also their benefits appear dependent upon the lifestyles and cultures in which such interventions are used. References [1] New York State Department of Health Publication No. 2535. December 1995. Lead poisoning prevention guidelines for prenatal care providers. [2] Miller RK. Environmental and occupational hazards involving reproduction. In: Leppert PC, Peipert JF, editors. Primary care for women. 2nd ed. Philadelphia, PA: Lippincott; 2004. p. 237–44 (Chapter 33). [3] Organization of Teratology Information Services (OTIS). Telephone: (866)626-OTIS or (866)626-6847 (free consultations with teratogen information specialists). Available on-line at: http://www.otispregnancy.org/. [4] Miller RK, Hendrickx AG, Mills JL, Hummler H, Wiegand UW. Periconceptional vitamin A use: how much is teratogenic? Reprod Toxicol 1998;12:75–88. [5] Delange FM, West Jr KP, editors. Micronutrient deficiencies in the first months of life. Karger, Switzerland; 2003. [6] Christian P, West Jr KP, Khatry SK, Lecerq SC, Pradhan EK, Katz J, et al. Effects of maternal micronutrient supplementation on fetal loss and

infant mortality: a cluster-randomized trail in Nepal. Am J Clin Nutr 2003;78:1194–202. [7] West Jr KP, Katz J, Khatry SK, LeClerq SC, Pradhan EK, Shrestha SR, et al. and the NNIPS-2 Study Group. Double-blind, cluster randomized trial of low dose supplementation with vitamin A or B-carotene on mortality related to pregnancy in Nepal. Br Med J 1999;318:570–5.

Acknowledgements Supported in part by NIH ES 02397 (RKM); Global Research Activity No. GHS-A-00-03-00019-00 between the Office of Health, Infectious Diseases, and Nutrition, US Agency for International Development (USAID), Washington, DC and the Center for Human Nutrition, Department of International Health, The Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD and the Bill and Melinda Gates Foundation, Seattle, WA (K.W., P.C.). 13. Infants of Mothers with Malignant Disease (IMMD) Paul Merlob Beilinson Teratology Information Service (BELTIS), Rabin Medical Center, Beilinson Campus, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel The occurrence of malignancy during pregnancy is rare: ∼0.2–1 case per 1000 pregnancies. The malignancies complicating pregnancy are those most frequently seen in young women: lymphoma, leukemia, melanoma, breast cancers, cervix, ovary, thyroid and colon. Except for delay in diagnosis, no convincing data exist that pregnancy per se adversely influences the prognosis or biology of maternal cancer, including breast cancer. No firm evidence exists that there is a greater likelihood of reactivation of cancer during pregnancy. There are only a few reports indicating that cancer per se adversely affects pregnancy. Metastases to the placenta and fetus are rare [1–4]. The IMMD fetus, in addition to impact of diagnostic procedures, cytotoxic chemotherapy, radiation therapy, maternal metastatic disease, has added risks such as growth impairment, toxicity, teratogenicity, genetic damage and carcinogenicity [5–7]. Regarding growth impairment an in-

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creased risk of low birth weight infants was confirmed; whereas the spontaneous preterm delivery incidence rate is the same as in the general population, induced preterm delivery, before pulmonary maturity, is the most frequent iatrogenic risk. Several pregnancy complications relating to toxicity have been raised, including: myelotoxicity (anemia, leucopenia, neutropenia, thrombocytopenia); cardiotoxicity (diffuse myocardial necrosis); alopecia (scalp hair loss); and endocrine toxicity (thyroid and adrenal dysfunction). Regarding teratogenicity, the incidence rates of fetal malformations from drug combinations appears only slightly higher than for single agents (25% versus 17%). Excluding folate antagonists and cases involving the concomitant use of irradiation, the incidence of major malformations for single agents declines to 6%. However, the probability of teratogenesis is also influenced by the trimester of exposure, drug dose, frequency of administration, duration of treatment, individual and genetic susceptibility, may be important but have not been defined. Regarding genetic damage, no increased risk of abortions, chromosomal aberration, singlegene defect or dominant mutation for the first generation have been indicated. Carcinogenicity risk is quite rare, almost negligible; very few cases of fetal malignancy and almost always melanoma. Vertical transmission of carcinogenetic factors was demonstrated only for some tumors with genetic predisposition (retinoblastoma, Wilm’s tumor, neuroblastoma). The influence of chemo- and radiotherapy in the IMMD depends on the timing of treatment [8,9]. If conception occurs a long time after treatment, no increase in genetic or teratogenic risks; when conception occurs shortly after treatment, then a genetic risk may exist. There is increased teratogenic risk with treatment during the first trimester, whereas the second and third trimester exposures may instead manifest effects of increased toxicity and growth impairment risks. Conclusions We may conclude in general that: (a) children born to mothers who survive malignant diseases have a good outcome if radiotherapy has been avoided during pregnancy; (b) current chemotherapeutic agents are well tolerated by the developing fetus, even in the first trimester; (c) radiotherapy (abdomino-pelvic) appears to produce an increased risk of low birth weight infants or perinatal death; and (d) offspring of patients treated for cancer in childhood bears no more risk of cancer than controls, with the exception of the rare cases of hereditary predisposition to cancer. References [1] Doll DC, Ringenberg QS, Yarbro JW. Management of cancer during pregnancy. Arch Intern Med 1988;148:2058–64. [2] Sutcliffe SB. Treatment of neoplastic disease during pregnancy: maternal and fetal effects. Clin Invest Med 1985;8:333–8. [3] Byrne J. Fertility and pregnancy after malignancy. Sem Perinatol 1990;14:423–29.

[4] Weisz B, Schiff E, Lishner M. Cancer in pregnancy: maternal and fetal implications. Hum Reprod Update 2001;7:384–93. [5] Arnon J, Meirow D, Lewis-Roness H, Ornoy A. Genetic and teratogenic effects of cancer treatments on gametes and embryos. Hum Reprod 2001;7:394–403. [6] Garcia L, Valcarcel M, Santiago-Borrero PJ. Chemotherapy during pregnancy and its effects on the fetus − neonatal myelosuppression: two case reports. J Perinatol 1999;19:230–3. [7] Ebert V, L¨offler H, Kirch W. Cytotoxic therapy and pregnancy. Pharmacol Ther 1997;74:207–20. [8] Chiarelli AM, Marrett OL, Darlington GA. Pregnancy outcomes in females after treatment for childhood cancer. Epidemiology 2000;11:161–6. [9] Green DM, Whitton JA, Stovall M, Mertens AC, Donaldson SS, Ruymann FB, et al. Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Am J Obstet Gynecol 2002;187:1070–80.

14. Cancer Chemotherapeutic Agents in Pregnancy Gideon Koren, MD, FRCPC1 , Michael Lishner, MD2 1 Motherisk

Program, University of Toronto, The Ivey Chair in Molecular Toxicology, University of Western Ontario, Canada; 2 Tel Aviv University Hospital for Sick Children Exchange Program, Tel Aviv University, Israel Essentially all cancer chemotherapeutic agents are teratogenic in animal studies. Human data are much more complex. Cancer chemotherapy is now often used in treating colitis, transplant, rheumatoid arthritis, and emerging data suggest that agents such as azathioprine and methotrexate, when used at clinical doses for non-oncological indications—may not be teratogenic. Cancer in pregnancy is an extreme example of a potential maternal–fetal conflict, when diagnostic and therapeutic procedures essential for the well being of the mother may be detrimental to the unborn baby. This field of maternal–fetal medicine is marred by the relative rarity of cases and, hence, by difficult decisions informed by poor epidemiology. In 1996 we created the Consortium of Cancer of Pregnancy Evidence (CCoPE), which continuously reviews published data and answers questions by patients and health professionals worldwide [1]. CCoPE database includes information based on cancer type, therapeutic agents, complications, surgery, fertility etc. All data including previous questions and answers are free on the Web [2]. Cancer chemotherapeutic agents in pregnancy In most cases of diagnosis of cancer during the first trimester of pregnancy, the family tends to choose termination of pregnancy to avoid long-term consequences of embryonic damage, and without withholding essential therapy from the mother. There are no published data to suggest that exposure to cancer chemotherapy beyond the first trimester is associated with teratogenic risk. Because all body organs except to the brain complete their development by 12 weeks of pregnancy, neurodevelopmental deficits are the focus of concern. Yet, systematic review of all available

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studies does not point to neurobehavioral risks after exposure beyond the first trimester [3]. When cancer is diagnosed during the third trimester of pregnancy, there should be a close dialogue between the oncologists and perinatologists to identify optimal time for delivery. If possible, allowing fetal lung maturation is critical (e.g., caesarian section by 34–36 weeks).

[3] Nulman I, Laslo D, Fried S, Uleryk E, Lishner M, Koren G. Neurodevelopment of children exposed in utero to treatment of maternal malignancy. Br J Cancer 2001;85:1611–8. [4] Trosler JM, Hales BF, Robaire B. Paternal cyclophosphamide treatment of rats fetal loss and malformations without affecting male fertility. Nature 1985;316:144–6.

Chemotherapy for non-oncologic conditions

15. Epidemiology Studies Dealing with the Etiology of Abortion: Frequent Errors and Misinterpretations

Use of chemotherapy for non-oncologic indications poses a new set of guidelines. For example, azathioprine is widely used for colitis and post organ-transplant. While the drug is teratogenic in animals at high dose, the doses used in these conditions have not been shown to be teratogenic in humans [2].

Robert L. Brent, MD, PhD

Male-mediated teratogenicity Presently, there are no human data to suggest that male survivors of cancer chemotherapy have an increased teratogenic risk. Yet, animal research has succeeded in producing teratogenicity (e.g., with cyclophosphamide) [4]. Much more research is needed to answer these questions. Meanwhile it is critical to inform men in whom chemotherapy is initiated of the option of banking sperm, as therapy may render them sterile, and the question of long-term sperm safety has not yet been fully answered. Other risks of chemotherapy In animal studies and human case reports, chemotherapy is associated with secondary cancer and mutagenesis. Epidemiologically, large cohorts are needed to evaluate the existence and magnitude of such risks, if exist in the clinical arena. Summary In summary, cancer and chemotherapeutic agents in pregnancy create unique challenges to clinicians. Future work will need to be much more specific regarding pharmacokinetics and pharmacodynamics of these agents in the maternal fetal unit. An international collaboration is needed to close the severe knowledge gap in this field. Acknowledgements Supported by the Lawson Foundation, Canada and Tel Aviv University—Hospital for Sick Children Exchange Program (funded by the Canadian Friends of Tel Aviv University). References [1] Lishner M, Koren G. Cancer chemotherapy during pregnancy. Consortium of cancer in pregnancy evidence. Can Fam Physician 2001;47:41–2. [2] The Motherisk Program, www.motherisk.org.

A.I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE, Philadelphia, PA, USA Spontaneous abortions, frequently referred to as miscarriages by the public, are common occurrences during pregnancy. According to the World Health Organization, 15% of women who know that they are clinically pregnant abort their pregnancies. Research studies indicate that a higher percentage of embryos are aborted before the first-missed menstrual period and before the mothers know that they are pregnant, and it has been estimated that up to 50% of all fertilized ova in the human are lost within the first three weeks of development. The lay population and the news media are under the impression that many abortions are due to exposures to some type of toxic agent during the woman’s pregnancy. Some epidemiologists perform epidemiological studies because they can be readily initiated, completed and receive attention by the press when the studies indicate that an environmental toxicant has been associated with an increase in the rate of abortion. Environmental causes of reproductive problems are evaluated by performing epidemiological studies, secular trend analysis, animal reproductive studies and by utilizing the scientific application of biological plausibility. Although reproductive effects are measured by determining the alterations in the frequency of (1) congenital malformations, (2) fetal growth retardation (3) stillbirths and (4) spontaneous abortion, epidemiologists frequently focus on the least complicated endpoint to measure; namely, spontaneous abortion. Yet reproductive biologists have known for a long time, that the importance and relevance of reproductive studies are improved if all the reproductive endpoints are evaluated in the same study. Studies that investigate the incidence of abortion as the only reproductive endpoint frequently obtain a statistical association with exposure to an environmental drug or chemical. These positive environmental studies, which indicate that a particular drug or chemical exposure is associated with an increase in the incidence of abortions do not make biological sense in many instances. Since most abortion epidemiology studies are case control studies and it is very difficult to obtain accurate information on abortions that have occurred months or years before, it is not surprising that many of these studies exaggerate the abortion risk of environmental exposures. Spontaneous abortions can result from inherited or acquired chromosomal abnormalities; inherited diseases; medi-

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cally or environmentally produced blighted (malformed) embryos; maternal illness; lupus anticoagulant factor (World Health Organization, 1970). Since each week of pregnancy has a different spontaneous abortion rate, that can vary considerably among populations of pregnant women, it is extremely difficult to match patients in case control studies and epidemiologists need very large populations to perform cohort studies that evaluate the risks of abortion. In many instances studies involving the reproductive risks of low frequency EMF of electrical currents and video display units (60 Hz and 17–20 Hz, respectively) only examined the risk of abortion. One of the advantages of reproductive biological effects is that there is frequently, but not always, concordance of effects involving more than one parameter (growth, malformations, abortion, stillbirth, prematurity, etc.) Isolated abortion studies that do not study the totality of reproductive effects are at a serious disadvantage, since spurious or non-etiological results may be misinterpreted as being causally related to an environmental toxicant. Epidemiological investigations dealing with the causes of spontaneous abortions must deal with formidable problems: (1) A majority of spontaneous abortions are due to chromosomal abnormalities that are unrelated to environmental exposures during pregnancy. (2) The risk of abortion changes with each day of pregnancy, so that it is essential to match controls, in order to eliminate the selection of two populations with different spontaneous abortion rates. (3) Attempts to control for the hidden incidence of therapeutic abortions have only limited success. Rarely do the epidemiolgists indicate the mechanism that caused the increase in abortion in their investigation. Since the majority of abortions that occur early in gestation are due to chromosome abnormalities and there are at least 30 other intrinsic etiologies for spontaneous abortion, it is readily apparent that if the spontaneous abortion rate has doubled in a particular study and one mechanism has been involved, then the doubling has to be due to an astronomical increase in abortion due to that particular mechanism. Miscarriage is perceived by the public, mothers, psychologists, obstetricians, attorneys and reproductive biologists much differently. The mother’s family, neighbors and friends perceive the miscarriage as the loss of a potentially normal child. The obstetrician and reproductive biologists know that a large percentage of miscarriages are due to the fact that the embryo had a chromosomal abnormality or/and anatomical malformation. In reality “nature” had eliminated a seriously defective embryo. In most instances the obstetrician or counselor is reluctant to inform the family that they have been fortunate to lose that baby. Instead the obstetrician, nurse, resident and other medical professionals offer their support and compassion to the family and never address the fact that the embryo may have been abnormal.

Unfortunately, in some instances, the patient may believe that a drug or chemical caused the miscarriage. Is the grief and depression the normal, instinctual response to the loss of a pregnancy, or is it a learned behavior of a compassionate society. Can this question be scientifically studied and can the answer be of benefit to pregnant women? It is suggested that at the first prenatal visit pregnancy risks should be discussed and a brochure should be prepared explaining that 3% of live births have congenital malformations and 15% spontaneously abort. The obstetrician or counselor should explain that the majority of abortuses have serious problems. If this information were known long before the occurrence of the miscarriage, the pain, depression and anxiety associated with abortion may be ameliorated. This issue is worth studying, because it possibly could reduce the psychological pain of having an abortion and lessen the impact of this traumatic experience. II. ABSTRACTS OF POSTERS PRESENTED 1. Pregnancy Outcome after Medication with HMG-CoA Reductase Inhibitors in the First Trimester Paulus Wolfgang1 , Schloemp Sabine1 , Sterzik Karl2 , Stoz Frank1 1 Institut

f¨ur Reproduktionstoxikologie, Krankenhaus St. Elisabeth, D-88212 Ravensburg, Germany; 2 ChristianLauritzen-Institut, D-89073 Ulm, Germany Introduction: Atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin are used in the treatment of hyperlipidemias. The mechanism of action is a competitive inhibition of hydroxymethylglutaryl (HMG) CoA reductase, the ratelimiting step in de novo cholesterol biosynthesis. Cholesterol binding to Sonic Hedgehog protein is required for this protein to play a signalling role in embryo development. Experimental animal studies do not indicate a substantial teratogenic risk; only high-dose lovastatin exposure of pregnant rats resulted in abnormalities of the skeleton and gastroschisis in the offspring. A collection of human malformations (e.g. CNS, holoprosencephaly) possibly linked to abnormal Sonic Hedgehog signalling after exposure to HMG-CoA reductase inhibitors, including lovastatin, simvastatin and atorvastatin, has been presented. Statins are generally contra-indicated in pregnancy since there is a possibility that they might affect fetal sterol synthesis. The patient instructions suggest to use an effective form of birth control to keep from getting pregnant while taking HMG-CoA reductase inhibitors. These warnings make patients uncertain after application of HMG-CoA reductase inhibitors in early pregnancy before they have been aware of their pregnancy. Methods: In a prospective follow-up study we collected data of pregnancy outcomes after medication with HMGCoA reductase inhibitors in the last ten years. Our Teratology Information Service (TIS) was contacted by physicians and patients after exposure to HMG-CoA reductase inhibitors in the first trimester. We compared the results with a control

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group (n = 528) of our TIS in the same interval, which was not severely exposed. Statistical evaluation was performed by chi-square test. Until now follow-up of pregnancy outcome has successfully been done in 45 cases (atorvastatin: n = 10, cerivastatin: n = 4, fluvastatin: n = 5, lovastatin: n = 9, pravastatin: n = 6, simvastatin: n = 11). Results: After exposure to HMG-CoA reductase inhibitors, six patients (13.3%) preferred termination of pregnancy. The incidence of elective terminations of pregnancy was much higher (p < 0.001) after medication with HMGCoA reductase inhibitors than in the control group (2.1%). The other 39 documented pregnancies ended with spontaneous abortion in six cases and delivery in 33 cases. The abortion rate did not differ significantly from the control group (15.4% versus 11.4%). Three congenital anomalies were reported after intrauterine exposure to HMG-CoA reductase inhibitors: two cases of umbilical hernia after exposure to lovastatine, one case of patent ductus arteriosus after exposure to simvastatin. The rate of congenital anomalies was not significantly higher after application of HMG-CoA reductase inhibitors (3/33 = 9.1% versus 19/459 = 4.1%; p = 0.18; relative risk 2.2; 95% confidence interval: 0.68, 7.04). Conclusions: Based on experimental animal studies and a small number of human cases, inadvertent exposure to HMG CoA reductase inhibitors during early pregnancy appears unlikely to increase the risk of adverse pregnancy outcome. Theoretical considerations concerning the role of cholesterol in embryo development plus the lack of demonstrated benefit of treating hyperlipidemia during gestation argue against intentional use of statins during pregnancy. Although data of our registry are limited we do not recommend termination of pregnancy after exposure to HMG-CoA reductase inhibitors in the first trimester. A detailed fetal ultrasound should confirm normal morphologic development, especially of the CNS and the abdominal wall.

Results: Between 1984 and December 2003, 9480 therapeutic enquiries were received; 1870 (19.7%) were about teratology (3854 drugs involved). The yearly number of enquiries has progressively increased during this period. A total of 1006 enquiries about teratology (53.8%) came from our hospital, 172 (9.2%) from other hospitals, 581 (31.1%) from primary health care and the rest from other sources. 1588 enquiries (85%) were made by physicians, 157 (8.4%) by nurses, 60 (3.2%) by patients, 31 (1.6%) by pharmacists and 34 (1.8%) by others. The medical specialities from which the majority of enquiries came were Obstetrics and Gynaecology (1432; 76.6%), General Practice (113; 6%), and others (325; 17.4%). The subgroups of drugs most commonly involved in the enquiries were N05 (benzodiazepines and antipsychotics) in 478 cases (14.7%), N06 (antidepressants) in 341 cases (10.5%), and J01 (systemic antiinfectives) in 169 cases (5.2%) and the specific drugs were alprazolam (in 76 cases), paroxetine (68), diazepam (62), fluoxetine (58), and lorazepam (55). The information available about teratology of drugs involved in more than half of the cases (56.8%) is limited; there is no information for some drugs (i.e. dipyrone), for some others only data in animals is available (i.e. ebastine) and for others, studies in pregnant women are scarce or inconclusive (i.e. some new antidepressants, antibiotics and antimalarials). Conclusions: Since the start of TC the number of enquiries per year concerning teratology has gradually increased. Benzodiazepines and antidepressants have been the most commonly involved drugs in the enquiries. The information available about teratology of drugs involved in more than half of the cases (56.8%) is limited.

2. Therapeutic Consultation Services About Teratology: A Growing Need for Drug Information

Teratology Information Service, Helsinki University Central Hospital, Finland

C. Aguilera, I. Dan´es, A. Agust´ı

Background: Some teratology information services (TIS) provide information only to health care personnel. In the Helsinki TIS, the number of calls has been rapidly increasing and the majority of inquiries come from the public. Aim of the Study: To evaluate the proportion of calls concerning potentially or clearly harmful drugs and coming from the public. Setting: Calls considering drug exposure during pregnancy in the year 2003. Methods: Linkage of each individual ATC code (fifth level) with the Swedish pregnancy safety categorisation FASS 2002. Drugs belonging to categories B3 (limited experience in pregnant women, animal studies indicative of increased fetal risk) and C (may cause pharmacological adverse effects on the fetus or neonate) were grouped as potentially harmful. Drugs belonging to category D (suspected or proven

Foundation Institut Catal`a de Farmacologia, Clinical Pharmacology Service, Hospital Vall d’Hebron. Barcelona, Spain Introduction: Therapeutic Consultation (TC) started in the Foundation Institut Catal`a de Farmacologia in 1984, as a service oriented towards the resolution of therapeutic questions. An increasing number of TCs about teratology has been observed. The aim of the present study is to describe the characteristics of the enquiries about teratology received in our service. Methods: An analysis of TCs registered on our database has been performed. We have selected all the teratologyrelated enquiries with the aim of describing their origins and the drugs most commonly involved.

3. Accepting Calls from the Public—The Helsinki Teratology Information Service Experience Heli Malm, Hannemari Leppiniemi

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to cause malformations or other irreversible damage) were considered clearly harmful. As a single inquiry may include several exposures, the first five ATC codes per inquiry were recorded in the study. The data were analysed with the SPSS Base system. Results: Of the total 1617 calls received, 1260 (77.9%) considered drug exposure only during pregnancy. The majority of calls (n = 957; 76.0%) came from the public and 296 calls (23.5%) came from health care personnel. Of the calls coming from the public, 427 (44.6%) concerned potentially harmful drugs, and 43 (4.5%) concerned clearly harmful drugs. The most common drugs considered as potentially harmful were the selective serotonin reuptake inhibitors citalopram (n = 32; 3.3% of calls from the public), fluoxetine (n = 24; 2.5%), paroxetine (n = 22; 2.3%) and labetalol (n = 34; 3.6%). In the clearly harmful group, the most common drugs were tetracycline (n = 10; 1.0%), valproic acid (n = 8; 0.8%) and azathioprine (n = 6; 0.6%). Conclusion: Our results indicate that approximately half of the calls received from the public concern potentially or clearly harmful drug exposures. Accepting calls from the public is therefore justified. 4. Preconceptional Counselling and Prevention of Fetal Malformations. Role of A Teratology Information Service: Telefono Rosso M. De Santis, G. Straface, A.F. Cavaliere, E. Nobili, B. Carducci, A. Caruso Telefono Rosso Teratology Information Service, Department of Obstetrics and Gynaecology Catholic University of Sacred Heart, Rome, Italy Introduction: Appropriate preconceptional counselling improves pregnancy outcome. Pre- and periconceptional folic acid supplementation can prevent neural tube defects Genetic counselling and targeted screening should be offered on the basis of age, ethnical group and family history. Before conception, women should be screened for common infectious diseases undergoing preconceptional vaccinations (rubella and varicella) and changes of hygienic, eating and behaviour habits are useful for prevention. Exposure to cigarette smoke, alcohol, street drugs, and chemicals like solvents and pesticides should be avoided. Before pregnancy, women with chronic disease such as diabetes, hypertension, epilepsy, thromboembolism, depression, and anxiety must be evaluated to optimize disease control; if necessary medications must be reviewed and changed. Counselling on physical exercise, obesity, nutritional deficiencies and excess of vitamins A and D supplementation is important too. Unfortunately 40–50% of pregnancies are unintended and many women undergo to their first prenatal medical consult at eight weeks of pregnancy or later, and this period carries the most fetal development risk. Thus, every opportunity may be useful for prencoceptional counselling in women in reproductive age.

Methods: All the cases of women who called our TIS between July 2002 and February 2004 in preconceptional period have been considered to evaluate the characteristics of this group and the importance of a counselling in term of prevention of congenital malformation and/or adverse pregnancy outcomes. Results: Between July 2002 and February 2004 (19 months) we evaluated 800 phone calls of women in preconceptional period, 8% of all the calls in this period. Main reason for calls was drugs consumption (81%) mainly for maternal chronic disease. Other categories were: diagnostic X-ray (2.25%) and chemical compounds (1.75%) exposure, infectious diseases (1.75%) and others (13.25%). We observed 24 cases of preconceptional vaccination with seven case for rubella. The last group was concerned about the waiting period. 2.0% of cases had paternal exposure and/or chronic disease. In the group of women drug exposed, 9% of substances were teratogens (30 antiepileptic drugs, 14 retinoids, 12 tapazole, 4 lithium, 2 ACE inhibitors, 2 coumarin derivates). We had 12 cases of previous chemotherapy, and 1 case of leflunomide exposure that needed an adequate counselling about waiting period. Regarding the importance of preconceptional consumption of folic acid only 13% of women were informed. Consequently, our Service informed the remaining 87% of the women who called, about the significance of folic acid. Conclusions: Our data confirm the importance of a TIS in preconceptional counselling for preventing congenital malformations and adverse foetal outcomes. In our experience, in 50% of drugs exposed cases, the phone contact was a good chance to choose the best treatment for maternal chronic disease. In conclusion, Teratology Information Service is an important way for preconceptional counselling, especially for selected patients, like women with chronic diseases affected women or drugs users. 5. New Antiepileptic Drugs: Case Series of Pregnancy Exposure M. De Santis, G. Straface, A.F. Cavaliere, E. Nobili, B. Carducci, A. Caruso Telefono Rosso—Teratology Information Service, Department of Obstetrics and Gynaecology—Catholic University of Sacred Heart, Rome, Italy Introduction: The new antiepileptic drugs (AEDs) have been marketed since 1993. These include gabapentin, felbamate, lamotrigine, topiramate, oxcarbazepine, vigabatrin, tiagabine and zonisamide. Currently there are poor data regarding the risk of fetal exposure to AEDs. Methods: Between July 2002 and February 2004 we enrolled 53 patients who had consulted our Teratology Information Service (TIS) on new AEDs exposure in early pregnancy. We collected data regarding dose, side effects, treatment indications, exposure period and other therapies.

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All patients were followed with phone interviews during pregnancy and until two years after delivery. They were asked about pregnancy outcome, birth defects and neonatal complications. Results: There were 53 pregnant women treated with new AEDs. We had 10 livebirths, 3 spontaneous abortions, 1 stillbirth, 6 terminations of pregnancy, 19 ongoing pregnancies and 14 lost to follow-up. We found one genetic disease, a Turner syndrome, and the patient chose to terminate the pregnancy. Oxcarbazepine: 11 patients were exposed to oxcarbazepine. There was one normal infant, a case of Turner syndrome, three were lost to follow-up and six are ongoing pregnancies. Lamotrigine: Eight patients were exposed to lamotrigine. There was one normal infant, five are ongoing pregnancies, one was lost to follow-up and one elective termination. Gabapentin: We had 25 cases of gabapentin exposure in the first trimester of pregnancy. Eight patients were lost to follow-up and three performed voluntary abortions. There were five normal infants, five ongoing pregnancies, three spontaneous abortions and one stillbirth at 32nd week of gestation. The fetus showed no malformations at autopsy. Topiramate: Seven women called our TIS for topiramate exposure in pregnancy. There were three normal infants, one termination of pregnancy, one lost to follow-up and five are ongoing pregnancies. Tiagabine: Only one patient took tiagabine, and it is an ongoing pregnancy. Vigabatrin: A woman contact our TIS for vigabatrin exposure in pregnancy but was lost to follow-up. Conclusions: Our case series is not enough to evaluate any teratogenic risk. Even in the literature, the number of reported pregnancies exposed to these drugs is not large enough to calculate risk rates. Few malformations have been described in pregnancy exposed to new AEDs. Moreover, in these studies concomitant treatment with other antiepilectic drugs are confounding factors. The lack of definitive data regarding the safety of the use of these drugs in pregnancy justifies the opportunity of collecting as many cases as possible to achieve enough experience. These drugs appear to be more favourable than the older ones in epilepsy treatment in women of childbearing age. They show a good pharmacokinetic profile that makes them more stable during pregnancy and a low potential for interaction with other drugs. Is less likely that these new AEDs will be metabolized in teratogenic compounds. Furthermore, most of them have no antifolate properties. To date, strict adherence to current recommendations relating to antiepileptics use during pregnancy is crucial: (1) II–III levels ultrasonographic examination; (2) maternal serum alpha fetoprotein evaluation. 6. Ultrastructural Morphology of Cellular Apoptosis in Embryonic Defective Tissues due to Retinoid Analogue E.-N. Emmanouil-Nikoloussi, DDS, PhD, MD, PhD Laboratory of Histology-Embryology & Anthropology Faculty of Medicine, Aristotle University of Thessaloniki

257

University Campus, Thessaloniki 54124, Greece Apoptosis in normal embryological differentiation, is characterized morphologically as a developmental process controlling cell number and morphogenesis of all systems and organs. The recent identification of the crucial role of cell apoptosis in multicellular organisms and the discovery of apoptotic genetic code regulation has given the ability to study the diverse procedures taking place during apoptosis. Programmed cell death, i.e. apoptosis, is now recognized as an important developmental event, not only in the accurate modelling of the embryo, but also in resolving cell-signalling conflicts. Treatment with Retinoid compounds during gestation, has been implicated for a variety of malformations in diverse embryonic tissues and organs. Diverse clinical reports have summarized the pattern of malformations which are caused by maternal use of retinoids, mostly, during the first trimester of pregnancy in humans. The present study was performed to shed light on and analyze several loci of defected embryonic tissues which were presented as “Teratomas”, i.e. embryonic masses combined with a short umbilical cord at a sub developed placenta in litters of pregnant rats treated with all-trans-retinoic acid. Those teratomatas were counted and collected during an extended experimental study, concerning the teratogenicity of all-trans-retinoic acid. Apoptosis is characterised in defective tissues by unique ultrastructural morphological characteristics such as cytoplasmic shrinkange, blebbing and swelling of the cytoplasm, resulting in cytoplasm apoptotic bodies, chromatin condensation and chromatin margination of the nuclei at the cells where apoptosis was identified. It has been proposed that programmed cell death acts as a default pathway to correct conflictive or stray signalling events in development, intermediating the multipotent embryonic development procedures. However, there is little evidence defining the identity, the types of sources, and the mechanisms of action of the teratogenic factors which are modulating cell survival and death during the critical periods of gastrulation, neurulation and further embryonic development. The results of this study discuss the ultrastructural morphology of defected apoptotic cells of embryonic tissues resulting from a teratogenic compound which can also act as a morphogen in experimental animal studies, as all-trans-retinoic acid. 7. Pregnancy Outcome After Suicide Attempt by Drug Ingestion: A Nine-year Prospective Study M. Mathieu-Nolf1 , C. Durak-Carpeza1 , D. Mathieu2 , D. Subtil3 , D. Peucelle1 1 Centre Antipoison, Lille, France; 2 Service D’urgence et Re-

animation Medicale, Lille, France; 3 Service de Gynecologie et Obstetrique, Hopital Regional Universitaire, Lille, France Suicide attempts during pregnancy are rare and few data on pregnancy and fetal outcome are available in the literature except a few studies and case reports.

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Objective: We undertake a prospective follow-up study to describe the fetal consequences of maternal drug selfpoisoning during a nine-year period (1995–2003). Methods: All pregnant women hospitalized in the emergency department or the intensive care unit of the regional hospital for suicide attempt by drugs were studied. Data collected included demographic data, medical history, clinical data concerning self-poisoning (symptoms developed, drugs used and estimated doses, symptoms and treatment). The severity of poisoning was evaluated using the Poisoning Severity Score based on severity of symptoms. After hospital discharge, women were included for follow-up till the pregnancy termination, and after delivery, live born infants were examined by a pediatrician. Results: From 1995 to 2003, 194 pregnant women attempted suicide by drugs in 198 separate episodes (four patients attempted suicide twice during the same pregnancy). Age ranged from 14 to 47 years (mean 25.81 years ± S.D., ±6.37 years). Of these, 21 women had medical history of depression, 9 of psychiatric disorders, 21 of previous self-poisoning, 4 of drug abuse, 6 of alcohol abuse and 33 of tobacco smoking. No severity or mild severity was observed in most cases (n = 187) and five poisonings were moderate and two were severe. No women died of intoxication. Complete follow-up was obtained for 121 patients (62%). Of these 121 evaluated pregnancy outcomes, 4 ended in spontaneous abortion, 10 in elective abortion, 3 in therapeutic pregnancy termination and 104 in live born infants. Focussing on the first trimester, the most vulnerable period for the fetus, 87 women (45%) attempted suicide during the first trimester after conception and 51 of them (59%) were followed. Pregnancy outcomes were 4 spontaneous abortions, 10 elective abortions, 3 therapeutic pregnancy terminations and 34 live born infants. The characteristics of these 34 live born infants are: sex ratio male/female: 1.66, mean weight 3009 ± 788 g (minimum 910, maximum 4200 g), mean height 33.8 ± 3.2 cm (minimum 29 cm, maximum 54 cm), mean cranial circumference 33.8 ± 2.1 cm (minimum 29, maximum 36 cm). Nine infants (26%) weighted less than 2500 g. Prematurity of birth (less than 38 weeks of amenorrhea (WA)) was diagnosed for 6 live born infants (18%). Out of them, one was severe (less than 33 WA), 3 were moderate (33–35 WA), 2 were mild (36–37WA). No malformation was observed within these 34 live born infants. Conclusion: This study supports earlier studies that reported that drug intoxication during the first trimester of conception does not seem to pose a substantial teratogenic risk but a tendency for an increase of the number of low birth weight and prematurity. However, continuation of this study is needed because of the small number of our sample and the difficulty to follow this population. 8. Pregnancy Outcome after Exposure to Cetirizine/Levocetirizine in the First Trimester—A Prospective Controlled Study

Paulus Wolfgang1 , Schloemp Sabine1 , Sterzik Karl2 , Stoz Frank1 1 Institut

f¨ur Reproduktionstoxikologie, Krankenhaus St. Elisabeth, D-88212 Ravensburg, Germany; 2 ChristianLauritzen-Institut, D-89073 Ulm, Germany Introduction: Cetirizine, a second-generation H1-receptor antagonist with low sedating properties, is widely used to treat allergic rhinitis and chronic urticaria, but the data on pregnancy outcome are very limited so far. There is even less information on levocetirizine, the active (R)-enantiomer of cetirizine. Methods: In a prospective follow-up study we collected data of pregnancy outcomes after medication with cetirizine (5–20 mg/d) and levocetirizine (5 mg/d) in the last 12 years. Cases were only included, when our Teratology Information Service (TIS) was contacted by physicians and patients after exposure to these substances in the first trimester. We compared the results with a control group (n = 542) of our TIS in the same interval, which was not severely exposed. Statistical evaluation was performed by chi-square test. Until now follow-up of pregnancy outcome has successfully been done in 150 cases (cetirizine: n = 144, levocetirizine: n = 6). Results: After exposure to cetirizine/levocetirizine nine patients (6.0%) preferred termination of pregnancy. The incidence of elective terminations of pregnancy was significantly higher (p = 0.01) after medication with cetirizine/levocetirizine than in the control group (2.0%). The remaining 141 documented pregnancies ended with spontaneous abortion in 18 cases and delivery in 123 cases. The rate of spontaneous abortion did not differ significantly from the control group (12.8% versus 11.5%). Seven congenital anomalies were reported after intrauterine exposure to cetirizine in the first trimester, but without a consistent pattern: one case of trisomy 18, one case of aortic valvular stenosis, one case of ventricular septal defect, one case of cleft palate, one case of inguinal hernia, one case of foot deformity, one case of auricular skin tags. The rate of congenital anomalies was not significantly higher after application of cetirizine/levocetirizine (7/123 = 5.7% versus 19/470 = 4.0%; p = 0.43; relative risk 1.53; 95% confidence interval: 0.66, 3.56). Conclusions: Therapeutic doses of cetirizine and levocetirizine during early pregnancy are unlikely to pose a substantial teratogenic risk, although data are not sufficient to state that there is no risk at all. 9. Pregnancy Exposure to Isotretionoin: A Continuing Problem J. Arnon, O. Diav-Citrin, S. Shechtman, R. Wajnberg, A. Ornoy The Israel Teratogen Information Service, Israel Ministry of Health, Israel The drug isotretinoin was first marketed in the USA in 1982. The approved indication was for severe recalcitrant

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nodular acne. The teratogenic effect of the drug on animals was well documented before it was approved for use in humans. In the months following the introduction of the drug into the market, a number of cases were reported of isotretinoin exposure during pregnancy. The drug is a potent teratogen in humans, and may cause multiple major malformations, such as CNS, cardiac, craniofacial and thymic malformations. In response, in 1988 the manufacturer, Roche Laboratories started the Pregnancy Prevention Program (PPP). The program included information for the prescribing physician and for the patient. The protocol called for two effective birth control methods while taking the drug, and starting the medication on the 2nd or 3rd day of the menstrual period. In spite of the absolute contraindications of drug use during pregnancy, women continue to become pregnant while taking the drug. Since first marketed in 1982, the manufacturer has reports on 2000 pregnancies with in utero exposure to isotretinoin. According to Honein, Accutane is the most commonly used teratogen in the USA and 2.5 of every 1000 women of child bearing age use this drug. In Israel, the situation is similar: 20,000 isotretinoin treated patients among 3.5 million members of Kupat Holim Klalit. This means 2.6/1000 reproductive aged women were treated with isotretinoin. In the year 2001, PPP was replaced by SMART—System to Manage Accutane Related Teratogenicty. The new recommendations include two negative pregnancy tests before starting the drug, two birth control devices, a monthly negative pregnancy test, enrollment in a follow-up study of women taking the medication, the prescription cannot be dispensed for more than a month and a consent form must be signed by the patient. In Israel the situation is very different. The patient does not need to sign an informed consent form, and any physician is allowed to prescribe isotretinoin. The use of the medication for acne has been rising. There is now a cheaper generic version of the drug, which will also increase the number of women using the drug. We were interested in examining the Israeli TIS experience. We summarized our data about the number of calls concerning use of isotretinoin in pregnancy. The results are summarized in Table 1. These women included those who were exposed to the drug in pregnancy or who conceived less than one month after discontinuation of the drug. Pregnancies with isotretinoin exposure is a continuing problem, is spite of the awareness of the medical community about the teratogenic potential of the drug. In the United States and Canada, Table 1 Israeli TIS experience with isotretionoin against the recommendations Year 1994–1997

1998

1999

2000

2001

2002

2003

Per 1000

0.52

1.85

1.78

3.08

2.67

3.04

3.49

No. of cases

6

8

9

18

17

24

29

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changes have been implemented in the dispensing of the drug in order to lower the potential exposure in pregnancy. It is important that in Israel and other countries that have less stringent rules concerning Isotretinoin to strive harder to avoid the exposure of the drug to women who may conceive during the course of the medication. 10. In Vitro Fertilisation: Case Report Eva Manakova CZTIS, Prague, Czech Republic A 30-year-old woman who became first pregnant after IVF had to undergo ETOP because micromelia (Chondrodysplasia punctata) had been detected on sonography. IVF was complicated by hyperstimulation syndrome treated by Prednisone, Enoxaparin, Algifen (metamizole, pitofenone, fenpiverinium), Furosemide, Aktiferrin, Omeprazole, and PAMBA. She suspected the treatment as a cause of malformation; therefore she contacted her geneticist and CZTIS. Are such drugs really risky for her pregnancy? Only Prednisone and Furosemide are referred as causes of malformations in animals. However, there is no evidence of an increase in malformations in human beings, but association of prednisone with clefts could not be excluded. Components of Algifen are either suspected having effects on haematopoesis or were not mentioned in teratologic databases. Hereditary diseases, which we have to take into consideration, are Chondrodysplasia punctata—autosomal recessive, Chondrodysplasia punctata X-linked dominant type (ConradiHonermann syndrome), or Beckwith–Wiedermann syndrome. Most studies have shown a negligible or only slight excess risk of birth defects in children coming from assisted reproduction. However, some recent studies report unexpectedly high incidence of Beckwith–Wiedermann syndrome (BWS) and cases of Angelman syndrome (AS). In 50–60% BWS and 5–10% AS are disorders probably due to epigenetic factors. Inadequate conditions during early embryogenesis are suspected for formation of errors in demethylation on imprinted genes. This hypothesis should be corrected on basis of recent findings. Tilly and co-workers demonstrated in work published in Nature in 2004 that germ line stem cells and follicular renewal take place also in the postnatal mammalian ovary. Similar findings were announced also for human being. Imprinted genes are differentially expressed according to their origin in either oocyte or spermatozoon and the inactive are epigenetically marked. This process was thought to be active in female only during prenatal period. According to the new knowledge in this field, disorder of imprinting could take place also during oocytes renewal. Hyperstimulation probably can activate immature oocytes that can accidentally be used for IVF. Conclusions: 1. The malformation was unlikely caused by any or combination of the used drugs.

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2. Genetic disease (Chondrodysplasia punctata) should be excluded. 3. Beckwith–Wiedermann syndrome is another explanation for this malformation. Acknowledgements Supported by Grant of VZ111200001 and LA198.

Ministry

of

Education

11. Drug exposure During Pregnancy: Pharmaceutical Advertising Paul Merlob Beilinson Teratology Information Service (BELTIS), Rabin Medical Center, Beilinson Campus, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Leacock defined advertising as the science of arresting the human intelligence long enough to get money from it. The annual spending on direct-to-consumer (DTC) advertising for prescription drugs tripled between 1996 and 2000, when it reached nearly US$ 2.5 billion. Regarding the scientific evidence of pharmaceutical advertising, the Institute for Evidence-Based Medicine in Cologne, Germany, evaluated 175 brochures containing information on 520 drugs since June 2003: 94% of the information has no basis in scientific evidence. In relation to drugs exposure during pregnancy, the most important problem is the lack of appropriate pharmacokinetic data and the inadequacy of most of the available information. It is essential to address the problem of pregnant women as “therapeutic orphans”. Drugs given to pregnant women must be studied in pregnant women. In conclusion, the education of patients and physicians is too important to be left to the pharmaceutical industry, whose primary aim is to sell drugs with pseudo-educational advertising.

St. Petersburg There seems to be a decreasing level of reproduction health of the population of the Russian Federation within the last 20 years. This seems to be corroborated by some fairly evident and illustrative objective information. (1) 12–15% of the registered marriages in Russia turn out to be not fertile; (2) the number of children with birth defects until 1 year old, including the ones which were stillborn is more than 30 for 1000; and (3) the number of disabled persons being such from childhood is 29% in St. Petersburg. And this sad statistics may be continued. All the above became the precondition for organizing in St. Petersburg a Teratogen Information Service on the basis of Perinatal Medical Center. The aim of the teratological counseling is to estimate the risk of the possibility of birth defects in general as a result of influence on the fetus of external environmental factors. The small experience of work of teratology consultation shows the increasing interest in this type of medical prophylactics service in the city. The primary analyses involved about 850 patients that have visited the Center during the first year of its existence. It is not possible to draw any global conclusion based on such small numbers of patients. Interestingly, there were no young patients under the age of 20. It seems that this group of women in St. Petersburg obtains “necessary” information about pregnancy and gynecological diseases in 34% of cases from the mass media and in 56% of cases from friends and acquaintances but not from the doctors. This phenomenon reveals the low responsibility of a pregnant woman for her health and the health of her child. Visit to the teratology consultation are encouraged not only for pregnant women that are in need for information but also in the case of planning of pregnancy, especially in women that may be of increased risk of having a child with birth defects.

12. The First Steps in Teratologic Counselling Service in St. Petersburg

Acknowledgements

E. Valkovich, E. Levin, J. Prochorova, N. Belobocova, E. Bogdanova

This workshop was made possible by grant LST ARW 980470 by NATO.