TERATOLOGY 42:629-634 (1990)
Experience of Two Teratology Information Services in Europe* JOHANNA M. GARBIS, ELISABETH ROBERT, AND PAUL W.J. PETERS Dewartment of Teratolom. National Institute of Public Health and Enuironmental Protect& Bilthoven, The Netherlands (J.M.G., P. W.J.P.); Institut Europeen des Genomutations, Lyon, France (E.R.1
ABSTRACT Teratology Information Services (TIS) are started in different countries in Europe in order to gather available data on exogenous agents, t o evaluate their pertinence to human subjects, and to apply this knowledge to specific cases. Most European centers can only be consulted by medical professionals. The experience of two such services (Lyon, France, and Bilthoven, The Netherlands) is described. Attention is given to the task of TIS, risk evaluation, operational methods, and functioning and future developments. Both individuals and their physicians are concerned with the possible effects of exogenous agents, such as drugs, pesticides, industrial and environmental chemicals, household products, radiation, vaccines, and infectious agents, on reproduction and development, including male and female fertility, conception, implantation, embryogenesis and foetal stage, birth, and postnatal health. Data on reproductive risk from these agents are not easily accessible for practitioners. Moreover, such data are difficult to interpret and to apply to a given patient situation. To answer these practical questions with respect to the possible effects of agents on reproduction, and especially on pregnancy, many different sources used to be called on to obtain information by those concerned with the primary care of the pregnant woman. These different sources included geneticists, obstetricians, poison control centers, adverse drug reaction bureaus, pharmacologists, chemical and pharmaceuticals industries, birth defects registration centers, teratologists, and consumer organisations. Some of the above-mentioned areas of expertise then decided to specialize in this activity. Thus, Teratology Information Services (TIS) were born in different countries in Europe. It is the task of these centers to gather available data, to evaluate their pertinence to the human subject, and to apply this knowledge to specific cases. Clearly, it is desirable that data on birth defects with a pos0 1990 WILEY-LISS, INC
sible exogenic etiology be freely exchanged between nationallregional TIS so that the information banks of individual centers can be expanded and their methodologies standardized. To explore ways of achieving such international cooperation, two European teratology information services, Lyon (France) and Bilthoven (The Netherlands), exchanged and compared each other's data and procedures. TASKOFTERATOLOGY INFORMATION SERVICES
The Lyon information service operates within the framework of the Institut Europeen des Genomutations, which runs a birth defects monitoring system (90,000 births annually) and which is privately funded (Mutualite Agricole). The service started in 1980, and the number of requests for information rapidly increased (Fig. 1). The Dutch information service operates within the Department of Teratology of the National Institute of Public Health and Environmental Protection and is supported by the Health Inspectorate of the Dutch government. The service started its activities in 1978 and experienced a comparative growth in numbers of requests (Fig. 1). Received and accepted July 10, 1990. Address reprint requests to Dr. Johanna M. Garbis, Department of Teratology, National Institute of Public Health and Environmental Protection, 3720 BA Bilthoven, The Netherlands. *We have accepted this paper for publication in Teratology as part of the International Federation Teratology Society Symposium held in Kyoto, Japan, June 1988.
630
=
J.M. GARBIS ET AL. Bilthoven
Lyon
700 1
I
to their family doctors. The information is free of charge. As can be seen from Figure 3a,b, most questions t h a t arise concern prescribed drugs during pregnancy. Figure 4a,b shows the kinds of drugs mostly involved. Inquiries may be prospective or retrospective. Prospective questions:
80
a1
a2 a3 a4 a5 86 a7 aa 89
1. “Because of a chronic illness (e.g., epilepsy or diabetes), a drug is prescribed to a woman who wants to become pregnant. Is i t safe? Is the risk of taking the drug greater than the risk from the illness itself?” 2. “A drug should be prescribed to a pregnant woman, for example, because of a n infectious disease. Is it safe, or which drug is the safest?” 3. “A drug has been prescribed to a woman unaware that she was pregnant (early pregnancy). What is the risk? Would termination of pregnancy be justified?“
Fig. 1. Number of questions.
Retrospective questions: In framing the response to a specific query, each center considers a number of factors. When a medicinal drug is involved, its pharmacology, dose, therapeutic indication, and duration of exposure in relationship to the last menstrual period are taken into account. When other chemicals, including drugs of abuse, are in question, the mode of exposure whether occupational, domestic, or by leisure, is considered along with the known teratological or reproductive toxicological potential of the agent. In both cases, the family history and the previous medical and reproductive history are also considered. As in most European centers, both information services consist of a small staff of highly specialized members having knowledge of embryology, teratology, pharmacology, and toxicology. Close working relationships exist with the Poison Control Centers and Adverse Drug Reaction Committees. In principle, only medical professionals, such a s physicians, pharmacists, and midwives, can consult our services. Information is sought mostly by telephone, and only occasionally are questions asked by letter. The types of inquiries are shown in Figure 2a,b. Information is very exceptionally given directly to patients: they are referred
1. “A baby was born with a birth defect. Can the defect be attributed to a drug or another agent to which the patient was exposed before or during pregnancy?’ Retrospective questions may also concern functional disorders detected a t a later stage of life. In those cases, many confounding factors must be taken into consideration. Some questions may also concern paternal exposure, intentional intoxications, risk of accidental exposure to chemicals (e.g., household products, pesticides), and passage of drugs into breast milk. EVALUATION OF THE RISK
For risk evaluation, the following sources are used: Handbooks of embryology, teratology, and pharmacology (Review) articles from the international scientific literature Literature search systems (TERIS, REPROTOX, TOXLINE, MEDLINE, BIOSIS) Accumulated data in the local centers with regard to pregnancy results after similar exposure For risk evaluation and assessment in a given case, epidemiological studies are the
631
EXPERIENCE OF TWO EUROPEAN TIS
'acr
obstetr c,an
72
99
071
ge-er.counseb
Y
73
59 genmac t i t Ion
obstetrician
;72
A
midwife
pat ien: 77 bur.adv.drugrea
24 gevet .coc;nselsr 4
I
cq JL
other physician :45
Fig. 2. Types of inquirers. a: Lyon. b: Bilthoven.
first source of information, supplemented by risk in the given case. Copies of articles are case reports from the literature and data in sent to th e inquirer, if needed. the local system. If no human data are The Dutch service cooperates with fetal available, data from experimental animal pathologists. If, on the basis of the risk asstudies may be included, but they only give sessment, the patient decides to have a n an indication of possible reproductive toxic- abortion, the physician is urged to send the ity and are never conclusive, as extrapola- abortion product to one of the fetal patholotion from the animal to the human is dim- gists for further examination. cult. OPERATIONAL METHODS AND FUNCTIONING The information is always given in terms OF THE SERVICES of a n increased risk with regard to the normal spontaneous frequency of malformaThe information services are open during tions. The information is given as soon as working days from 9:00 AM until 500 PM. All possible by telephone, usually within a few relevant data concerning a question are hours or at the latest the next day. The noted on a receipt form. Each form is proFrench center confirms the telephone call vided with a case number (year and subseby a letter with a short evaluation of the quent number), the date of receipt, and the
632
J.M. GARBIS ET AL.
occupat I on/home
5 i nf ect.di
s/vacc
drugs
Fig. 3. Types of questions. a: Lyon. b: Bilthoven.
expected date of birth. The requested information consists of Identification of the physician: name, specialty, name of institution, address, telephone number Identification of the patient: name, age or date of birth, date of last menstrual period (LM), obstetrical history Drug(s), chemical(s), or other agent(s): generic name, dose, route of administration or exposure, period of pregnancy (in weeks after LM or exact dates), indication or circumstances of exposure With respect to prospective questions, a confidential questionnaire is sent to the physician in the month following the expected date of birth with questions concerning the course of pregnancy and the health of the baby at birth and during the following
days. In case of no answer, a second request is sent 3 months later. About 90% of questionnaires are returned. The data on the receipt forms and questionnaires are filed in a computer. All data are treated with strict confidentiality. DESIRABLE FUTURE DEVELOPMENTS
The increasing number of questions regarding reproductive toxicity, including teratogenicity of exogenous agents and the increasing number of chemicals, makes collaboration between information services necessary. If (inter)national cooperation in this area is to be effective, there must be agreement between services as to the number and relative importances of the factors used in the
633
EXPERIENCE OF TWO EUROPEAN TIS
other hormones ant antiasthmatics
52
CNS drugs 1 cn U”
\
astroint drugs
\
a
64 other
136
hormones
anti hypertens.
antiasthmatics ant i histaminics
\
antibiotics
h
1R
7
gastroint.drugs
51
Fig. 4. Types of drugs. a: Lyon. b: Bilthoven.
risk assessment. A typical problem involves a woman who was treated with Primolut N (5 mg norethisteron once a day), to “correct the menstrual cycle” when she was 14 days overdue. The pregnancy test was negative at that time. Treatment was continued for 10 days. When she was 28 days overdue, the pregnancy test turned out to be positive. When 2 months overdue, she was beset by several anxieties and sought advice from both professional and nonprofessional sources. She wanted to know whether she risked bearing a n abnormal child and whether, in case there was a n increased
risk, tests were available to establish that possibility. She also wondered whether termination of pregnancy might not be the wisest course. The response of different institutions and centers at different places in her country are shown in Table 1.These different answers are intrinsically a source of anxiety and could lead to unnecessary abortion; they also illustrate the need for a consensus within and between countries. Standardization of the information is clearly needed in order to prevent the dispensation of the kind of confusing information illustrated by our example. Standard-
634
J.M. GARBIS ET AL.
TABLE 1 . Response of different centers with respect to risk assessment of the use of norethisteron in early pregnancy Risk of developmental Institute disorder Abortion Pro Family, B Yes Yes 1 Pro Family, M No Anthropogenetics, M No No Anthropogenetics, G No No Anthropogenetics, B No No Clinical Pharmacology, B Yes Yes Drug Information, B Yes Yes Department of Obstetrics, M No No Ministry of Health Yes Yes Schering No No 1 No Foundation Malformation Child Action Right to Live Yes No Woman Health Center, B Yes Yes 'No answer
ization of methodologies in different services is also necessary if they are to assimilate each other's stored information and experience (e.g., receipt forms, replies, questionnaires, way of recall, database).
Individual records on the outcome of pregnancy are a valuable source of information on drugs (both old and new drugs). The number of cases in each center is probably too small to be significant, but in a collaborative system they might be a useful source of information on the reproductive toxicity or teratogenic potential of drugs and other chemicals. Last May 1990, a n European Network of Teratology Information Services (ENTIS) was established with great support from the Italian association of patients and parents concerned with hereditary and congenital diseases (ASM). Collaboration between European TIS makes i t possible to review exposure data of drug treatment related to reproduction on a broader basis. This postmarketing surveillance is urgently needed to really establish lists of preferential drugs to be used in fertile women. ACKNOWLEDGMENT
We thank Dr. J.G. Bannigan for his advice.
Experience of Two Teratology Information Services in Europe* JOHANNA M. GARBIS, ELISABETH ROBERT, AND PAUL W.J. PETERS Dewartment of Teratolom. National Institute of Public Health and Enuironmental Protect& Bilthoven, The Netherlands (J.M.G., P. W.J.P.); Institut Europeen des Genomutations, Lyon, France (E.R.1
ABSTRACT Teratology Information Services (TIS) are started in different countries in Europe in order to gather available data on exogenous agents, t o evaluate their pertinence to human subjects, and to apply this knowledge to specific cases. Most European centers can only be consulted by medical professionals. The experience of two such services (Lyon, France, and Bilthoven, The Netherlands) is described. Attention is given to the task of TIS, risk evaluation, operational methods, and functioning and future developments. Both individuals and their physicians are concerned with the possible effects of exogenous agents, such as drugs, pesticides, industrial and environmental chemicals, household products, radiation, vaccines, and infectious agents, on reproduction and development, including male and female fertility, conception, implantation, embryogenesis and foetal stage, birth, and postnatal health. Data on reproductive risk from these agents are not easily accessible for practitioners. Moreover, such data are difficult to interpret and to apply to a given patient situation. To answer these practical questions with respect to the possible effects of agents on reproduction, and especially on pregnancy, many different sources used to be called on to obtain information by those concerned with the primary care of the pregnant woman. These different sources included geneticists, obstetricians, poison control centers, adverse drug reaction bureaus, pharmacologists, chemical and pharmaceuticals industries, birth defects registration centers, teratologists, and consumer organisations. Some of the above-mentioned areas of expertise then decided to specialize in this activity. Thus, Teratology Information Services (TIS) were born in different countries in Europe. It is the task of these centers to gather available data, to evaluate their pertinence to the human subject, and to apply this knowledge to specific cases. Clearly, it is desirable that data on birth defects with a pos0 1990 WILEY-LISS, INC
sible exogenic etiology be freely exchanged between nationallregional TIS so that the information banks of individual centers can be expanded and their methodologies standardized. To explore ways of achieving such international cooperation, two European teratology information services, Lyon (France) and Bilthoven (The Netherlands), exchanged and compared each other's data and procedures. TASKOFTERATOLOGY INFORMATION SERVICES
The Lyon information service operates within the framework of the Institut Europeen des Genomutations, which runs a birth defects monitoring system (90,000 births annually) and which is privately funded (Mutualite Agricole). The service started in 1980, and the number of requests for information rapidly increased (Fig. 1). The Dutch information service operates within the Department of Teratology of the National Institute of Public Health and Environmental Protection and is supported by the Health Inspectorate of the Dutch government. The service started its activities in 1978 and experienced a comparative growth in numbers of requests (Fig. 1). Received and accepted July 10, 1990. Address reprint requests to Dr. Johanna M. Garbis, Department of Teratology, National Institute of Public Health and Environmental Protection, 3720 BA Bilthoven, The Netherlands. *We have accepted this paper for publication in Teratology as part of the International Federation Teratology Society Symposium held in Kyoto, Japan, June 1988.
630
=
J.M. GARBIS ET AL. Bilthoven
Lyon
700 1
I
to their family doctors. The information is free of charge. As can be seen from Figure 3a,b, most questions t h a t arise concern prescribed drugs during pregnancy. Figure 4a,b shows the kinds of drugs mostly involved. Inquiries may be prospective or retrospective. Prospective questions:
80
a1
a2 a3 a4 a5 86 a7 aa 89
1. “Because of a chronic illness (e.g., epilepsy or diabetes), a drug is prescribed to a woman who wants to become pregnant. Is i t safe? Is the risk of taking the drug greater than the risk from the illness itself?” 2. “A drug should be prescribed to a pregnant woman, for example, because of a n infectious disease. Is it safe, or which drug is the safest?” 3. “A drug has been prescribed to a woman unaware that she was pregnant (early pregnancy). What is the risk? Would termination of pregnancy be justified?“
Fig. 1. Number of questions.
Retrospective questions: In framing the response to a specific query, each center considers a number of factors. When a medicinal drug is involved, its pharmacology, dose, therapeutic indication, and duration of exposure in relationship to the last menstrual period are taken into account. When other chemicals, including drugs of abuse, are in question, the mode of exposure whether occupational, domestic, or by leisure, is considered along with the known teratological or reproductive toxicological potential of the agent. In both cases, the family history and the previous medical and reproductive history are also considered. As in most European centers, both information services consist of a small staff of highly specialized members having knowledge of embryology, teratology, pharmacology, and toxicology. Close working relationships exist with the Poison Control Centers and Adverse Drug Reaction Committees. In principle, only medical professionals, such a s physicians, pharmacists, and midwives, can consult our services. Information is sought mostly by telephone, and only occasionally are questions asked by letter. The types of inquiries are shown in Figure 2a,b. Information is very exceptionally given directly to patients: they are referred
1. “A baby was born with a birth defect. Can the defect be attributed to a drug or another agent to which the patient was exposed before or during pregnancy?’ Retrospective questions may also concern functional disorders detected a t a later stage of life. In those cases, many confounding factors must be taken into consideration. Some questions may also concern paternal exposure, intentional intoxications, risk of accidental exposure to chemicals (e.g., household products, pesticides), and passage of drugs into breast milk. EVALUATION OF THE RISK
For risk evaluation, the following sources are used: Handbooks of embryology, teratology, and pharmacology (Review) articles from the international scientific literature Literature search systems (TERIS, REPROTOX, TOXLINE, MEDLINE, BIOSIS) Accumulated data in the local centers with regard to pregnancy results after similar exposure For risk evaluation and assessment in a given case, epidemiological studies are the
631
EXPERIENCE OF TWO EUROPEAN TIS
'acr
obstetr c,an
72
99
071
ge-er.counseb
Y
73
59 genmac t i t Ion
obstetrician
;72
A
midwife
pat ien: 77 bur.adv.drugrea
24 gevet .coc;nselsr 4
I
cq JL
other physician :45
Fig. 2. Types of inquirers. a: Lyon. b: Bilthoven.
first source of information, supplemented by risk in the given case. Copies of articles are case reports from the literature and data in sent to th e inquirer, if needed. the local system. If no human data are The Dutch service cooperates with fetal available, data from experimental animal pathologists. If, on the basis of the risk asstudies may be included, but they only give sessment, the patient decides to have a n an indication of possible reproductive toxic- abortion, the physician is urged to send the ity and are never conclusive, as extrapola- abortion product to one of the fetal patholotion from the animal to the human is dim- gists for further examination. cult. OPERATIONAL METHODS AND FUNCTIONING The information is always given in terms OF THE SERVICES of a n increased risk with regard to the normal spontaneous frequency of malformaThe information services are open during tions. The information is given as soon as working days from 9:00 AM until 500 PM. All possible by telephone, usually within a few relevant data concerning a question are hours or at the latest the next day. The noted on a receipt form. Each form is proFrench center confirms the telephone call vided with a case number (year and subseby a letter with a short evaluation of the quent number), the date of receipt, and the
632
J.M. GARBIS ET AL.
occupat I on/home
5 i nf ect.di
s/vacc
drugs
Fig. 3. Types of questions. a: Lyon. b: Bilthoven.
expected date of birth. The requested information consists of Identification of the physician: name, specialty, name of institution, address, telephone number Identification of the patient: name, age or date of birth, date of last menstrual period (LM), obstetrical history Drug(s), chemical(s), or other agent(s): generic name, dose, route of administration or exposure, period of pregnancy (in weeks after LM or exact dates), indication or circumstances of exposure With respect to prospective questions, a confidential questionnaire is sent to the physician in the month following the expected date of birth with questions concerning the course of pregnancy and the health of the baby at birth and during the following
days. In case of no answer, a second request is sent 3 months later. About 90% of questionnaires are returned. The data on the receipt forms and questionnaires are filed in a computer. All data are treated with strict confidentiality. DESIRABLE FUTURE DEVELOPMENTS
The increasing number of questions regarding reproductive toxicity, including teratogenicity of exogenous agents and the increasing number of chemicals, makes collaboration between information services necessary. If (inter)national cooperation in this area is to be effective, there must be agreement between services as to the number and relative importances of the factors used in the
633
EXPERIENCE OF TWO EUROPEAN TIS
other hormones ant antiasthmatics
52
CNS drugs 1 cn U”
\
astroint drugs
\
a
64 other
136
hormones
anti hypertens.
antiasthmatics ant i histaminics
\
antibiotics
h
1R
7
gastroint.drugs
51
Fig. 4. Types of drugs. a: Lyon. b: Bilthoven.
risk assessment. A typical problem involves a woman who was treated with Primolut N (5 mg norethisteron once a day), to “correct the menstrual cycle” when she was 14 days overdue. The pregnancy test was negative at that time. Treatment was continued for 10 days. When she was 28 days overdue, the pregnancy test turned out to be positive. When 2 months overdue, she was beset by several anxieties and sought advice from both professional and nonprofessional sources. She wanted to know whether she risked bearing a n abnormal child and whether, in case there was a n increased
risk, tests were available to establish that possibility. She also wondered whether termination of pregnancy might not be the wisest course. The response of different institutions and centers at different places in her country are shown in Table 1.These different answers are intrinsically a source of anxiety and could lead to unnecessary abortion; they also illustrate the need for a consensus within and between countries. Standardization of the information is clearly needed in order to prevent the dispensation of the kind of confusing information illustrated by our example. Standard-
634
J.M. GARBIS ET AL.
TABLE 1 . Response of different centers with respect to risk assessment of the use of norethisteron in early pregnancy Risk of developmental Institute disorder Abortion Pro Family, B Yes Yes 1 Pro Family, M No Anthropogenetics, M No No Anthropogenetics, G No No Anthropogenetics, B No No Clinical Pharmacology, B Yes Yes Drug Information, B Yes Yes Department of Obstetrics, M No No Ministry of Health Yes Yes Schering No No 1 No Foundation Malformation Child Action Right to Live Yes No Woman Health Center, B Yes Yes 'No answer
ization of methodologies in different services is also necessary if they are to assimilate each other's stored information and experience (e.g., receipt forms, replies, questionnaires, way of recall, database).
Individual records on the outcome of pregnancy are a valuable source of information on drugs (both old and new drugs). The number of cases in each center is probably too small to be significant, but in a collaborative system they might be a useful source of information on the reproductive toxicity or teratogenic potential of drugs and other chemicals. Last May 1990, a n European Network of Teratology Information Services (ENTIS) was established with great support from the Italian association of patients and parents concerned with hereditary and congenital diseases (ASM). Collaboration between European TIS makes i t possible to review exposure data of drug treatment related to reproduction on a broader basis. This postmarketing surveillance is urgently needed to really establish lists of preferential drugs to be used in fertile women. ACKNOWLEDGMENT
We thank Dr. J.G. Bannigan for his advice.
