Retinoids and teratogenicity

SUPPORTED BY AN UNRESTRICTED EDUCATIONAL GRANT FROM ORTHO DERMATOLOGICAL

Retinoids and teratogenicity Hershel Jick, MD Lexington, Massachusetts In considering the topic of retinoids and teratogenicity, it is useful to start with an overview of what has been established with considerable certainty in the area of the relationship of retinoids to congenital disorders. First, it is generally accepted that large doses of vitamin A and related compounds have been shown to be teratogenic in animal studies. Second, retinoic acid is well documented as a potent teratogen in humans when taken orally.1 The teratogenicity of etretinate appears to be uncertain because there are very few studies of its effect on the fetus. The congenital malformations that are found in animal studies on the effect of high doses of vitamin A are similar to those associated with retinoic acid in humans. The toxic effect is primarily on the cephalic neural crest, and it results in congenital malformations that are cranial/facial, cardiac, and thymic.2 There are two questions that remain unanswered. First, are topical retinoids associated with an increased risk of congenital malformations? This is obviously a very serious and important question, because many young women use these drugs. A second question is, are high doses of oral vitamin A associated with an increased risk of congenital malformations in humans, and if so, what is the dose above which the increased risks begin to become manifest? Unfortunately, the background and knowledge necessary to understand and interpret results of studies on teratogenicity are often complex and subtle. The principles and methods used in such studies are not well understood, and as a result, it is difficult for most people to reach an informed opinion about the quality of From the Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Lexington. Reprint requests: Hershel Jick, MD, Associate Professor of Medicine, Boston University School of Medicine, Director, Boston Collaborative Drug Surveillance Program, Boston University Medical Center, 11 Muzzey St., Lexington, MA 02173. (J Am Acad Dermatol 1998;39:S118-22.) Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/0/91119

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various studies that are published. There is a wide range of quality from poorly designed studies, which are uninterpretable, to those that provide reliable and interpretable results. If there is interest and concern in this area, it is necessary to learn about the principles and methods that yield a good study or a poor study.2 Some of the published studies illustrate where it is appropriate to rely to a considerable degree on the interpretation of the results, and other studies where it is not appropriate. A critical data element in an observational drug safety study is the drug exposure experienced by the subjects in the study. Drug exposure information can be obtained either by interviewing patients, or with the use of large, longitudinal, computerized databases that record all the drugs that are prescribed in a defined population. The automated databases are the most reliable means of determining what drugs people have obtained prescriptions for. In the case of dermatologic preparations, there is reasonable confidence that if patients obtained a prescription for topical tretinoin, the chances are high that a substantial majority actually used the compound. The outcome of interest in relation to retinoids is congenital disorders. Congenital disorders can be identified either by reviewing clinical records, which is inefficient, or through surveillance systems present in many countries. Surveillance systems are comprised of a variety of hospitals that have agreed to provide information to a central registry on babies who are born with certain congenital disorders. Finally, comprehensive computerized records can be used to identify babies with congenital disorders. There are now some large computerized systems that record diagnoses on all babies who are born in a defined population, and these systems can directly identify those babies who have congenital disorders. In pharmacoepidemiologic studies, there is always concern about so-called confounding

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factors, because most of the comparisons are between one drug and another, or between one drug and no drug, and because people who use different drugs vary by age, sex, calendar time, and geography in all cases. Therefore when a drug safety study is done that involves a comparison of two groups, the results must be adjusted to take into account differences in these four factors. There are two types of formal epidemiologic studies relating to congenital disorders. One type is the so-called follow-up or cohort design. In the cohort study, a study population is identified before the subjects display the outcome of interest. Therefore, in the study of congenital disorders, one has actually identified pregnant women early in pregnancy and followed them forward before it is known whether the baby is normal or has a congenital disorder. In this study, people who were exposed to a drug of interest, for example, topical tretinoin, are compared with a group of people who were not exposed to the drug. Thus, the comparison is between users of a drug and nonusers. The second type of study, which is more common, uses a case-control design. In the case-control study, babies who were already born with congenital disorders are identified and compared with babies who were not born with congenital disorders. The exposure to the drugs of interest in the two groups are then compared. Although the methods are somewhat complex, it is worthwhile learning about them because these are the types of studies that have been published on dermatologic products and congenital disorders. In summary, there are cohort studies and case-control studies. The cohort, or follow-up design, has a number of important strengths worth recognizing. First, the information on drug exposure is obtained before the outcome is known. This is important in terms of certain biases that might exist if it is already known whether a baby does or does not have a congenital disorder before collecting information on exposure. A second strength is that rates of disorder can be calculated by means of the followup design. There are a known number of subjects who used the drug of interest, and there are a known number of infants who had, for example, a cranial/facial defect, and therefore a rate or prevalence can be calculated. This rate can

Jick S119 then be compared with that of subjects who did not use the study drug, e.g., the rate among tretinoin users versus nonusers, or vitamin A users versus nonusers. The limitation of the cohort design is that, without computerized data, it is extremely expensive to do these studies and obtain complete follow-up. In general, there are few such studies, although the results of one such study, which took many years to complete and was very expensive, have been published. The Boston Collaborative Drug Surveillance Program (BCDSP) organized that study and has published results based on it.3 The case-control design’s strength is that it can be completed rapidly and at relatively little cost. A group of cases and a group of controls can be identified. The problem with the case-control design is that without computerized records, information on drug exposure must normally be obtained by patient interview, and the interview is always done long after the exposure has occurred in the first trimester of pregnancy. There are studies that show quite clearly that if there is a delay of 6 months or more after the first trimester of pregnancy, the information obtained from patients on drug exposure during the first trimester is of uncertain quality.4 Thus, there is always a question in the case-control studies as to how detailed and accurate the information on first-trimester drug exposure is. Finally, the results of case-control studies provide only relative risks rather than actual risks. When dealing with information on exposure, particularly with pregnancy, timing is essential because the developmental phase of the fetus is during the first trimester and, therefore, the time at which the exposure occurred is critical to any interpretation of the results. In one of the published studies,5 the exposure to vitamin A was defined as use at any time during pregnancy without actually dividing it up into first-, second-, or third-trimester use. This provides a very crude measure of exposure. Thus, when evaluating a study, it is important to carefully consider how exposure was defined, how accurate the exposure information was, and what the timing of the exposure was. Dosage is often important, and the absence of information on dose is a potentially serious limitation. The outcome of interest — congenital mal-

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S120 Jick Table I. Topical tretinoin and teratogenicity Fetal abnormalities

Patients who were exposed to tretinoin Patients who were not exposed to tretinoin

1.9% 2.6%

formation — is often defined differently in epidemiologic studies. The definition varies from a well-described specific major congenital developmental disorder, e.g., those of cephalic neural crest origin, to the broad category of any abnormality that was noted in the baby. This leads to differences in rates of congenital disorders that vary from 1% to 2% when investigators are careful about defining congenital disorder,6 to as high as 20%,5 where investigators include all disorders, major and minor. These considerations are critical when evaluating published studies. The publications that are available address two issues relevant to this review. First, do topical retinoids cause congenital disorders? Second, do high doses of vitamin A cause congenital disorders, and if so, what type of disorder and at what dose? Studies appear to indicate that application of topical retinoids does not cause congenital disorders in animals. According to the Physicians’ Desk Reference, there is no evidence of teratogenicity from topical retinoids in animals. With regard to human studies, it is now well accepted that topical retinoids do not produce an important increase in the blood level of these retinoids.7 Therefore, one would not expect them to be teratogenic. There is one published, well-designed study on this subject. The study used computerized records that covered a 20-year period; data were derived from a health maintenance organization in the state of Washington, Group Health Cooperative.6 A computer record of all the prescriptions filled at its pharmacies is available, and thus it is possible to identify a group of topical tretinoin users and nonusers according to date of prescription. The available data include a record of all deliveries, and all outcomes of pregnancy with details of dates. The authors

were able to identify 212 women who filled prescriptions for topical tretinoin in or near the first trimester of pregnancy. Major developmental disorders were the outcome definition. The number of congenital disorders in 212 users of topical tretinoin was compared with the number in 430 women who did not fill prescriptions for topical retinoids, matched on age and year of delivery. A major disorder was defined as any structural abnormality of surgical, medical, or cosmetic importance. The results of this study were as follows: Among the 212 women who were presumed to be exposed to topical tretinoin, there were four with liveborn babies who had one of the congenital disorders of interest; among those who were not exposed, 11 of 427 had a baby with one disorder (Table I). The relative risk, a term used to describe the risk of having a baby with an anomaly in those exposed to topical tretinoin compared with those who were not exposed, was 0.7. None of the four anomalies that occurred in the 212 exposed women involved the cephalic neural crest, which is the area where there is thought to be a teratogenic effect of retinoids. This well-documented study provides substantial reassurance that topical tretinoin rarely, if ever, causes congenital disorders. Obviously it does not rule out the possibility that topical tretinoin can rarely cause a disorder of interest under very special circumstances. It is, however, the only study of its kind, because these are difficult studies to do and the required resources are available only under certain circumstances. The next subject relates to the possible teratogenicity of vitamin A. The first paper published on this subject was by Martinez-Frias and Salvador5 entitled “Epidemiological Aspects of Prenatal Exposure to High Doses of Vitamin A in Spain.” The authors used an unmatched casecontrol design. They had access to a surveillance system that informed them about outcomes of pregnancies that occur in certain areas of Spain. A total of 11,293 cases of congenital disorders, defined as any major or minor disorder, was identified. They compared exposure to vitamin A in babies who had alleged congenital disorders with a comparable number of babies who did not. The exposure was defined as vitamin A use at any time during pregnancy. The

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interview took place 3 days after delivery. Therefore women had to recall the use of vitamin A during pregnancy. The authors obtained the dose of vitamin A when women volunteered that they had taken vitamin A supplements. The relative risk for users of less than 40,000 IU of vitamin A versus nonusers was 0.5, which is consistent with no increased risk. For those who reported use of more than 40,000 IU, the relative risk comparing those who took vitamin A with nonusers was 2.7. The 95% confidence intervals are wide, which means that one can have little confidence that an increased risk is present. Because most of the disorders were minor, and about half of those exposed to vitamin A were exposed after the first trimester of pregnancy, this study does not provide useful information on this topic. It is a good example of a study that took much work and effort, but actually does not help with regard to the question of real interest, i.e., the effect of vitamin A on fetal development. A second study by Werler et al.8 is interesting from the methodologic point of view. This is similar in design to the aforementioned study, namely a case-control design. The authors identified 2658 cases and a comparable number of controls. The fascinating aspect of this study was that the cases were actually babies with neural crest defects, and the controls were patients with other defects. In their surveillance system, the authors only study babies with defects. Therefore, if they want to compare one group to another, they have to identify a specific defect and compare babies who have that defect with babies who have some other defect. The authors again had to obtain information on vitamin A supplement use after the delivery of the baby, which meant that the exposure information was of questionable quality. No information on dose was obtained, and therefore the effect of dose of supplemental vitamin A cannot be evaluated. They reported a relativerisk estimate for exposure to vitamin A in the first months of pregnancy of about 2.5. This result was of borderline statistical significance, and the authors indicated that the study provided modest evidence that there might be a teratogenic effect of high doses of vitamin A. The last reported study was a large follow-up study that was implemented by the BCDSP. The

Jick S121 data were analyzed by Rothman and colleagues.9 This study was derived from the same body of data that clearly demonstrated a protective effect of folic acid taken in the first 8 weeks of pregnancy on the incidence of neural tube defects.3 Thus, this particular body of data had already shown itself to have enough validity to demonstrate an effect that is now accepted. A prospective cohort study, encompassing about 22,000 pregnancies, was on the basis of exposure information obtained while the women were in the first trimester of pregnancy before knowledge of the outcome. The information on exposure was detailed and of high quality, and the outcome of interest was cranial/facial defects. Outcome information was obtained by mailed questionnaires to obstetricians and, in some cases, directly to the women. This study identified 121 defects considered to be of cranial neural crest origin. The relative risk for a neural crest defect among women who took less than 10,000 IU of vitamin A was 1.0 compared with women who did not. In those who took very high doses of vitamin A, particularly over 40,000 IU, the relative risk was considerably higher, i.e., 4.8 compared with nonusers. Thus, this study provides considerable evidence that very high doses of vitamin A can cause congenital disorders of neural crest origin. This is not unexpected, because the same effect can be produced in animals. In summary, a well-conducted study indicates that topical tretinoin use is not associated with an increased risk of congenital disorders. Based primarily on the Rothman study,9 there is evidence that very high doses of vitamin A can increase the risk of disorders of the cephalic neural crest in humans. Together with similar evidence in animals, it seems likely that high doses of vitamin A taken orally in the early months of pregnancy do increase the risk of congenital disorders of neural crest origin in humans. REFERENCES 1. Lammer EJ, Hayes AM, Schunior A, Holmes LB. Risk for major malformation among human fetuses exposed to isotretinoin (13-cis-retinoic acid). Teratology 1987; 35:68A. 2. Jick H, Vessey MP. Case-control studies in the evaluation of drug-induced illness. Am J Epidemiol 1978;107:1-7. 3. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al. Multivitamin/folic acid supple-

S122 Jick mentation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989;262:2847-52. 4. Klemetti A, Saxen L. Prospective versus retrospective approach in the search for environmental causes of malformations. Am J Public Health 1967;57:2071-5. 5. Martinez-Frias ML, Salvador J. Epidemiological aspects of prenatal exposure to high doses of vitamin A in Spain. Eur J Epidemiol 1990;6:118-23. 6. Jick SS, Terris BZ, Jick H. First trimester topical tretinoin use and congenital disorders. Lancet 1993;341: 1181-2.

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7. Latriano L, Tzimas G, Wong F, Wills RJ. The percutaneous absorption of topically applied tretinoin and its metabolites after single doses or long-term use. J Am Acad Dermatol 1997;36:S37-S46. 8. Werler MM, Lammer EJ, Rosenberg L, Mitchell AA. Maternal vitamin A supplementation in relation to selected birth defects. Teratology 1990;42:497-503. 9. Rothman KJ, Moore LL, Singer MR, Nguyen UDT, Mannino S, Milunsky A. Teratogenicity of high vitamin A intake. N Engl J Med 1995;333:1369-73.