TERIS

The Teratogen Information System

Preamble

Every infant has at least a 5% risk of being born with a serious congenital anomaly. This includes not only malformations but also mental retardation and other important functional deficits which may not become apparent until later in life. The cause of most congenital anomalies is unknown. Purely genetic factors, i.e., chromosomal aberrations and abnormalities of a single gene or gene pair, account for about 1/4 of all congenital anomalies; environmental factors by themselves probably account for no more than 1/10 (Brent & Beckman, 1990). Nevertheless, congenital anomalies caused by environmental agents are especially important because they are potentially preventable.

A teratogen may be defined as an agent that can produce a permanent abnormality of structure or function in an organism exposed during embryonic or fetal life. Identification of human teratogens requires careful interpretation of data obtained from several kinds of studies (Cordero & Oakley, 1983; Brent, 1995; Shepard, 2010). The first evidence that an agent is teratogenic in humans often comes from clinical case reports. Case reports are most useful if they reveal a pattern of anomalies in children who experienced similar well-defined exposures at similar points during embryonic or fetal development. Case reports cannot provide reliable quantitative estimates of the risk of anomalies in an exposed pregnancy. While case reports are important in raising causal hypotheses, most such hypotheses are incorrect. Coincidental occurrence of an environmental exposure in a pregnant woman and congenital anomalies in her child is very common, especially if the exposure or the defects or both are relatively frequent.

Epidemiologic studies provide the only means of obtaining quantitative estimates regarding the strength and statistical significance of associations between agent exposures in pregnant women and abnormalities in their children. Epidemiologic investigations used in teratology are primarily of two types: cohort studies and case-control studies. In cohort studies, the frequencies of certain anomalies are compared in the children of women exposed and unexposed to the agent in question. In case-control studies, the frequency of prenatal agent exposure is compared among children with and without a given anomaly. If a teratogenic agent increases the risk of anomalies only slightly, very large studies may be necessary to demonstrate the increase. On the other hand, spurious associations often occur in investigations involving large numbers of comparisons between exposed and unexposed or affected and unaffected subjects. In interpreting epidemiologic studies, one must remember that the maternal disease or situation which occasioned the exposure rather than the agent itself may be responsible for an observed association. Biases of ascertainment and recall may also produce spurious associations. One can never assume that a statistically significant association in an epidemiologic study indicates causality without adducing other evidence to support such a conclusion. Moreover, the usefulness of most published epidemiological studies is limited by failure to consider the etiologic heterogeneity of human congenital abnormalities or the subtle patterns of anomalies characteristic of many human teratogens.

Although human investigations are necessary to demonstrate that an agent is teratogenic in humans, such studies are not informative until the agent has already damaged many children. Experimental animal studies sometimes provide a means of identifying agents with teratogenic potential before humans have been harmed. Unfortunately, it is usually impossible to extrapolate findings in animals to a clinical situation involving an individual pregnant woman. Species differences in placentation, pharmacodynamics, embryonic development, and innate predisposition to various fetal anomalies are well recognized. Moreover, teratology experiments in animals often employ agent dosages which are many times greater than those likely to occur in humans, and maternal toxic effects may confound interpretation of fetal outcome. It is even more difficult to assess the relevance of in vitro teratology assays to pregnant women.

In TERIS, analysis of each agent's teratogenicity has been made on the basis of the reproducibility, consistency, and biological plausibility of available clinical, epidemiological, and experimental data. Reproducibility is judged by whether similar findings have been obtained in independent studies. Concordance is considered to be particularly important if the studies are of different design and if the types of anomalies observed in various studies are consistent. Effects seen in animal investigations are weighed more heavily if the exposure is similar in dosage and route to that encountered clinically and if the species tested are closely related to humans phylogenetically.

Of critical importance is that observed associations make biological sense. Exposures which produce malformations in the embryo or fetus should do so only during organogenesis or histogenesis, and affected structures should only be susceptible to the teratogenic action of an agent at specific gestational times. Systemic absorption of the agent by the mother and its presence at susceptible sites in the embryo or placenta should be demonstrable. In most cases, exposure to a greater quantity of the agent should increase the likelihood of abnormalities. Such dose-response relationships are expected in experimental studies but are often not demonstrable in human data because of the limited dose range encountered clinically. Finally, a causal inference is supported if a reasonable pathogenic mechanism can be established for the observed effect.

TERIS includes data on teratogenicity, transplacental carcinogenesis, embryonic or fetal death, and fetal and perinatal pharmacologic effects of drugs and selected environmental agents. Information regarding the pharmacodynamics of the agents, their excretion in breast milk, and their maternal and neonatal pharmacology is not included but is available elsewhere (Brunton et al., 2011; Sweetman, 2011; Briggs et al., 2011; O’Neil, 2013). The mutagenicity of agents is also usually excluded. Although many agents have been shown to be mutagenic in experimental systems (Shepard, 2010), there is no evidence in humans that exposure of an individual to any mutagen measurably increases the risk of congenital anomalies in his or her offspring (Crow & Denniston, 1985).

TERIS agent summaries are written by J.M. Friedman, M.D., Ph.D. (University of British Columbia) and Janine E. Polifka, Ph.D. (University of Washington). Each agent summary is based on a thorough review of published data identified through PubMed, TOXLINE, and DART bibliographic searches. References provided in the Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk (Briggs et al., 2011), Catalog of Teratogenic Agents (Shepard, 2010), Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment (Schaefer et al., 2007), Medication Safety in Pregnancy & Breastfeeding: The Evidence-Based A-to-Z Clinician’s Pocket Guide (Koren, 2007), and Chemically Induced Birth Defects (Schardein, 2000) are also used extensively. Statements regarding the absence of published studies are made on the basis of this literature review and are true to the best of our knowledge. Unpublished studies, such as those submitted by pharmaceutical or chemical companies to regulatory agencies, are not included because their unpublished state precludes conventional peer review and assessment. Mention of these unpublished studies is often included in package inserts, the Physicians’ Desk Reference (2014), and similar information provided by manufacturers. Such sources should be consulted to obtain a broader perspective on the teratogenicity of an agent.

Lists of agent names and synonyms included in the index were obtained from Martindale: The Complete Drug Reference (Sweetman, 2011), and ChemIDplus of the National Library of Medicine Toxicology Information Program.

Near the beginning of each agent summary is an aphorism printed entirely in capital letters. It should be noted that the risk rating in the aphorism refers only to the risk of teratogenic effects after maternal exposure to commonly encountered doses. Exposures to unusually high doses, especially to doses that are toxic to the mother, may be associated with a higher risk. Other adverse effects, such as alterations of perinatal adaptation or transplacental carcinogenesis, are considered separately in the narrative and, if deemed sufficiently important, are also mentioned in the aphorism under Comments.

The aphorism rates the risk of teratogenic effects in the children of women exposed to the agent during pregnancy as None, Minimal, Small, Moderate, High, Undetermined, or Unlikely. In some instances, this rating is amplified by a comment. For example, an agent may be rated as Undetermined with a comment that “a small risk cannot be excluded, but there is no indication that the risk of congenital anomalies in the children of women treated with this agent during pregnancy is likely to be great.” Similarly, the risk of teratogenic effects may be rated as Unlikely with a comment that it is “unlikely to pose a substantial teratogenic risk with usual exposures” if available data are negative but insufficient to conclude that there is no risk. Such statements are made on the basis of general pharmacology, animal data, or analogy to a closely-related agent that has been studied more thoroughly.

In general, risks that are Minimal or less ought not alter decisions regarding continuation or termination of an exposed pregnancy. Moderate or High risks may be considered important enough to influence such decisions, at least in some cases.

The aphorism also rates the available data on which the risk assessment is based as None, Limited, Fair, Good, or Excellent. Risk assessments based on evidence that is Limited or Fair ought to be considered tentative and may change as more information becomes available. Even with Good data, only crude estimates of the magnitude of the risk are often possible. The aphorism for each agent is based on a consensus of ratings by the authors and six internationally-recognized authorities in clinical teratology. These six individuals, who comprise the TERIS Advisory Board, are Drs. Robert Brent, J. David Erickson, Kenneth Jones, Richard Miller, Gary Shaw, and Thomas Shepard.

The aphorism is followed by a brief discussion of the data upon which it is based. Emphasis has been placed primarily on information obtained from human studies. Experimental animal data are also included to amplify and clarify the analysis, but, in general, only experiments in mammals are considered. The aphorism should always be read in context of the discussion which follows it.

The references included in the agent summaries have been selected for their quality and accessibility. These references are not intended to provide a comprehensive bibliography but rather to help the clinician obtain a broader understanding of the agent's effects on the embryo and fetus.

TERIS is not intended as a guide for prescribing medications to pregnant women. Physicians should consult approved package inserts for such guidance. Proprietary names are used only for purposes of identification, and such use does not imply any recommendation regarding the agent.

The agent summaries are designed to assist physicians and other health professionals in counseling pregnant patients who have concerns about possible effects of drugs and other agents on their developing babies. The agent summaries comprise only part of the comprehensive pregnancy risk assessment that is necessary to provide counseling for such patients. It is always necessary to determine as accurately as possible what the route and dose of the exposure was and whether there were concurrent exposures to other agents. Accurate assessment of when the exposure occurred is critical. The greatest risks of teratogenesis exist during the period of organogenesis, i.e., between about 18 and 60 days after conception. Prior to this time, malformations are less likely to be induced, but death of the embryo can be caused by certain exposures. Later in pregnancy, insults to the fetus are unlikely to produce malformations but can cause death, growth retardation, disruptions, or functional deficits.

The evaluation of each patient must also include obtaining information on her state of health, previous and current pregnancy history, and family history. Counseling provided as the result of this comprehensive risk assessment should be tailored to each patient's intellectual, educational, psychosocial, and cultural background. The risk associated with an exposure should be presented with reference to the background risk of congenital anomalies which attends every pregnancy for every woman. Decisions regarding prenatal diagnosis and continuation or termination of pregnancy should be made by the patient in consultation with her physician, family, and other appropriate individuals.

Counseling a pregnant woman about possible effects of an environmental or drug exposure on her developing embryo or fetus is an important component of her medical care. Such counseling should be provided by physicians and other professionals under their supervision with competence in clinical teratology. Difficult or complex cases should be referred to appropriate specialists.

BIBLIOGRAPHY

Brent RL: The application of the principles of toxicology and teratology in evaluating the risks of new drugs for treatment of drug addiction in women of reproductive age. NIDA Res Monogr 149:130-184, 1995.

Brent RL, Beckman DA: Environmental teratogens. Bull N Y Acad Med 66(2):123-163, 1990.

Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins, 2011.

Brunton LL, Chabner BA, Knollmann BC (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed. New York: The McGraw-Hill Companies, 2011.

Cordero JF, Oakley GP Jr: Drug exposure during pregnancy: some epidemiologic considerations. Clin Obstet Gynecol 26(2):418-428, 1983.

Crow JF, Denniston C: Mutation in human populations. Adv Hum Genet 14:59-123, 1985.

Koren G: Medication Safety in Pregnancy & Breastfeeding: The Evidence-Based, A-to-Z Clinician’s Pocket Guide. New York: The McGraw-Hill Companies, 2007.

O’Neil MJ (ed): The Merck Index. An Encyclopedia of Chemicals, Drugs, and Biologicals, 15th ed. Cambridge: The Royal Society of Chemistry, 2013.

Physicians’ Desk Reference, 68th ed. Montvale, N.J.: PDR Network, LLC, 2014.

Schaefer C, Peters P, Miller RK (eds): Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd ed. Burlington, Mass.: Academic Press, 2007.

Schardein JL: Chemically Induced Birth Defects, 3rd ed. New York: Marcel Dekker, 2000.

Shepard TH: Catalog of Teratogenic Agents, 13th ed. Baltimore, Md.: The Johns Hopkins University Press, 2010.

Sweetman SC: Martindale: The Complete Drug Reference, 37th ed. London: Pharmaceutical Press, 2011.