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 & Lemire, 2007). 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., 2006;
O’Neil et al., 2006; Sweetman, 2007; Briggs et al., 2008). The mutagenicity of agents is also usually
excluded. Although many agents have been
shown to be mutagenic in experimental systems (Shepard & Lemire, 2007),
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. (
Lists of agent names and synonyms included in the index were obtained
from Martindale: The Complete Drug Reference (Sweetman,
2007), 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 five 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.
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, 8th ed.
Brunton LL, Lazo JS, Parker
KL (eds): Goodman & Gilman’s The Pharmacological
Basis of Therapeutics, 11th ed.
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.
O’Neil MJ, Heckelman PE,
Koch CB, Roman KJ (ed): The
Merck Index. An Encyclopedia of
Chemicals, Drugs, and Biologicals, 14th ed.
Physicians’ Desk Reference, 62nd ed.
Schaefer C, Peters P,
Miller RK (eds):
Drugs During Pregnancy and
Lactation, 2nd ed.
Schardein JL: Chemically
Induced Birth Defects, 3rd ed.
Shepard TH, Lemire RJ: Catalog
of Teratogenic Agents, 12th ed.