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Teratogenicity of Recently Introduced Medications in Human Pregnancy

From the Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Address reprint requests to: J. M. Friedman, MD, PhD, University of British Columbia, Department of Medical Genetics, 6174 University Boulevard, Vancouver, British Columbia V6T 1Z3, Canada; E-mail: frid{at}interchange.ubc.ca.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
OBJECTIVE: To determine how long it takes after a new drug is marketed to establish whether or not its use by pregnant women is likely to pose a substantial teratogenic risk.

METHODS: We used standard clinical teratology resources to assess the teratogenic risks in human pregnancy of therapeutic treatment with 468 drugs approved by the US Food and Drug Administration between 1980 and 2000. The teratogenic risk of each treatment was classified using the current online version of TERIS into one of three categories: 1) no risk, minimal risk, or unlikely to produce an increased risk; 2) associated with a small, moderate, or high risk; or 3) risk undetermined.

RESULTS: We found that the teratogenic risk in human pregnancy was still undetermined for 91.2% of drug treatments approved in the United States between 1980 and 2000. The proportion of treatments classified as having an "undetermined" teratogenic risk was more than 80% for drugs approved for marketing 0–4, 5–9, 10–14, or 15–20 years ago, but the highest proportion of drugs with an "undetermined" teratogenic risk was found among those approved 15–20 years ago. The agreement between TERIS risk ratings and Food and Drug Administration Use-in-Pregnancy Categories for 163 drugs that had been assessed by both systems was poor ( ± standard error = 0.082 ± 0.042).

CONCLUSION: We conclude that inadequate information is available for pregnant women and their physicians to determine whether the benefits exceed the teratogenic risks for most drug treatments introduced in the past 20 years.

A teratogenic exposure can be defined as one that may produce a permanent abnormality of structure or function in an organism exposed during embryonic or fetal life. Pregnant women and their physicians frequently have concerns about potential teratogenic effects of medical treatments. Unfortunately, the information necessary to determine whether treatment with a particular medication during pregnancy poses a teratogenic risk and whether the magnitude of the risk is likely to be greater than the benefit of treatment is often unavailable. Every year, many new drugs are approved by the US Food and Drug Administration (FDA) and introduced into the market. Although these drugs must undergo preclinical animal teratology testing, animal studies are not always predictive of either the occurrence or lack of occurrence of a teratogenic effect in human pregnancy. Clinical trials to assess safety and efficacy are also required before FDA approval, but most clinical trials exclude pregnant women and focus on immediate adverse effects. Consequently, most new drugs have almost no human data available regarding possible teratogenic effects in humans at the time of FDA approval.

The FDA usually requires neither clinical studies nor active surveillance for teratogenic effects once a drug has been approved for marketing, and such studies are rarely performed by drug sponsors. New drugs may or may not be included in epidemiologic studies or surveillance systems undertaken by others. The FDA does require sponsors to report possible teratogenic effects that are noted in drug experience reports submitted voluntarily by health care providers, but passive collection of drug experience is a notoriously inefficient and often misleading method of identifying teratogenic effects. Sponsors of approved drugs are not required to submit detailed results of additional teratology studies they undertake or that have been reported in the literature unless these studies show a risk that might warrant a label change. Studies that show a lack of risk need not be reported.

Nevertheless, pregnant women often receive newly approved drugs. Women may become ill during pregnancy and require drug treatment to protect their own life and health as well as the life and health of the fetus. Medical treatment of psychiatric diseases, seizure disorders, diabetes mellitus, hypertension, or other chronic illnesses may be necessary to enable affected women to become pregnant and to continue their pregnancies safely. In other instances, a woman may become pregnant while undergoing treatment, or she may take a medication before she is aware that she is pregnant. Both of these are common occurrences. Approximately 11% of women between the ages of 15 and 44 become pregnant each year,^1,2 and 50–60% of all pregnancies in the United States are unintended.^3,4 Pregnancy is usually not recognized until embryogenesis is well under way, often at about the time of the second missed menstrual period.

Clinicians who provide teratogen risk counseling frequently encounter drug treatments for which the teratogenic risks are unknown.⁵ To characterize the magnitude and importance of this problem better, we investigated how long it takes after a new drug is marketed to determine whether or not its use by pregnant women is likely to pose a substantial teratogenic risk.

	MATERIALS AND METHODS

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We obtained from the FDA a list of 511 drugs that were approved for marketing in the United States between 1980 and 2000. We excluded radioactive agents and drugs that were subsequently withdrawn from the US market. For drugs that were structural variants of a single active entity (eg, insulin, lispro insulin, and insulin glargine), we only considered the one that was first approved. The remaining 469 drugs were selected for this study.

The risk of teratogenic effects associated with use of each of these drugs at conventional therapeutic doses at a critical time in human pregnancy was classified by the system developed for TERIS, a computer-based clinical teratology resource.⁶ TERIS assigns teratogenicity risk ratings to each treatment by consensus of opinion of an expert advisory board. The current members of this board are Dr. Robert Brent, Dr. Kenneth Lyons Jones, Dr. Richard Miller, Dr. Cynthia Moore, and Dr. Thomas Shepard. Each advisor independently rates the magnitude of teratogenic risk associated with maternal use during pregnancy of each agent at conventional doses as "none," "unlikely," "minimal," "small," "moderate," "high," or "undetermined." In some instances, this rating is amplified by one or more comments. In general, risks that are "minimal" or less ought not to 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. Each exposure is also rated with respect to the quality and quantity of data on which the assessment of teratogenic risk in human pregnancy is based. The quality of data available for this purpose is classified as "none," "limited," "fair," "good," or "excellent."

We were unable to establish rigorous criteria for assigning TERIS risk classifications because the data for various agents differed greatly with respect to types, number, size, and limitations of the studies that were available. However, all of the experienced clinicians who rated the agents were comfortable with ranking risks and quality of data on a semiquantitative scale. This ranking is similar to that used by clinicians to rate the loudness of cardiac murmurs or the strength of deep tendon reflexes on scales of 1–6 or 1–4. Our approach was supported by the finding that all of the advisors’ independent ratings fell within one grade of each other for more than 90% of agents assessed. Agents for which this degree of agreement was not achieved initially were discussed among the participants until a consensus regarding the rating was reached. Usually, this involved clarifying the terminology, defining risk components better, or reviewing critical publications again.

These ratings were made after reviewing summaries of published information available on the teratogenicity of each exposure. The summaries are based on a thorough search of the MEDLINE and TOXLINE databases and of additional references provided in the current electronic versions of the Catalog of Teratogenic Agents⁷ and REPROTOX⁸ and the current print editions of Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk⁹ and Chemically Induced Birth Defects.¹⁰ The teratogenic potential of each exposure is considered with respect to the reproducibility, consistency, and biological plausibility of available clinical, epidemiologic, and experimental data. Animal studies are used in this assessment, but only experimental teratology studies conducted in mammals are considered. The results of animal studies are weighed more heavily if the treatments are similar in dosage and route to those encountered clinically, if the malformations produced are analogous to those reported in humans, and if the species tested are closely related to humans phylogenetically. Associations between congenital anomalies in infants and a maternal drug treatment during pregnancy are considered causal only if the data do not contradict accepted biologic principles regarding absorption of the agent, gestational timing of the exposures, and dosage.

For the purposes of this study, we used the current online version of TERIS⁶ and grouped exposures into one of three classes:

1. Treatments associated with a TERIS risk rating of "unlikely," "none," or "minimal";
   
2. Treatments associated with a TERIS risk rating of "small," "moderate," or "high"; and
   
3. Treatments associated with a TERIS risk rating of "undetermined."
   

We chose these three classes to facilitate statistical analysis and because they provided groups that correspond generally to the categories that are of most clinical interest. This classification is extremely crude and should not be used for counseling patients. The TERIS ratings themselves are only intended to be used in conjunction with the associated narrative summaries. Decisions regarding use of medication during pregnancy should, of course, be made on the basis of the clinical indication for treatment, the efficacy of the drug being considered, and its safety for the mother as well as for the fetus. TERIS ratings relate only to the last of these issues.

For the 303 drugs that were not included in the TERIS database,⁶ we consulted the current online versions of Shepard’s Catalog⁷ and REPROTOX⁸ to determine the information that was available on teratogenicity in human pregnancy. None of these drug treatments had sufficient information to be classified as having a TERIS risk rating of "none," "minimal," "unlikely," "small," "moderate," or "high" according to the procedures used in TERIS. We, therefore, considered conventional treatment with each of these medications to have an "undetermined" risk of producing teratogenic effects in human pregnancy. Information on one drug, cefpiramide sodium, could not be found in any of the databases. This drug was excluded from the study, which was performed on the remaining 468 drugs.

For each of the drugs in either the "unlikely," "none," or "minimal" risk category or in the "small," "moderate," or "high" risk category, we used references in the TERIS database⁶ to determine when sufficient information had been published to classify the teratogenic risk into that particular category. One drug, triazolam, did not have any human data to support its "unlikely" teratogenicity rating; this rating was based on analogy to a closely related agent, diazepam, which had been more thoroughly studied. In this case, we used the critical published study of diazepam as the supporting evidence for the risk classification of triazolam. For drugs that had critical studies reported before FDA approval, the length of time between approval and acquisition of sufficient knowledge for rating was considered to be zero. When the critical studies for a particular drug were reported over a period of years, we assigned a range of time (eg, 1992–1995) rather than a single year and used the average of this range for our calculations. From these data, we estimated the average time between FDA approval and the publication of sufficient information to permit assignment of a TERIS risk rating for each group of drugs, along with the corresponding standard deviation.

Although the FDA Use-in-Pregnancy Categories are not intended to be a means of classifying drugs by teratogenic risk, many clinicians use the FDA Categories for this purpose.¹¹ Therefore, we also compared the TERIS risk ratings with the FDA Use-in-Pregnancy Categories assigned to these drugs in the official package labeling. The FDA Categories are defined as follows¹²:

A. Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.

B. Animal studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women OR animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.

C. Animal studies have shown an adverse effect, and there are no adequate and well-controlled studies in pregnant women OR no animal studies have been conducted, and there are no adequate and well-controlled studies in pregnant women.

D. Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.

X. Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant.

Because we wanted to compare treatments that had been categorized by both systems, we excluded drugs that were not found in the TERIS database or that did not have an FDA Use-in-Pregnancy Category assigned. In this comparison, we equated the following categories:

TERIS FDA "None," "minimal," or "unlikely" A or B "Small," "moderate," or "high" D or X "Undetermined" C

This comparison is not really between two different classifications of teratogenic risk because the FDA Categories are not intended to serve as teratogenic risk ratings, although they are frequently used for this purpose clinically.

We calculated the statistic to estimate agreement between the two ratings.¹³ = 1 indicates perfect agreement between two systems; = 0 shows no more agreement than is expected by chance.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
According to information available in standard clinical teratology knowledgebases, the teratogenic risk in human pregnancy associated with therapeutic use of 91.2% of 468 drug treatments approved by the FDA between 1980 and 2000 was still undetermined at the time of this study (Table 1). The distribution of treatments among the three categories—1) teratogenic risk "none," "minimal," or "unlikely"; 2) teratogenic risk "small," "moderate," or "high"; or 3) "undetermined" teratogenic risk—differed significantly in the four time intervals studied (²₃ = 13.86, P = .003, for classification as "undetermined" or not), but more than 80% of exposures were classified as "undetermined" in every interval. The group with the highest proportion of drugs with an "undetermined" risk was that approved 15–20 years ago (96.6%). The list of drug treatments with undetermined human teratogenic risks contains many that are used frequently, including albuterol, atenolol, azithromycin (Zithromax), clarithromycin (Biaxin), loratadine (Claritin), and zolpidem (Ambien) (Table 2).

On average, it took 6.0 ± 4.1 years (mean ± standard deviation) after FDA approval to determine that the 11 drug treatments associated with a human teratogenic risk carry such a risk. Treatment with two of the drugs on this list, fosphenytoin sodium and thalidomide, was known to be potentially teratogenic in humans at the time of FDA approval. For the other drugs in this group, the length of time between FDA approval and demonstration of teratogenicity in human pregnancy varied from 3 to 12 years. The human teratogenicity of each of these treatments was initially recognized in case reports or clinical series, although in some instances epidemiologic studies subsequently permitted more precise quantitation of the risk.

Thirty (6.4%) of the drug treatments were considered unlikely to pose a teratogenic risk in human pregnancy or had teratogenic risk ratings of "none" or "minimal." The risk rating for econazole was based on topical use, and the risk for fluconazole was specific for treatment with a single low oral dose. The time from FDA approval required to determine that these treatments were unlikely to be teratogenic in humans averaged 9.1 ± 4.5 years. The apparent safety of acebutolol and dronabinol was known at the time of their introduction; for the other treatments in this group, the time to recognition of apparent safety ranged from 2 to 19 years. The determination that these treatments were unlikely to pose a substantial teratogenic risk to humans was usually based on clinical series or exposure cohort studies. The quality and quantity of data available to make this assessment was considered to be no better than fair for all but four of these 30 treatments.

Both TERIS risk ratings and FDA Use-in-Pregnancy Category assignments were available for 163 of the drugs included in this study (Table 2). Agreement between the teratogenic risk classification provided by these two systems was poor ( ± standard deviation = 0.082 ± 0.042) (Table 3).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

The purpose of this study was to determine how often the information needed to make a clinical assessment of teratogenic risk was available for drug treatments that had been approved by the FDA in the past 20 years. We found that available data are insufficient to determine the human teratogenic risk associated with treatment with most of these drugs. It is of great concern that this is true not only for drugs that were introduced recently but also for those approved more than 10 or even 15 years ago.

Treatment of pregnant women with only a small fraction (2.4%) of these 468 drugs has been associated with a substantial teratogenic risk, but it took an average of 6 years after FDA approval for this recognition to occur. Only 6.4% of these newly approved treatments have been shown to produce no more than a minimal teratogenic risk in human pregnancy. It took an average of 9 years after FDA approval to recognize the apparent safety of these 30 drugs.

The poor agreement between TERIS risk ratings and FDA Use-in-Pregnancy Categories for the treatments included in this study is not unexpected. The findings were similar in a previously reported comparison of these systems for 157 frequently prescribed drug components, although only ten drugs were common to both studies.¹⁵ The FDA system is not intended to provide an estimate of the teratogenic risk associated with use of a drug in pregnancy, although the FDA Categories are widely used for this purpose clinically.¹¹ The FDA Categories are based largely on data from unpublished premarketing animal studies. Although such studies are a valuable means of identifying treatments that may have teratogenic potential in humans, animal teratology studies are not always predictive of either teratogenic risk or safety in human pregnancy. In addition, the FDA Categories take into account both the potential benefit and the potential risk of drug treatment during pregnancy. FDA Use-in-Pregnancy Categories are assigned through a structured regulatory process and negotiation with the drug’s sponsor. In contrast, TERIS ratings are determined by a consensus of opinion among an independent group of experienced clinical teratologists. These ratings are based largely on information from human studies and only consider data that have been published. TERIS ratings reflect the risk of teratogenic effects but not the potential benefits or risks of treatment to the mother.

The fact that so little is known about the teratogenicity of so many drug treatments in human pregnancy presents a serious problem for both pregnant women and their physicians. Women often overestimate the fetal risk associated with medication use during pregnancy, and the uncertainty produced by lack of information can sometimes lead to the unnecessary termination of a wanted pregnancy.¹⁶ Many pregnant women are reluctant to use any medication during pregnancy, especially if the safety of such use has not been established. As a consequence, women and their fetuses may not receive the benefits of treatment, even when treatment is actually safer than leaving a disease untreated. Alternatively, treatment with a familiar drug, even one known to be associated with a teratogenic risk, may be preferred to use of a more efficacious newer drug for which the teratogenic risk has not been determined.

Efforts have been undertaken by the US Centers for Disease Control,¹⁷ various state and national birth defects registries,^18–20 teratogen information services,²¹ academic centers,²² and others²³ to learn more about the potential teratogenicity of drug treatments in human pregnancy. These efforts are largely or entirely independent of the FDA’s responsibility for assuring the safety of medicines used in the United States. The FDA has required the development of industry-sponsored registries to collect information on the outcome of pregnancies in women who are treated with thalidomide²⁴ or isotretinoin,²⁵ two treatments associated with exceptionally high teratogenic risks in humans. In addition, the FDA has encouraged sponsors to collect information on the outcome of pregnancies in women treated with several other drugs that are of particular interest, including anticonvulsants²⁶ and antiretroviral agents.²⁷ These registries are of value, but concerns have been raised about their methodologic limitations.²⁸

The FDA has recently considered more active approaches to postmarketing surveillance of drugs for teratogenic effects (Rodriguez EM. Postmarketing surveillance: Update on pregnancy registries [abstract]. Teratology 2001;63:270). Improving our knowledge of such effects would greatly benefit pregnant women and their physicians.

	Footnotes

 
Statement of potential conflict of interest: Dr. Friedman is senior author of the TERIS database.

PII S0029-7844(02)02122-1

Received November 8, 2001. Received in revised form March 14, 2002. Accepted April 4, 2002.

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