Determination of human teratogenicity by the astute clinician method: Review of illustrative agents and a proposal of guidelines

Carey, John C.; Martinez, Lynn; Balken, Elizabeth; Leen-Mitchell, Marsha; Robertson, Jennifer

doi:10.1002/bdra.20533

Cited by 56 publications

(38 citation statements)

References 35 publications

(41 reference statements)

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“…Congenital anomalies counted as major such as hip dysplasia or pyelectasia might be minor, if they were mild and did not require further therapy. But most importantly, no distinct pattern of malformations was observed, which would have indicated a teratogenic risk [15]. In addition, 21.1% of the patients were concomitantly treated with MTX, a known teratogen, for which a risk of 6.6% for major birth defects was reported [16].…”

Section: Discussionmentioning

confidence: 96%

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

Hoeltzenbein

Beck

Rajwanshi

et al. 2016

Seminars in Arthritis and Rheumatism

127

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Section: Discussionmentioning

confidence: 96%

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

Hoeltzenbein

Beck

Rajwanshi

et al. 2016

Seminars in Arthritis and Rheumatism

127

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“…As a consequence, it is very hard to collect data on enough infants to demonstrate a statistically significant effect. However, if the exposure produces a characteristic pattern of congenital anomalies that is almost never seen in other circumstances, careful documentation of the dysmorphic features in only a handful of cases may provide compelling evidence of a teratogenic effect, as has recently occurred with mycophenolate mofetil treatment during pregnancy (Carey et al, 2009). …”

Section: Low-risk Teratogenic Exposuresmentioning

confidence: 96%

“…Its use in pregnancy is infrequent, and no statistical evaluation of the risk of birth defects in women who were treated with this drug in comparison to the risk in untreated women has been reported. Nevertheless, there is no doubt that maternal mycophenolate mofetil treatment can cause a striking and very unusual teratogenic effect: a syndrome that includes microtia or anotia, orofacial clefts, congenital heart defects, and minor dysmorphic facial features (Carey et al, 2009). Although this association has not been shown to be statistically significant, clinical recognition of this syndrome among infants of women who are treated with mycophenolate mofetil is important and has influenced clinical management (FDA Alert, 2008).…”

Section: Statistical and Clinical Significancementioning

confidence: 97%

Big risks in small groups: The difference between epidemiology and counselling

Friedman

2009

Birth Defects Research

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Congenital anomalies do not occur in all babies born after a teratogenic exposure. Whether a given exposure is teratogenic depends on the chemical nature and physical properties of the agent, the dose and route of exposure, when in pregnancy the exposure occurs, and genetic and other factors that affect susceptibility. Teratogenic birth defects are inherently multifactorial. Absolute risk, relative risk, and population attributable risk provide useful but different information regarding teratogenic effects. Statistical significance and clinical significance also are important considerations, but they may not be concordant. Demonstrating a teratogenic effect is easier if it is sought in a subgroup of patients in whom the effect is likely to be particularly prominent. The ability to detect a significant risk is, therefore, generally increased by subgroup analysis of epidemiology studies, but the greater the number of analyses performed, the higher the probability of finding associations that reach nominal statistical significance by chance alone. This problem is well recognized, but it is difficult to solve. The only compelling evidence for the reality of an association between maternal exposure to an agent during pregnancy and teratogenic effects in the children is replication of the findings in independent studies, but this is hard to obtain. As a consequence, there are very few exposures for which the available information is sufficient to make evidence-based recommendations regarding the clinical management of teratogenic risks. It is important to admit these limitations and to learn more about exposures that cause birth defects and how to prevent them.

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“…The strongest data indicate that valproate exposure is associated with a 1-2% risk of neural tube defects (NTDs), a 10-to 20-fold increase over the general population (EURAP), an increased risk of neurodevelopmental deficits, reduced verbal abilities, and poorer attentional tasks Kantola-Sorza et al, 2007;McVearry et al, 2009;Meador et al, , 2011Nadebaum, 2011;. The astute clinician has always been credited with being the primary means of identifying potential human teratogens [Crombie, 1984;Carey et al, 2009], and this has been the case for AEDs as well.…”

Section: Introductionmentioning

confidence: 99%

Antiepileptic Drugs and Pregnancy Outcomes

Wlodarczyk

Palacios

George³

et al. 2012

Obstetrical &Amp; Gynecological Survey

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The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos.

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Determination of human teratogenicity by the astute clinician method: Review of illustrative agents and a proposal of guidelines

Abstract: The basic premise of this approach depends on the rarity of both the exposure and the outcome. We propose guidelines for utilization of this approach in the determination of human teratogenicity.

Cited by 56 publications

References 35 publications

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

Big risks in small groups: The difference between epidemiology and counselling

Antiepileptic Drugs and Pregnancy Outcomes

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