ABCDXXX: The obscenity of postmarketing surveillance for teratogenic effects

Abstract

Our current system of postmarketing surveillance, which is based on voluntary reporting of suspected teratogenic effects, is a failure. Postmarketing surveillance should, at a minimum, provide reassurance that every approved drug treatment does not produce a teratogenic effect as great as thalidomide embryopathy or fetal alcohol syndrome. This means that postmarketing surveillance should be able to detect a twofold or greater increase in the frequency of major congenital anomalies, a fivefold or greater increase in the frequency of intellectual disability, or a characteristic pattern of minor anomalies and functional abnormalities that occurs with a frequency of at least 10% among the children of women who were treated with the drug during pregnancy. Effective surveillance for teratogenic effects could be accomplished through a complementary set of mechanisms that includes pregnancy exposure registries or cohorts as well as direct examination of a small subset of infants whose mothers received the treatment during various periods of pregnancy. If this routine surveillance reveals a "signal" (i.e., an indication suggesting a possible teratogenic effect), further study would be needed to establish whether the observed effect is real and causal. Once a signal of possible teratogenicity in humans has been recognized, validating or refuting it would become an urgent matter.

A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection

“…These issues must be addressed if PERs are to succeed as an early warning system. [4][5][6][7] Our study sought to systematically evaluate protocol-specified study methods used in PERs including (i) pre-specified pregnancy outcomes; (ii) target sample size based on power calculations; and (iii) comparator selection. Knowledge obtained from this study will help inform scientific methods needed to improve safety data collection in pregnant women.…”

Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential?

“…The more common outcome under investigation the fewer participants needed to ensure an adequately powered cohort and therefore this works in favour of the researcher investigating neurodevelopmental outcomes [29]. Whilst large numbers of children are required to study the risk of major malformations, fewer children are required to investigate cognitive ability.…”

“…Power is also affected by the size of the effect under investigation and therefore large effect sizes will be detectable with smaller groups than more moderate or milder effect sizes which will require larger numbers of participants. Typically papers in this area report power calculations to require between 40 and 50 participants per group for adequate power to detect moderate to large effect sizes [29][30][31], the detection of even larger effect sizes would be possible with smaller groups [29], however, knowing the effect size you are looking at prior to the onset of a study is difficult. Thus, although the assessment and follow up is more time consuming fewer children in comparison to malformation studies are required for neurodevelopmental studies to detect large effect sizes.…”

Systematic procedure for the classification of proven and potential teratogens for use in research

“…Pregnant women living in developed countries frequently take prescription and over‐the‐counter (OTC) medications, with prevalence estimates ranging between 27% and 99%, depending on the medications examined and the data sources used (Mitchell et al, ; Daw et al, ; Friedman, ). Moreover, the number of women taking medications during pregnancy is growing as maternal age increases, and with the increasing use of medications in developed countries (Wysowski et al, ; Shahin and Einarson, ; Thorpe et al, ; Mazer‐Amirshahi et al, ).…”