EUROmediCAT signal detection: an evaluation of selected congenital anomaly‐medication associations

Abstract

AimsTo evaluate congenital anomaly (CA)‐medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation.MethodsData from 15 EUROCAT registries (1995–2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity.ResultsThirteen out of 27 CA‐medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70–8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99–14.20/OR 28.20, 95% CI 4.63–122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70–22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10–1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28–2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining six signals involving the ordinary salt combinations, propulsives, bulk‐forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists.ConclusionSignals which strengthened prior evidence should be prioritized for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.

EUROmediCAT signal detection: a systematic method for identifying potential teratogenic medication

“…We report here the statistical methodology and assess its validity by comparing the results with known associations already reported in the literature . The validation of the individual signals found and their correspondence with current scientific knowledge is reported in an accompanying paper .…”

Bayesian hierarchical methods in the detection of potentially teratogenic first‐trimester medications

“…We may expect a teratogen to act in a similar way regardless of where it is taken; however, certain medications may have varying usages and/or availability in different EUROmediCAT registries and countries. As many medication‐CA combinations have very small numbers, the best approach to an ongoing signal detection process is considered to be investigation of any potential registry effects at a later stage in the analysis; as such, after potential signals are generated, the next step of the EUROmediCAT signal detection process includes the adjustment of estimates for confounding by registry …”

“…The proportion of category A medications being identified as potential signals was also considered, as a measure of the likely number of “false positive” associations. The total number of unique medications in the set of potential signals identified by each method is referred to as the “effective workload.” Note that we refer only to potential signals as the aim of this study is to assess signal generation methods for CA data, and we do not further evaluate the potential signals here (since this has already been done for this dataset).…”

“…As many medication-CA combinations have very small numbers, the best approach to an ongoing signal detection process is considered to be investigation of any potential registry effects at a later stage in the analysis; as such, after potential signals are generated, the next step of the EUROmediCAT signal detection process includes the adjustment of estimates for confounding by registry. 28 This analysis excludes all chromosomal anomalies; these anomalies could theoretically be analysed as a negative control outcome as no medications are expected to be associated with any chromosomal anomalies. However, the risk of a chromosomal anomaly is strongly associated with maternal age, and methods to adjust for this confounder in signal detection analyses would need to be developed.…”

Spatial analysis of hypospadias cases in northern France: Taking clinical data into account.

“…[5][6][7] The suspected causal factors include iatrogenic factors (e.g. medications taken during pregnancy [8][9][10] or conception via assisted reproductive technologies (ART) [11,12]) and environmental factors (e.g. fetal exposure to endocrine-disrupting chemicals or other chemical hazards).…”