Comment from Anonymous

Please see the attached supplemental comment and supporting references regarding the limitations of sibling-control analyses in prenatal neurodevelopment research. Recent literature suggests that sibling comparison designs may attenuate or obscure true associations in certain contexts involving developmental exposures, particularly where exposure misclassification, carryover effects, shared environmental susceptibilities, epigenetic mechanisms, or bias amplification may be present. These concerns are directly relevant to the interpretation of prenatal acetaminophen studies, where several large maternal recall studies employing sibling-control methodologies have been treated as disproportionately determinative in evaluating risk. Importantly, the recently published JAMA study by Ahlqvist et al. (2024) on prenatal acetaminophen exposure and neurodevelopmental outcomes demonstrated substantial attenuation of associations in sibling analyses despite strong associations in population-level analyses, while contemporaneous methodological literature has cautioned that sibling-control methods may themselves introduce important bias under certain conditions. Additional large-scale prenatal neurodevelopment studies, including Madley-Dowd et al. (2024), similarly emphasize that sibling comparisons should be interpreted as one methodological tool among many, rather than as definitive evidence against causality. Accordingly, these materials are submitted in support of the Americans for Scientific Integrity citizen petition requesting pediatric precautionary labeling for acetaminophen. At minimum, the evolving methodological literature suggests that null sibling-control findings should not be treated as dispositive when evaluating the overall weight of evidence regarding potential neurodevelopmental risk.