Epidemiological Association of Cannabinoid- and Drug- Exposures and Sociodemographic Factors with Limb Reduction Defects Across USA 1989-2016: A Geotemporospatial and Causal Inference Study

Reports of major limb defects after prenatal cannabis exposure (PCE) in animals and of human populations in Hawaii, Europe and Australia raise the question of whether the increasing use of cannabis in USA might be spatiotemporally associated with limb reduction rates (LRR) across USA. Geotemporospatial analysis conducted in R. LRR was significantly associated with cannabis use and THC potency and demonstrated prominent cannabis-use quintile effects. In final lagged geospatial models interactive terms including cannabinoids were highly significant and robust to adjustment. States in which cannabis was not legalized had a lower LRR (4.28 v 5.01 /10,000 live births, relative risk reduction = −0.15, (95%C.I. −0.25, −0.02), P=0.021). 37-63% of cases are estimated to not be born alive; their inclusion strengthened these associations. Causal inference studies using inverse probabilty-weighted robust regression and e-values supported causal epidemiological pathways. Findings apply to several cannabinoids, are consistent with pathophysiological and causal mechanisms, are exacerbated by cannabis legalization and demonstrate dose-related intergenerational sequaelae. Highlights Limb reduction rates (LRR) were associated with cannabis use, and THC potency These relationships were robust to adjustment for ethic and economic covariates They were maintained at geospatiotemporal regression LRR elevated as stillborn and aborted cases were considered Criteria of causality was fulfilled