Epidemiological Association of Cannabinoid- and Drug- Exposures and Sociodemographic Factors with Limb Reduction Defects Across USA 1989-2016 Dataset: 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.

针对动物群体以及夏威夷、欧洲、澳大利亚人群开展的产前大麻暴露（Prenatal Cannabis Exposure, PCE）后严重肢体缺陷相关研究报告，引发了美国大麻使用量持续增长是否与全美肢体发育不全率（Limb Reduction Rates, LRR）存在时空关联的疑问。本研究借助R语言开展时空地理分析，结果显示肢体发育不全率与大麻使用水平及四氢大麻酚（THC）效力显著相关，且呈现出显著的大麻使用五分位数效应。在最终的滞后地理空间模型中，包含大麻素在内的交互项具有高度统计学显著性，且经协变量校正后结果依然稳健。未实施大麻合法化的州，其肢体发育不全率更低（4.28 vs 5.01/10000活产儿，相对风险降低率=-0.15，95%置信区间(95%C.I.)：-0.25~-0.02，P=0.021）。据估算，37%~63%的病例为死产；纳入死产病例后，上述关联得到进一步增强。采用逆概率加权稳健回归及e值开展的因果推断研究，验证了因果流行病学通路的合理性。本研究结果适用于多种大麻素，与病理生理学机制及因果推断逻辑相符，且因大麻合法化而加剧，同时呈现出剂量依赖性的代间后遗症效应。