Broad Spectrum Epidemiological Contribution of Cannabis, Tobacco and Alcohol to the Teratological Profile of Northern New South Wales Dataset: Geospatial and Causal Inference Analysis

Background. Whilst cannabis commercialization is occurring rapidly guided by highly individualistic public narratives, evidence that all congenital anomalies (CA) increase alongside cannabis use in Canada, a link with 21 CA’s in Hawaii, and rising CA’s in Colorado indicate that transgenerational effects can be significant and impact public health. It was therefore important to study Northern New South Wales (NNSW) a known cannabis use centre. Methods. Design: Cohort. 2008-2015. Setting: NNSW and Queensland (QLD), Australia. Participants. Whole populations. Exposures. Tobacco, Risky Alcohol, Annual cannabis. Source: National Drug Strategy Household Surveys 2010, 2013. Main Outcomes. CA Rates. NNSW-QLD comparisons. Geospatial and causal regression. Results. Cardiovascular, respiratory and gastrointestinal anomalies rose with falling tobacco and alcohol but rising cannabis use rates across Queensland. Maternal age NNSW-QLD was not different (2008-2015: 4,265/22,084 v. 96,473/490,514 >35 years, Chi.Sq.=1.687, P=0.194). A higher rate of NNSW cannabis-related than cannabis-unrelated defects occurred (prevalence ratio (PR)=2.13, 95%C.I. 1.80-2.52, P=3.24x10-19). CA’s rose more potently with rising cannabis than with rising tobacco or alcohol use. Exomphalos and gastroschisis had the highest NNSW:QLD PR (6.29(2.94-13.48) and 5.85(3.54-9.67)) and attributable fraction in the exposed (84.11%(65.95-92.58%) and 82.91%(71.75-89.66%), P=2.83x10-8 and P=5.62x10-15). In multivariable geospatial models cannabis was significantly linked with cardiovascular (atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus), genetic (chromosomal defects, Downs syndrome), gastrointestinal (small intestinal atresia), body wall (gastroschisis, diaphragmatic hernia) and other (hypospadias) (AVTPCDSGDH) CA’s. In linear modelling cannabis use was significantly linked with anal stenosis, congenital hydrocephalus and Turner syndrome (ACT) and was significantly linked in borderline significant models (model P<0.1) with microtia, microphthalmia, and transposition of the great vessels. In robust and mixed effects inverse probability weighted multivariable regression cannabis was related to 18defects. E-Values in spatial models were generally >1.3 ranging up to 3.8x1030 making uncontrolled confounding unlikley. Conclusions. These results suggest that population level CA’s react more strongly to small rises in cannabis use than tobacco or alcohol; cardiovascular, chromosomal, body wall and gastrointestinal CA’s rise significantly with small increases in cannabis use; and that cannabis is a bivariate correlate of AVTPCDSGDH and ACT anomalies and is robust to adjustment for other substances.

背景。尽管大麻商业化正以高度个人主义的公共叙事为指引快速推进，但现有证据显示，加拿大境内所有先天性畸形（congenital anomalies, CA）发生率均随大麻使用量上升而升高，夏威夷地区已发现大麻使用与21种先天性畸形存在关联，而科罗拉多州的先天性畸形发生率也在持续攀升，这些证据均表明跨代效应可能十分显著，并会对公共卫生造成影响。因此，对作为已知大麻使用高发区域的新南威尔士州北部（Northern New South Wales, NNSW）展开研究具有重要意义。研究方法。研究设计：队列研究，时间跨度为2008年至2015年。研究地点：澳大利亚新南威尔士州北部与昆士兰州（Queensland, QLD）。研究对象：全人群。暴露因素：烟草、危险饮酒行为、年度大麻使用情况。数据来源：2010年、2013年全国药物战略家庭调查（National Drug Strategy Household Surveys）。主要结局指标：先天性畸形发生率、新南威尔士州北部与昆士兰州的对比分析、空间地理与因果回归分析。研究结果。在昆士兰州境内，随着烟草与酒精使用量下降、大麻使用量上升，心血管、呼吸与消化系统畸形的发生率随之升高。新南威尔士州北部与昆士兰州的产妇年龄并无显著差异（2008-2015年：4265/22084 vs 96473/490514，年龄≥35岁，卡方检验=1.687，P=0.194）。新南威尔士州北部与大麻使用相关的畸形发生率显著高于非相关畸形（患病率比（prevalence ratio, PR）=2.13，95%置信区间（confidence interval, CI）1.80~2.52，P=3.24×10^-19）。相较于烟草或酒精使用量上升，大麻使用量升高与先天性畸形发生率的关联强度更高。脐膨出（exomphalos）与腹裂（gastroschisis）在新南威尔士州北部与昆士兰州的患病率比最高，分别为6.29（2.94~13.48）与5.85（3.54~9.67），暴露人群归因分值（attributable fraction in the exposed）分别为84.11%（65.95%~92.58%）与82.91%（71.75%~89.66%，P=2.83×10^-8，P=5.62×10^-15）。在多变量空间地理模型中，大麻使用与以下几类先天性畸形存在显著关联：心血管系统畸形（房间隔缺损、室间隔缺损、法洛四联症、动脉导管未闭）、遗传性畸形（染色体异常、唐氏综合征（Downs syndrome））、消化系统畸形（小肠闭锁）、体壁畸形（腹裂、膈疝）及其他类型畸形（尿道下裂（hypospadias）），可缩写为AVTPCDSGDH。在线性模型中，大麻使用与肛门狭窄、先天性脑积水、特纳综合征（Turner syndrome）存在显著关联，可缩写为ACT；同时在边缘显著的模型（模型P<0.1）中，大麻使用与小耳畸形、小眼畸形、大动脉转位存在关联。在稳健回归与混合效应逆概率加权多变量回归分析中，大麻使用与18种畸形存在关联。空间模型中的E值普遍大于1.3，最高可达3.8×10^30，提示未控制混杂因素的可能性极低。研究结论。上述结果表明，人群层面的先天性畸形发生率对大麻使用量小幅上升的响应强度高于烟草或酒精；心血管、染色体、体壁及消化系统畸形的发生率会随大麻使用量小幅升高而显著上升；大麻与AVTPCDSGDH及ACT类畸形存在双变量关联，且在校正其他物质使用因素后结果依然稳健。