Dataset Information

European Epidemiological Patterns of Cannabis- and Substance-Related Body Wall Congenital Anomalies: Geospatiotemporal and Causal Inferential Study.

ABSTRACT: As body wall congenital anomalies (BWCAs) have a long history of being associated with prenatal or community cannabis exposure (CCE), it was of interest to investigate these epidemiological relationships in Europe given the recent increases in cannabis use prevalence, daily intensity, and Δ9-tetrahydrocannabinol (THC) potency.

Methods

This study makes use of BWCA data from Eurocat, drug exposure data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank.

Results

The mapping analysis showed that BWCARs increased in France, Spain, and the Netherlands. The bivariate mapping analysis showed that the BWCA rates (BWCAR) and the cannabis resin THC concentration rose simultaneously in France, the Netherlands, Bulgaria, Sweden, and Norway. The bivariate ranking of the BWCARs by median minimum E-value (mEV) was omphalocele > diaphragmatic hernia > abdominal wall defects > gastroschisis. With inverse probability weighted multivariable panel regression, the series of BWCAs, including gastroschisis, omphalocele, and diaphragmatic hernia, was positively related to various metrics of cannabis use from p = 2.45 × 10^-14, 4.77 × 10^-7 and <2.2 × 10^-16. With geospatial regression, the same series of BWCAs was related to cannabis metrics from p = 0.0016, 5.28 × 10^-6 and 4.88 × 10^-9. Seventeen out of twenty-eight (60.7%) of the E-value estimates were >9 (high range), as were 14/28 (50.0%) of the mEVs.

Conclusion

The data confirm the close relationship of the BWCARs with the metrics of CCE, fulfill the quantitative criteria of causal inference, and underscore the salience of the public health impacts of cannabinoid teratogenicity. Of major concern is the rising CCE impacting exponential cannabinoid genotoxic dose-response relationships. CCE should be carefully restricted to protect the food chain, the genome, and the epigenome of coming generations.

SUBMITTER: Reece AS

PROVIDER: S-EPMC9330494 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:As prenatal and community cannabis exposures have recently been linked with congenital heart disease (CHD), it was of interest to explore these associations in Europe in a causal framework and space-time context. Congenital anomaly data from Eurocat, drug-use data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Countries with rising daily cannabis use had in general higher congenital anomaly rates over time than those without (time: status interaction: β-Est. = 0.0267, P = 0.0059). At inverse probability-weighted panel regression, cannabis terms were positive and significant for CHD, severe CHD, atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, vascular disruptions, double outlet right ventricle, transposition of the great vessels, hypoplastic right heart, and mitral valve anomalies from 1.75 × 10-19, 4.20 × 10-11, <2.2 × 10-16, <2.2 × 10-16, 1.58 × 10-12, 4.30 × 10-9, 4.36 × 10-16, 3.50 × 10-8, 5.35 × 10-12, <2.2 × 10-16, 5.65 × 10-5 and 6.06 × 10-10. At spatial regression, terms including cannabis were positive and significant for this same list of anomalies from 0.0038, 1.05 × 10-10, 0.0215, 8.94 × 10-6, 1.23 × 10-5, 2.05 × 10-5, 1.07 × 10-6, 8.77 × 10-5, 9.11 × 10-6, 0.0001, 3.10 × 10-7 and 2.17 × 10-7. 92.6% and 75.2% of 149 E-value estimates and minimum E-values were in high zone >9; 100.0% and 98.7% >1.25. Data show many congenital cardiac anomalies exhibit strong bivariate relationships with metrics of cannabis exposure. Causal inferential modelling for the twelve anomalies selected demonstrated convincing evidence of robust relationships to cannabis which survived adjustment and fulfilled epidemiological criteria for causal relationships. Space-time regression was similarly confirmatory. Epigenomic pathways constitute viable potential mechanisms. Given exponential genotoxic dose-response effects, careful and astute control of cannabinoid penetration is indicated.

Project description:Introduction. Of the many congenital anomalies (CAs) recently linked with community cannabis exposure, arguably the most concerning are neurological CAs (NCAs). We therefore conducted a detailed study of this in fourteen European nations. Methods. Congenital anomaly data were from Eurocat. Drug exposure data were from European Monitoring Centre for Drugs and Drug Addiction. Income from World bank. Results. The Netherlands, Spain, France and Bulgaria reported increasing rates of many NCAs. The NCA rate (NCAR) was higher in nations with increasing daily cannabis use when compared to those without (p = 0.0204, minimum E-value (mEV) = 1.35). At bivariate analysis, the mEVs of the following NCAs were significantly cannabis related: severe microcephaly 2.14 × 1013, craniosynostosis 5.27 × 1011, nervous system 4.87 × 1011, eye 2.73 × 107, microphthalmos 4.07 × 106, anencephalus 710.37, hydrocephalus 245.64, spina bifida 14.86 and neural tube defects 13.15. At inverse probability, weighted panel regression terms including cannabis were significantly related to the following series of anomalies: nervous system, anencephalus, severe microcephalus, microphthalmos, neural tube defect and spina bifida from p = 5.09 × 10−8, <2.2 × 10−16, <2.2 × 10−16, 4.84 × 10−11, <2.2 × 10−16 and 9.69 × 10−7. At geospatial regression, this same series of anomalies had terms including cannabis significant from p = 0.0027, 1.53 × 10−7, 3.65 × 10−6, 2.13 × 10−8, 0.0002 and 9.76 × 10−12. 88.0% of 50 E-value estimates and 72.0% of mEVs > 9. This analysis therefore demonstrates both close association of cannabis exposure with multiple NCAs across space-time and also fulfills the quantitative criteria of causal inferential analysis. Conclusions. Nine NCARs on bivariate and six NCARs on multivariable regression were cannabis related and fulfilled quantitative epidemiological criteria for causality and are consistent with other series. Particular concerns relate to exponential dose−response effects demonstrated in the laboratory and epidemiological studies. Great caution with community cannabinoid penetration is warranted. Data indicate that cannabis is a significant environmental teratogen and thus imply that cannabinoids should be regulated similarly to the manner in which all other important genotoxins are carefully controlled by communities for their self-sustaining longevity and the protection of generations yet to come.

Project description:IntroductionSince high rates of congenital anomalies (CAs), including facial CAs (FCAs), causally attributed to antenatal and community cannabis use have been reported in several recent series, it was of interest to examine this subject in detail in Europe.MethodsCA data were taken from the EUROCAT database. Drug exposure data were downloaded from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Income was taken from the World Bank's online sources.ResultsOn the bivariate maps of both orofacial clefts and holoprosencephaly against resin, the Δ9-tetrahydrocannabinol concentration rates of both covariates increased together in France, Bulgaria, and the Netherlands. In the bivariate analysis, the anomalies could be ranked by the minimum E-value (mEV) as congenital glaucoma > congenital cataract > choanal atresia > cleft lip ± cleft palate > holoprosencephaly > orofacial clefts > ear, face, and neck anomalies. When nations with increasing daily use were compared to those without, the former had generally higher rates of FCAs (p = 0.0281). In the inverse probability weighted panel regression, the sequence of anomalies-orofacial clefts, anotia, congenital cataract, and holoprosencephaly-had positive and significant cannabis coefficients of p = 2.65 × 10-5, 1.04 × 10-8, 5.88 × 10-16, and 3.21 × 10-13, respectively. In the geospatial regression, the same series of FCAs had positive and significant regression terms for cannabis of p = 8.86 × 10-9, 0.0011, 3.36 × 10-8, and 0.0015, respectively. Some 25/28 (89.3%) E-value estimates and 14/28 (50%) mEVs were >9 (considered to be in the high range), and 100% of both were >1.25 (understood to be in the causal range).ConclusionRising cannabis use is associated with all the FCAs and fulfils the epidemiological criteria for causality. The data indicate particular concerns relating to brain development and exponential genotoxic dose-responses, urging caution with regard to community cannabinoid penetration.

Project description:Cannabinoid exposure is increasing in some European nations. Europe therefore provides an interesting test environment for the recently reported link between cannabis exposure and congenital limb anomaly (CLA) rates (CLARs). Exponential genotoxic dose-response relationships make this investigation both intriguing and imperative. Annual CLAR in 14 nations were from Epidemiological Surveillance of Congenital Anomalies. Drug use rates were from European Monitoring Centre for Drugs and Drug Dependency. Median household income was from the World Bank. E-values provide a quantitative measure of robustness of results to confounding by extraneous covariates. Inverse probability weighting is an important technique for equalizing exposures across countries and removing sources of bias. Rates of CLA, hip dysplasia and the whole group of limb anomalies were higher in countries with increasing daily cannabis use (P = 1.81 × 10-16, 0.0005 and 2.53 × 10-6, respectively). In additive inverse-probability-weighted panel models, the limb reduction-resin Δ9-tetrahydrocannabinol (THC) concentration E-value estimate was 519.93 [95% lower bound (mEV) 49.56], order Resin > Herb ≫ Tobacco > Alcohol. Elevations were noted in 86% E-value estimates and 70.2% of mEVs from 57 E-value pairs from inverse-probability-weighted panel models and from spatial models. As judged by the mEV the degree of association with metrics of cannabis exposure was hip dysplasia > polydactyly > syndactyly > limb anomalies > limb reductions with median E-value estimates from 3.40 × 1065 to 7.06 and median mEVs from 6.14 × 1033 to 3.41. Daily cannabis use interpolated was a more powerful metric of cannabis exposure than herb or resin THC exposure. Data indicate that metrics of cannabis exposure are closely linked with CLAR and satisfy epidemiological criteria for causality. Along with Hawaii and the USA, Europe now forms the third international population in which this causal link has been demonstrated. Cannabis as a predictor of limb anomalies was more potent than tobacco or alcohol. Cannabinoid access should be restricted to protect public health and the community genome/epigenome transgenerationally.

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Project description:BackgroundAge-adjusted US total pediatric cancer incidence rates (TPCIR) rose 49% 1975-2015 for unknown reasons. Prenatal cannabis exposure has been linked with several pediatric cancers which together comprise the majority of pediatric cancer types. We investigated whether cannabis use was related spatiotemporally and causally to TPCIR.MethodsState-based age-adjusted TPCIR data was taken from the CDC Surveillance, Epidemiology and End Results cancer database 2003-2017. Drug exposure was taken from the nationally-representative National Survey of Drug Use and Health, response rate 74.1%. Drugs included were: tobacco, alcohol, cannabis, opioid analgesics and cocaine. This was supplemented by cannabinoid concentration data from the Drug Enforcement Agency and ethnicity and median household income data from US Census.ResultsTPCIR rose while all drug use nationally fell, except for cannabis which rose. TPCIR in the highest cannabis use quintile was greater than in the lowest (β-estimate = 1.31 (95%C.I. 0.82, 1.80), P = 1.80 × 10- 7) and the time:highest two quintiles interaction was significant (β-estimate = 0.1395 (0.82, 1.80), P = 1.00 × 10- 14). In robust inverse probability weighted additive regression models cannabis was independently associated with TPCIR (β-estimate = 9.55 (3.95, 15.15), P = 0.0016). In interactive geospatiotemporal models including all drug, ethnic and income variables cannabis use was independently significant (β-estimate = 45.67 (18.77, 72.56), P = 0.0009). In geospatial models temporally lagged to 1,2,4 and 6 years interactive terms including cannabis were significant. Cannabis interactive terms at one and two degrees of spatial lagging were significant (from β-estimate = 3954.04 (1565.01, 6343.09), P = 0.0012). The interaction between the cannabinoids THC and cannabigerol was significant at zero, 2 and 6 years lag (from β-estimate = 46.22 (30.06, 62.38), P = 2.10 × 10- 8). Cannabis legalization was associated with higher TPCIR (β-estimate = 1.51 (0.68, 2.35), P = 0.0004) and cannabis-liberal regimes were associated with higher time:TPCIR interaction (β-estimate = 1.87 × 10- 4, (2.9 × 10- 5, 2.45 × 10- 4), P = 0.0208). 33/56 minimum e-Values were > 5 and 6 were infinite.ConclusionData confirm a close relationship across space and lagged time between cannabis and TPCIR which was robust to adjustment, supported by inverse probability weighting procedures and accompanied by high e-Values making confounding unlikely and establishing the causal relationship. Cannabis-liberal jurisdictions were associated with higher rates of TPCIR and a faster rate of TPCIR increase. Data inform the broader general consideration of cannabinoid-induced genotoxicity.

Project description:BackgroundCannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum. We examined these issues including contextual space-time relationships and formal causal inferential analysis in USA.MethodsState congenital anomaly (CA) rate (CAR) data was taken from the annual reports of the National Birth Defects Prevention Network 2001-2005 to 2011-2015. Substance abuse rates were from the National Survey of Drug Use and Health a nationally representative longitudinal survey of the non-institutionalized US population with 74.1% response rate. Drugs examined were cigarettes, monthly and binge alcohol, monthly cannabis and analgesic and cocaine abuse. Early termination of pregnancy for abortion (ETOPFA) rates were taken from the published literature. Cannabinoid concentrations were from Drug Enforcement Agency. Ethnicity and income data were from the US Census Bureau. Inverse probability weighted (IPW) regressions and geotemporospatial regressions conducted for selected CAs.ResultsData on 18,328,529 births from an aggregated population of 2,377,483,589 for mid-year analyses 2005-2013 comprehending 12,611 CARs for 62 CAs was assembled and ETOPFA-corrected (ETOPFACAR) where appropriate. E-Values for ETOPFACARs by substance trends were elevated for THC (40 CAs), cannabis (35 CAs), tobacco (11 CAs), cannabidiol (8 CAs), monthly alcohol (5 CAs) and binge alcohol (2 CAs) with minimum E-Values descending from 16.55, 1.55x107, 555.10, 7.53x1019, 9.30 and 32.98. Cardiovascular, gastrointestinal, chromosomal, limb reductions, urinary, face and body wall CAs particularly affected. Highest v. lowest substance use quintile CAR prevalence ratios 2.84 (95%C.I. 2.44, 3.31), 4.85 (4.08, 5.77) and 1.92 (1.63, 2.27) and attributable fraction in exposed 0.28 (0.27, 0.28), 0.57 (0.51, 0.62) and 0.47 (0.38, 0.55) for tobacco, cannabis and cannabidiol. Small intestinal stenosis or atresia and obstructive genitourinary defect were studied in detail in lagged IPW pseudo-randomized causal regressions and spatiotemporal models confirmed the causal role of cannabinoids. Spatiotemporal predictive modelling demonstrated strongly sigmoidal non-linear cannabidiol dose-response power-function relationships (P = 2.83x10-60 and 1.61x10-71 respectively).ConclusionsData implicate cannabinoids including cannabidiol in a diverse spectrum of heritable CAs. Sigmoidal non-linear dose-response relationships are of grave concern. These transgenerational genotoxic, epigenotoxic, chromosomal-toxic putatively causal teratogenic effects strongly indicate tight restrictions on community cannabinoid penetration.