European Epidemiological Patterns of Cannabis- and Substance-Related Body Wall Congenital Anomalies: Geospatiotemporal and Causal Inferential Study.
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ABSTRACT: 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
Similar Datasets
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.
| S-EPMC9364688 | biostudies-literature
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.
| S-EPMC9819725 | biostudies-literature
Project description:With reports from Australia, Canada, USA, Hawaii and Colorado documenting a link between cannabis and congenital anomalies (CAs), this relationship was investigated in Europe. Data on 90 CAs were accessed from Eurocat. Tobacco and alcohol consumption and median household income data were from the World Bank. Amphetamine, cocaine and last month and daily use of cannabis from the European Monitoring Centre for Drugs and Drug Addiction. Cannabis herb and resin Δ9-tetrahydrocannabinol concentrations were from published reports. Data were processed in R. Twelve thousand three hundred sixty CA rates were sourced across 16 nations of Europe. Nations with a higher or increasing rate of daily cannabis use had a 71.77% higher median CA rates than others [median ± interquartile range 2.13 (0.59, 6.30) v. 1.24 (0.15, 5.14)/10 000 live births (P = 4.74 × 10-17; minimum E-value (mEV) = 1.52]. Eighty-nine out of 90 CAs in bivariate association and 74/90 CAs in additive panel inverse probability weighted space-time regression were cannabis related. In inverse probability weighted interactive panel models lagged to zero, two, four and six years, 76, 31, 50 and 29 CAs had elevated mEVs (< 2.46 × 1039) for cannabis metrics. Cardiovascular, central nervous, gastrointestinal, genital, uronephrology, limb, face and chromosomalgenetic systems along with the multisystem VACTERL syndrome were particularly vulnerable targets. Data reveal that cannabis is related to many CAs and fulfil epidemiological criteria of causality. The triple convergence of rising cannabis use prevalence, intensity of daily use and Δ9-tetrahydrocannabinol concentration in herb and resin is powerfully implicated as a primary driver of European teratogenicity, confirming results from elsewhere.
| S-EPMC8824558 | biostudies-literature
Project description:Δ8-Tetrahydrocannabinol (Δ8THC) is marketed in many US states as 'legal weed'. Concerns exist relating to class-wide genotoxic cannabinoid effects. We conducted an epidemiological investigation of Δ8THC-related genotoxicity expressed as 57 congenital anomaly (CA) rates (CARs) in the USA. CARs were taken from the Centers for Disease Control, Atlanta, Georgia. Drug exposure data were taken from the National Survey of Drug Use and Health, with a response rate of 74.1%. Ethnicity and income data were taken from the US Census Bureau. National cannabinoid exposure was taken from Drug Enforcement Agency publications and multiplied by state cannabis use data to derive state-based estimates of Δ8THC exposure. At bivariate continuous analysis, Δ8THC was associated with 23 CAs on raw CA rates, 33 CARs after correction for early termination for anomaly estimates and 41 on a categorical analysis comparing the highest and lowest exposure quintiles. At inverse probability weighted multivariable additive and interactive models lagged to 0, 2 and 4 years, Δ8THC was linked with 39, 8, 4 and 9 CAs. Chromosomal, cardiovascular, gastrointestinal, genitourinary, limb, central nervous system (CNS) and face systems were particularly affected. The minimum E-values ranged to infinity. Both the number of anomalies implicated and the effect sizes demonstrated were much greater for Δ8THC than for tobacco and alcohol combined. Δ8THC appears epidemiologically to be more strongly associated with many CAs than for tobacco and alcohol and is consistent with a cannabinoid class genotoxic/epigenotoxic effect. Quantitative causality criteria were fulfilled, and causal relationships either for Δ8THC or for cannabinoid/s, for which it is a surrogate marker, may be in operation.
| S-EPMC9245652 | biostudies-literature
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.
| S-EPMC7908679 | biostudies-literature
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.
| S-EPMC8767720 | biostudies-literature
Project description:BACKGROUND:Cardiovascular anomalies are the largest group of congenital anomalies and the major cause of death in young children, with various data linking rising atrial septal defect incidence (ASDI) with prenatal cannabis exposure. Objectives / Hypotheses. Is cannabis associated with ASDI in USA? Is this relationship causal? METHODS:Geospatiotemporal cohort study, 1991-2016. Census populations of adults, babies, congenital anomalies, income and ethnicity. Drug exposure data on cigarettes, alcohol abuse, past month cannabis use, analgesia abuse and cocaine taken from National Survey of Drug Use and Health (78.9% response rate). Cannabinoid concentrations from Drug Enforcement Agency. Inverse probability weighted (ipw) regressions. Analysis conducted in R. RESULTS:ASDI rose nationally three-fold from 27.4 to 82.8 / 10,000 births 1991-2014 during a period when tobacco and alcohol abuse were falling but cannabis was rising. States including Nevada, Kentucky, Mississippi and Tennessee had steeply rising epidemics (Time: Status ?-estimate?=?10.72 (95%C.I. 8.39-13.05), P?<?2.0?×?10 -?16). ASDI was positively related to exposure to cannabis and most cannabinoids. Drug exposure data was near-complete from 2006 thus restricting spatial modelling from 2006 to 2014, N?=?282. In geospatial regression models cannabis: alcohol abuse term was significant (?-estimate?=?19.44 (9.11, 29.77), P?=?2.2?×?10 -?4); no ethnic or income factors survived model reduction. Cannabis legalization was associated with a higher ASDI (Time: Status ?-estimate?=?0.03 (0.01, 0.05), P?=?1.1?×?10 -3). Weighted panel regression interactive terms including cannabis significant (from ?-estimate?=?1418, (1080.6, 1755.4), P?=?7.3?×?10 -15). Robust generalized linear models utilizing inverse probability weighting interactive terms including cannabis appear (from ?-estimate?=?78.88, (64.38, 93.38), P?=?1.1?×?10 -8). Marginal structural models with machine-aided SuperLearning association of ASDI with high v. low cannabis exposure R.R.?=?1.32 (1.28, 1.36). Model e-values mostly >?1.5. CONCLUSIONS:ASDI is associated with cannabis use, frequency, intensity and legalization in a spatiotemporally significant manner, robust to socioeconomicodemographic adjustment and fulfilled causal criteria, consistent with multiple biological mechanisms and similar reports from Hawaii, Colorado, Canada and Australia. Not only are these results of concern in themselves, but they further imply that our list of the congenital teratology of cannabis is as yet incomplete, and highlight in particular cardiovascular toxicology of prenatal cannabinoid and drug exposure.
| S-EPMC7702707 | biostudies-literature
Project description:Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. However the effects of cannabinoid genotoxicity have not been assessed on whole populations and formal consideration of effects as a broadly acting genotoxin remain unexplored. Our study addressed these knowledge gaps in USA datasets. Cancer data from CDC, drug exposure data from National Survey of Drug Use and Health 2003-2017 and congenital anomaly data from National Birth Defects Prevention Network were used. We show that cannabis, THC cannabigerol and cannabichromene exposure fulfill causal criteria towards first Principal Components of both: (A) Down syndrome, Trisomies 18 and 13, Turner syndrome, Deletion 22q11.2, and (B) thyroid, liver, breast and pancreatic cancers and acute myeloid leukaemia, have mostly medium to large effect sizes, are robust to adjustment for ethnicity, other drugs and income in inverse probability-weighted models, show prominent non-linear effects, have 55/56 e-Values > 1.25, and are exacerbated by cannabis liberalization (P = 9.67 × 10-43, 2.66 × 10-15). The results confirm experimental studies showing that cannabinoids are an important cause of community-wide genotoxicity impacting both birth defect and cancer epidemiology at the chromosomal hundred-megabase level.
| S-EPMC8260794 | biostudies-literature
Project description:ObjectiveTo report and compare the proportion of children with and without congenital anomalies undergoing gastrostomy for tube feeding in their first 5 years.MethodsA European, population-based data-linkage cohort study (EUROlinkCAT). Children up to 5 years of age registered in nine EUROCAT registries (national and regional) in six countries and children without congenital anomalies (reference children) living in the same geographical areas were included. Data on hospitalisation and surgical procedures for all children were obtained by electronic linkage to hospital databases.ResultsThe study included 91 504 EUROCAT children and 1 960 272 reference children. Overall, 1200 (1.3%, 95% CI 1.2% to 1.6%) EUROCAT children and 374 (0.016%, 95% CI 0.009% to 0.026%) reference children had a surgical code for gastrostomy within the first 5 years of life. There were geographical variations across Europe with higher rates in Northern Europe compared with Southern Europe. Around one in four children with Cornelia de Lange syndrome and Wolf-Hirschhorn syndrome had a gastrostomy. Among children with structural anomalies, those with oesophageal atresia had the highest proportion of gastrostomy (15.9%).ConclusionsThis study including almost 2 million reference children in Europe found that only 0.016% of these children had a surgery code for gastrostomy before age 5 years. The children with congenital anomalies were on average 80 times more likely to need a gastrostomy before age 5 years than children without congenital anomalies. More than two-thirds of gastrostomy procedures performed within the first 5 years of life were in children with congenital anomalies.
| S-EPMC9234789 | biostudies-literature
Project description:ObjectivesCannabis is a known teratogen. Data availability addressing both major congenital anomalies and cannabis use allowed us to explore their geospatial relationships.MethodsData for the years 1998 to 2009 from Canada Health and Statistics Canada was analyzed in R. Maps have been drawn and odds ratios, principal component analysis, correlation matrices, least squares regression and geospatial regression analyses have been conducted using the R packages base, dplyr, epiR, psych, ggplot2, colorplaner and the spml and spreml functions from package splm.ResultsMapping showed cannabis use was more common in the northern Territories of Canada in the Second National Survey of Cannabis Use 2018. Total congenital anomalies, all cardiovascular defects, orofacial clefts, Downs syndrome and gastroschisis were all found to be more common in these same regions and rose as a function of cannabis exposure. When Canada was dichotomized into high and low cannabis use zones by Provinces v Territories the Territories had a higher rate of total congenital anomalies 450.026 v 390.413 (O.R. = 1.16 95%C.I. 1.08-1.25, P = 0.000058; attributable fraction in exposed 13.25%, 95%C.I. 7.04-19.04%). In geospatial analysis in a spreml spatial error model cannabis was significant both alone as a main effect (P < 2.0 × 10) and in all its first and second order interactions with both tobacco and opioids from P < 2.0 × 10.ConclusionThese results show that the northern Territories of Canada share a higher rate of cannabis use together with elevated rates of total congenital anomalies, all cardiovascular defects, Down's syndrome and gastroschisis. This is the second report of a significant association between cannabis use and both total defects and all cardiovascular anomalies and the fourth published report of a link with Downs syndrome and thereby direct major genotoxicity. The correlative relationships described in this paper are confounded by many features of social disadvantage in Canada's northern territories. However, in the context of a similar broad spectrum of defects described both in animals and in epidemiological reports from Hawaii, Colorado, USA and Australia they are cause for particular concern and indicate further research.
| S-EPMC7547880 | biostudies-literature