Both “Epidiolex” (cannabidiol) registered in the USA by the Food and Drug Administration (FDA) and Sativex (Δ9-tetrahydrocannabinol (THC) - cannabidiol) registered by the Medicines and Healthcare Products Regulatory Authority (MHRA) of the United Kingdom carry strong warnings on their Product Information and Prescribers Information leaflets against their use in pregnancy and breast feeding which is the standard warning for genotoxic effects which routinely accompanies medicines including cytotoxic and cancer agents [1, 2]. Similar warnings occur on the labelling of “Hemp Oil” which is made freely accessible to the Australian public on supermarket shelves. Such overt warnings relating to acknowledged genotoxicity by the distributors and marketers of cannabinoids, and mandated warnings required by official drug regulators on both sides of the Atlantic directly imply that the genotoxicity of these agents is acknowledged in laboratory and preclinical studies and is in truth an established fact of science.

Paradoxically what might be termed the “standard” or “establishment” view of the risks posed by the use of cannabinoid products in pregnancy is relatively benign. Major authorities and several smaller convenience sample series claim that the use of cannabis in pregnancy is associated with increased prematurity, smaller head circumference, increased small for gestational age, low birth weight and relative infertility in male and female users [3–5]. This view which enjoys widespread currency in the medical profession, is clearly at odds with the official governmental view endorsed in the requirements on registered product information for the medical profession and consumers, but is nevertheless typical of the community-wide confusion relating to much of the information on cannabis and cannabinoids.

A broader and more concerning view on cannabinoid teratogenicity is expressed by other authorities including the Centres for Disease Control (CDC) Atlanta, Georgia, the American Heart Association (AHA) and the American Academy of Paediatrics (AAP) who have together warned of increased rates of six birth defects after prenatal cannabis exposure including ventricular septal defect, Epsteins anomaly, gastroschisis, diaphragmatic hernia, oesophageal atresia with or without tracheoesophageal fistula and anencephalus [6–8]. The American College of Obstetricians and Gynaecologists (ACOG) strongly warn against the use of cannabis products in pregnancy [9]. Longitudinal studies of neurological and psychomotor development in prenatally exposed children conducted in Pittsburgh, Toronto and Netherlands uniformly indicate worrying levels of autism-like and ADHD-like features with altered neurological development and impairments of emotional development, motor tone and fine motor skills and cortical executive and visuospatial processing [10].

The most useful experimental animal models in which to study the effects of prenatal drug exposure are New Zealand white rabbits and hamsters. Classical studies from 1969 performed in rodents and hamsters showed a variety of defects including limb reduction, exencephaly, spina bifida, omphalocele, multiple malformations and myelocoele [11, 12]. As was noted at the time “this is a formidable list” [12]. However clinical confirmation of such a concerning and wide-ranging spectrum of congenital anomalies was mostly lacking. In 2007 a novel report from Hawaii listed 21 birth defects as being elevated after prenatal cannabis exposure, particularly affecting the cardiovascular, gastrointestinal, urinary and chromosomal systems and including arm defects, syndactyly and polydactyly however this study remained very much an exception and outlier for many years [13].

In an historical case series of illicit poly-drugs users from Washington DC 148 pregnancies amongst 140 women produced 12 embryos or infants with major congenital abnormalities, 43% had spontaneous first trimester abortions and four of eight serial pregnancies produced infants or embryos with major abnormalities [14]. The major congenital anomaly rate was a calculated by the authors at 96/1000 live births or 16 times the then control rate in USA in 1972 [14]. The usually quoted rate for spontaneous abortions at that time in USA was up to 20%. Of the eight infants whose major congenital anomaly was listed six had neural tube closure defects (meningomyelocele, myelocele, spina bifida or hydrocephalus), one had a cardiovascular defect (Tetralogy of Fallot), one had neuroblastoma and one had limb abnormalities (absent feet, absent finger and absent phalanges from fingers). All patients smoked cannabis [14, 15].

A report on atrial septal defect secundum type from the CDC database showing much higher rates and a steep acceleration of the rate of increase of atrial septal defect in high cannabis use states in the USA in recent years appeared which carried two major corollaries [16]. Firstly it implied that the list of cardiovascular anomalies jointly proposed by the AAP and AHA was incomplete. Secondly it implied that our knowledge of the subject of clinical cannabinoid teratogenesis including the list of cannabis-related congenital anomalies was similarly incomplete.

The concerning Hawaiian study has since been supported by studies from other locations. Confirmation of the experimentally identified spina bifida and encephalocele findings recently came from an analysis of Canadian data [17]. Indeed total congenital anomalies, particularly including cardiovascular defects and chromosomal anomalies were recently noted to be three times higher in the northern Territories of Canada which traditionally smoke two to three times as much cannabis as Canadians living in the south [18]. An Australian report showed that 18 congenital defects were higher in high cannabis using parts of Northern New South Wales [19]. Colorado was noted to have a 29% jump in the expected rate of total birth defects across the period of cannabis legalization 2000–2013 and included particularly cardiovascular, central nervous system, genitourinary, musculoskeletal and chromosomal CAs [20].

Cannabinoids including cannabidiol have been implicated in direct damage by oxidation to DNA bases which is a major genotoxic and mutagenic lesion [21]. They have long been known to be toxic to chromosomes which are the natural way in which DNA is packaged inside the cell nucleus [22]. It was shown long ago that cannabinoids reduce the synthesis of the major molecules of biology DNA, RNA proteins and histones [23–34]. Such gross level changes necessarily impact the genomic code. Translated into a twenty-first century understanding this would imply major interference in the epigenetic code where genome accessibility, controlled by histone modifications, the formation of euchromatin and the assembly of topologically organized transcriptionally active domains (the chromosomal “A compartment”) within the nucleus constitutes a major portion of normal gene regulation, cell function and indeed epigenetic cell specification and lineage determination [35]. And it has been well established that cannabinoids carry a heavy epigenetic footprint which is inheritable for several subsequent generations [35–41].

As was recently observed chromosomal toxicity, genotoxic and epigenotoxic lesions can reasonably be expected to manifest in congenital anomaly profiles and patterns of cancerogenesis [42]. What is clearly lacking in the literature is a genotoxic survey of a national teratological database to study the issue of patterns of teratogenesis as they relate to substance exposure. The application of the formal techniques of geospatial analysis and causal inferential analysis to the whole database tracked by CDC of 62 birth defects is a massive task which can only be commenced in this forum. It is therefore our purpose in the present paper to present an overview and introduction to this topic with a few teratological case examples to illustrate the way in which such studies can be extended and the power of these analytical techniques. Formal treatment of the whole field must be left for another occasion. Since the required teratological and substance exposure and related data is available for USA that nation has been chosen for the present investigation.

As has been pointedly observed it is vitally important in any review of teratological epidemiology to consider the impact of early termination of pregnancy for anomalies (ETOPFA) [43, 44]. Our study provides estimates of these ETOPFA practices which are used to complete applicable datasets for affected congenital anomalies (CAs).

Given the rapid increase in the penetration of cannabis and cannabinoids into modern American society, all studies related to cannabinoid teratogenesis and cannabinoid genotoxicity must be regarded as urgent and of high priority in the national research agenda.

A related concern is the potential for cannabinoids to enter the food chain. Cases of babies born without limbs have been noted in France and Germany where cannabis has become widely available [45–50] however this has not been seen in nearby Switzerland where its entry into the food chain is not permitted. Rapid introduction of cannabis into Colorado recently was associated with a 29% jump in total congenital anomalies [20] and Kentucky saw a massive and sharp spike in the incidence of atrial septal defect in recent years as cannabis has increasingly replaced tobacco as a major cash crop [16].

Not since Distillers unleashed thalidomide on the global market in 1957 has an agent which is known to be genotoxic been aggressively marketed for commercial reasons [51]. Of note the thalidomide debacle was avoided in the USA primarily because of genotoxic concerns [52, 53]. This international tragedy of recent history is also the foundational reason for the development of the modern drug regulatory scheme in many nations [53].

Aside from the fact of cannabis mutagenicity and genotoxicity itself one of the aspects of this subject which we find of most concern is the clear replication in many predictive geotemporospatial models of a sigmoidal relationship between cannabidiol and cannabinoid exposure and teratogenic outcomes for many congenital anomalies which is clearly highly reminiscent of the exponential dose-response relationships observed in numerous in vitro studies of cannabinoid genotoxicity and mitochondriopathy-epigenotoxicity [24, 26, 31, 54–65]. It is the non-linear power function of dose-response between increased cannabinoid exposure and teratological outcomes which must be of particular concern to any community moving into a higher cannabinoid exposure zone. Equally of concern an exponential relationship was observed in both actual and predicted modelled trend studies of the relationship between cannabinoid exposure and US autism incidence [66]. Taken together such findings imply exponentiation both of major neurotoxic and major genotoxic developmental outcomes.

It is self-evident that with the endocannabinoids playing critical roles in many body systems drugs modulating the endocannabinoid system will increasingly enter the international therapeutic marketplace in the coming years. We also feel that in order to assist cannabinoid therapeutics to find their appropriate niche in the global market that a proper understanding and appreciation of their long term neurotoxic and genotoxic activities is an absolute requirement both for regulators and for the public at large so that intergenerational community safety continues to be prioritized as a central and principal concern.

The overall purpose of the present analysis was to investigate substance and particularly cannabinoid exposure as a putative environmental risk factor for the observed spectrum of congenital anomalies. This was done directly using ecological USA data in bivariate analysis of continuous covariates. Key epidemiological parameters of public health interest such as the prevalence ratio, the aetiological fraction in the exposed and the population attributable risk were calculated from an analysis of categorized data. Detailed multivariable regression was undertaken using inverse probability weighted mixed effects, robust and panel regression for two selected CAs and spatiotemporal regression was also conducted for these CAs. Extensive use of the formal techniques of causal inference namely E-Values and inverse probability weighting was engaged to correct for the ecological fallacy and convert data into a pseudo-randomized quasi-experimental design. Finally predictive mathematical modelling was conducted to study overall trends of selected CAs as a function of cannabinoid exposure.

The minimum E-Value indicates the minimum strength of association required of some extraneous confounder covariate with both the outcome of interest and the exposure of concern to explain an observed assocation [67–69]. It plays a central role in formal epidemiological assignment of causal relationships.

An overview and survey of a geospatial consideration of the field of genotoxicity manifested as cancerogenesis is the subject of a series of companion papers.