Whilst it is often said that prenatal cannabis exposure has relatively benign implications in postnatal life [1–3], recent independent reports from Hawaii [4], Colorado [5], Canada [6, 7], Australia [8] and USA [9–11] indicate that dozens of congenital anomalies (CAs; birth defects) are likely epidemiologically causally associated with rising rates of community cannabis consumption. Systems that are particularly affected include the cardiovascular, gastrointestinal, chromosomal, genitourinary, limb and body wall systems. Concerns regarding prenatal exposure were provided with heightened salience by reports from many places indicating increased use of cannabis and cannabinoid products by pregnant women in recent times [12], by rates of cannabis use in pregnancy amongst teenagers as high as 25% [13], by increased use of cannabis in pregnancy since the COVID-19 pandemic [12] and by reports that 69% of cannabis dispensaries positively recommend cannabis use to women whilst pregnant [14]. Moreover, recent reports note a quadruple convergence of rising rates of cannabis use, Δ9-tetrahydrocannabinol (THC) potency, intensity of daily use and cannabis use disorder in Europe, suggesting that the modern era is actually experiencing a confluence of concerning teratogenic trends [15, 16].

The implications of cannabinoid genotoxicity are further highlighted with the recent data suggesting that multiple cancers (of breast, pancreas, thyroid, liver and acute lymphoid and myeloid leukaemias) are also epidemiologically causally related to cannabis use [17, 18] and, with the formal experimental demonstration in mice, that epigenomic programming actually controls the organism-wide ageing epigenomic cassettes [19]. The recent demonstration that cannabis is a major driver of the rise in USA paediatric cancer rates underscores the transgenerational nature of this mutagenesis [17, 20]. These data together indicate that cannabinoid-related epigenomic disturbances likely have broad public health implications for diverse communities extending to cancerogenesis on the one hand and pan-systemic ageing on the other and including transgenerational effects.

Key to any consideration of the possible causal relationships of cannabis with mutagenesis and teratogenesis is the elucidation of the biological pathways, which may underlie any apparently causal relationship. Multiple cannabinoids have long been known to be toxic to chromosomes, genes, DNA strands, DNA nucleosides, the epigenome, sperm, oocytes, mitosis and meiosis and the male and female reproductive tracts in multiple respects [21–38]. Several studies have also shown cannabis to have a major effect perturbing DNA methylation [31–37], with these changes shown to be inheritable to subsequent generations [31–37], to perturb DNA methylation in the nucleus accumbens of offspring and affect behaviour [33, 34], to be seen in human sperm [31, 32] and to improve in both rats and humans after cessation of cannabis exposure [32]. Cannabis has an adverse effect on protein synthesis including histone formation, a change which necessarily opens up chromatin for aberrant gene expression [40, 41]. Thus cannabinoids derange the ‘histone code’. They also adversely affect tubulin synthesis and the post-translational modifications (particularly glycosylation) of tubulin, which have been collectively referred to as the ‘tubulin code’ [42], which adversely affects both the microtubules of the mitotic spindle and the anaphase separation of chromosomes, and also the motility of sperm flagella and their ability to maintain linear forward progression in fertilization assays [42]. Numerous cannabinoids have adverse effects on mitochondrial metabolism in neurons, sperm, lymphocytes and pulmonocytes [22, 23, 43–51], which necessarily impairs the supply of methyl, acetyl, ubiquinyl, propyl, adenosine-ribose and many other groups for the epigenomic machinery, impairs ATP energy supply for the numerous energy-dependent genomic and epigenomic reactions required for normal genome maintenance and also deranges the delicate mitonuclear balance [52, 53].

Ready acces to various European metrics of cannabis exposure indicating the quadruple convergence of rising cannabinoid exposure [15, 16] along with access to comprehensive congenital anomaly rates from multiple national European registries together with newer statistical techniques allowing the examination of multiple models in a single analytical run for all anomalies considered together in a space-time context have provided an ideal opportunity to investigate these relationships in the contemporary European context. The hypothesis to be tested in this investigation was that the well-described genotoxicity and epigenotoxicity of cannabinoids seen in vitro may be manifested clinically in vivo at the level of child population health with various of the described metrics for cannabis use. Furthermore, we sought to employ statistical techniques of formal causal inference to allow epidemiologically causal relationships to be investigated beyond merely those of simple association. It was also relevant to compare links described in other jurisdictions with the European findings and to compare the relative effects of the known teratogens tobacco and alcohol.

In terms of anomaly classes of special interest, we were particularly interested to study those that had been previously identified in the literature as being cannabis related, such as chromosomal and genetic, cardiovascular, central nervous, gastrointestinal, urogenital and nephrological and limb anomalies [4–9, 15–18, 20, 54, 55]. Interestingly, the presence in the European data of a rare multisystem anomaly known as vertebral, anorectal, cardiac, tracheo-esophageal fistula ± oesophageal atresia, renal anomalies and limb abnormalities (VATER/VACTERL), which was described from Great Ormond St Hospital as a group of co-occurring anomalies [56] whose aetiology was recently ascribed to inhibition of sonic hedgehog signalling in utero, which is a known target of many cannabinoids [57], was of particular interest. All hypotheses were formulated prior to study commencement.