Animal studies
ECS involvement
Mounting evidence suggests the ‘Western’ diet contains excess omega-6 PUFAs, which can lead to adverse pregnancy outcomes. One study found that omega-6-derived endocannabinoids during pregnancy desensitize CB1, disrupting CB1 signaling during neuronal differentiation leading to epigenetic reprogramming and increased anxiety and depression-like behavior in offspring (Cinquina et al., 2019).
Dairy cows fed with omega-3-rich linseed were found to have 7.7-fold increased NAAA, 2-fold increased MAGL, 4.3-fold decreased CB2, 20-fold decreased NAPE-PLD and unaltered FAAH. This resulted in 3-fold increased conception rate and a 100% improvement in pregnancy loss prevention (Dirandeh and Ghaffari, 2018) suggesting that decreased endocannabinoid levels may positively influence conception and pregnancy.
In order to test the effects of cannabis use during pregnancy, rats were injected with AEA (3 mg/kg, i.p. from gestational day 7). This significantly reduced the number of live births and offspring weight (Amlani et al., 2017), but did not alter endothelin B receptor, NGF, VEGF or CB1 expression in offspring. While this suggests a negative effect of cannabis use on pregnancy outcome, please note that the dose was very high for human standards and that THC would have been a better test substance for this study.
In rats, prenatal exposure to the cannabinoid receptor agonist WIN55,212‐2 (WIN; 0.5 mg·kg−1 from gestational day 5 to 20) male infant pups emitted less isolation‐induced ultrasonic vocalizations compared with male control pups, when separated from the dam and siblings and showed increased locomotor activity while females were spared. These effects were normalized when male pups were treated with the positive allosteric modulator of mGlu5 receptor CDPPB. When tested at the prepubertal and pubertal periods, WIN‐prenatally exposed rats of both sexes did not show any difference in social play behaviour, anxiety and temporal order memory (Manduca et al., 2019). While the used drug and dose would correspond to very high levels of THC in humans these results suggest some sex-differences in the vulnerability of offspring social behaviour after prenatal cannabinoid exposure.
In pregnant mice, B-lymphocytes show upregulated CB1 and downregulated CB2 compared to non-pregnant mice. Stimulation of CB1 boosted anti-inflammatory IL-10 production by B-lymphocytes (Wolfson et al., 2016).
Mice genetically deficient for CB1 and CB2 are sub-fertile due to defective blastocyst implantation. Histological analysis suggests that particularly absence of CB2 in uterine blood vessel endothelium leads to blood leakage and disrupted blastocyst implantation (Li et al., 2019).
In rats, a maternal high-fat diet leads to offspring obesity. In male offspring, high-fat diet reduced CB1 and CB2 in subcutaneous adipose tissue. In female offspring, high-fat diet increased visceral CB1 and decreased subcutaneous CB1. High-fat diet increased CB1 in brown adipose tissue in both sexes (Almeida et al., 2017). The results suggest that the ECS is important in fetal development and the prevention of metabolic disease.
Rats with fetal exposure to WIN55,212-2 (0.5 mg/kg/d from gestational day 5-16) were less effective in eliminating intestinal parasites as adults; moreover, this effect was correlated with a deficiency in mucus production, lower recruitment of eosinophils in the duodenum, and a reduced percentage of Tγδ and NK cells (Hernández-Cervantes et al., 2019), suggesting prenatal cannabinoid exposure can have lasting effects on the immune system. It should be noted that the used drug and dose would correspond to very high doses of THC in humans.
In cultured murine fetal gonads, stimulation of CB2 (by 1 M JHW133 for 48 hours) activated the meiotic program in both male and female fetal gonads. While this did not affect spermatogenenis in male offspring, in female offspring the speeding-up of meiosis resulted in increased DNA damage and oocyte apoptosis leading to reduced ovarian reserve and female fertility/reproduction (De Domenico et al., 2017). While the results indicate a risk for cannabis consumption during pregnancy regarding female offspring fertility, it should be noted that the conditions, drugs and doses are quite far removed from the human situation.
In mice, CB1 and, to a lower extent, CB2 receptor activation results in selective inhibition of myometrial contractility, without un-specific relaxing effects on the smooth muscle, suggesting cannabis may have potential as a tocolytic agent (Pagano et al., 2016).

Plant cannabinoids
The adolescent offspring of pregnant rats treated with THC (2 mg/kg s.c.) showed (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber (Brancato et al., 2020). This suggests that gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. Please note that the used dose of THC is very high for human standards.
In pregnant rats, daily injection of 3 mg/kg THC (i.p.) from gestational day 6 until birth, female but not male offspring was glucose intolerant (blunted insulin response) at 50 days after birth (Gillies et al., 2020). This was accompanied by reduced pancreatic beta cell mass in female offspring. Please note that the used doses of THC are very high for human standards.
In adult offspring from pregnant rats treated daily with THC (5 mg/kg, p.o.) from gestational day (GD)5 through GD20, extracellular kynurenic acid levels were increased which may be functionally related with decreased short-term memory (Beggiato et al., 2020). While this suggests a mechanistic link between prenatal THC exposure and cognitive defects it must be noted that the doses used here are very high for human standards.
In adult offspring from pregnant rats treated daily with THC (5 mg/kg, s.c.) or WIN55,212-2 (0.5 mg/kg) from gestational day (GD)5 through GD20, males but not females showed reduced social interaction, ablated endocannabinoid long-term depression and increased prefrontal cortex excitability (Bara et al., 2018). It should be noted that the used dose was very high for human standards.

Human studies
ECS involvement
In human placental explants, AEA down-regulated BCRP/ABCG2 transporter activity, negatively influencing toxicant efflux and fetal protection. This effect is mediated by CB2 (Szilagyi et al., 2019).
In the BeWo human placental trophoblast cell line AEA and 2AG (10 M, 24 h) induced apoptosis via CHOP/ER stress induction suggesting these endocannabinoids are involved in trophoblast proliferation, differentiation and apoptosis and in placental development (Pereira et al., 2017).
In a similar study with BeWo cells and human primary cytotrophoblasts 2AG induced trophoblast apoptosis in a CB2-dependent way via the eIF2α/CHOP pathway (Almada et al., 2020).
A telomerase-immortalized human endometrial stromal cell line (St-T1b) expresses CB1, but not CB2. Primary cultures of human decidual fibroblasts express both CB1 and CB2. The expression of fatty acid amide hydrolase (FAAH), the main degrading enzyme of AEA, increased during stromal cell differentiation. AEA inhibited cell proliferation, through deregulation of cell cycle progression and induced polyploidy. Moreover, through CB1 binding receptor, AEA also impaired cell differentiation. Therefore, AEA is proposed as a modulator of human decidualization (Almada et al., 2016).
In a human-derived endometrial cell line (St-T1b), AEA has an anti-proliferative activity through a direct effect on cell cycle progression by inducing G2/M arrest. Moreover, high levels of AEA increased COX-2 activity, triggering apoptotic cell death, with loss of mitochondrial membrane potential, induction of caspase -9 and -3/-7 activities, and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, the involvement of intracellular reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress was verified. These effects were prevented by pre-incubation with a selective COX-2 inhibitor (Almada et al., 2017).
In an immortalized human endometrial stromal cell line (St-T1b) and human decidual fibroblasts (HdF) derived from human term placenta exposed to a differentiation stimulus, AEA-treatment prevents the increase of the expression of CYP19A1 gene encoding aromatase, E2 levels and of estradiol receptor expression, that are observed in differentiating cells. Regarding CYP19A1 mRNA levels, the effect was partially reverted by a CB1 receptor antagonist and by a COX2 inhibitor. In addition, AEA presents anti-aromatase activity in placental microsomes and may affect E2 signaling crucial for the decidualization process, indicating that a deregulation of the endocannabinoid system may be implicated in endometrial dysfunction and in fertility/infertility disorders (Almada et al., 2019a).
In endometrial samples from unexplained infertility patients, collected at midluteal phase, FAAH and leukemia inhibitory factor (LIF) levels were significantly decreased, whereas endometrial CB1 was slightly increased. LIF production was promoted by low amount of AEA administration (1-10 μM), while the promotion was reduced by higher concentration of AEA (50 μM). LIF levels were decreased by AM251 or AM630, compared with AEA alone. Expressions of FAAH and LIF were closely associated with uterus receptivity and implantation rate of unexplained infertility patients, suggesting a role for the ECS in fertilization (Cui et al., 2017).
In human cultured stromal cells, it was found that NADA in the concentration range of 1-20 μM produces more selective cytotoxic effect on the stromal cells of the ectopic endometrium due to interaction with CB1. In concentrations below 1 μM, NADA stimulated the proliferation of stromal cells of the eutopic endometrium in a CB2-dependent manner and did not affect the division of ectopic endometrium cells (Ashba et al., 2019).
In human, non-labor, cesarean section placentas, application of AEA increased oxytocin release and receptor expression (Accialini et al., 2020), suggesting a role for AEA in parturition. 
In a primary culture of undifferentiated stromal cells isolated from pregnant rat uterus, AEA treatment markedly interfered with the differentiation program, as revealed by α2-macroglobulin (α2-MG) expression and alkaline phosphatase activity. Additionally, it was evaluated the effects of AEA in decidual establishment in the pseudopregnant rat model. The abundance of AEA in the uterine lumen disrupted the decidualization process accompanied by a decreased expression of COX-2 and VEGF. It was also observed that uterine lumen, which failed the progression of decidualization in response to AEA, also presented lower expression of NAPE-PLD and FAAH. Thus, the mechanisms by which AEA inhibits decidualization can be either via direct actions on stromal cell differentiation within the reproductive tract system or by the inhibition of COX-2 derived products and, consequently, the vascular remodeling required to proper decidualization. In addition, the previous observations showing that higher AEA levels in pre-implantation sites are hostile to blastocyst survival may result from problems in decidual cell reaction more than with implantation failure (Fonseca et al., 2015).
In cultured human uterine NK cells from first trimester decidua, AEA and TNF levels were increased in miscarriage decidua (compared with abortive decidua) leading to interference with endometrial stromal cell decidualization (Fonseca et al., 2020). This suggests a role for AEA in decidualization. 
In human placenta samples it was found that normal term delivery placentas has increased CB1, AEA and inflammatory cytokines (IL-6 and TNF-α) and reduced TRPV1 compared to preterm delivery placentas, suggesting that CB1 stimulation and TRPV1 inhibition may help prevent preterm births (Torella et al., 2019).
During pregnancy, apoptosis plays a physiological role in remodeling of the placenta. This apoptosis, induced by hypoxia inducible factor-1 alpha (HIF-1α) is CB1-dependent (Abán et al., 2016), suggesting a physiological role for CB1 in placental development.
Human miscarriage is often caused by Gram-negative bacterial infection and heparin is often used to prevent miscarriage. In murine uterine explants, LPS induces uterine apoptosis and (leading to embryonic resorption) and heparin prevents apoptosis by increasing FAAH activity (Salazar et al., 2016) providing a mechanistic explanation for the protective effect of heparin.
Plasma AEA and PEA concentrations were significantly higher in women who delivered prematurely. An AEA concentration >1.095 nM predicted preterm birth, the gestational age at delivery and the recruitment to delivery interval. A PEA concentration >17.50 nM only predicted PTB; FAAH enzyme activity was not related to these changes (Bachkangi et al., 2019). The results suggest AEA and PEA levels can predict the risk of preterm birth as well the date of birth.

Plant cannabinoids
The offspring of mothers who continued to use cannabis in the first ten weeks of pregnancy or longer displayed decreased repeated sound evoked potential inhibition and poorer behavioral self-regulation (Hoffman et al., 2019). This effect is a suspected result of cannabinoid binding to CB1 and is ameliorated by higher gestational choline levels.
Cannabis use during pregnancy is suspected to induce adverse behavior in offspring via altered dopaminergic signaling. However, infant dopamine receptor D4 methylation was not significantly altered by maternal cannabis use (Fransquet et al., 2017). While this does not disprove a link between maternal cannabis use and offspring behavior, DRD4 does not seem to be mechanistically involved.
Placentas from 3 women who smoked cannabis at least once a month during pregnancy showed increased syncytiotrophoblastic knots and fibrin exudation in the villous stroma. In the HTR-8/ SVneo and BeWo trophoblast cell lines, 3 M THC did not affect cell migration but 15 M THC impaired migration. Also, 30 M THC induced cell death but up to 15 M THC had no effect on proliferation. These effects were partially reversed by CB1 and CB2 inhibitors and were mediated by STAT3 (Chang et al., 2017). These results suggest that THC negatively affects placental physiology during pregnancy but please note that the number of women tested was only three and the in vitro experiments used very high THC concentrations compared to human standards.
In the BeWo human placental trophoblast cell line synthetic cannabinoids JHW-018, JHW-122 and UR-144 (0.01 -10 M) and THC (only at 15 M, not below) all caused a significant decrease in cell viability via apoptotic cell death. For THC and JHW-018 this effect was mediated via CB1 and CB2. The effect of JHW-122 was CB receptor independent. The effect of UR-144 was CB1 dependent (Almada et al., 2019b). The results suggest cannabinoids like THC can potentially disrupt gestation.
In the BeWo human placental trophoblast cell line THC 3-30 μM) led to a dose-dependent increase in all ER stress markers and CHOP; these effects could be blocked with CB1R/CB2R antagonists. THC also diminished mitochondrial respiration and ATP-coupling due to decreased abundance of mitochondrial chain complex proteins. Collectively, these findings indicate that THC can directly augment ER stress resulting in aberrant placental gene expression and impaired mitochondrial function (Lojpur et al., 2019).
In human full-term villous placenta explants the effect of 1, 10, 20 and 40 M THC was measured after 24 and 72 hours of application. AEA was increased after 72 but not 24 hours and only reached significance with 40 M while CB1 and CB2 expression was unaltered by any treatment. The results suggest that chronic cannabis use may increase AEA levels and consequently affect placental development and fetal growth (Maia et al., 2019) although it is questionable whether the concentrations used here can be achieved with normal human consumption.
In immortalized human endometrial stromal cells the effect of increasing concentrations of THC, CBD and CBN on decidualization was tested. During decidualization CB1 and CB2 mRNA are upregulated 17-fold and 6-fold respectively. THC, CBD and CBN were not cytotoxic in undecidualized cell up to 2 μM (7 days of continuous exposure). For reference, cannabis users have THC plasma concentrations ranging from 0.09 to 0.73 μM. In decidualizing cells, CBN was cytotoxic at 2 μM and THC and CBD were cytotoxic at 20 μM in a CB1-dependent manner. While the results suggest an inhibitory and cytotoxic effect of plant cannabinoids on decidualization it should be noted that the concentrations used here are high for human standards (Neradugomma et al., 2019).
In human placental amnion tissue, CB1 and CB2 were primarily expressed in the epithelial layer. Cell proliferation was significantly inhibited in both primary and clonal amniotic epithelial cells by 30 M THC but not 10 or 20 M although these concentrations did suppress epithelial cells migration (Neradugomma et al., 2019). These results suggest THC may negatively affect pregnancy outcome it should be noted that these concentrations of THC are not likely to be achieved with normal human consumption.
Cannabis consumption during pregnancy significantly increases CB1 and CB2 expression in human endometrium (from first and early second trimester pregnancies) but only has minor effects on placental CB expression (Neradugomma et al., 2018).
In one study, women who smoked cannabis at least once a month without alcohol or   tobacco during pregnancy had an impaired placental blood vessel development. In human umbilical vein endothelial cell explants, exposure to 5 or 10 M THC inhibited cell proliferation, migration and angiogenesis (Chang et al., 2018), suggesting a negative impact of cannabis use on placental development.
Perinatal asphyxia is a common complication during childbirth and risk factor for Hypoxic-ischemic encephalopathy after birth and cerebral palsy on the longer term. CBD has been suggested to be protective during/after perinatal asphyxia (Al et al., 2019).

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