[DRAFT] The Endocannabinoid System – Ch 4: Pregnancy & The ECS

Introduction

The prevalence and perceived safety of cannabis use in pregnancy are increasing with expanding legalization. The proportion of women using cannabis during pregnancy increased from 2.37% in 2002 to 3.85% in 2014 based on self-reported data from the National Surveys of Drug Use and Health. However, self-reports likely underestimated the prevalence of use. In a Kaiser population with universal self-report and urine toxicology screening, the rate of use was 7.1% in 2016, and over half of the women using cannabis were identified only by toxicology testing. There is also an increasing perception of safety. Utilizing data from the National Surveys of Drug Use and Health from 2005– 12 the proportion of pregnant women without use in the past 30 days who reported: “no risk” of harm increased from 3.5% to 16.5% over the study time period. The proportion of pregnant women with recent use who reported “no risk” of harm was even higher increasing from 25.8% to 65.4%. Many women are using it at conception, and many continue to use it as a natural remedy for morning sickness, depression, stress, and anxiety. The scientific literature regarding cannabis in pregnancy is mixed resulting in confusion among practitioners as to how to counsel women about the risks of use. The confusion surrounding the effect of cannabis on perinatal outcomes does not stem from a lack of available literature. Instead, the lack of clarity regarding anticipated outcomes is a result of the heterogeneity of findings for the association between cannabis use and adverse pregnancy outcomes. Moreover, many studies fail to adjust for important confounding factors such as tobacco use and sociodemographic differences. Despite the limitations of the existing evidence, there are animal and human data suggesting the potential harms of cannabis use. The harms are biologically plausible given the role of the endocannabinoid system in pregnancy implantation, placentation, and fetal neurological development.

The endocannabinoid system plays an important role in implantation and pregnancy maintenance. The pregnancy implantation site expresses low levels of anandamide while adjacent sites express higher levels of anandamide to assure highly synchronized communication between the embryo and the endometrium. Maintaining a balance of anandamide synthesis and degradation is required for successful embryonic passage through the oviduct and implantation. Upon implantation, activated blastocysts have higher expression of CB1 receptors than dormant blastocysts and anandamide levels remain tightly regulated without variation in the first and second trimesters of pregnancy. During fetal life, the CB1 receptor plays a major role in brain development by regulating neural progenitor differentiation into neurons and glia and guiding axonal migration and synaptogenesis. By 19 weeks’ gestation, the fetus has a complete array of cannabinoid receptors. However, the number of CB1 receptors is substantially higher in fetal brains compared to adult brains. The increased concentration of CB1 receptors in the fetus has been attributed to key developmental events including cell proliferation and migration, and axonal elongation with eventual synaptogenesis and myelogenesis. Cannabis consumption during pregnancy has been associated with gestational disorders such as preterm birth, intrauterine growth restriction, low birth weight, and increased risk of miscarriage, though the underlying biochemical mechanisms are still unknown. In addition, the neurodevelopmental data in humans and animals suggest a link between prenatal cannabis consumption and changes in some aspects of psychological well-being and higher-level cognition in school years. Cannabis is able to cross the placenta and passes into breast milk, resulting in fetal and neonatal exposure. This is a cause of concern, since cannabis consumption during pregnancy may negatively impact the fetus’s birth status and development either by the direct actions of THC or by a possible disruption of the endocannabinoid system homeostasis.

Literature

A review published by the University of Colorado and the Denver Health and Hospital Authority in the USA went over the effects of cannabis consumption during pregnancy and while breastfeeding. They found an association between cannabis use and adverse perinatal outcomes, especially with heavy cannabis use. In addition, studies reviewed demonstrated a possible effect of prenatal cannabis exposure on long-term neurobehavioral outcomes. Cannabis use may be associated with growth restriction, stillbirth, spontaneous preterm birth, and neonatal intensive care unit admission. Moreover, the researchers found insufficient evidence to support or refute associations between cannabis and later outcomes in the offspring such as cognition and academic achievement. These associations seen so far are biologically plausible given the importance of the endocannabinoid system in pregnancy implantation and placental formation. For example, repeated delta-9-THC exposure disrupts endocannabinoid signaling, particularly with the CB1 cannabinoid receptor, resulting in a “rewiring” of the fetal cortical circuitry. Therefore, women should be advised to refrain from using cannabis during pregnancy and lactation.

Furthermore, a study by the University of Porto, the University of Aveiro, and the maternal-infant center of the Porto Hospital in Portugal examined the effects exerted by THC on the ECS homeostasis, with regard to understanding the impact of THC on placental development and reproductive health. They demonstrated on human term placentae (38–40 weeks of gestation; n=12) from Caucasian women who were non-users of cannabis with live singleton births that THC (10–40 µM) impairs the placental endocannabinoid system by disrupting the endocannabinoid anandamide (AEA) levels and the expression of AEA synthetic and degrading enzymes N-arachidonoylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), respectively. Although, no alterations in cannabinoid receptors CB1 and CB2 expression were observed. Thus, long-term local AEA levels are associated with a shift in the enzymatic profile to re-establish ECS homeostasis. In chronic cannabis users, high AEA levels in the placenta may disturb the delicate balance of trophoblast cell turnover leading to alterations in normal placental development and fetal growth. At the cellular and molecular level, several studies with THC in the µM range (up to 30 µM), which represents heavy cannabis consumption, have shown that THC directly interferes with CTs (cytotrophoblasts, inner layer of the trophoblast) proliferation and gene transcription, migration, and invasion, as well as angiogenesis in placentas of cannabis consumers. In addition, our group reported that THC impairs CTs differentiation into syncytiotrophoblasts (STs), an essential process for placenta development. These short-term alterations may be later overcome, therefore, replenishing the placental endocannabinoid system status. Although they have only studied the impact on the main cannabinoid receptors and on the major endocannabinoid AEA biochemistry, and not on related compounds, like 2-AG, OEA (N-oleoylethanolamine), or PEA (N-palmitoylethanolamine), their findings may be the missing link to the observed clinical negative outcomes in pregnant cannabis consumers.

Finally, a study by the University of Colorado in the USA investigated whether higher maternal choline levels mitigate the effects of cannabis on fetal brain development. Cannabis use was assessed during pregnancy by women who later brought their newborns for study. The 137 mothers were informed about choline and other nutrients, but not specifically for cannabis use. Most women smoked cannabis 1–3 times per week. Maternal serum choline was measured at 16 weeks gestation. Cannabis use for the first 10 weeks gestation or more by 15% of mothers decreased newborns’ inhibition of evoked potentials to repeated sounds. This effect was ameliorated if women had higher gestational choline. At 3 months of age, children whose mothers continued cannabis use through their 10th gestational week or more had poorer self-regulation. This effect was also ameliorated if mothers had higher gestational choline. Maternal choline levels correlated with the children’s improved duration of attention, cuddliness, and bonding with parents. Choline transported into the amniotic fluid from the mother activates α7-nicotinic acetylcholine receptors on fetal cerebrocortical inhibitory neurons, whose development is impeded by cannabis blockade of their cannabinoid-1(CB1) receptors. Moreover, stopping cannabis use before 10 weeks of gestational age prevented these effects. Care would appear from this study to include enhancing the mother’s choline level to protect the fetus’s brain development.

Limitations

In regards to the review done by the University of Colorado and the Denver Health and Hospital Authority warns that practitioners should be aware that there are significant limitations to the existing literature. Cannabis use is often not quantified and studies are limited by ascertainment of cannabis exposure through self-report which underestimates the prevalence of use. Biological sampling should be used to accurately determine the effects of prenatal cannabis use on maternal and neonatal outcomes. Important confounders, such as education level and concurrent tobacco use, will need to be measured thoughtfully and prospectively in order to evaluate the independent role of cannabis use in pregnancy outcomes.

On the other hand, a limitation of the observational study by the University of Colorado is that the effects of cannabis and choline cannot be rigorously isolated from other environmental and genetic influences on fetal development. Factor analysis of socio-economic, maternal health, and neonatal status parameters were used to construct summary covariates of these many possible influences. None of the three factors had significant effects on cannabis–choline interaction.

Conclusions

The heterogeneity of findings in the scientific literature leads to uncertainty in counseling women regarding cannabis use in pregnancy. While more evidence is needed for informed decision-making, it seems reasonable to follow ACOG guidelines recommending that women be discouraged from using cannabis during pregnancy and lactation. The rationale to follow these recommendations stems from a growing body of studies showing potential harm to fetuses with evidence of decreased growth (in particular with heavy use), and concern from longitudinal studies for long-term neurologic effects. Cannabis use may be associated with spontaneous preterm birth, stillbirth, and neonatal intensive care unit admission. The health effects on the mother remain largely unknown.

The paucity of clinical evidence has made it difficult for organizations to make definitive recommendations regarding cannabis use during lactation. Both ACOG and the American Academy of Pediatrics recommend that women refrain from using cannabis while lactating. The Academy of Breastfeeding Medicine states breastfeeding mothers “should be counseled to reduce or eliminate their use of cannabis to avoid exposing their infants and advised of the possible long-term neurobehavioral effects from continued use”. They ask clinicians to consider the wide range of occasional, regular medical, and heavy exposure to cannabis and urge caution when breastfeeding occurs with cannabis use. Discontinuation of cannabis provides the least risk and highest safety profile for mother and baby. If discontinuation is not possible, women should be encouraged to limit use as much as they can. For women who use cannabis for medical indications, alternative therapies with more safety data during breastfeeding should be considered. Recommendations regarding breastfeeding will evolve as more evidence becomes available. In the meantime, the lack of data should not be interpreted as an endorsement of safety.

Fortunately, higher choline levels seem to improve fetal brain development and early childhood behavior in studies that found positive behavioral effects through 4 years of age. Healthy women and women with mental illness, infection, and alcoholism benefit also from it. The most common reasons for continuing cannabis were the mothers’ belief that it was safer and more effective than pharmaceuticals for morning sickness, depression, and stress. Ideally, expectant parents will heed warnings about the adverse effects of prenatal cannabis use on their child, but, regardless of the parent’s decision, clinicians have a dual obligation to respect their autonomy and to provide the best possible health care for the mother and fetus.

Hoffman MC, Hunter SK, D’Alessandro A, Noonan K, Wyrwa A, Freedman R (2019). Interaction of maternal choline levels and prenatal Marijuana’s effects on the offspring. Psychological Medicine 1–11. https://doi.org/10.1017/S003329171900179X

Maia, J., Midão, L., Cunha, S.C. et al. Arch Toxicol (2019) 93: 649. https://doi.org/10.1007/s00204-019-02389-7

Metz TD, Borgelt LM. Marijuana Use in Pregnancy and While Breastfeeding. Obstetrics and Gynecology. 2018 Nov;132(5):1198-1210. DOI: 10.1097/AOG.0000000000002878.