Cannabis and Pregnancy: A review

Abstract

Importance:

Prenatal cannabis use is rising and is a major public health issue. Cannabis use in pregnancy and during lactation has been associated with increased maternal and offspring morbidity and mortality.

Objective:

This review aims to summarize the existing literature and current recommendations for cannabis use during pregnancy or lactation.

Evidence Acquisition:

A PubMed, Cochrane Library, and Google Scholar literature search using the following terms was performed to gather relevant data: “cannabis,” “cannabinoid,” “delta-9-tetrahydrocannabinol,” “THC,” “cannabidiol,” “fetal outcomes,” “perinatal outcomes,” “pregnancy,” and “lactation.”

Results:

Available studies on cannabis use in pregnancy and during lactation were reviewed and support an association with increased risk of preterm birth, neonatal intensive care unit admission, low birth weight, and small for gestational age infants.

Conclusion and Relevance:

There is a critical need for research on the effects of cannabis use in pregnancy and during lactation. This is a necessary first step prior to furthering patient education, developing interventions, and targeting antenatal surveillance to ameliorate the adverse impacts on maternal and fetal health.

Target Audience:

Obstetricians and gynecologists, family physicians, pediatricians

Learning Objectives:

After participating in this activity, the learner will be better able to describe options for treatment of cannabis use disorder, explain common forms of cannabinoids available for use, and discuss screening options for cannabis use in pregnancy.

INTRODUCTION

Cannabis use in the United States is rising steeply, especially amongst adults of reproductive age. In the last decade, past-year prevalence of cannabis use amongst reproductive-age adults increased from 10.4% to 18.0% and daily or almost daily use (e.g., 300 or more days per year) rose from 1.3% to 3.9%¹. Similarly, cannabis use in pregnancy has also increased from 3.4% in 2002 to 7.0% in 2017², and by 25% during the COVID-19 pandemic³. Prevalence of use is highest amongst pregnant individuals between 18 and 25 years of age⁴ and in the first trimester when the fetus is most sensitive to adversity².

These trends are in contrast to patterns of alcohol and tobacco use in pregnancy, which have decreased over time⁵. This difference is partly a result of changing cannabis legislation, which has increased the availability of cannabis and decreased perceived risks with use. Studies have shown that legalization of cannabis in states such as Colorado and California have been associated with increased use in pregnancy⁶. Prior reports have also highlighted that the true prevalence of cannabis use in pregnancy is likely underreported in survey data⁷.

The American College of Obstetricians and Gynecologists has advised individuals to abstain from cannabis when pregnant and breastfeeding, but these individuals often continue to use partly because current safety data is limited⁸. There is concern for adverse pregnancy outcomes given that delta-9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) can readily cross the placenta⁸. The limited available evidence suggests that prenatal cannabis exposure is associated with stillbirth, fetal growth restriction, impaired fetal neurodevelopment, preterm delivery, increased neonatal intensive care unit admissions, and small for gestational age infants^9–12.

However, there is still a paucity of knowledge related to the safety of using cannabis in pregnancy because the majority of published studies are limited by a retrospective or observational study design, rely primarily on patient self-report, are confounded by polysubstance use, have a small sample size, lack biological drug testing, have inconsistent dose information, and mostly focus on the effects of smoking cannabis rather than other contemporary forms of cannabis use¹³. In addition, it is difficult to compare the different modes of delivery and concentration of cannabis consumption. Unlike alcohol where a shot is equivalent to a beer and a glass of wine, smoking cannabis versus vaping, dabbing, or consuming edibles achieve different THC concentrations and there is a wide range in onset and duration of effect. This is also complicated by issues with poor labeling accuracy of available cannabis products^{14, 15}.

The purpose of this review is to provide an updated overview regarding the association between prenatal cannabis exposure, and pregnancy and offspring outcomes.

HEALTH POLICY

Currently, in the United States, 37 states and Washington DC have legalized medical cannabis use and of those, 21 states have legalized non-medical cannabis use. Despite these recent moves at the state-level towards legalization, in the last two decades there has also been a trend towards more punitive policies on cannabis use in pregnancy that mandate health professional reporting and child welfare notification¹⁶. These measures stand in contrast to the legalization of cannabinoids for recreational and medical use at the state level and the implied safety with legislative acceptance of cannabis use¹⁷. In response, some states have implemented supportive policies aimed at reducing barriers to treatment¹⁶.

PROFESSIONAL GUIDELINES

American College of Obstetricians and Gynecologists

The American College of Obstetricians and Gynecologists (ACOG) recommends discontinuing cannabis use in individuals who are contemplating pregnancy or are currently pregnant¹⁸. ACOG guidelines recommend that pregnant individuals should be asked about cannabis use and counseled on the potential risks of continued use in pregnancy. These recommendations include encouraging pregnant individuals who use cannabis for medicinal purposes to consider alternative therapies with more sufficient pregnancy-specific safety data. ACOG also discourages cannabis use when breastfeeding given the absence of sufficient data to evaluate the effects of cannabis use on infants during lactation.

American Academy of Pediatrics

The American Academy of Pediatrics (AAP) recommends against cannabis use during pregnancy. In addition, the AAP recommends that pregnant individuals should be informed about the lack of definitive safety information and counseled on the potential adverse effects of cannabis use on fetal and child development¹⁹. The AAP also discourages use of any cannabis during breastfeeding due to insufficient evidence regarding the potential risks associated with exposure during lactation. Clinicians are encouraged to include cannabis use when discussing the use of other substances, such as tobacco and alcohol, during pregnancy and breastfeeding.

Centers for Disease Control and Prevention

The Centers for Disease Control and Prevention (CDC) advise pregnant individuals to refrain from cannabis use in pregnancy, citing potential birth complications and adverse impacts on fetal development²⁰. Overall, the CDC recognizes the need for more research on the potential long-term consequences of cannabis use in pregnancy.

Academy of Breastfeeding Medicine

The Academy of Breastfeeding Medicine (ABM) protocol highlights the need for research on the long-term effects of cannabis use during breastfeeding because the available information remains limited²¹. The ABM advises healthcare providers to counsel lactating individuals that use cannabis to avoid or reduce use while breastfeeding²¹.

PERCEPTIONS OF CANNABIS USE

Amongst reproductive-aged women in the United States, the perception that cannabis has no associated risks has increased three-fold from 2005 to 2015²². An analysis of the National Survey of Drug Use and Health from 2007 to 2012 demonstrated that 70% of pregnant and non-pregnant females believe there is a slight or no risk of harm from using cannabis one to two times per week²³. Cannabis use prior to pregnancy has been associated with increased acceptability of use during pregnancy^{22, 24}, and cannabis legalization has also influenced these attitudes and beliefs. In a study surveying 306 pregnant individuals, 10% reported that they would use cannabis more if it were legalized²⁴. In states where cannabis has been legalized, women were more likely to use cannabis in the preconception, prenatal, and postpartum periods²⁵.

Currently, information regarding the risks of cannabis use in pregnancy are obtained from different sources that may not consistently reflect evidence-based recommendations. A study conducting a series of 26 semi-structured interviews with pregnant participants found that commonly cited sources of information included the internet or anecdotal advice, with few reporting receiving useful information from a healthcare provider^{22, 26}. Another study examining recommendations given by randomly selected Colorado cannabis dispensaries when approached by a pregnant mystery caller reported that 69% of dispensaries recommended the treatment of morning sickness with cannabis, one third stated that cannabis use is safe in pregnancy, and that these recommendations were based largely on personal opinion²⁷.

Prior research has demonstrated that healthcare providers are not always consistently counseling patients, nor do they feel comfortable with counseling on the risks associated with cannabis use in pregnancy²⁸. Several studies have assessed the counseling given by healthcare providers regarding prenatal cannabis use. A prior study sent a questionnaire to healthcare providers in France and demonstrated that 68.1% did not feel well informed about the risks of cannabis use in pregnancy²⁹. In addition, another study using semi-structured interviews with 51 providers in the United States found that most were not familiar with the risks of cannabis use in pregnancy and that counseling practices focused more on legal risks than safety of use^{30, 31}. This study also recorded the initial prenatal visits with these providers and in almost half of the visits, healthcare providers did not respond to disclosures of cannabis use or counsel patients^{30, 31}. Crowley et al., conducted a survey-based assessment of postpartum mothers and found that most were aware that cannabis use while breastfeeding may be harmful to their newborn, but very few received counseling about the risks of use with lactation³².

FACTORS ASSOCIATED WITH CANNABIS USE IN PREGNANCY

Cannabis use in pregnancy is more prevalent in individuals who are younger, and with lower levels of education and household income^{33, 34}. In pregnant individuals who co-use other substances such as tobacco, alcohol, and illicit drugs, these disparities are more pronounced, indicating that socioeconomic factors are associated with these higher-risk behaviors³⁵. For example, individuals involved in the United States criminal justice system who use cannabis in pregnancy are also more likely to co-use cocaine and opioids³⁶. In addition, there is a high incidence of cannabis use among pregnant and postpartum individuals with HIV. Yee et al., found that 11.7% of pregnant and 23.7% of postpartum individuals with HIV used cannabis in 2019 compared to 7.1% and 10.2% respectively in 2008³⁷.

In addition to socioeconomic factors, mental health also plays a role in patterns of use in pregnancy. Individuals with depression are more than three times more likely to use cannabis during pregnancy³⁸. Prenatal cannabis use has also been associated with anxiety and trauma diagnoses³⁹.

CANNABIS USE DISORDER

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), cannabis use disorder is defined as a pattern of continued use despite clinically significant impairment or distress⁴⁰. The prevalence of cannabis use disorder among adults in the United States who have past-year cannabis use ranges from 9% to 31% depending on the different survey method used⁴¹. The National Surveys on Drug Use and Health collected data from 2007–2012 and reported that the prevalence of cannabis use disorder was 18.1% amongst past-year cannabis users who were pregnant²³. A recent study by Wicken et al., surveying postpartum individuals who tested positive for cannabis use by urine toxicology at time of admission for delivery noted that 26.1% of survey respondents met criteria for cannabis use disorder⁴².

There are also notable gender-based differences associated with cannabis use disorder. While treatment-seeking rates are low for both men and women, women with cannabis use disorder are more likely to have concurrent mood and anxiety disorders⁴³. Specific to pregnancy, the effects of prenatal cannabis use disorder are relatively understudied, but studies have shown that cannabis use disorder is associated with a greater risk of major adverse neonatal and infant outcomes^{44, 45}. A retrospective cohort study of 4.83 million individuals who delivered a singleton birth from 2001 to 2012 reported that prenatal cannabis use disorder was associated with higher odds of small for gestational age, preterm birth, low birth weight, and death within one year of birth⁴⁵.

COMMON FORMS OF CANNABIS USE IN PREGNANCY

Inhaled marijuana

This is the most common form^{46, 47} of cannabis use and includes smoking, vaporizing and dabbing (Figure 1). Smoking and vaporizing are the quickest method for THC to enter systemically, and provides a rapid onset (1–3 minutes) and short duration (1–3 hours) of symptoms^{48, 49}. Dabbing refers to the inhalation of extremely concentrated THC made from hash oil that is vaporized^{48, 50}.

Figure 1.

Different formulations of cannabis

Oral or gastrointestinal absorption of marijuana

This is the second most popular mode of cannabis use amongst pregnant individuals and those of reproductive age⁴⁶. Oral absorption includes drops, tinctures, sprays, lollipops, or breath strips with symptoms occurring after approximately 20 minutes that can last 1 to 3 hours^{48, 50} (Figure 1). Gastrointestinal absorption includes edibles, candies, drinks, snacks and capsules with an onset of action ranging from 30 to 90 minutes after consumption and persisting for 6 to 8 hours⁴⁸ (Figure 1). As a result of the delayed onset of symptoms, these methods have a higher likelihood of overconsumption^{48, 50}.

Skin absorption of marijuana

There are two types of skin-applied formulations of cannabis, they include topicals and transdermals (Figure 1). Topicals are absorbed through the epidermis or hair follicles and bind to cannabinoid receptors to provide localized effects. These include balms, salves, lotions, liniments, and bath soaks. Their onset of action is approximately 15 to 30 minutes after application with effects lasting for 3 to 6 hours^{48, 50}. Topicals will not result in a positive urine drug screen because they do not enter the bloodstream. Transdermals are absorbed into the bloodstream with a similar onset of action of 15 to 30 minutes after applying and can persist for 6 to 8 hours⁴⁹. These include gels and patches that are time-released^{48, 50}.

Suppositories

Suppositories can be inserted rectally or vaginally and are especially suitable for individuals who cannot or do not want to ingest or inhale cannabis (Figure 1). Vaginal suppositories have an onset time of approximately 20 minutes and last for 3 to 6 hours⁴⁸. Rectal suppositories are less psychoactive because they are not as readily absorbed into the bloodstream^{48, 50}.

OTHER CANNABINOIDS USED IN PREGNANCY

Cannabidiol (CBD)

Cannabidiol, or CBD, is a component of the Cannabis sativa plant that does not have psychotropic activity⁵¹. Its mainstream use has increased in the United States due to its therapeutic potential through anxiolytic, anti-inflammatory, and antiemetic effects⁵². Data on the effects of cannabidiol use in pregnancy however, are extremely limited despite increasing use within this population for the treatment of symptoms such as nausea and chronic pain⁵³. In an in vitro study examining the effects of cannabidiol on trophoblast cell and placental function, cannabidiol was found to interfere with trophoblast turnover and placental remodeling⁵¹. A prior study in mice noted that the transfer of cannabidiol from maternal blood to fetal blood was rapid, with accumulations of compound found in the fetal brain, liver, and gastrointestinal tract, as well as within amniotic fluid⁵⁴.

Delta-8-tetrahydrocannabinol and delta-10- tetrahydrocannabinol

There is increasing interest in less commonly known cannabinoid formulations. In addition to delta-9-THC, there are other analogues of THC, including delta-8-THC and delta-10-THC, that are molecularly different due to the location of the double-bonded carbon chain (Figure 2). Although lawmakers have specified that hemp is only federally legal if it contains no more than 0.3% delta-9-THC, delta-8-THC and delta-10-THC are less regulated and can be synthesized using CBD from legal hemp. Currently, delta-8-THC is commonly labeled as a hemp product and can be purchased online or in stores, but has not been approved by the FDA.

Figure 2.

Popular types of cannabinoid formulations available.

Delta-8-THC has psychoactive and intoxicating effects, similar to delta-9-THC, but studies have shown that delta-8-THC differs mechanistically in how it binds to the cannabinoid receptors in the body⁵⁵ which may lead to differing effects⁵⁵. Currently, delta-8-THC is used for its potential relaxing, euphoric, antiemetic, anxiolytic, appetite stimulating, and analgesic effects⁵⁶. There are reportedly fewer adverse effects associated with use of delta-8-THC versus delta-9-THC, but studies have shown that individuals can still experience difficulty concentrating, issues with short-term memory, and an altered sense of time with use of delta-8-THC⁵⁶. Limited research has been conducted on delta-10-THC, but some studies have indicated that it may have less potent psychoactive effects than delta-9-THC or delta-8-THC. Similar to delta-8-THC, delta-10-THC is not regulated or approved for use by the FDA.

Synthetic Cannabinoids

Different than delta-8-, delta-9- and delta-10-THC, synthetic cannabinoids (e.g., K2, spice, AK-47, Mr. Happy, Scooby Snax, Kush, or Kronic) are human-made mind-altering chemicals that are either in a liquid form that can be vaporized and inhaled in e-cigarettes, or are sprayed on a dried plant material that can be smoked. Synthetic cannabinoids were first synthesized in the 1970s, and initially were structurally similar to THC. Since then, a wide variety of compounds with structures differing from THC have been produced that also readily interact with cannabinoid receptors.

Despite their differences from THC, they are referred to as “cannabinoids” because they are similar to chemicals found in the cannabis plant. Synthetic cannabinoids are often marketed as “safe, legal alternatives” to cannabis, but can have more intense mind-altering effects that are unpredictable, more dangerous, and potentially life-threatening. In mice, synthetic cannabinoids are also reported to have adverse reproductive and pregnancy consequences, including an impact on preimplantation embryonal growth, and placental transport and development⁵⁷. Of note, these synthetic cannabinoid compounds were not originally synthesized for intended human consumption, have not undergone necessary safety testing, and little is known about the scope of their effects in humans.

CANNABIS AND THE ENDOCANNABINOID SYSTEM (ECS)

The endocannabinoid system regulates aspects of the human nervous and immune systems via five different cannabinoid receptors, the two best-studied cannabinoid receptors are CB1 and CB2^{58, 59}. CB1 and CB2 receptors are present throughout the body, but are primarily found in central nervous system cells and immune cells, respectively. Endocannabinoids, or endogenous cannabinoids, and other factors are involved in complex human processes, such as thermoregulation, sensory and time perception, sleep, pain, pleasure, memory, appetite and more⁶⁰. Through activation and inactivation of these receptors, cannabinoid use results in the classic symptoms of polyphagia, dry eyes and neuronal depression or activation depending on the strain, potency and route used⁶¹. Furthermore, the use of cannabis and exogenous cannabinoid formulations can cause disruption of the complex processes regulated by the endocannabinoid system. This is concerning because THC can bind to CB1 and CB2 receptors in the placenta, as well as cross the placenta and bind to these receptors in cells and tissues of the developing fetus.

Understanding how cannabinoids affect the endocannabinoid system is important as more people continue to use cannabis. There is recent evidence showing that the effects of cannabinoids, THC and CBD may not be as straightforward as previously understood. Studies have noted that CBD has a low affinity for the known CB1/CB2 receptors and THC can behave as an agonist or antagonist depending on the type of receptor and its location⁴⁹. This highlights the complexity and heterogeneity of the endocannabinoid system and the potential impact of exogenous cannabinoid use.

PHARMACOKINETICS IN PREGNANCY

Existing human studies on the pharmacokinetics of cannabis have largely focused on non-pregnant adults and consumption of cannabis products through smoking^62–64. Prior human and animal studies have demonstrated that THC crosses the placenta resulting in fetal blood concentrations similar to maternal concentrations in some species^65–68. Older studies, using rodent and rabbit models, have reported on the pharmacokinetics and placental transfer of THC, but at a lower THC dose than that commonly experienced today, as most of this prior research was performed in the 1960s-1980s^{64, 69–76}. In the rat, fetal blood concentrations are one-tenth of maternal concentrations after maternal ingestion of THC^11,37 and one-third of maternal concentrations following maternal inhalation or intravenous use of THC^{67, 68}.

As the potency of cannabis has increased significantly the last few decades, there is limited data regarding the quantity of THC transferred in relation to the concentration of THC in contemporary cannabis products, frequency of use, and maternal blood concentrations. The route of use (e.g., ingestion, inhalation) can affect the amount of THC absorbed. Oral cannabis use is associated with THC absorption greater than 90%⁷⁷, but due to significant first pass hepatic metabolism, bioavailability is less than 20%⁷⁸. In contrast, smoking cannabis avoids first pass hepatic metabolism, but there is loss of THC in sidestream smoke, the cigarette butt, and from pyrolysis, resulting in low THC absorption and variability in bioavailability from 2 to 56%^{79, 80}. Studies have also suggested variability in placental transport and physiology of THC⁸¹. Prior dizygotic twin studies, where both fetuses theoretically are exposed to similar maternal drug levels, have demonstrated large disparities in cannabinoid concentrations of hair and meconium samples between twins, including undetectable levels in one twin while positive in the other⁸².

CANNABIS USE IN PREGNANCY

Common Uses of Cannabis in Pregnancy

Despite the growing evidence demonstrating adverse outcomes associated with cannabis in pregnancy, many pregnant individuals continue to use. Thus, understanding the reasons why pregnant individuals use cannabis is an opportunity to provide additional support and targeted therapies. The most common reasons for cannabis use during pregnancy include treatment of hyperemesis gravidarum, anxiety, insomnia, nausea, and chronic pain^{83, 84}. Importantly, many of these reasons have alternative treatments that are better studied in pregnancy. A prior study surveying pregnant and lactating individuals using cannabis identified three categories of reasons for use during pregnancy and lactation⁸⁴. These include: 1) sensation-seeking for fun and enjoyment, 2) symptom management of chronic conditions and conditions related to pregnancy, and 3) coping with the unpleasant, but nonpathologized, experiences of life. Prior to pregnancy, individuals endorsed reasons for cannabis use in these three categories with similar proportions⁸⁴. However, during pregnancy, the reason for use was largely for symptom management; during lactation, reasons for use resembled those expressed preconception⁸⁴.

Screening for Cannabis Use in Pregnancy

ACOG recommends universal screening for substance use in pregnancy through validated questionnaires¹⁸. A variety of drug use screening tools exist and have been validated in pregnancy⁸⁵, including the Screening, Brief Intervention, and Referral to Treatment approach (SBIRT), which involves assessing the severity of substance use, risk stratification, with subsequent counseling, intervention, or referral to specialty care⁸⁶.

Self-reported cannabis use can underestimate the prevalence of use in pregnancy^{83, 87, 88}. In a prior study, when compared to screening through urine drug testing, only 36% of patients who tested positive for cannabis disclosed current use to their healthcare provider⁸⁹. Given the likelihood of underreporting, one study aimed to develop a more sensitive tool for identifying women using cannabis in pregnancy. In this study, 400 participants who had recently given birth were surveyed on direct assessment of drug use (directly asking about recent drug use), semi-indirect assessment (asking only about use prior to pregnancy), or indirect assessment (no mention of drug use); survey answers were then compared with urine and hair sample testing⁹⁰. The study found that the indirect screening tool predicted toxicology results more accurately than direct questioning, although the clinical utility of indirect screening has not been elucidated, especially in the setting of false positive results⁸⁵.

Despite underreporting through screening, ACOG does not recommend routine urine drug screening¹⁸. Biological sampling should only be obtained when indicated for clinical care and after obtaining maternal consent, especially when considering mandatory reporting⁹¹. In addition, patients are often selected for biological sampling in a biased fashion. In a retrospective cohort study of all deliveries at a tertiary care center from 2015 to 2019, after adjusting for commonly used diagnoses that prompted screening, non-Hispanic Black patients were significantly more likely to have urine drug screening performed (OR 2.0, 95% CI 1.6–2.4) despite being as likely to have a negative screen result as White patients⁹².

When biologic sampling is indicated, it may be performed through testing of maternal urine, serum, saliva, or hair (Figure 3). The most common method is urine toxicology, which identifies use in the preceding 3–5 days through detection of the most stable cannabis metabolite, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH)⁹³. Urine toxicology cannot capture use outside of an assay’s detection window⁹³. Thus, a single urine toxicology result likely underestimates prevalence and may be biased towards individuals with heavier or longer-term use, as an urinalysis in this population is more likely to be positive⁸⁷. If screening immunoassay tests are positive, a confirmatory test using gas chromatography-mass spectrometry analysis is recommended due to the high false-positive rate of screening point-of-care tests⁹¹.

Figure 3.

Different methods for maternal cannabis drug testing

Infant testing involves sampling of umbilical cord homogenate, meconium, serum, or urine. Umbilical cord homogenate testing for THC-COOH can detect use from the third trimester onwards^{83, 94} (Figure 4). Immunoassay screening of fetal meconium extracts measures exposure from the end of the second trimester through the third trimester, but may be difficult to collect due to early passage in utero or requiring several days after birth for complete passage⁹⁵ (Figure 4).

Figure 4.

Postnatal methods for detecting prenatal cannabis exposure.

Treatment

Although admissions for cannabis use in pregnancy have risen from 1992 to 2012⁹⁶, there remains no current evidence-based interventions for cannabis use in pregnancy. There are limited existing studies examining the feasibility of interventions. One prior study randomized 45 pregnant individuals to electronic screening and brief intervention, tailored text messaging, or both; this study found that both intervention strategies had strong feasibility and modest to high acceptability⁹⁰. Another study performed a randomized controlled trial of 50 pregnant individuals and examined the acceptability and preliminary efficacy of a computer-based, single-session, brief motivational intervention followed by a booster session in the reduction of both substance use and sexually transmitted infection risk⁹⁷. This study also found high acceptability and significant reduction in cannabis or alcohol use in the intervention group.

Despite an increased prevalence of cannabis use disorder, treatment of cannabis use disorder in pregnancy has not been well studied. In the general adult and adolescent population, psychotherapeutic interventions remain first-line for treatment of cannabis use disorder as no pharmacological agent has been found to be clinically effective⁹⁸. The evidence most consistently supports a combined approach of cognitive-behavioral therapy, motivational enhancement therapy, and potentially abstinence-based incentives⁹⁸. When referring to specialty care in pregnancy, it is important to note that pregnant individuals using substances face particular barriers to accessing care. These challenges include difficulty finding treatment, a paucity of suitable treatment options, and skipping treatment due to a fear of being detected by health or criminal justice authorities⁹⁹.

Treatment of cannabis use in pregnancy can also include addressing withdrawal symptoms. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), defines cannabis withdrawal syndrome as having at least three of the following symptoms occurring within seven days of reduced use: 1) irritability, anger, or aggression; 2) nervousness or anxiety; 3) sleep disturbance; 4) appetite or weight disturbance; 5) restlessness; 6) depressed mood; and 7) somatic symptoms (e.g., nausea, vomiting, headaches)⁴⁰. In a recent meta-analysis, the prevalence of cannabis withdrawal syndrome amongst regular cannabis users was reported to be 47%¹⁰⁰. Additionally, concurrent tobacco or other substance use and daily cannabis use were associated with a higher incidence of cannabis withdrawal syndrome¹⁰⁰. Given the high prevalence of withdrawal symptoms in regular cannabis users, treatment of pregnant individuals should incorporate consideration for supportive therapies to manage withdrawal symptoms.

Pharmacologic Treatment for Withdrawal

In regular and heavy cannabis users, symptoms of withdrawal can occur after abrupt cessation or reduction in the quantity of cannabis used. Most commonly people identify symptoms of anxiety, irritability, anger or aggression, disturbed sleep, depressed mood and loss of appetite¹⁰¹. Symptom onset occurred at 24–48 hours after cessation and peak symptoms at 2 to 6 days¹⁰¹. Some studies have explored pharmacologic intervention for cannabis withdrawal, but most are limited by small sample size. Within the studies that used a standardized scoring system, for withdrawal, such as the 16-item marijuana withdrawal check list or the 19-item cannabis withdrawal scale, six reported greater improvement of symptoms in individuals administered a cannabinoid medication versus placebo. These medications included dronabinol¹⁰², quetiapine¹⁰³, nabiximols¹⁰⁴, gabapentin¹⁰⁵, and oral THC¹⁰⁶. Pharmacologic intervention can be tailored to individual withdrawal symptoms.

Intrapartum Analgesic Considerations

Cannabis use in pregnancy should not affect clinical decision-making regarding timing or mode of delivery. With regards to anesthesia however, cannabis use may enhance central nervous system depression if combined with other sedative hypnotic drugs¹⁰⁷. Significant preoperative cannabis use should prompt consideration of additional postoperative nausea and vomiting prophylaxis, possible greater depth of anesthesia during induction and maintenance of anesthesia, and increased postoperative analgesia requirements¹⁰⁸.

MATERNAL OUTCOMES FROM PRENATAL CANNABIS USE

The data on prenatal cannabis use on maternal health are limited, but overall does not consistently support any pregnancy-related adverse maternal outcomes^{10–12, 109}. Several prior studies have examined the association between cannabis use in pregnancy and hypertensive disorders with conflicting results. Some studies have reported no association^110–112, while others, including a retrospective cohort study of singleton deliveries in California from 2011 to 2017, noted that cannabis-related diagnoses were associated with an increased odds of hypertensive disorders (OR 1.2, 95% CI 1.2–1.3)¹¹³. Similarly, another retrospective cohort study also found increased odds of gestational hypertension (aOR 1.19, 95% CI 1.06–1.34), preeclampsia (aOR 1.16, 95% CI 1.0–1.28), and severe maternal morbidity (aOR 1.22, 95% CI 1.02–1.47) with maternal cannabis use¹¹⁴. Co-use of cannabis with cigarette smoking in pregnancy has also been linked to increased odds of preeclampsia (aOR 2.5, 95% CI 1.4–5.0) and maternal asthma (aOR 2.4, 95% CI 1.0–5.9)¹¹².

Data on associations of cannabis use with gestational diabetes are similarly mixed¹⁰⁹. With regards to other maternal outcomes, a previous retrospective cohort study of births in the United States from 1999 to 2013 found increased odds of prolonged hospital stay (OR 1.17, CI 1.11–1.23)¹¹⁵ and a former meta-analysis of 24 studies determined higher odds of anemia with cannabis use during pregnancy (pooled OR 1.36, 95% CI 1.10–1.69)⁹.

PLACENTAL OUTCOMES FROM CANNABIS EXPOSURE IN PREGNANCY

Components of the endocannabinoid system have been documented in the placenta starting at mid-gestation and play a role in placenta development, including placentation and trophoblast differentiation, and placental function¹¹⁶. At term, CB1 receptor expression has also been demonstrated in the amniotic epithelium, reticular and decidual cells¹¹⁷. Prior human studies have reported that THC can affect amnion development by inhibiting migration of the epithelial layer of placental amnion tissue, which may increase the risk for preterm labor and other adverse pregnancy outcomes¹¹⁸. Other human studies have also reported THC-induced altered placental steroidogenesis and estrogen signaling¹¹⁹, diminished placental blood flow^{120, 121}, and histologic studies demonstrating increased syncytiotrophoblast knotting and fibrin deposition in the placental villi of cannabis users¹²².

Non-human primate studies have similarly reported that chronic prenatal THC exposure adversely impacts placental development and function¹²³. Roberts et al., showed that THC-exposed pregnancies had significantly decreased placental perfusion and fetal oxygen availability suggestive of placental insufficiency. In addition, placental histological analyses demonstrated evidence of ischemic injury with microinfarctions in THC-exposed placentas only. Placental bulk RNA-sequencing was also notable for THC-induced alterations in the placental transcriptome and pathway analysis was suggestive of dysregulated vascular development and angiogenesis. Prior rodent studies have also reported that prenatal THC use is associated with an increased fetal/placental weight ratio due to observed fetal growth restriction and increased placental weight^{122, 124, 125}. Lastly, in vitro studies have demonstrated that THC can negatively impact placental development by impairing cytotrophoblast fusion and biochemical differentiation, and inhibiting trophoblast cell turnover¹²⁶.

FETAL OUTCOMES FROM MATERNAL CANNABIS USE

Prenatal Cannabis Exposure and Neurodevelopment

There is growing evidence of THC-associated adverse effects for fetal and neonatal developmental outcomes.¹²⁷ In utero exposure to THC has been found to impact fetal brain development, including interruption of normal brain maturation, that may increase the risk for later in life neurocognitive and neuropsychiatric disorders^128–130. Maternal cannabis use has also been associated with “withdrawal”-like syndrome in newborns¹³¹ and increased aggressive behavior and attention deficits in offspring as early as 18 months of age^{131, 132}.

Currently, the underlying mechanisms for these observations are not fully understood. The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is present early in the developing fetal brain in humans and works as hormone/growth and differentiation factor¹³³. Serotonin plays a central role in brain development, mood regulation, stress reactivity and risk of neuropsychiatric disorders, such as schizophrenia, affective disorders and anxiety¹³⁴. Therefore, alterations in serotonin signaling during intrauterine life has critical implications for behavior and mental health later in life.

Expression of cannabinoid receptors in the human placenta has been associated with the regulation of the serotonin transporter activity. Prenatal cannabis may affect the placental clearance of serotonin through the serotonin transporter leading to hyperserotoninemia¹³⁵. Due to the immaturity of the blood brain barrier in the fetus, serotonin can reach the developing brain. It has been shown that increased levels of serotonin during fetal development results in a dysfunction of the hypothalamic-pituitary axis that affects the amygdala as well as the regulation of oxytocin, a prosocial hormone, leading to neuropsychiatric disorders. To this point, high levels of serotonin are seen in the blood of over 30% of children with autism spectrum disorder, highlighting the role of serotonin in neuropsychiatric disorders^{136, 137}.

Offspring Epigenetic Regulation

A growing body of literature has demonstrated that environmental stimuli, including maternal substance use, can alter epigenetic regulation and impact gene transcription¹³⁸. Epigenetic mechanisms are increasingly recognized as a key link between early life experiences and risk of longer-term psychopathology.¹³⁹ Cannabis exposure preconception or during pregnancy has been shown to alter epigenetic processes (e.g., DNA methylation and histone modifications) with functional consequences for gene expression including genes involved in the development of autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, addiction, and other psychiatric diseases¹⁴⁰.

Congenital anomalies

At this time, the literature does not consistently support an association of maternal cannabis use with an increased risk of fetal anomalies. A prior study found that cannabis use was associated with higher rates of birth defects involving the cardiac, genitourinary, gastrointestinal, and cerebral nervous system in addition to cleft lip and/or palate and Trisomy 21¹⁴¹. Other studies also support an increased risk of fetal cardiac defects, specifically ventricular septal defects¹⁴², neural tube defect¹⁴³, minor physical anomalies¹⁴⁴, gastroschisis¹⁴⁵, diaphragmatic hernias¹⁴⁵, and esophageal atresia¹⁴⁵. However, most studies have not found a positive association between periconceptional cannabis use and birth defects^146–149, including fetal gastroschisis^{150, 151} and Ebstein anomaly¹⁵². A future review on this topic might consider a meta-analysis of these outcomes.

Fetal growth

Currently, the evidence suggests that prenatal cannabis exposure is associated with small for gestational age, defined as a birth weight less than the 10^th percentile^9–12. Although some studies did not adjust for confounders such as prenatal nicotine exposure, the most recently published systematic review observed that prenatal cannabis use significantly increased the likelihood of small for gestational age¹⁰. Lo et al., reported in unadjusted (18 studies; N=1,774,485) and adjusted (6 studies; N=686,336) meta-analyses that prenatal cannabis use significantly increased the odds of small for gestational age (unadjusted OR, 2.06; 95% CI, 1.76 to 2.41; aOR, 1.76; 95% CI, 1.52 to 2.05; I², 86%)¹⁰. There is less consistent literature supporting the association between maternal cannabis use and fetal growth restriction, defined as an overall estimated fetal weight or an abdominal circumference measurement of less than the 10^th percentile.

Preterm birth

Many studies have consistently reported that prenatal cannabis use is associated with an increased risk of preterm birth, defined as delivery prior to 37 weeks gestation, even after adjusting for confounders such as tobacco use^{9–12, 153}. In general, most studies reported the results of any preterm birth, but only a few stratified results by spontaneous versus indicated preterm births.

Apgar score

The Apgar (Appearance, Pulse, Grimace, Activity, and Respiration) score is a quick assessment of newborn health at 1 and 5 minutes after birth to determine the need for resuscitation. While some studies reported a decreased Apgar scores at 1 minute¹⁵⁴, overall, the majority of studies comparing Apgar scores between pregnancies with and without prenatal cannabis exposure found no significant differences between groups^{10, 12}.

Neonatal Intensive Care Unit Admission (NICU)

The literature consistently supports an association between prenatal cannabis exposure and a significantly higher likelihood of neonatal intensive care unit (NICU) admissions^{10–12, 110, 111, 154, 155}. Overall, results were homogenous with little variability in findings between studies.

Perinatal Death

There is no consistent association amongst existing studies between prenatal cannabis use and perinatal death^{9, 10, 12, 156}. However, the definition of perinatal mortality varied across studies from stillbirth to the inclusion of miscarriage, spontaneous abortions, or death before hospital discharge. In addition, some studies did not adjust for confounders such as tobacco use. Varner et al., reported the findings of the Stillbirth Collaborative Research Network, a case-control study from 2006 to 2008, and noted that cannabis use was associated with an increased risk of stillbirth (OR 2.34, 95% CI 1.13–4.81), but the effect was partially confounded by smoking¹⁵⁷.

CHILDHOOD OUTCOMES

Cognitive Development and Behavior

The extant literature consists of three large, longitudinal prospective studies examining the effects of prenatal cannabis exposure on offspring neurocognitive development; all controlling for several different covariates. The oldest is the Ottawa Prenatal Prospective Study (OPPS), a landmark study initiated in 1978 that examined the effects of cannabis use in pregnancy amongst white, predominantly low-risk middle class families (n=583)¹⁵⁸. Offspring were followed annually until at least 6 years of age and less frequently through 14 years of age. In 1982, the Maternal Health Practices and Child Development (MHPCD) study (n=763) was conducted to examine the effects of prenatal alcohol and cannabis exposure on offspring up to 16 years of age. Participants of this study were primarily lower income, and half of the cohort identified as African American¹⁵⁹. The most recent is the Generation R study, a population-based birth cohort study that followed 7,452 participants in the Netherlands launched in 2002 with follow up of offspring that is still ongoing¹⁶⁰.

Overall, these three studies demonstrated an association between prenatal cannabis exposure and adverse offspring neurodevelopmental and behavioral outcomes, despite a relatively small sample size of exposed offspring and limited data on the amount and potency of cannabis exposure in each study. There were some inconsistent findings across all three studies that may be partly attributed to maternal characteristics that differ amongst the studies. The MHPCD study reported that prenatal cannabis use was associated with decreased infant development at 9 and 19 months of age¹⁶¹. In contrast, a more recent observational cohort study of 3,435 individuals that used cannabis in pregnancy found no association with abnormal development screens in exposed infants at 3 and 9 months of age, but was associated with an increased risk for abnormal developmental screens at 12 months of age (aRR 1.90, 95% CI 0.92–3.91)¹⁶². At 36 months of age, the MHPCD study found that offspring exposure to cannabis in the first and second trimesters of pregnancy had significantly lower childhood performance on the Stanford-Binet Intelligence Scale¹⁶³. By 6 years old, children exposed to heavy cannabis use in utero, defined as consumption of one or more cigarettes per day, had significant deficits in short-term memory and lower verbal reasoning scores¹⁶⁴. These findings persisted in prenatally exposed children through 10 and 14 years of age and included deficits in reading and spelling scores^{165, 166}, as well as lower ratings on teacher’s evaluations, negative effects on memory, and increased impulsivity, hyperactivity, inattention, and delinquency^{165, 167, 168}.

Some of these findings of the MHPCD study were also noted in the earlier OPPS, which found that at 4 years of age and older, children exposed to cannabis in utero were found to have increased behavioral problems, as well as decreased language comprehension, decreased sustained attention and memory, and lower performance on visual perceptual tasks¹⁶⁹. At 9 to 12 years of age, prenatal cannabis exposure was noted to be negatively associated with executive function tasks requiring impulse control, but not with global intelligence scores¹⁷⁰. Similar findings were reported in a more recent secondary analysis of two multi-center randomized-controlled trials, which found that prenatal cannabis exposure was not associated with a difference in offspring intelligence quotient (IQ) at 60 months of age, but was associated with worse attention scores⁹¹.

In the Generation R study, female offspring at 18 months of age with prenatal cannabis exposure were found to have increased aggression and attention problems⁸⁷. At 7 to 10 years of age, offspring exposed to cannabis in utero were noted to have behavioral problems, but not emotional problems, suggesting that the association was due to residual confounding¹⁷¹. Both the Generation R study as well as the OPPS specifically examined brain morphology in children with prior prenatal cannabis exposure. 54 children from the Generational R study, ages 6 to 8 years old, underwent brain magnetic resonance imaging and were found to have no change in global brain volumes¹⁷². However, when compared to unexposed children, offspring with in utero cannabis exposure had thicker frontal cortices¹⁷². This suggests that prenatal cannabis exposure may be associated with changes in brain morphology. Of note however, most of the children in the cannabis-exposed study group also had prenatal tobacco exposure. 16 participants from OPPS were also examined at 18–22 years of age and compared to 15 non-exposed adolescents; exposed individuals were found to have variations in neural activity while performing visuospatial tasks¹⁷³.

Other studies have also noted associations between prenatal cannabis exposure and autism spectrum disorder and sleep disturbance. A retrospective cohort study of all births in Ontario, Canada from 2007 to 2012 found an association between cannabis use in pregnancy and autism spectrum disorder in offspring (aHR 1.51, 95% CI 1.17–1.96)¹⁷⁴. Another prospective study found that prenatal cannabis exposure was associated with disturbed nocturnal sleep in exposed children at 3 years of age¹⁷⁵. However, this study was limited by a small cohort size of 18 exposed children and 20 controls.

Mental Health

There have been several studies examining the association between prenatal cannabis exposure and the subsequent development of psychiatric disorders or symptoms in exposed children. One of these studies, the Adolescent Brain and Cognitive Development Study (ABCD Study), was a cross-sectional study of 11,489 children starting at ages 9 to 11 to track their biological and behavioral development through adolescence into young adulthood. Drawing data from the ABCD Study, a prior cohort study included 4,361 children that completed a questionnaire designed to assess psychotic-like experiences to understand the association between prenatal cannabis exposure and psychosis-proneness in offspring¹⁷⁶. This cohort study showed that maternal cannabis use after knowledge of pregnancy was associated with a small increase in psychosis proneness (p=0.004)¹⁷⁶.

The ABCD Study also determined that cannabis exposure after maternal knowledge of pregnancy was associated with a small increased risk of psychopathology in children at middle age (e.g., 9 to 11 years old), in addition to attention and social problems¹⁷⁷. More recent published findings from the ABCD Study by Baranger, et al., similarly noted that prenatal cannabis exposure was associated with persistent vulnerability to psychopathology in offspring throughout early adolescence that was not ameliorated by age¹⁷⁸. Increased psychopathology may result in greater risk for later-in-life psychiatric disorders and problematic substance use during peak periods of vulnerability during late adolescence. In contrast, a prior longitudinal cohort study of 6,356 children who completed a semi-structured interview for psychotic symptoms at 12 years of age reported that maternal cannabis use in pregnancy was not shown to have an association with psychotic symptoms in offspring at age 12¹⁷⁹.

In addition to examining the associations between prenatal cannabis exposure and psychotic symptoms, a systematic review of studies on maternal use of cannabis in pregnancy and subsequent development of psychiatric disorders in offspring found that prenatal exposure may be associated with attention-deficit hyperactivity disorder and affective symptoms¹⁸⁰. These findings are consistent with the above-mentioned longitudinal studies that demonstrated associations with decreased attention an increased impulsivity and hyperactivity, as well as an increase in offspring depressive symptoms at 10 years of age¹⁸¹. A prior meta-analysis also found that maternal cannabis use was associated with increased odds of offspring conduct disorder problems (OR 1.29, 95% CI 0.93–1.81)¹⁸².

Increased Risk of Substance Use and Addiction Vulnerability

There is evidence that prenatal cannabis exposure may increase the risk of offspring cannabis and tobacco use later in life, and addiction vulnerability. A prior human study examined the neurobiology underlying the risk of addiction vulnerability in mothers using cannabis that underwent elective abortions between 18 and 22 weeks of gestation¹⁸³. This study reported reduced dopamine receptor D2 mRNA expression in the nucleus accumbens of fetal brains exposed to cannabis prenatally compared to controls The nucleus accumbens has is an important component of motor and reward circuits¹⁸⁴, and disruptions in the dopamine signaling pathways can increase the risk of adverse psychiatric outcomes.¹⁸⁵

Drawing on data from the OPPS, 152 offspring, ages 16 to 21 years old, completed a Drug History Questionnaire (DHQ) to determine if maternal cannabis use in pregnancy was associated with offspring cannabis and cigarette smoking¹⁸⁶. This study found that maternal cannabis use was associated with both offspring cannabis use (OR=2.76) and daily tobacco cigarette smoking (OR=2.36) and that this use increased in a dose-responsive pattern¹⁸⁶. A secondary analysis from the MHPCD study examined 590 offspring at 22 years old who completed a structured diagnostic interview to assess for an association between prenatal cannabis exposure and the development of cannabis use disorder in offspring¹⁸⁷. Although there was no association between cannabis exposure and the development of cannabis use disorder, offspring who were prenatally exposed had increased risk of initiating cannabis use prior to 16 years of age (RR=1.16)¹⁸⁷. The association between prenatal cannabis exposure and early onset of cannabis use in offspring was also demonstrated by another study that utilized MHPCD data¹⁸⁸.

CANNABIS USE DURING LACTATION

Incidence of Use

Postnatal infant exposure to cannabis through breastfeeding remains poorly understood and may confer further risk to the infant. This topic is of particular importance as cannabis is the most commonly used recreational drug among lactating individuals^{83, 189, 190}. Data from a recent cross-sectional study in Colorado estimated the prevalence of cannabis use in the breastfeeding postpartum period to be 5%¹⁹¹. Another study surveying lactation professionals attending the 2014 Vermont Lactation Consultant Association conference estimated that 15% of their breastfeeding clients used cannabis¹⁹².

Concentration of THC in Breast Milk

Individuals who use cannabis during breastfeeding risk infant exposure to the drug and its metabolites in breast milk. Studies have demonstrated that THC is secreted into breast milk and absorbed and metabolized by the breastfed infant^{50, 193}. A prior study found that THC concentration are eight times higher in maternal milk relative to plasma, and infants are exposed to 0.8% of the mother’s consumed dose in a single feeding¹⁹³. Baker et al., similarly studied the transfer of THC into the breast milk of eight individuals after smoking cannabis and detected a mean of 2.5% of the maternal dose within four hours after use⁵⁰. While further research is needed to minimize confounders and with larger sample sizes, these studies provide preliminary evidence of the transfer and accumulation of THC in breast milk.

The concentration of THC in breast milk is partly influenced by maternal dose and the frequency of use. A study of 50 breastfeeding individuals who reported cannabis use while lactating found the greatest concentration of THC was one hour after consumption and was highest in mothers with daily use¹⁹⁰. This study also demonstrated that THC was measurable in breast milk up to six days after maternal use.

Offspring Outcomes from Cannabis Use While Breastfeeding

There remains a paucity of clinical evidence regarding the developmental impact of exposure to cannabis through breastfeeding. However, as THC is highly lipophilic, it can be inferred that THC may be stored in infant brain tissue, which may have long-term effects on neurodevelopment. Astley and Little examined the impact of cannabis use on infant psychomotor development at one year of age¹⁹⁴. Using a matched cohort study of 68 infant-mother pairs, the study found that offspring cannabis exposure in the first month postpartum was associated with decreased motor development at 1 year of age. However, this study was limited by the inability to control for the effects of prenatal THC exposure. In contrast, a study of 27 breastfed infants exposed to cannabis postnatally demonstrated no differences in motor and mental development relative to 35 unexposed infants¹⁹⁵.

In the absence of definitive data on infant safety, professional guidelines encourage reducing or eliminating cannabis use while breastfeeding. The ABM suggest that breastfeeding mothers be counseled to reduce or eliminate use to avoid possible neurobehavioral effects on the infant²¹. The ACOG and AAP recommend refraining from cannabis use during lactation^{18, 19}. Despite these recommendations, cannabis use remains prevalent and is often perceived as safe among postpartum populations¹⁸⁹.

CONCLUSION

In this review, we have summarized the available data on prenatal cannabis exposure. Cannabis use in pregnancy is rising in part due to increased availability and greater societal acceptance. Of concern is the increasing potency of cannabis products and the growing body of evidence suggesting an increased risk of adverse prenatal and offspring outcomes associated with cannabis use in pregnancy^{10–12, 83}. In addition, most healthcare providers lack evidence-based knowledge regarding the potential effects of cannabis use and are unable to advise or counsel patients adequately. With many cannabis-based products now on the market, this is an area of significant public health relevance where additional research is needed to delineate the effects of different formulations (e.g., CBD, synthetic cannabinoids, delta-8-, delta-9-, and delta-10-THC) and methods of use (e.g., inhalation versus ingestion). An improved understanding of the issues surrounding maternal cannabis use is necessary to better educate and counsel individuals regarding the safety of use preconception, in pregnancy, and during breastfeeding, and to develop targeted antenatal surveillance strategies to mitigate maternal and offspring morbidity and mortality.