Neurodevelopmental and Psychiatric Risks in Children of Pregnant Mothers Who Use Cannabis

By Ahizechukwu C. Eke, MD, PhD, MPH

Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore

SYNOPSIS: Although current research has not conclusively established a direct link between prenatal cannabis use and an increased risk of autism spectrum disorder (ASD), psychotic symptoms, anxiety, or depression in offspring, there is evidence suggesting that prenatal cannabis exposure may modestly elevate the risk of attention-deficit/hyperactivity disorder (ADHD). Additionally, children exposed to cannabis in utero may be more likely to use cannabis later in life.

SOURCE: Bassalov H, Yakirevich-Amir N, Reuveni I, et al. Prenatal cannabis exposure and the risk for neuropsychiatric anomalies in the offspring: A systematic review and meta-analysis. Am J Obstet Gynecol 2024; Jun 20. doi: 10.1016/j.ajog.2024.06.014. [Online ahead of print].

The use of cannabis during pregnancy is a significant public health concern, driven by the increasing legalization of marijuana worldwide.¹ Although self-reported prevalence studies estimate that between 2% and 5% of pregnant women use marijuana, a Centers for Disease Control and Prevention (CDC) analysis found that 4.2% of women in eight states within the United States who recently gave birth reported using marijuana during their pregnancy.^2,3

Cannabis use during pregnancy is associated with various adverse health outcomes, including low birth weight and impaired neurodevelopment in exposed offspring.⁴ The primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), can cross the placental barrier and affect fetal brain development, leading to neurocognitive deficits.⁵ Understanding the extent and nature of these neuropsychiatric issues is crucial for informing public health policies and aiding pregnant women in making safer choices.

One of the primary neurodevelopmental concerns associated with prenatal cannabis exposure is cognitive impairment.^5,6 Research indicates that prenatal cannabis exposure often results in deficits in motor skills, including deficits in attention, memory, and executive function in offspring.⁶ These cognitive impairments are believed to stem from the disruption of endocannabinoid signaling pathways during crucial periods of fetal brain development.⁷ The endocannabinoid system is essential for processes such as neurogenesis, neuronal migration, and synaptic pruning, all of which are vital for normal cognitive development.⁷ Exposure to exogenous cannabinoids, such as THC, can interfere with these processes, leading to long-term cognitive abnormalities in affected offspring.^7,8 However, there is conflicting evidence on the risks of prenatal exposure to cannabis on the neurodevelopment of offspring in women who used cannabis. To investigate the association between cannabis use during pregnancy and the risk for long-term neuropsychiatric pathology in the offspring, Bassalov and colleagues hypothesized that prenatal cannabis exposure increases the risk of neurodevelopmental and psychiatric complications in the offspring.⁹

The researchers conducted a systematic review and meta-analysis of all observational studies and randomized clinical trials that reported long-term neuropsychiatric outcomes of interest in the offspring of mothers who used cannabis during pregnancy, whether for medical or recreational purposes, through any route, and during any trimester.⁹ These outcomes were compared to those in offspring who were not exposed to cannabis during pregnancy.

Studies were included if they reported at least one of the following outcomes: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, anxiety, and psychotic disorders, as well as cannabis and other substance use (e.g., cigarette smoking, illicit drug use).⁹ Studies were excluded if they were case reports, case series, guidelines, expert opinions, editorials, reviews, letters to the editor, comments, animal studies, studies focusing on internalizing problems or mixed expressions of anxiety/depressive symptoms, or those reporting only isolated ADHD symptoms, such as attention problems, hyperactivity, and impulsivity. Manuscripts that did not provide a comprehensive evaluation of ADHD, such as those lacking an ADHD diagnosis or not using Diagnostic and Statistical Manual of Mental Disorders (DSM)-oriented scales, also were excluded. Additionally, studies that reported concomitant use of cannabis with tobacco, alcohol, or other illicit drugs without separate analysis for cannabis exposure were excluded.⁹

The authors pooled fully adjusted effect size estimates from each trial to compare neuropsychiatric outcomes in the offspring of women who used cannabis during pregnancy with those who did not.⁹ Additionally, crude effect size estimates were analyzed to assess the potential effect of confounding variables on the relationship between prenatal cannabis exposure and neuropsychiatric outcomes, including anxiety, psychotic symptoms, ADHD, and ASD. To quantify heterogeneity among studies, Q and I² statistics were employed. Sensitivity analyses were conducted by excluding studies with significant discrepancies in offspring age ranges compared to other studies within each outcome category. This approach aimed to assess the effect of variations in offspring age on overall effect size estimates. Results were presented using odds ratio (OR) and 95% confidence intervals (CIs). A P-value of less than 0.05 was considered statistically significant.

A total of 534,445 women were included in the systematic review from 18 eligible observational studies, with 17 studies included in the final quantitative analysis. The overall pooled prevalence of prenatal cannabis use was 7.7% (95% CI, 3.0%, 18.2%). The pooled ORs revealed varying levels of association between prenatal cannabis exposure and different neuropsychiatric outcomes in offspring. The pooled OR was 1.13 (95% CI, 1.01-1.26) for ADHD, 1.04 (95% CI, 0.74-1.46) for ASD, 1.29 (95% CI, 0.97-1.72) for psychotic symptoms, 1.34 (95% CI, 0.79-2.29) for anxiety, 0.72 (95% CI, 0.11-4.57) for depression, and 1.20 (95% CI, 1.01-1.42) for cannabis use in the offspring after controlling for confounding variables (maternal substance abuse, family history of neuropsychiatric disorders, preexisting maternal mental health disorders). Sensitivity analyses did not change the primary results.

COMMENTARY

These findings highlight the complex relationship between prenatal cannabis exposure and neuropsychiatric outcomes. Although some associations, such as with ADHD and offspring cannabis use, reached statistical significance, others, such as ASD, psychotic symptoms, and depression, did not. The variability in these results underscores the importance of considering confounding factors and the need for further research to clarify these associations. Studies have demonstrated that offspring exposed to cannabis in utero are disproportionately vulnerable to developing anxiety, depression, and even psychotic symptoms during adolescence and young adulthood.^10,11 Despite the evidence linking prenatal cannabis exposure with adverse mental health outcomes, the exact biological mechanisms driving these associations remain unknown.

Current research suggests that alterations in brain structure and function play a pivotal role, particularly affecting regions implicated in emotion regulation and stress response.¹² These neural changes are hypothesized to disrupt normal developmental trajectories, predisposing individuals to enduring psychiatric vulnerabilities.¹² Further investigation is warranted to elucidate the molecular, cellular, and circuit-level alterations induced by prenatal cannabis exposure, thereby enhancing our understanding of its long-term neurobehavioral consequences. Such insights are crucial for informing public health strategies aimed at minimizing prenatal cannabis exposure and mitigating its detrimental effects on offspring mental health.

The effect of cannabis on neuropsychiatric outcomes during pregnancy demonstrates a correlation with both the timing and frequency of exposure.^13,14 Heavy and early cannabis use appears particularly detrimental, indicating a dose-response relationship where higher levels of THC exposure exert more pronounced disruptions in embryonic development.¹³ Such early exposure phases, critical for neurodevelopmental processes, may heighten vulnerability to enduring neuropsychiatric sequelae.

Conversely, occasional or later-term cannabis use exhibits comparatively milder effects, although caution is warranted, since any exposure can influence fetal brain development.² These findings underscore the critical need for comprehensive education initiatives targeting expectant mothers about the potential risks associated with cannabis use during pregnancy. Advocating for abstinence during this crucial developmental period is essential to safeguarding offspring neurodevelopmental trajectories and mitigating the long-term effects on mental health outcomes.

In summary, prenatal cannabis exposure is linked to a range of neuropsychiatric issues affecting behavioral, psychiatric, and cognitive domains in offspring. However, there is a critical need for more research, particularly well-designed prospective studies, to further elucidate these associations.

The American College of Obstetricians and Gynecologists (ACOG) strongly advises against the use of cannabis during pregnancy because of concerns regarding impaired neurodevelopment, as well as maternal and fetal exposure to the adverse effects of smoking.² ACOG recommends that pregnant individuals and those considering pregnancy should be informed about the potential adverse effects of cannabis on fetal development and pregnancy outcomes.² ACOG emphasizes that there is insufficient evidence to support the safety of cannabis use during pregnancy and encourages healthcare providers to counsel patients about the risks associated with cannabis use, including its potential effect on fetal growth and neurodevelopment, and advocates for avoiding cannabis use entirely during pregnancy and lactation to promote the best possible health outcomes for pregnant women and their offspring.²

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