“We’ed” Better Work Together to Address Cannabis Use in Pregnancy

Authors:
Courtney Cameron, PharmD, BCACP

Reviewers:
Leah Sera, PharmD, MA, BCPS
Stuart T Haines, PharmD, BCACP, BCPS

Citation:
Metz TD, Allshouse AA, McMillin GA, et al. Cannabis Exposure and Adverse Pregnancy Outcomes Related to Placental Function. JAMA. 2023;330(22):2191-2199. doi:10.1001/jama.2023.21146

The Problem

Over the last several decades, the popularity of cannabis (aka marijuana, weed) has increased significantly, and the recognition of medical benefits is evolving. Recent proposed federal legislation would reclassify cannabis as a Schedule III rather than a Schedule I substance.¹ Cannabis is often celebrated in popular culture as a relaxation-promoting, pain-relieving, harmless substance, and its use among young adults and pregnant women is increasing steadily.^2,3 By one national survey, use among pregnant women of any age in the past month increased 62% from 2002 to 2014.³ Despite the explosion in popularity and impending federal rescheduling, many available products have unregulated potency and purity.  Furthermore, clinical studies regarding the health outcomes of cannabis use during pregnancy are limited.¹

What’s Known

Pregnant women may be motivated to use cannabis for its proposed health claims. One qualitative study that aimed to describe motives for use identified that women use cannabis for:⁴

•    Sensation seeking: fun, relaxation

•    Therapeutic seeking: relieve depression, anxiety, pain

•    Coping or escape seeking: sleep, stress relief, focus

Women in the pre-pregnancy and lactation period reported using cannabis for all of these reasons. However, pregnant women who participated in this study reported using cannabis principally as a therapeutic solution to symptoms that pre-existed prior to their pregnancy, such as chronic pain exacerbated by weight gain during pregnancy, or symptoms that were related to pregnancy, such as depression, anxiety, or nausea, especially nausea refractory to prescription medicines.⁴

Symptoms of depression and anxiety are common during pregnancy and after delivery. The American College of Obstetricians and Gynecologists (ACOG) estimates that 10% of women are affected by depression during pregnancy, sometimes for the first time in their lives.⁵ Nausea is also a common occurrence during pregnancy, especially during the first trimester. An estimated 70-80% of women will experience nausea or vomiting at some time in their pregnancy.⁶

To better understand the risks of cannabis use during pregnancy, it is important to understand fetal development over time. Major milestones are outlined in the table below:

Table 1. Fetal Development by Trimester⁷

First Trimester	– Organogenesis. Neural tube (early brain and spinal cord), digestive system, heart, circulatory system, lungs form.  – Fingers, toes, eyes, nose, mouth, ears, and external genitalia become distinct.  – Fetus is most susceptible to damage from maternal substance use.
Second Trimester	– Muscle tissue and bone develop. Fetal movements can be felt.  – Bone marrow begins making blood cells. – Lower airways develop.
Third Trimester	– Nervous system can control some body functions.  – Fetus is growing quickly and storing fat.  – Bones and muscles are fully developed. Fetus begins storing iron, calcium, and phosphorus.

What’s New 

A recently published ancillary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) aimed to characterize the association between maternal cannabis use and adverse pregnancy outcomes.⁸The primary outcome of interest in this analysis was a composite of small-for-gestational-age birth, medically indicated preterm birth, stillbirth, or hypertensive disorders of pregnancy. Secondary outcomes of interest were the individual components of the primary outcome, cesarean birth, spontaneous preterm birth, placental abruption, admission to the neonatal intensive care unit, neonatal morbidity, and neonatal death. Cannabis use was assessed using urine immunoassay and grouped according to (A) no exposure, (B) exposure during the first trimester only or (C) ongoing exposure throughout the pregnancy. 

The analysis included 9257 individuals, of which, 610 (6.6%) were exposed to cannabis. Of these 610 individuals, 197 (32.4%) were exposed to cannabis in the first trimester only. The remaining 413 participants (67.6%) were exposed throughout the pregnancy (first through third trimester). In terms of baseline demographics, individuals exposed to cannabis were more commonly exposed to nicotine and illicit substances (cocaine, opioids, amphetamines, benzodiazepines) compared to non-cannabis-exposed individuals. 

Results of the primary and secondary outcomes are available in Table 2. Adjusted risk accounted for notable covariates by matching individuals on: sociodemographic factors, nicotine exposure, body mass index, and maternal comorbidities. Overall, cannabis exposure at any time during pregnancy was associated with an adjusted 27% increased risk of the primary outcome. Additionally, cannabis exposure was associated with an adjusted 52% increased risk of small-for-gestational-age birth. No other secondary outcomes were statistically significant in the adjusted models. 

Table 2. Primary and Secondary Outcomes

	Cannabis exposure	No exposure	Unadjusted absolute difference (95% CI)	Relative risk (95% CI) Adjusted
Primary Outcome: Composite adverse pregnancy outcomes	25.9%	17.4%	8.5  (4.9 to 12.1)	1.27 (1.07 to 1.49)
Hypertensive disorders of pregnancy	16.0%	12.9%	3.1 (0.1 to 6.1)	1.13 (0.91 to 1.40)
Small-for-gestational-age birth (less than fifth percentile)	8.6%	4.2%	4.4 (2.1 to 6.7)	1.52 (1.08 to 2.14)
Medically indicated preterm birth	3.9%	3.2%	0.7 (−0.9 to 2.3)	0.78 (0.49 to 1.24)
Stillbirth	1.5%	0.5%	1.0 (0 to 2.0)	1.63 (0.69 to 3.88)
Cesarean birth	26.5%	27.8%	−1.2 (−4.9 to 2.4)	0.98 (0.84 to 1.14)
Abruption	0.5%	0.9%	−0.4 (−1.0 to 0.2)	0.45 (0.13 to 1.64)
Spontaneous preterm birth (before 37 weeks)	7.7%	5.1%	2.5 (0.3 to 4.7)	1.06 (0.75 to 1.49)
Any preterm birth (before 37 weeks)	11.4%	8.3%	3.2 (0.5 to 5.8)	0.94 (0.72 to 1.22)
Neonatal intensive care unit admission	18.6%	14.2%	4.4 (1.2 to 7.6)	1.16 (0.95 to 1.41)
Neonatal morbidity or mortality	1.9%	1.3%	0.6 (−0.5 to 1.8)	1.15 (0.59 to 2.26)

Ongoing cannabis exposure throughout pregnancy (Group C) was associated with greater risk than no exposure (Group A) or exposure only during the first trimester (Group B). See Table 3. Description of the adjustment for confounders is available in the original publication.

Table 3. Secondary Analysis of the Primary Composite Outcome

	Adjusted relative risk (95% CI)
Any cannabis exposure	1.27 (1.08-1.51)
Cannabis exposure only during first trimester (Group B) vs no exposure (Group A)	1.18 (0.87-1.59)
Ongoing cannabis exposure (Group C) vs no exposure (Group A)	1.33 (1.09-1.61)

Lastly, a higher urine level of THC-COOH (11-nor-9-carboxy-Δ9-tetrahydrocannabinol), the cannabis metabolite measured in the study, during the first trimester and across the pregnancy was associated with a greater probability of the primary outcome. 

My Critical Appraisal

A critical evaluation of this publication reveals the strengths of its study design. Firstly, the authors adjusted for confounders associated with growth restriction, such as hypertension and pregestational diabetes, as well as maternal nicotine use, all of which negatively influence birth outcomes. Additionally, the conclusions of this study are consistent with prior findings that birth risks are most strongly associated with frequent and repeated cannabis use, perhaps use more than once weekly, as evidenced by the evaluation of cumulative urine cannabis levels.⁹

However, there are several limitations to this analysis, and additional research will be needed in pregnant and postpartum women to confirm (or refute) these findings. Recall that pregnant women most often seek cannabis for its therapeutic effect on chronic syndromes, such as pain and depression.⁴ Although this study evaluated postpartum depression scores, the analysis was not designed to evaluate the confounding role of antepartum depression on birth outcomes in women who use cannabis. Prior studies have demonstrated a positive correlation between antepartum depression and preterm birth, small for gestational age, stillbirth, low birth weight, and maternal morbidity.¹⁰

Additionally, this study did not evaluate the presence of fetal growth restriction in infants born small for gestational age. Infants born small for gestational age, without fetal growth restriction, are not necessarily at higher risk of morbidity and mortality solely because they are small.¹¹ Rather, it is the presence of fetal growth restriction that drives morbidity in small for gestational age infants. The incidence rate of fetal-growth-restricted, small-for-gestational-age infants in the United States and Australia (high-income countries) is approximately 11%. Lastly, it is important to consider the methods for which cannabis exposure was assessed. Urine was collected at three visits (one per trimester) over the course of the pregnancy, and levels of THC-COOH were quantitatively measured. However, THC-COOH levels may have fluctuated in an unpredictable manner over time. Assuming a period of several weeks between visits, it would be plausible to consider that patients identified as “negative” may have indeed been exposed to cannabis in small or infrequent amounts, leading to a false negative result. Conversely, cannabis exposure could have been falsely positive for women who were perhaps heavily exposed prior to pregnancy but, after becoming pregnant and despite cessation, could have detectible cannabis urine levels due to redistribution from fat tissue and hair. All of these possibilities may have influenced the findings, highlighting the importance of evaluating quantitative THC-COOH levels in relation to outcomes.

The Bottom Line

Marijuana use was associated with a greater risk of adverse birth outcomes in a dose- and exposure-dependent manner. These data raise concerns, but the results are not irrefutably convincing after adjusting for important confounders. Most notably, the primary outcome was driven by a statistically significant greater risk of small for gestational age birth, while the other components of the primary outcome (hypertensive disorders of pregnancy, medically indicated preterm birth, stillbirth) were nonsignificant after adjusting for confounders. Despite these caveats, this study is a welcomed addition to our (limited) body of knowledge.  Open, non-judgmental, and honest conversations with women planning to conceive and those who are pregnant about the available data related to cannabis exposure are needed so that women can make wise, informed choices. 

Key Points

• Shifting attitudes and greater recognition of the risks and benefits of cannabis have led to rescheduling cannabis, mirroring public opinion about cannabis use in the United States. 
• A small but growing percentage of women use cannabis to manage symptoms such as pain, anxiety, and nausea during pregnancy. 
• Cannabis exposure during pregnancy may increase the risk of poor pregnancy outcomes, particularly small-for-gestational-age birth (less than the fifth percentile) — but more research is needed to understand the potential risks (and benefits) of cannabis use during pregnancy.

---

CONTINUING EDUCATION CREDIT

Click on this link to obtain continuing education credit for reading this commentary and listening to the associated podcast episode. Or you can visit PharmacyCPD.org and enroll in this course. You’ll need to sign into the learning management system in order to claim credit. If you do not already have an account with PharmacyCPD.org, you’ll need to create one.

The University of Mississippi School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is approved for 0.5 hour of continuing education credit. UAN: 0032-0000-24-046-H01-P

At the completion of this activity, the participant will be able to:
1. Identify current trends of marijuana use between pre-pregnancy, antepartum, and postpartum women.
2. State the potential risks of marijuana use in pregnancy on birth outcomes.
3. Formulate an appropriate treatment plan for a patient case that considers the risks of marijuana use in pregnancy.

In order to claim CE, you’ll need to read the commentary, listen to the podcast episode in its entirety, and correctly answer 2 out of 3 self-assessment questions. The questions go beyond the information in the study, and you may need to consult additional resources using the reference list below.

Cost = Free

References