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Use of cannabis and nicotine together during pregnancy was associated with higher risks for infant death and maternal and neonatal morbidity compared with no exposure to either substance, with dual-use risk estimates higher than with either substance alone, according to a retrospective population-based cohort study.

Compared with use of neither substance, the risk of infant death was more than twice as high with combined use in pregnancy after controlling for possible confounders (adjusted risk ratio [aRR] 2.18, 95% CI 1.82-2.62), reported Jamie O. Lo, MD, MCR, of Oregon Health & Science University in Portland, and colleagues.

By comparison, risks were 65% higher with cannabis use only (aRR 1.65, 95% CI 1.41-1.93) and 62% higher with nicotine use only (aRR 1.62, 95% CI 1.45-1.80) versus no exposure, the researchers detailed in .

For those with both cannabis and nicotine use, risks were also highest for neonatal death, preterm delivery, admission to the neonatal intensive care unit (NICU), and being small for gestational age.

"Although the risk of infant mortality was higher in both cannabis and nicotine users than controls, the risk in individuals who used both was much higher than the risk associated with cannabis or nicotine use alone," the authors pointed out, noting that the increased rate of infant death suggests a "possible synergistic effect" from combined use of the two substances.

Lo told 番茄社区app in an email that she and her colleagues were surprised to see the increased infant death rate in the combined cannabis and nicotine users compared with those using each substance alone.

"We also did not expect so many maternal and neonatal/infant outcomes to be worse with combined cannabis/nicotine use," she added.

Severe maternal morbidity events -- including acute myocardial infarction, aneurysm, acute kidney failure, acute respiratory distress syndrome, eclampsia, and heart failure, among others -- were highest in patients using both cannabis and nicotine compared with controls (aRR 1.46, 95% CI 1.29-1.64), but also significantly elevated for those using only cannabis (aRR 1.33, 95% CI 1.22-1.45) or nicotine (aRR 1.42, 95% CI 1.34-1.50).

"The severe maternal morbidity is likely a reflection not only of cannabis/nicotine use in pregnancy, but use prior to pregnancy as well, since more than half of individuals using cannabis continue to use cannabis when pregnant," Lo said.

Previous studies have examined the effects of cannabis and nicotine exposure individually, but the effects of their combined use are largely unknown, Lo and team noted.

Other studies in U.S. adults have suggested a link between cannabis use and increased cardiovascular risks. The relationship between tobacco use and high blood pressure is also well-known, Lo said.

The new study findings highlight the need for more effective public health measures and clinician counseling prior to conception or during pregnancy to help mitigate adverse outcomes, she noted. "Although it is ideal for patients to abstain from both substances ... cessation of one is still better than none."

It is also important that clinicians emphasize that "there is currently no known safe amount of cannabis or nicotine to be used in pregnancy," she stressed.

For this study, Lo and colleagues used linked hospital discharge data from the California Department of Health Care Access and Information and vital statistics from the California Department of Public Health from January 2012 through December 2019. Pregnant individuals with singleton gestations and gestational ages of 23 to 42 weeks were included, for a total of 3,129,259 participants.

Mean age was 29.3, 52.9% were Hispanic, 28.5% were white, 13.1% were Asian or Native Hawaiian or Other Pacific Islander, and 5.2% were Black.

Of the total study sample, 0.7% used cannabis, 1.8% used nicotine, and 0.3% used both during pregnancy.

Unadjusted rates of infant deaths were 1.2% with combined use, 0.7% with cannabis or nicotine use only, and 0.3% with use of neither. Of note, rates of hypertensive disease were highest in patients who used cannabis only (12.3%) compared with controls (7.6%), those who used nicotine only (9.6%), or those who used both nicotine and cannabis (11.2%).

For the combined versus no exposure group, rates were as follows for the other outcomes studied: preterm delivery (<37 weeks; 17.5% vs 6.6%, respectively), very preterm delivery (<32 weeks; 2.9% vs 0.8%), severe maternal mortality (2.6% vs 1.3%), non-transfusion severe maternal morbidity (1% vs 0.4%), NICU admission (22.5% vs 10%), small for gestational age (18% vs 8.5%), respiratory distress syndrome (7.5% vs 3.4%), neonatal death (0.6% vs 0.2%), post-neonatal death (0.6% vs 0.1%), hypoglycemia (3.8% vs 2.1%), and bronchopulmonary dysplasia (0.2% vs 0.1%).

Compared with no exposure, adjusted values showed elevated risks for nearly all outcomes with cannabis or nicotine alone, and with combined use. The highest risks with combined use were also observed for the following:

• Preterm delivery: aRR 1.83 (95% CI 1.75-1.91)
• Very preterm delivery: aRR 1.61 (95% CI 1.43-1.81)
• Non-transfusion severe maternal morbidity: aRR 1.63 (95% CI 1.34-1.99)
• NICU admission: aRR 1.78 (95% CI 1.71-1.84)
• Small for gestational age: aRR 1.94 (95% CI 1.86-2.02)
• Neonatal deaths: aRR 1.76 (95% CI 1.36-2.28)
• Post-neonatal deaths: aRR 2.87 (95% CI 2.21-3.73)
• Hypoglycemia: aRR 1.49 (95% CI 1.35-1.65)

Compared with controls, participants who used both cannabis and nicotine were more likely to be white (50.7% vs 27.9%), to have public or no insurance or be self-insured (87.5% vs 52.3%), and to have had fewer than five prenatal visits (20.5% vs 2.2%). Additionally, those who used both cannabis and nicotine had a higher proportion of mental health disorders, chronic hypertension, and pre-existing diabetes compared with controls.

Lo and colleagues noted that they relied on ICD-9-CM and ICD-10-CM codes, which means the study is subject to misclassification bias and may underestimate the true prevalence of both substances used and their associated outcomes. In addition, their data come from only one state, so the results may not be generalizable to other parts of the U.S. They were also not able to differentiate the timing, duration, quantity, dose, frequency, or mode of cannabis/nicotine administration used.

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