Should cannabis products include warning labels for pregnant women? Project CBD responds to a public comment request from the California Office of Environmental Health Risk Assessment.
Project CBD firmly maintains that current scientific research does not support the designation of cannabis, THC, cannabis extracts or cannabis smoke as a developmental toxin under Proposition 65.
Key Findings:
There is insufficient evidence that maternal use of cannabis causes low birthweight or long-term adverse developmental outcomes.
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No negative effects are attributed to cannabis exposure when tobacco and alcohol consumption are taken into account.
Designation of cannabis and THC as reproductive toxins under Proposition 65 would divert public health and harm efforts to reduce known teratogens (fetal toxins), such as alcohol and tobacco.
Although cannabinoids are not inherently toxic, they can amplify the toxic effects of alcohol, nicotine and other teratogens. Therefore, public health messages should be tailored to pregnant women who use multiple substances.
INTRODUCTION
Labelling cannabis, cannabis extracts, cannabis smoke or THC as reproductive toxins is not justified on the basis of high quality scientific evidence.
Concerns about cannabis in pregnancy have far outweighed scientific data showing negative effects.
These fears are engendered by poorly designed studies that do not account for exposure to well-established teratogens, such as tobacco and alcohol, as well as confirmation bias and lack of understanding of the statistics.
In almost all primary studies that claim that cannabis use during pregnancy is harmful, the authors admit that the results are confused with the use of other drugs.
But instead of designing better studies, these repetitive failures can accumulate, creating a body of research that seems to show that cannabis is dangerous in pregnancy.
In fact, proper analysis of currently published data indicates otherwise.
The consensus of meta-analyses actually provides some evidence (albeit weak) that cannabis does not produce negative pregnancy outcomes, as highlighted in a 2016 publication by the American College of Obstetricians and Gynecologists:
"While these data do not imply that marijuana use during pregnancy should be encouraged or tolerated, the lack of a meaningful association with adverse neonatal outcomes suggests that the focus should be on helping pregnant women stop using substances that have adverse effects on pregnancy, such as tobacco," not cannabis.1
WHY ARE ONLY META-ANALYSES CONSIDERED "HIGH QUALITY" EVIDENCE?
This public comment only considers meta-analyses, a type of study that attempts to draw firm conclusions from the weight of published evidence. Meta-analyses are considered the highest standard of evidence in medical research, although they are limited by the quality of the publications they review.
There is a high rate of false positives in scientific research,2 mainly due to misinterpretation of statistics and publication bias (a tendency to ignore contradictory data and, preferably, to publish positive results).
This can sometimes be corrected by meta-analysis, which can be detected to detect confounding variables even when primary research is unable to do so. It is related to the Simpson paradox,3 where aggregate analysis demonstrates the opposite effect of many small studies.
In the context of cannabis, almost all studies on cannabis and pregnancy are confused with the use of teratogens (fetal toxins) such as tobacco or alcohol. It is true that primary studies often find harmful effects in the cannabis group.
But the aggregation of many studies into a meta-analysis allows the real culprit (tobacco) to be adequately controlled, and the apparent harms associated with cannabis disappear.
EVIDENCE ON ADVERSE PREGNANCY OUTCOMES
Three meta-analyses have been published on cannabis and pregnancy outcomes. They focus primarily on the effect of cannabis and tobacco on birth weight, as well as on preterm birth and other indicators of the health of babies. The most recent meta-analysis, published in 2016 by Connor4, analysed 31 separate studies.
Comparing about 8,000 babies born to mothers who use cannabis with more than 120,000 control babies, they conclude that "the association between maternal marijuana use and adverse pregnancy outcomes can be attributed to concomitant tobacco use and other confounding factors and not just to marijuana".
Unlike most primary sources they considered, their study was pre-registered, which is known to dramatically reduce the risk of false positive results.
LOW BIRTH WEIGHT AND LONG-TERM EFFECTS
The first meta-analysis of the effect of cannabis on developmental outcomes was published in 1997 by English et al. 7 They analyzed ten studies, considering only publications that explained tobacco use among pregnant mothers.
The results are quite similar to those of Connor et al.: they found that cannabis was associated with a 9% increased risk of low birth weight, which was not statistically significant.8
English et al. note that there is a bias toward false-positive results. For example, one study did not report numbers for cannabis because it did not have any harmful effects; therefore, this safety-showing result could not be included in its analysis.
It is remarkable that although this publication bias promotes false positive results, the meta-analysis was negative: it did not show a statistical effect of cannabis.
They conclude that "there is insufficient evidence that maternal cannabis use, at commonly reported levels of use, causes low birthweight".
The final study on this topic, a 2016 meta-analysis published by Gunn et al., 9 is straightforward about its limitations. "It is not known whether the effects found in this manuscript are related to cannabis or are a by-product of alcohol and tobacco consumption," they caution.
Their analysis published 24 studies and attributed some damage to cannabis (an average decrease of 109 grams in birth weight, a seventy-seven per cent increase in odds of low birth weight, increased risk of anaemia and other complications).
However, unlike the Connor and English studies, this report does not attempt to disentangle the known toxicity of tobacco from the postulated effect of cannabis. As a result, Gunn's analysis does not clearly demonstrate the reproductive toxicity attributable to cannabis use.
The researchers explicitly acknowledge this: "In conclusion, the effects of cannabis on maternal and fetal outcomes remain generally unknown. 11
TOBACCO TOXICITY
A 2017 report from the National Academies of Science, Engineering and Medicine indicated that there is evidence of a statistical association between cannabis and low birth weight12. It is not clear why Connor's meta-analysis was not considered.
In summary, accounting for tobacco use among pregnant women improves the quality of reviews and eliminates any verifiable harm due to cannabis. The available research provides some evidence against the idea that cannabis causes complications in pregnancy.
All three meta-analyses conclude that harm cannot be attributed to cannabis, although they do not definitively prove that such harm does not exist.
More research is needed, but current scientific results do not support the designation of cannabis, THC, cannabis extracts, or cannabis smoke as a developmental toxin under California Proposition 65.
Project CBD could only find another meta-analysis that evaluated how prenatal cannabis exposure affects development in humans.13 The study sought to predict the likelihood of future behavioral problems.
Only three studies on cannabis were included in the analysis. If cannabis caused an effect, it was too small to be detected statistically.
The researchers "report that there are no clear effects of exposure [in utero] to cannabis" on behavioral problems.14 Therefore, there is not enough evidence to suggest that cannabis causes long-term adverse developmental outcomes.
COMMENTARY ON PRECLINICAL RESEARCH
If researchers are concerned about the harmful effects of cannabis on pregnancy, it is clearly unethical to intentionally expose pregnant women to cannabis. Preclinical research is an alternative to the cross-sectional and longitudinal studies on which previous meta-analyses are based.
Despite many limitations, preclinical studies have shed light on an important direction for human research and harm reduction. Although cannabinoids do not appear to cause adverse developmental outcomes, they may amplify the toxic effects of alcohol, nicotine and other teratogens.
Preclinical studies in mice and rats consistently indicate that activation of the endocannabinoid system exacerbates fetal alcohol syndrome.
Cannabinoids normally regulate cell death. In the combined presence of fetal growth factors and inflammatory molecules, cannabinoids can activate endogenous systems used to kill cancer cells.17 This leads to
Darleen Prangue writes for CBD and other drug-related issues.