Marijuana adverse neonatal outcomes

 

A systematic review and meta-analysis found that neonates exposed to marijuana in utero may have increased likelihood of several adverse outcomes (see marijuana adverse neonatal outcomes jama2022 in dropbox, or doi:10.1001/jamanetworkopen.2021.45653).

 

Details:

-- 16 studies with 59,138 patients were included. studies were all cohort studies: 14 in the US, one in Canada, and one in Jamaica

-- study group sizes varied from 30 using marijuana versus 25 not, to 1245 using marijuana and 11,178 not

-- the studies were reported as early as 1983, with six of them before the year 2000

-- primary outcomes: the rate of babies born at low birth weight (<2500g), small for gestational age (SGA, weight less <5^th percentile), rate of preterm delivery (<37 weeks), birth weight, rate of neonatal intensive care unit admission, gestational age at the time of delivery, rate of five-minute Apgar score <7, Apgar score at 1 minute, infant head circumference, infant length, and Apgar score at 5 minutes

 

Results:

-- comparing those who used marijuana versus nonusers:

    -- low birth weight (8 studies, 47,310 patients): twice the risk, RR 2.06 (1.25-3.42), p=0.005

    -- small for gestational age (6 studies, 22,928 patients): 61% increased risk, RR 1.61 (1.44-1.79), p<0.001

    -- birth weight (10 studies, 18,405 patients): mean decrease of 112.30 g (- 167.19 to -57.41), p<0.001

    -- preterm delivery (12 studies, 48,864 patients):28% increased risk, RR 1.28 (1.16-1.42), p=0.001

    -- neonatal ICU (6 studies, 18,615 patients): 38% increased risk, RR 1.38 (1.18-1.62), p<0.001

    -- neonatal head circumference (3 studies, 2425 patients): mean difference -0.52 centimeters (-0.95 to -0.09), p=0.02

    -- infant length (4 studies, 2480 patients): no significant difference

    -- gestational age at the time of delivery (8 studies, 9864 patients): no significant difference

    -- Apgar score at 1 minute (2 studies, 1253 patients): decreased, mean difference -0.26 (-0.43 to -0.09), p=0.002

    -- Apgar score at 5 minutes (3 studies, 1415 patients): no significant difference

    -- Apgar score <7 at 5minutes (3 studies, 9740 patients): no significant difference

-- almost all of these results had significant heterogeneity between the studies, most of which they were not able to adjust for mathematically

 

Commentary:

-- the % of women using marijuana while pregnant varies pretty dramatically between studies, several citing 2-5% range. Much of this is self-reported and subject to inaccuracy/underreporting (lab tests at time of delivery tend to indicate higher usage than self-reported use). Other studies done in inner-city communities suggest 15-28% range. Studies in different countries (US, Australia, Canada, France, UK, the Netherlands) also find prevalence up to 22.6%: see https://pubmed.ncbi.nlm.nih.gov/31529594/

-- a survey study of 306 women (see https://pubmed.ncbi.nlm.nih.gov/28252456/) found that:

    -- 35% reported using cannabis at time of pregnancy diagnosis

    -- 34% of those using cannabis pre-pregnancy continued who use marijuana during the pregnancy 

    -- 69% who had used cannabis thought it might be harmful during pregnancy

        -- 26% of those who thought cannabis would be harmful still continued using it

    -- 10% also stated that they would use marijuana if it were legalized

    -- women's motivation to quit:

        -- 74% of quitters stopped because of fear it could do harm to infant, but 69% of those who continued cannabis thought it was okay for the infant

        -- 16% of quitters stopped because their doctor told them so, and only 31% of cannabis continuers stopped on doctor's advice

            -- these last two points really bring up the issue of how well we clinicians are talking about marijuana use in pregnant (and pre-pregnant) women. simply stating that they should stop may not be nearly enough. here is where motivational interviewing might really help, which really elicits the woman's perceptions/fears/etc and involves them directly in discussion about how they might be best motivated to quit, in a patient-centered way

            --and, this study really highlights one of the downsides of legalizing marijuana: in the above study, more women thought they would use marijuana if legalized

 

-- the above meta-analysis/systematic review found major adverse infant effects in women using marijuana while pregnant in almost all of the outcomes measured, other than mean gestational age, risk of 5-minute Apgar score <7, mean Apgar score at 5minutes, or mean infant length

-- there are potential confounders in the studies (and as a meta-analysis, measurement and controlling for these confounders varied from study to study), but of particular note many studies did not control for tobacco use. Some of these studies in a prior meta-analysis found that several of these adverse neonatal associations with marijuana use were not significant when controlling for tobacco use and other confounding factors, however a newer robust study does suggest that tobacco use did not explain the differential outcomes: see https://doi.org/10.1016/j.drugalcdep.2021.108507, which specifically controlled for cigarette smoking status, and found that 1 in 4 infants with prenatal cannabis exposure (per patient report) was small for gestational age, 1 in 8 were low birth weight, and cannabis use >1x/wk was associated with low birth weight

--There are no studies looking at ingestion of cannabinoids versus inhalation of marijuana smoke

 

-- there are potential physiologic mechanisms that might account for these adverse changes in neonates:

    -- cannabinoid receptors are detected very early in embryonic development

    -- the endocannabinoid system plays a role in the early stages of neonatal neuronal development and cell survival

    -- cannabis is also associated with regulation of glucose and insulin, which could affect fetal growth

    -- a recent report found that delta-9-tetrahydrocannabinol (THC) disrupts estrogen signaling in the human placenta

 

Limitations:

-- these studies spanned a 40-year period, with the largest study by far being reported in 1983. The THC content of marijuana has changed dramatically in this period of time, with many more different varieties and much higher potency over the past several years. A meta-analysis such as this one, especially with one quarter of the total participants being reported in 1983, limits the generalizability of these results to the present time

-- there is no quantification of the amount or intensity of marijuana used. most of the studies had a single questionnaire and one cannot differentiate those pregnant women who tried marijuana once vs those who were habitual users

-- as with meta-analyses in general, there was no consistency with how the studies were done. For example 75% of the studies did not examine differences in the frequency of marijuana use or the amount, and 88% did not assess the marijuana exposure more than once (i.e. no longitudinal data)

-- also, 91% of the studies did not blind outcome assessors to the exposure status of the patients

-- as mentioned above, as a meta-analysis these studies did not all control for appropriate confounders in a systematic way. to the extent they did, it was mostly focused on cigarette smoking. However there are an array of important potential confounders, including adequacy of prenatal care, nutrition, stress, domestic violence, illicit drugs/alcohol, depression, other psychosocial factors, etc, all of which might be different between marijuana users versus nonusers during pregnancy.  And these biopsych0social factors could all affect pregnancy outcomes.

-- as a constellation of observational studies, one is not able to determine causality, only association. And, it is pretty unlikely that we will have a randomized controlled trial with some pregnant women randomized to smoking marijuana versus placebo....

 

So, a disturbing article in that marijuana use during pregnancy may have very significant long-term effects on the infant (and perhaps spanning their whole life). In this light, there do seem to be some important imperatives:

-- we clinicians should regularly and routinely inquire about marijuana use and provide clear education (whether the patient states they use marijuana or not) about the clear potential for long-term harm to the infant.

-- we should also employ the well-tested motivational interviewing technique when appropriate to help women understand the risks of marijuana

-- there is certainly concern that the legalization of marijuana will be seen as a societal legitimization of marijuana that trivializes the risks and may well lead to increased use

-- and there really should be aggressive public health initiatives to publicize these risks

 

and, the new wrinkle: the increased use of cannabis gummies by teens https://www.wsj.com/articles/talking-to-teens-about-cannabis-gummies-as-use-booms-11646717498 . and also the increased use of alcohol/drugs during covid/social isolation: http://gmodestmedblogs.blogspot.com/2020/08/covid-severe-psych-substance-use.html

 

geoff

 

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