CANNABIS USE DURING PREGNANCY AND RISK OF ADVERSE NEONATAL OUTCOMES: A LONGITUDINAL COHORT STUDY Svetlana Skurtveit, Ingunn Olea Lund, Jørgen G. Bramness, Roman Gabrhelik, Randi Selmer, Eva Skovlund and Marte Handal Norwegian Institute of Public Health, Norway University of Oslo, Norway Charles University, Czech Republic

Background Cannabis is one of the most frequently used recreational drugs Female use is increasing Reviewsa suggest that in utero exposure to cannabis is associated with adverse neonatal outcomes however there are several methodological limitations in the studies included a Gunn JK eta al. BMJ open. 2016. Huizink AC et al. P Prog Neuropsychopharmacol Biol Psychiatry. 2014. Metz TD et al. Am J Obstet Gynecol. 2015.

Background Liberalization and legalization of recreational cannabis use Use of cannabis for medical purposes is increasing Cannabis products contain more delta-9-tetrahydrocannabinol (THC)

Aim To estimate the strength of the association between cannabis use during pregnancy and neonatal outcomes. - The aim of this study was to examine whether there was an association between use of anxiolytics and hypnotics in pregnancy and language competence at 3 years of age

The Norwegian Mother and Child Cohort Study (MoBa) Prospective population-based pregnancy cohort Pregnant women recruited from 1999 – 2008 40.6 % participation rate Self-administered questionnaires during pregnancy and after birth (ongoing) MoBa cohort Number of individuals Women 92 500 Men 75 200 Children 114 500 In this study we have used data from the norwegian mother and child cohort study (MoBa) Prospective population-based pregnancy cohort Pregnant woman recruited from 1999 – 2008 Data collection is based on self-administered questionnaires that the women receive both during pregnancy and after birth The cohort study is still ongoing

MoBa Questionnaires Child Mother Father Pregnancy start to week 18 Week 19-29 Week 30 to birth Q1 Q3 Q4 Self-reported drug use in pregnancy Week 18 Week 30 Birth 6 months Q1 Q3 Q4 Ultra-sound Child Mother Father

Study population 74 641 pregnancies 65 412 women Exclusions: Where the woman did not answer all questionnaires where cannabis use during pregnancy was to be reported Pregnancies with multiple fetuses The study population consisted of 51 748 pregnancies and 45 266 women The following individuals were excluded from the study…

Definition of exposure and outcome Cannabis user: The women answered questions regarding illegal drug use at pregnancy week 18 and 30, and 6 months postpartum. Duration of cannabis use: 1: earlier in life 2: use the last month before pregnancy only 3: use during pregnancy one period only at least two periods Individuals were defined as users of these drugs if they had reported use of any anxiolytic/hypnotic in at least one of the three periods The individuals were divided into different categories based on duration of use These categories are… Birth outcomes obtained from the Medical Birth Registry of Norway

Possible confounders, mediators and effect modifiers Maternal education Paternal education Maternal age Paternal age Planned pregnancy Maternal smoking Alcohol intake in pregnancy Analgesic opioids use in pregnancy Benzodiazepines use in pregnancy Parity Marital status Pre-pregnancy BMI Maternal working status

Analysis strategy and Statistical methods We chose to restrict the analyses to women with use of cannabis one month before pregnancy or in pregnancy and women smoking in pregnancy Linear regression analysis was used to estimate crude effects on neonatal outcomes We performed propensity score (PS) adjusted linear regression analyses.

No cannabis, but tobacco smoking in pregnancy   No cannabis, but tobacco smoking in pregnancy Cannabis 1 month before pregnacy Cannabis use one period in pregnancy only Cannabis use at least two periods in pregnancy N (%) Number, N 4955 (6.6) 309 (0.4) 209 (0.3) 63 (0.1) Maternal tobacco smoking in pregnancy % No 64.5 54.4 27.3 Sime times 61.4 23.2 30.9 36.4 Daily 38.6 12.3 14.8 Maternal use of illegal drugs % 99.8 27.7 14.7 4.4 Yes, earlier no pregnancy 0.2 70.0 55.9 84.4 Yes, in pregnancy 0.0 2.3 29.4 11.1 Paternal use of illegal drugs % 83.4 9.7 22.4 6.4 Yes, earlier 15.1 20.9 24.8 17.0 Yes, last 6 months before pregnancy 1.3 60.7 44.8 53.2 8.7 8.0 23.6 Maternal alcohol intake in pregnancy % Never 46.6 21.3 20.3 19.0 sometimes 35.8 46.3 40.6 36.5 regularly/binge 17.6 32.3 39.1 44.4 Maternal benzodiazepines use in pregnancy % 98.7 95.8 92.3 90.5 Yes 1.2 4.2 7.7 9.5

Birth outcomes We found that in 395 pregnancies, the women reported use of anxiolytics/hypnotics during pregnancy Of these use during at least two periods was reported in 79 pregnancies Use of these drugs before pregnancy only was reported in 258 pregnancies; these women stopped using the drugs when they got pregnant

Linear regression analysis. Unadjusted analysis   B 95% CI P value Birth weight Cannabis in pregnancy during one period 20 (-135, 175) 0.797 Cannabis in pregnancy during at least two periods -269 (-485, -53) 0.015 Birth length -0.4 (-1.0, 0.03) 0.288 Cannabis in pregnancy during at least two periods -1.5 (-2.5, -0.6) 0.002 Head circumference -0.2 (-0.6, 0.3) 0.528 -0.7 (-1.4, -0.0) 0.042

Linear regression analysis. Propensity score adjusted analysis   B 95% CI P value Birth weight Propensity score adjusted Cannabis in pregnancy during one period 30 (-152,213) 0.743 Cannabis in pregnancy during at least two periods -255 (-510, 0) 0.050 Birth length -0.2 (-1.0, 0.6) 0.546 Cannabis in pregnancy during at least two periods -1.4 (-2.6, -0.3) 0.015 Head circumference -0.1 (-0.6, 0.5) 0.847 -0.6 (-1.3, 0.2) 0.172

Methodological consideration Size of the cohort and the prospective design Controlling for several important potential confounders is possible Information about drug use in several periods Information about dosage is not available Selection bias Under-reporting of drug use Strengths are: - Prospective design → data on exposure is collected before the outcome is measured - Since the women received questionnares quite frequently during pregnancy the risk of recall bias was minimized - Controlling for several important potential confounders is possible - We have information about drug use in several periods;makes it possible to estimate duration and timing of treatment - Information about dosage is not available - From validity studies comparing data in MoBa and the norwegian prescription database it seems that there is a probability for under-reporting of use of these drugs in MoBa. - This is often seen for drugs that are used sporadically - Small study population; although MoBa is a large pregnancy cohort the number of exposures is very low compared to the number of pregnancies, so exposure is rare - We did not have the power to study each drug separately

Conclusions Short-term use did not indicate adverse effects on birth outcome. Pregnant women reporting cannabis use in at least two time period during pregnancy delivered children with lower birth weight and birth length, even after adjusting for potential confounders as for instance smoking. Need further studies

Conclusions Women reporting cannabis use during pregnancy had lower socioeconomic status, used more alcohol, tobacco and prescribed drugs, and had more psychiatric symptoms compared both to lifetime users, tobacco smokers and never users. This illustrates the importance of adjusting for all possible confounders that could influence outcome. Need further studies