The number of episodes of marijuana use over 3 months was also recorded at 15 weeks and 20 weeks of gestation. Other drug use was also recorded, including cocaine, amphetamines, substance 1 a scale between 10 and 90 generated using an algorithm involving age, income and education. A higher score indicates higher socioeconomic status.It is a validated measure of individual socioeconomic status. P, Ecstasy, opiates, and hallucinogens, with less than 0.6% of women who have taken these drugs 3 months prior to or during pregnancy in SCOPE, but there were insufficient data to be included for analysis. Self- reported marijuana and cigarette smoking status were classified into five categories in univariable and multi-variable analysis, with ‘non-smoking’ or ‘never used marijuana’ as the reference categories. The number of reported episodes of marijuana use was included as a continuous variable for frequency effect estimation. Use was self-reported where women provided the number of joints or cones used. Spontaneous preterm birth was defined as birth at less than 37 weeks of gestation that was not a result of medical or obstetric intervention. Small for gestational age was defined as a birthweight of less than the 10th customised centile, adjusted for maternal height, weight, parity, ethnicity, gestational age at delivery and infant sex. Preeclampsia was defined as gestational hypertension accompanied by proteinuria.Gestational diabetes mellitus was defined as a fasting glucose of 5.5 mmol/L or higher in a Glucose Tolerance Test, a 2 h level of 8 mmol or higher, or a random glucose level of 11 nmol/L or higher. Universal screening was not employed for GDM in the UK and Ireland, where only women identified at risk based on factors such as family history and BMI were screened.
A total of 5588 participants were included in the analysis, with 1155participants recruited from Australia, 2014 from New Zealand, 1765 from Ireland, and 654 from the United Kingdom. Within the 1514 pregnancies with complications, 278 had PE, 633 had SGA, 236 had SPTB, 470 had GHT, and 143 had GDM.Details on age, BMI, SEI, as well as marijuana grow system use and cigarette smoking status were complete for all participants. Marijuana and cigarette smoking status were compared between non-cases and each of the outcomes separately using Fisher’s exact test. Although about 4% of women had more than one pregnancy complication, each outcome was analysed separately compared with non-cases. Continuous factors, including maternal age, BMI and SEI were compared using Student’s t-test. To investigate the effects of marijuana use between smokers and non-smokers, analysis of marijuana use, stratified by cigarette smoking status for each outcome was performed. Breslow-Day test was used to assess the homogeneity of the odds of marijuana use between cigarette smokers and non-smokers, along with an adjusted common odds estimated from Mantel-Haenszel test.Marijuana and cigarette smoking status were then analysed with mixed effects logistic regression to determine the association with pregnancy outcomes, adjusting for maternal age, BMI and SEI, and with recruiting centre differences accounted for as a random effect. Interaction tests were also performed by comparing logistic regression models that included interaction terms. A linear mixed model was also fitted for length of gestation, with quadratic terms for the number of times marijuana was used over the preceding 3 months at 15 and 20 weeks of gestation, age, and BMI, to investigate the dose effect of marijuana and cigarette smoking status on the length of gestation adjusted for other factors in the model. The estimated power of this analysis, involving logistic regression with interaction terms, is 0.99.
All statistical analyses were performed using R version 3.2.0.Breslow Day test showed no evidence of heterogeneity in the association of marijuana use and pregnancy outcomes between smokers and nonsmokers,which indicates that the association between marijuana and SPTB was consistent regardless of cigarette smoking status. Hence, when comparing any marijuana use, three months prior to or during pregnancy, between cigarette smokers and non-smokers, there was a significant independent association between any marijuana use and SPTB.While the association between marijuana use and SPTB was independent of smoking status, the Mantel-Haenszel test further indicated that the overall association was also significant,with an adjusted common odds of 2.28.That is, the odds of SPTB for any marijuana use three months prior to or during pregnancy was more than doubled for both cigarette smokers and non-smokers. Regarding the interaction effect of marijuana in women who ceased cigarette smoking during pregnancy, results from Breslow Day test on the homogeneity of the odds of any marijuana use,between women who continued cigarette smoking before 20 weeks’ gestation and those who stopped smoking, showed no evidence of heterogeneity,with a Mantel-Haenszel adjusted odds of 1.97.This indicated that the effect of marijuana use was not only independent of any cigarette smoking three months prior to or during pregnancy,but was also consistent, with nearly doubled odds, irrespective of whether cigarette smoking ceased prior to 20 weeks’ gestation. Results from Logistic regression with an interaction term between marijuana use and cigarette smoking status also showed no significant interaction effects on SPTB .Marijuana use is increasing in women of reproductive age and its continued use in pregnancy has been of concern for some time.In addition, we have anecdotal evidence to suggest that some pregnant women are using marijuana to reduce nausea in early Fig. 2. Predicted length of gestation and number of episodes of marijuana use in women who did or did not also smoke cigarettes in the previous 3 months.Note: actual range of marijuana use 0–450 episodes in 3 months. pregnancy.
In this large prospective cohort of nulliparous women we have demonstrated that continued maternal use of marijuana at 20 weeks’ gestation is a major contributing risk factor for SPTB. Univariable analysis showed a significant association of marijuana use at 20 weeks’ gestation with SPTB and also SGA, but when adjusted for other factors, in particular cigarette smoking, marijuana use was only a significant independent risk factor for SPTB. Furthermore, if marijuana use was continued at 20 weeks’ gestation, women were over five times more likely to deliver preterm than nonusers. Of the women who continued to use marijuana at 20 weeks’ gestation and delivered preterm, nearly 64% delivered at less than 32 weeks’ gestation. Our data do not have sufficient power to determine whether there is a gestational age prior to 20 weeks by which it is advisable to cease marijuana use. Hence, at this stage we recommend that it is prudent to abstain from marijuana use during pregnancy. Based on the current findings and some earlier reports, it is likely that maternal marijuana use is an independent risk factor for SPTB. It has been shown that the active compound of marijuana and its metabolites are able to cross the placental barrier and thereby have the potential to directly affect perinatal outcomes. Whereas the results from this study are in agreement with other studies, it needs to be noted that a few American and a UK prospective cohort studies did not find an association between marijuana use and SPTB. However, these studies have a higher percentage of black race, whereas there are 89.9% Caucasians in this study. Although the studies have also adjusted for ethnicity, age, BMI, and other lifestyle factors, interaction tests were not performed in the analysis to examine the interaction effects of marijuana use and cigarette smoking on pregnancy outcomes.While African American ethnicity has been associated with an increased risk of SPTB, it has also been commonly associated with lower socio-economic status. The relationship of low SEI with pregnancy complications was apparent in this study, where SEI was significantly negatively associated with PE, GHT, GDM, SGA, and SPTB. When adjusted for age, BMI, cigarette smoking, and marijuana use, higher SEI was a protective factor, with a 1–2% decrease in the risk of PE per unit increase in SEI. Similar trends were also seen in previously published SCOPE data. However, the results from the current study showed no significant interaction effects between marijuana use and SEI, suggesting that the association between marijuana use and SPTB was also independent of socio-economic status.
Despite a borderline significance for alcohol consumption at 15 weeks’ gestation for PE risk, our results are consistent with a study by Klonoff-Cohen et al., which showed that maternal alcohol consumption does not appear to have a significant association with preeclampsia. Alcohol consumption during first trimester was not associated with SPTB, consistent with a previous SCOPE publication.However, continued alcohol consumption at 20 weeks’ gestation is a protective factor for SPTB, and a recent study by Lundsberg et al. also showed that alcohol consumption during third trimester was associated with a decreased risk of PTB but not when consumed during early pregnancy. The mechanism of this effect is still unknown. However, as maternal alcohol consumption may damage the fetus we cannot recommend it during pregnancy and indeed the National Health and Medical Research Council Guidelines recommend against its use in pregnancy. Maternal cigarette smoking is typically considered to be a risk factor for SPTB and SGA. Indeed, maternal cigarette smoking at 20 weeks’ gestation was significantly associated with risk of SPTB and SGA in univariable tests, but no longer significant for SPTB when adjusted for other factors, including BMI, SEI, age, and marijuana. Similar results have been found previously in a study by Dekker et al., which incorporated multiple novel risk factors for SPTB. In the current study an association was seen between smoking and SPTB,but cigarette smoking was not found to be an independent risk factor for SPTB after adjustment for marijuana use. Nevertheless, continued cigarette smoking is a significant risk factor for many pregnancy complications including stillbirth, placental abruption and SGA and women should be encouraged to quit before or in early pregnancy. The association between smoking and marijuana is often considered as an interaction effect for pregnancy complications, as the majority of women who use marijuana also smoke cigarettes. In fact, amongst women who used marijuana in the SCOPE cohort, 74% also smoked cigarettes. With a high concurrence rate, the independent effect of cannabis vertical farming on pregnancy outcomes has generally been unrecognised and just considered to be subsidiary, partly due to the low availability of data on marijuana use compared to cigarette smoking for statistical analysis. However, our data from the SCOPE cohort, with 316 participants who were marijuana users, demonstrate that the association of marijuana use with SPTB is consistent across cigarette smokers and non-smokers.
The consistent effect of marijuana use is also apparent when analysing the effect of the estimated number of episodes of marijuana use during pregnancy on the length of gestation. While there was a slight decrease in the predicted length of gestation amongst smokers, the trend for smokers and non-smokers was similar. In contrast, the predicted length of gestation for women who continued to use marijuana at 20 weeks’ gestation was significantly decreased compared to those who ceased earlier ingestation, regardless of smoking status. This is consistent with similar studies which showed that marijuana use is associated with a decreased length of gestation. Furthermore, apart from a cigarette smoking-marijuana interaction, it is also well recognised that cigarette smoking and illicit drug use are associated with low socio-economic status, along with a complex inter-relationship with obesity, where smoking cessation may also lead to obesity. As described in many studies, the prevalence of cigarette smoking and obesity is higher amongst those who are socio-economically disadvantaged, and the incidence of SPTB is higher amongst women with lower income and lower educational status, which may indicate associations with other lifestyle risk factors. Furthermore, if there was no maternal marijuana exposure, with an estimated population attributable risk of 0.003 for marijuana use, the incidence of SPTB would be expected to decrease by 3 cases per 1000 pregnant women. With an overall rate of SPTB of 4.2% in this study, this represents an estimated 6.2% reduction in the incidence of SPTB in the population, i.e. about 3 out of 50 SPTB cases would be attributed to marijuana use. If we consider the Australian centre only, where any marijuana usage occurred in 11.6% of women compared to 3.6–4.5% in the other centres, the estimated PAR was 0.009 for marijuana use with an expected reduction of SPTB of 9 cases per 1000 pregnant women, and a 11.68% reduction in the incidence of SPTB in this centre if women did not use marijuana. That is, in the Australian study centre, almost 12% of SPTB could be attributable to maternal marijuana use.