Received: 26 April 2022 | Revised: 28 July 2022 | Accepted: 29 July 2022 DOI: 10.1111/aogs.14439 ORIGINAL RESEARCH ARTICLE Intrauterine cannabis exposure and fetal and maternal blood flow: a case–­control study Maia Brik1 | Miguel Sandonis2,3 | Judit Gil1 | Alina Hernandez-­Fleury1 | Gemma Parramón-­Puig2 | Nerea Maiz1 | Anna Suy1 | Elena Carreras1 1 Obstetrics Department, Maternal-­Fetal Medicine Unit, Hospital Universitari Vall Abstract d'Hebron, Barcelona, Spain Introduction: Cannabis consumption during pregnancy increases the risk of preg- 2 Psychiatry Department, Hospital Universitari Vall d'Hebron, Barcelona, nancy and neonatal complications. Since the underlying mechanism is unknown, the Spain purpose of this study is to evaluate the changes in maternal and fetal blood flow in 3 Department of Psychiatry and Forensic pregnancies exposed to cannabis, Δ9-­tetrahydrocannabinol (THC). Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain Material and methods: A case–­control study between 2013 and 2020, included women with continued cannabis exposure during the pregnancies, defined by qualitative detec- Correspondence Maia Brik, Maternal and Fetal Medicine tion of THC in urine (Cannabis Group), and low-­risk pregnancy women divided into tobacco Research Group, Hospital Universitari Vall smokers (Tobacco Group), and non-­tobacco smokers (Control Group). We evaluated the d'Hebron, Passeig de la Vall d´Hebron 119 08035, Barcelona, Spain. association between cannabis consumption and maternal and fetal blood flow parameters Email: maia.brik@vallhebron.cat measured by Doppler ultrasound: uterine artery at 11–­14, 20–­22 and 33–­35 weeks, umbilical artery and middle cerebral artery at 33–­35 weeks. Cerebral-­placental ratio was calculated. Results: Overall, 275 participants were included, 60 in the Cannabis Group, 17 in the Tobacco Group and 198 in the Control Group. At 33–­35 weeks, differences were found in the umbilical artery pulsatility index (PI) (1.05 ± 0.23, 1.06 ± 0.19, 0.93 ± 0.15, P < 0.01), middle cerebral artery PI (1.75 ± 0.35, 1.90 ± 0.45, 1.88 ± 0.34, P < 0.05), cerebral-­placental ratio (1.69 ± 0.40, 1.85 ± 0.53, 2.07 ± 0.47, P < 0.05) and mean uter- ine artery PI (0.89 ± 0.26, 0.73 ± 0.19, 0.74 ± 0.20, P < 0.01), respectively. On logistic regression analysis, adjusted for maternal age, maternal body mass index, maternal weight and white ethnicity, both cannabis and tobacco were predictors for increased umbilical artery PI, but only cannabis was a predictor for a decreased cerebral-­ placental ratio and an increased uterine artery PI at 33–­35 weeks. Conclusions: Data from a large cohort of continuous cannabis exposure pregnan- cies show that cannabis is associated with maternal and fetal blood flow changes. However, it is not possible to disentangle the association of the tobacco and cannabis. KEYWORDS cannabis, Doppler, drugs, fetal blood flow, pregnancy, uterine artery, Δ9-­tetrahydrocannabinol Abbreviations: CPR, cerebral-­placental ratio; MCA, middle cerebral artery; PI, pulsatility index; THC, Δ9-­tetrahydrocannabinol; Umb Art, umbilical artery; Ut Art, uterine artery. This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. © 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Acta Obstet Gynecol Scand. 2022;101:1207–1214.  wileyonlinelibrary.com/journal/aogs | 1207 1208 | BRIK et al. 1 | I NTRO D U C TI O N Key message Cannabis is the most commonly used illicit drug among general and preg- Cannabis consumption during pregnancy is associated nant populations. The prevalence of consumption during pregnancy is with maternal and fetal blood flow changes. However, it around 4.5%.1 Cannabis consumption during pregnancy increases the is not possible to disentangle the association of tobacco risk of maternal, fetal and neonatal complications such as fetal growth and cannabis. restriction or preterm birth and is, later in life, associated with poor neurodevelopmental outcomes in the infants.2–­4 Nevertheless, the mechanisms underlying these effects are still unknown. checked routinely to assess the cannabis consumption by urine anal- Exogenous cannabis such as Δ9-­tetrahydrocannabinol (THC) and ysis in all three trimesters of pregnancy using enzyme immunoassay. its metabolites freely pass the placental barrier and act over the two The local antenatal care protocol includes a routinely check on cannabinoid-­receptors identified: CB1-­receptor, highly expressed in drug abuse. If women confirm drug abuse during the routine medical the brain, but also in the peripheral tissues, and CB2-­receptor, pre- anamnesis, they are referred to a hospital-­based perinatal mental dominantly expressed in immune and hematopoietic cells, but also in health specialized unit, where, after consent, a urine analysis for the the heart and endothelial cells of various origins.5 Endogenous can- detection of drugs is performed. nabinoid system plays an important role in cardiovascular regulation, and exogenous cannabinoid such as THC, acting via endogenous cannabinoid receptor, shows a cardiovascular effect similar to the 2.2 | Control group endogenous cannabinoid. They reduce the tone of the blood vessel with a decrease in blood pressure and increased vascular flow.6 Participants in the control group were selected from the ultrasound THC is consumed mixed with tobacco most of the time, and it database (Viewpoint) and only included women with low-­risk preg- is difficult to determine the isolated effect of cannabis in the pla- nancies. Women with prenatal risk factors, fetal growth restriction, cental and fetal vascular system. It has been reported that nicotine diagnosis of hypertension, diabetes, multiple pregnancies and con- exposure during pregnancy impairs the uterine vascular function, genital abnormalities were excluded. The rationale for excluding leading to an increased vascular resistance and a decrease in uter- these women was that the objective of the study was to analyze 7 ine blood flow. Few studies have focused on the cannabis vascular the effect of cannabis on the vascular system, and therefore a priori adaptations during pregnancy. It has been suggested that cannabis women with high risk of complications may have an altered vascular use during pregnancy is indeed associated with adaptations in fetal system. This group was divided into tobacco smokers during preg- placental and cardiac blood flow, but not with cerebral blood flow.8 nancy group and control group, according to tobacco smoking after However, the maternal and fetal hemodynamic changes related to the first trimester of pregnancy. Women consuming other drugs cannabis exposure during the pregnancy need to be investigated (cocaine, opioids, alcohol, etc.) tested by urine analysis and or self-­ further. Therefore, this study aims to analyze the changes in ma- reported, were excluded in order to isolate the effect of cannabis in ternal and fetal blood flow through the pregnancy, in pregnancies all the study groups. exposed to cannabis, for a better understanding of the physiopa- All women included in the study were followed up at the hos- thology of the cannabis effect. pital antenatal clinics, and delivered at Vall d'Hebron Hospital. Antenatal care of women included three scans during pregnancy: in the first trimester (performed at 11 to 13+6 weeks), second 2 | M ATE R I A L A N D M E TH O DS trimester (performed at 20–­22 weeks) and third trimester (per- formed at 33–­35 weeks). The local routine antenatal care in most A case–­control study over an 8-­year period, from January 2013 of the cases includes the third trimester scan performed in the to December 2020, was performed. Women consuming canna- primary health care centers; as it was not possible to obtain ultra- bis during pregnancy, and having a follow-­up and birth at Hospital sound data for these women for the study purposes, they there- Universitari de Vall d'Hebron (Barcelona), were included in the study. fore were excluded. For the cannabis group, any scan performed within these pe- riods of pregnancy was included, whereas in the other groups all 2.1 | Continued cannabis use group three scans were performed during the pregnancy in the hospital. Fetal Doppler assessments were performed using a Voluson S10 Women with cannabis use disorder were included if they had a (GE Healthcare; Zipf, Austria) ultrasound machine with convex positive urine test for THC in the first trimester, and in the third tri- transducer (RAB6-­RS) at every scheduled antenatal appointment. mester or peripartum. Qualitative detection of THC in human urine, Pulsed-­wave Doppler ultrasound was used for the maternal and fetal using enzyme immunoassay to analyze its main inactive metabolite vascular variables. 11-­nor-­carboxi-­delta9-­THC (THC-­COOH), was performed, after The following demographic variables were recorded: maternal self-­report of cannabis consumption. Participants in this group were age, maternal weight before pregnancy, body mass index, ethnicity BRIK et al. | 1209 F I G U R E 1 Flow diagram. 131.072 ultrasound Reports Ultrasound Reports 2008-2020 82 Cannabis 215 Controls Women included 22 disconnued cannabis consumpon during pregnancy 60 Connued 17 Tobacco 198 Non-Tobacco cannabis use smokers smokers during pregnancy (caucasian vs non-­caucasian), cigarette smoking during pregnancy for categorical variables. A Chi-­square analysis for proportions (yes or no), parity (parous or multiparous, according to previous and analysis of variance (ANOVA) for continuous data were used delivery at ≥24 weeks' gestation), and gestational age in weeks and to determine differences between the study groups. Scheffé's days from the last menstrual period calculated according to the first method was used for multiple comparisons. When a difference trimester ultrasound. Birthweight at delivery was recorded in grams. was detected, a multivariate regression analysis was performed to Main outcomes were feto-­placental blood flow during preg- determine whether cannabis and tobacco use were independently nancy. Uterine artery (Ut Art) pulsatility index (PI) was assessed associated with these blood flow parameters. We adjusted for ma- at the 11–­14, 20–­22 and 33–­35-­week scans. Mean Ut Art PI was ternal age, maternal body mass index, maternal weight and white calculated (Right Ut Art PI + Left Ut Art PI/2). At the 33–­35-­week ethnicity. scan, the umbilical artery (Umb Art) PI and middle cerebral artery Analysis of repeated measures with a mixed-­effects linear model (MCA) PI were measured. Cerebral-­placental ratio (CPR) was calcu- (fixed effects and random effects) was performed for Ut Art PI. The lated (MCA PI/ Umb Art PI). Estimated fetal growth was assessed fixed effect component included up to second-­order polynomial at the 33–­35-­week scan using Hadlock IV formula including femur terms of gestational age, group (control, tobacco or cannabis) and length, head, abdominal circumference and biparietal diameter. The first-­order interaction between gestational age and each group. The outcomes Ut Art PI, MCA PI, Umb Art and CPR were normalized random effect component includes the intercept as well as linear according to gestational age by multiples of the median.9,10 The pro- effects of gestational age. portion of fetuses with Umb Art and Ut Art PI values >95th centile, SPSS 23.0 and “R” packages were used for calculations. P < 0.005 9,10 and of MCA PI and CPR <5th centile in each group was calculated. was considered statistically significant. 2.3 | Bias 2.5 | Ethics statement Women abusing other drugs were excluded for analysis purposes, The study was approved by the Local Research Ethics Committee since they were potential confounders. It was not possible to dif- (Ethics Committee of Vall d'Hebron Institute of Research; reference ferentiate the effect of cannabis from that of tobacco in the can- number PR[AMI]204/2021) on May 5, 2021. Patient consent was nabis group, since most women consuming cannabis mixed it with waived. tobacco. However, as there is a group of only tobacco-­smokers, it was possible to approximate the isolated cannabis effect. 3 | R E S U LT S 2.4 | Statistical analyses 3.1 | Participants Mothers were categorized in three groups: (1) continued cannabis A total of 131 072 scan reports were analyzed for the selection of use (n = 60), (2) tobacco smokers during pregnancy (n = 17), and (3) the cannabis, tobacco and control cases. A total of 275 participants controls (n = 198). were included in the study, 60 in the continued cannabis use group, A descriptive analysis was performed using median (interquar- 17 in the tobacco smokers group and 198 in the control group. The tile range) for continuous variables, and frequency and percentage flow diagram is shown in Figure 1. 1210 | BRIK et al. 3.2 | Descriptive data with the blood flow parameters that showed differences among groups in the previous ANOVA. A one-­way analysis of variance was conducted to evaluate the null We adjusted for maternal age, maternal body mass index, ma- hypothesis that there were no differences among the three study ternal weight and white ethnicity since they can increase the risk groups in maternal characteristics including maternal age, body mass for fetal growth restriction with affected maternal and fetal Doppler index, maternal weight, white ethnicity and parity (Table 1). Women parameters. This analysis showed that the both cannabis and to- in the cannabis group were younger than women in the control bacco were predictors for Umb Art PI, but only cannabis was a pre- group (28.5 ± 5.21 vs 30.7 ± 4.2 years, P = 0.001). dictor for CPR (coef. −0.476, 95% confidence interval [CI] –­0.225 to −0.097, P < 0.001), and Mean Ut Art PI (coef. 0.092, 95% CI 0.013–­ 0.131, P = 0.017) in the 33–­35-­week scan (Table 3). 3.3 | Outcome data A longitudinal analysis of Ut ArtPI was performed and a quadratic decrease in Ut Art PI with gestational age was found. Although in can- Table 2 shows the result of the fetal and maternal Doppler measure- nabis and tobacco consumers, Ut Art PI did not differ significantly from ments in the study groups. One-­way ANOVA was performed and the control group, there was a significant interaction between gesta- differences were found in the MCA PI and CPR at 33–­35 weeks, tional age and cannabis, with higher Ut Art PI towards the third trimes- showing lower results in the cannabis group than in the control ter in the cannabis group than in the control group (Figure 2, Table 4). group (1.75 ± 0.35 vs 1.88 ± 0.34, P < 0.05; 1.69 ± 0.40 vs 2.07 ± 0.47, P < 0.05, respectively). Umb Art Doppler PI at 33–­35 weeks showed higher results in both the cannabis group and tobacco group com- 4 | DISCUSSION pared with the control group (1.05 ± 0.23, 1.06 ± 0.19, 0.93 ± 0.15, P < 0.01, respectively). The aim of this study was to analyze the changes in maternal and fetal At the 11–­14 and 20–­22-­week scans, no differences were found blood flow through the pregnancy, in pregnancies exposed to canna- in the Mean Ut Art PI among all three study groups, but at 33–­ bis. The main findings of this study are, first, that cannabis exposure 35 weeks, the cannabis group women showed higher levels com- during pregnancy is associated with a vascular effect on the fetal and pared with the control group women (0.89 ± 0.26 vs 0.74 ± 0.20, maternal blood flow that is evident from the third trimester. Secondly, P < 0.01, respectively). The tobacco group showed lower levels com- the effect of a continued cannabis exposure during pregnancy re- pared with the control group (0.73 ± 0.19 vs 0.74 ± 0.20; P < 0.01). sulted in a higher Ut Art pulsatility index, which is independent of the In addition, the tobacco smokers group showed lower Mean Ut Art tobacco effect. Thirdly, cannabis is associated with an increase of the PI compared with the cannabis group (0.73 ± 0.19 vs 0.89 ± 0.26, Umb Art pulsatility, and a decrease in the MCA pulsatility. P < 0.01; Figure 2). The main strengths of the present study are the sample size, the classification of women in the cannabis group according to biological sample (measured in the first and third trimesters—­ 3.4 | Main results peripartum) and the exclusion of other drug consumption. This study represents the first study that includes at least 60 women A multivariate regression analysis was performed to determine consuming cannabis during pregnancy to study maternal and fetal whether cannabis and tobacco use were independently associated vascular adaptations. TA B L E 1 Maternal demographics according to the study group (n = 275) Continued cannabis (n = 60) Tobacco smokers (n = 17) Control (n = 198) P a Maternal age, years 28.5 ± 5.21 (27.7–­29.3) 31.2 ± 3.4 (30.2 ± 32.1) 30.7 ± 4.2 0.001 (30.3 ± 31.1) Body mass index (BMI)a 23.2 ± 6.4 (22.2–­24.2) 22.8 ± 2.1 (22.2–­23.4) 23.2 ± 2.6 0.760 (23.03–­23.4) Nulliparousb 22/39.3 (26.0–­52.4) 8/47.1 (20.6–­73.5) 94/55 (47.4–­62.5) 0.118 b Ethnicity Caucasian 53/88.4 17/100 167/84.3 0.332 (88–­97) –­ (79–­89) Maternal tobacco use at first –­ 17/100 –­ 0.001 trimester (%) a Mean ± standard deviation (IQR). b Number/frequency (95% confidence interval). BRIK et al. | 1211 TA B L E 2 Feto-­placental blood flow characteristics according to study group Continued cannabis (n = 60) Tobacco smokers (n = 17) Control (n = 198) Umbilical artery 33–­35 weeks' assessment 33.93 ± 1.25 33.76 ± 0.90 34.24 ± 1.04 Umbilical artery PI 1.05 ± 0.23* 1.06 ± 0.19 0.93 ± 0.15 Umbilical artery MoMs 1.138 ± 0.25* 1.142 ± 0.20* 1.014 ± 0.16 Umbilical artery PI >95th centile 16/63 (25.4%)* 2/17(11.8%) 4/193(2.0%) Scans included 63 17 193 Middle cerebral artery 33–­35 weeks' assessment 33.93 ± 1.25 33.76 ± 0.90 34.24 ± 1.04 Middle cerebral artery PI 1.75 ± 0.35** 1.90 ± 0.45 1.88 ± 0.34 Middle cerebral artery PI MoMs 0.957 ± 0.19** 1.023 ± 0.23 1.030 ± 0.18 Middle cerebral artery PI <5th centile 8/57 (14%)** 3/17 (17.6%)** 10/182 (5.5%) Scans included 57 17 182 Cerebral placental ratio 33–­35 weeks' assessment Cerebral placental ratio 1.69 ± 0.40* 1.85 ± 0.53 2.07 ± 0.47 Cerebral placental ratio MoM 0.855 ± 0.20* 0.929 ± 0.26 1.042 ± 0.24 Cerebral placental ratio <5th centile 9/53 (16.9%)** 2/17 (11.8%) 6/174 (3.4%) Scans included 53 17 174 Uterine arteries 11–­14 weeks' assessment 11.93 ± 0.75 11.94 ± 0.42 12.16 ± 0.74 Right uterine artery PI 1.72 ± 0.54 1.54 ± 0.49 1.75 ± 0.66 Left uterine artery PI 1.83 ± 0.57 1.63 ± 0.48 1.80 ± 0.59 Mean uterine arteries PI 1.77 ± 0.48 1.59 ± 0.41 1.77 ± 0.53 Mean uterine arteries PI MoMs 1.046 ± 0.27 0.942 ± 0.24 1.069 ± 0.32 Mean uterine artery PI >95th centile 1/43 (2.3%) 0 (0%) 20/186 (10.7%) Scans included Missing data 42 17 186 20–­24 weeks' assessment 20.95 ± 1.69* 20.29 ± 0.68 20.17 ± 0.61 Right uterine artery PI 0.98 ± 0.38 0.87 ± 0.24 0.98 ± 0.34 Left uterine artery PI 0.97 ± 0.36 1.02 ± 0.42 0.98 ± 0.32 Mean uterine arteries PI 0.98 ± 0.31 0.95 ± 0.28 0.98 ± 0.27 Mean uterine arteries PI MoMs 0.930 ± 0.31 0.876 ± 0.25 0.906 ± 0.25 Mean uterine artery PI >95th centile 2/53 (3.7%)** 0 (0%) 5/196 (2.6%) Scans included 53 17 196 33–­35 weeks' assessment 33.93 ± 1.25 33.76 ± 0.90 34.24 ± 1.04 Right uterine artery PI 0.91 ± 0.43* 0.67 ± 0.24 0.74 ± 0.26 Left uterine artery PI 0.86 ± 0.29* 0.79 ± 0.21 0.75 ± 0.25 Mean uterine artery PI 0.89 ± 0.26* 0.73 ± 0.19* 0.74 ± 0.20 Mean uterine artery PI MoMs 1.270 ± 0.37* 1.042 ± 0.26* 1.070 ± 0.29 Mean uterine artery PI >95th centile 12/53 (22.6%) 1/15 (6.6%) 14/161 (8.7%) Scans included 52 15 161 EFW at 33–­35 weeks 2107 ± 360* 2222 ± 294 2407 ± 300 Gender, percentage of boys 31 (49.2%) 8 (47.5%) 97 (49.5%) Gestational age at birth 37.3 ± 1.4* 38.5 ± 1.5 38.9 ± 1.3 Birthweight 2556 ± 533* 3035 ± 569 3288 ± 438 Note: *P < 0.01, **P < 0.05, compared with the control group. Abbreviations: EFW, estimated fetal weight; MoM, multiples of the median; PI, pulsatility index. 1212 | BRIK et al. F I G U R E 2 Longitudinal changes of the mean uterine artery pulsatility index (PI) during pregnancy according to study group. TA B L E 3 Multivariable logistic regression analysis of maternal-­fetal Doppler Umbilical artery PI MoM 33–­35 weeks CPR MoM 33–­35 weeks Coefficient 95% CI P Coefficient 95% CI P Cannabis 0.273 0.072–­0.187 0.000 −0.476 −0.225 to −0.097 0.000 Tobacco 0.152 0.028–­0.220 0.011 −0.116 −0.232 to 0.008 0.067 Maternal weight −0.033 −0.004 to 0.003 0.741 −0.552 −0.006 to 0.004 0.582 BMI 0.013 −0.009 to 0.011 0.898 −0.139 −0.015 to 0.013 0.890 Maternal age −0.067 −0.008 to 0.002 0.278 0.064 −0.003 to 0.010 0.329 White 0.061 −0.033 to 0.103 0.313 −0.060 −0.130 to 0.047 0.355 MCA MoM 33–­35 weeks Mean uterine artery PI MoM 33–­35 weeks Coefficient 95% CI P Coefficient 95% CI P Cannabis −0.129 −1.117 to 0.002 0.058 0.092 0.013 to −0.131 0.017 Tobacco −0.013 −0.102 to 0.084 0.843 −0.045 −0.148 to 0.036 0.231 Maternal weight −0.099 −0.006 to 0.002 0.276 −0.068 −0.007 to 0.002 0.354 BMI 0.041 −0.008 to 0.002 0.661 0.086 −0.005 to 0.021 0.245 Maternal age −0.001 −0.005 to 0.005 0.987 −0.066 −0.009 to 0.001 0.085 Caucasian −0.004 −0.070 to 0.066 0.954 −0.031 −0.099 to 0.041 0.412 Abbreviations: BMI, body mass index; CPR, cerebral-­placental ratio; MCA, middle cerebral artery; MoM, multiples of the median; PI, pulsatility index. The main limitations are overestimation due to misclassification, Furthermore, the fact that the women included in the cannabis since women in the control group were not checked for cannabis group were younger could represent a bias. However, maternal age consumption in biological sample like the ones in the cannabis group, is not a factor that affects Doppler measurements, and this was and the retrospective study design. To improve the quality of canna- shown in the multivariate regression analysis. bis use data, a 2-­step approach starting with self-­report, and whether Since the cannabis active ingredient Δ-­9-­tetrahydrocannabinol positive urine analysis should be used.11 On the other hand, in the (THC) readily crosses the placenta, and studies have demonstrated cannabis group, some factors about cannabis such as frequency of expression of cannabinoid receptors in fetal brain and placenta,12,13 consumption or levels ofΔ9-­tetrahydrocannabinol in cannabis prod- there is concern about adverse fetal outcomes. Maternal cannabis ucts were not recorded; only women consuming during the whole use has been associated with fetal growth restriction, preterm birth pregnancy, and not just during the first trimester, were included. and fetal neurodevelopmental consequences. 2,14 BRIK et al. | 1213 TA B L E 4 Fixed effects in the prediction of mean uterine artery pulsatility index Fixed part Estimate SE P Intercept 3.870 0.098 <0.001 Gestational age (weeks) −0.210 0.008 <0.001 Gestational age (weeks)2 0.003 0.000 <0.001 Tobacco −0.219 0.170 0.196 Cannabis −0.197 0.116 0.091 Interaction between GA and tobacco 0.007 0.006 0.186 Interaction between GA and cannabis 0.009 0.004 0.015 The long-­term effects of cannabis consumption in pregnancy, lead to inappropriate activation of the cannabis pathways in the pla- during the childhood, can be due to environmental factors, since ma- centa, which can be associated with placental insufficiency later in ternal cannabis use can be associated with other multiple unfavor- pregnancy, producing fetal growth restriction with a Doppler pattern able characteristics.15 In addition, there could also be a physiological of increased uterine and umbilical artery pulsatility, and decreasing effect, such as the regulation of the cardiovascular system, on the the MCA pulsatility, meaning a redistribution of the blood flow. mother and the fetus. This study shows that cannabis has an effect Cannabis use is often combined with tobacco, which makes that can be evident during the third trimester on the maternal and disentangling the specific effect of cannabis difficult. The associ- fetal vascular systems. ation of the continued cannabis exposure with the vascular effect Few studies have analyzed changes on the blood flow measured on the fetal and maternal blood flow could be explained by the co-­ by Doppler ultrasound in regard to cannabis consumption during preg- occurrence of tobacco use during the pregnancy. Nevertheless, we 8,16 nancy. Prenatal continued cannabis exposure was associated with found a statistically significant specific association between ma- changes in the hemodynamic programming of the vascular system of ternal cannabis use and the increase of the mean Ut Art PI, which the fetus in late pregnancy, mainly due to tobacco exposure, but intra- remained present after taking into account maternal tobacco use, uterine cannabis exposure did demonstrate a specific effect on the uter- which has already been reported.8 ine blood flow.8 This study, including only nine women with continued The results of the present study highlight the fact that the can- cannabis use, showed an increase of the Ut Art PI in the third trimester. nabis vascular effect during pregnancy is evident in the third trimes- Another study reported an increase in the Umb Art systolic to diastolic ter, which may explain the poor outcomes associated with the use ratios in the second and third trimesters, reflecting an impaired fetal of cannabis during pregnancy. However, a better understanding of 16 growth and increased placental vascular resistance. These results the physiopathology of the cannabis exposure during pregnancy is agree with our study results and may indicate an increased placental still needed. resistance during pregnancy leading to placental insufficiency, which is one of the causes of fetal growth restriction. This may be an important aspect of the pathophysiology, which explains the association between 5 | CO N C LU S I O N daily cannabis use and fetal growth restriction.17 The main differences with our study are that we included Ut Art Doppler in the first and sec- The current study suggests that cannabis exposure during preg- ond trimesters, but results were similar among the study groups, leading nancy is associated with maternal and fetal blood flow changes. to the conclusion that the vascular effect of cannabis on the uterine However, it was not possible to disentangle the association of to- arteries is evident from the third trimester of pregnancy but not early bacco and cannabis in these changes. in the pregnancy. In addition, as opposed to the El Marroun8 study, our study resulted in a decrease in the MCA pulsatility and CPR in the can- AC K N OW L E D G M E N T S nabis group. The rationale for this discrepancy could be the lower sam- We want to thank Dr M.T. Higueras for her support in the data col- ple size in the continuous cannabis exposure group of that study, and lection for this project and her expertise in ultrasound research the fact that they included cannabis case based on self-­report rather projects. than on biological samples, as used in our study. Animal studies have shown that cannabis receptors are expressed AU T H O R S ' C O N T R I B U T I O N in placental tissues in early pregnancy.18 It has been reported in an- MB: Protocol and project development, data analysis, manuscript imal studies that Δ9-­THC-­exposed pregnancies exhibited a phe- writing and editing. MS: protocol and project development, data notype characterized by increased labyrinth area, reduced Epcam analysis. JG: data collection or management, data analysis. AH: data expression (marker of labyrinth trophoblast progenitors), altered ma- collection or management, data analysis. GP: protocol and project ternal blood space, decreased fetal capillary area and an increased development, manuscript writing and editing. NM: protocol and pro- recruitment of pericytes with greater collagen deposition.19 We hy- ject development, data analysis, manuscript writing and editing. AS: pothesized that exposure to cannabinoids during pregnancy could protocol and project development, data analysis, manuscript writing 1214 | BRIK et al. 10. Ciobanu A, Wright A, Syngelaki A, Wright D, Akolekar R, Nicolaides and editing. EC: protocol and project development, manuscript writ- KH. Fetal Medicine Foundation reference ranges for umbilical ar- ing and editing. tery and middle cerebral artery pulsatility index and cerebroplacen- tal ratio. Ultrasound Obstet Gynecol. 2019;53:465-­472. 11. el Marroun H, Tiemeier H, Jaddoe VWV, et al. 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