Another nested case-control study in the US among 993 high-risk pregnant women showed that smoking during pregnancy was associated a higher PlGF and lower soluble endoglin –an anti-angiogenic factor– in the second trimester, but no association with sFlt-1 was observed . The subclinical association of maternal smoking with a higher pro-angiogenic state may be attributable to alterations in trophoblastic invasion and differentiation, and explain the previously reported association with a lower risk of preeclampsia . The current study also showed that cannabis use before and during pregnancy was related to a pro-angiogenic state with lower sFlt-1 and higher PlGF concentrations in both the first and second trimester, whereas cannabis use in early pregnancy showed an anti-angiogenic state in cord blood at delivery. To the best of our knowledge, no previous human studies have examined the associations of maternal cannabis use in pregnancy with angiogenic factors during pregnancy. However, previous animal studies have shown that exposure to Delta-9- tetrahidrocannabinol during pregnancy alters the placental microvasculature impairing trophoblast cell migration,cannabis grow tray narrowing the vascular network and increasing the labyrinth area .
The impairment in the placental development could be potentially mediated by cannabinoid receptors, since chronic Δ9-THC exposure leads the down-regulation of cannabinoid receptors . Δ9-THC may play a pivotal role in impairing placental angiogenesis . In sum, maternal tobacco and cannabis use in pregnancy may disrupt the normal angiogenesis processes and thereby result in suboptimal placental development. We also observed that maternal tobacco use before pregnancy was associated with higher placental weight, while continued tobacco use during pregnancy was associated with lower placental weight. Maternal continued tobacco and cannabis use were also associated with a higher PW/BW ratio and a higher risk of pregnancy complications. Altered placental growth may be an important predictor of short- and long-term adverse outcomes for the mother and her offspring . In line with our findings, previous studies have shown that pregnant women who stopped smoking had larger placentas, whereas pregnant women who continued smoking had lighter placentas, a higher PW/BW ratio and an increased risk of pregnancy complications . A higher PW/BW ratio also suggests less efficient placental function and reduced nutrient supply to the fetus .
Consistent with our findings, previous observational studies at mid- and late-pregnancy have reported a higher umbilical and/or uterine artery resistance indices in maternal tobacco or cannabis users than non-users, which is a proxy measure for an abnormal placental villous vascular tree . The subclinical association of maternal tobacco and cannabis use with higher umbilical and/or uterine artery resistance indices and the imbalance in angiogenic factors could be attributable to alterations in trophoblastic placental tissue . Therefore, vertical grow system maternal tobacco and cannabis use during pregnancy may have the capacity to alter the placental morphometry and function. Alterations in placental development may lead to subsequent pregnancy complications. The association of maternal tobacco or cannabis use with higher risk of pregnancy complications has long been studied and well documented by observational studies . In our study, no association was observed between maternal tobacco or cannabis use and preeclampsia, gestational hypertension or preterm birth. However, the direction of the odds of these associations seem to be in line with previous studies . Consistent with previous findings, our study showed that continued tobacco or cannabis use during pregnancy was strongly associated with a higher risk of being small for gestational age . Several studies have reported that the risk of preeclampsia was lower among women smokers than non-smokers .
Thus, tobacco and cannabis might have differential effects on placental development and pregnancy complications. Further studies are needed to disentangle the underlying mechanism of these associations. The strengths of our study are the population-based prospective design, the large sample size, and the availability of different angiogenic biomarkers of placental development at different time points, as well as extensive information on potential confounders. Some limitations need to be discussed. First, the Generation R Study consists of a healthy population of pregnant women with relatively few pregnancy complications. Second, while blood samples were available for 94.5% of the mothers, cord blood samples were only available for 48.4% of the newborns. Third, the self-reported assessment of tobacco and cannabis is a valid method, but misclassification may be possible. Participants may have underreported their tobacco and/or cannabis use, which could potentially have led to an underestimation of the observed associations.