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BACKGROUND: Exposure to toxins during pregnancy is the main modifiable behavior that affects the placenta and, consequently, the fetus. In particular, smoking is a recognized risk factor for negative outcomes. Our study pretended to examine gross and microscopic placental features in women who reported exposure to tobacco, alcohol, or other psychoactive substances. METHODS: In this observational case-control study, we collected 706 placentas to assess precise substance exposure histological-interaction features of in the placenta. We examined gross and microscopic placental features, and then recorded maternal and newborn clinical conditions. RESULTS: We found that 4.8% of mothers admitted to consumption of some type of (harmful) substance. The most common pre-existing maternal condition was obesity (20.3%); predominant complications included amniotic infection (32.3%), urinary tract infection (14.5%) and hypertensive disorders of pregnancy (14.5%). In newborns, we discovered positive associations as respiratory distress syndrome. Macroscopically, exposed mothers had heavier placentas, more true knots, and single umbilical artery; microscopically, they were more likely to exhibit fetal vascular malperfusion (FVM). CONCLUSIONS: Until our present study, no research linked umbilical cord defects to toxic substance exposure; our study results do confirm association with adverse outcomes in neonates and alterations in the neuro-cardio-placental circuit through FVM. IMPLICATIONS: The results are confirming the importance of this modifiable risk factor and how its presence may potentially affect the course of pregnancy, as well as the health of both mother and child. [ABSTRACT FROM AUTHOR]