FORMATION AND RETENTION OF COTININE DURING PLACENTAL-TRANSFER OF NICOTINE IN HUMAN PLACENTAL COTYLEDON

Maternal smoking during pregnancy causes reduction of fetal breathing movements, an effect attributed to nicotine in fetal blood. Nicotine i s metabolized to cotinine which has a long plasma half-life and exhibi ts slow clearance across membrane barriers. It is also known to activa te placental phospholipase-A(2)-like enzymes, resulting in formation o f prostaglandins. Therefore, we studied transport of nicotine in isola ted perfused cotyledon of normal human term placenta. The placental co tyledon was perfused with aerated (21% O-2, 5% CO2) Krebs-Ringer bicar bonate buffer (pH 7.4, 37 degrees C) containing 2% albumin on both mat ernal (230 ml, 15 ml/min, 35 mm Hg) and fetal (93 ml, 1.75 ml/min, 70 mm Hg) sides in a closed recirculating system. Nicotine (2 mg) was add ed to the maternal perfusate; perfusate samples (1 ml) were collected from both sides at regular intervals and analyzed for nicotine and cot inine by high-pressure liquid chromatography. This study gave the foll owing results: (1) In about 60-80 min, 18.6% of the nicotine added to the maternal perfusate was transferred to the fetal perfusate, and the maternal/fetal concentration ratio reached 1.0. These results show ra pid placental transfer of nicotine, consistent with its high lipid sol ubility. (2) Less than 1% is metabolized to cotinine in placenta. The ratio of cotinine concentrations in maternal and fetal perfusates reac hed 1.0 in about 40 min. These studies were also verified using C-14- nicotine. (3) Maximal reduction in fetal breathing movements occurs at about 30 min, and recovery occurs at 90 min after tobacco smoking by the mother. These observations agree with the rate of placental transf er of nicotine. (4) When nicotine was added on the fetal side, part of it was metabolized to cotinine. However, the maximal concentration of cotinine was twice higher on fetal than on maternal side. These obser vations suggest that accumulation of cotinine on fetal side may activa te prostaglandin formation and trigger spontaneous abortions in pregna nt smokers.