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There are increasing numbers of reports on the tobacco smoking and ingestion of abused drugs (e.g. morphine, cocaine) by pregnant women and the effects of the substances on the developing fetus and newborn infant. The passage of drugs and chemicals from the mother to the fetus is influenced by the placental transport and metabolism of the substances. Further, these drugs and chemicals affect the nutrient transport systems in the placenta. The three major drugs of abuse-nicotine, morphine and cocaine-depress both active amino-acid uptake by human placental villi and transplacental amino-acid transport by reason of the drugs' influence on placental cholinergic and opiate systems. Part of this depression (10-16%) is not reversible. Nicotine blocks the cholinergic receptor and thus blocks acetylcholine (ACh)-facilitated amino-acid transport. Morphine stimulates opiate kappa receptors and depresses ACh release. Cocaine blocks Ca2+ influx and thus blocks ACh release. ACh causes dilation of blood vessels and maintains placental blood flow by the activation of endothelial muscarinic receptors. By interfering with ACh release and placental blood flow, the three drugs of abuse may depress the diffusion of amino acids and other nutrients from the trophoblast into the placental circulation. Three regulatory systems are delineated for amino-acid uptake by the placenta: placental ACh, phospholipid N-methyltransferase, and the gammaglutamyl cycle. These systems operate in concert with one another and are dependent on cellular formation of adenosine 5'-triphosphate (ATP). Placental hypoxia induced by carbon monoxide and other tobacco gases depresses the energy-dependent processes and thus the ATP levels of placental cells. Maternal tobacco smoking and drug abuse cause placental insufficiencies for amino-acid transport, which may partially explain the fetal intrauterine growth retardation caused by these substances. Part of the amino-acid deficits may be compensated for by the induction of new amino-acid transport systems. Specific receptors or drug-binding proteins for the three drugs of abuse are present in the placenta. A DNA adduct selective for maternal smoking has been demonstrated in the placenta. DNA adducts selective for cocaine, morphine and other environmental chemicals have yet to be demonstrated ins the placenta.

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Maternal smoking during pregnancy causes reduction of fetal breathing movements, an effect attributed to nicotine in fetal blood. Nicotine is metabolized to cotinine which has a long plasma half-life and exhibits slow clearance across membrane barriers. It is also known to activate placental phospholipase-A₂-like enzymes, resulting in formation of prostaglandins. Therefore, we studied transport of nicotine in isolated perfused cotyledon of normal human term placenta. The placental cotyledon was perfused with aerated (21% O₂, 5% CO₂) Krebs-Ringer bicarbonate buffer (pH 7.4, 37°C) containing 2% albumin on both maternal (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 added to the maternal perfusate; perfusate samples (1 ml) were collected from both sides at regular intervals and analyzed for nicotine and cotinine by high-pressure liquid chromatography. This study gave the following 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 rapid placental transfer of nicotine, consistent with its high lipid solubility. (2) Less than 1% is metabolized to cotinine in placenta. The ratio of cotinine concentrations in maternal and fetal perfusates reached 1.0 in about 40 min. These studies were also verified using ¹⁴C-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 transfer 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 observations suggest that accumulation of cotinine on fetal side may activate prostaglandin formation and trigger spontaneous abortions in pregnant smokers.

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