Morphological and biological effects of maternal exposure to tobacco smoke on the feto-placental unit

Abstract

Active and passive maternal smoking has a damaging effect in every trimester of human pregnancy. Cigarette smoke contains scores of toxins which exert a direct effect on the placental and fetal cell proliferation and differentiation and can explain the increased risk of miscarriage, fetal growth restriction (FGR) stillbirth, preterm birth and placental abruption reported by epidemiological studies. In the placenta, smoking is associated from early in pregnancy, with a thickening of the trophoblastic basement membrane, an increase in collagen content of the villous mesenchyme and a decrease in vascularisation. These anatomical changes are associated with changes in placental enzymatic and synthetic functions. In particular, nicotine depresses active amino-acid (AA) uptake by human placental villi and trophoblast invasion and cadmium decreases the expression and activity of 11 beta-hydroxysteroid dehydrogenase type 2 which is causally linked to FGR. Maternal smoking also dysregulates trophoblast expression of molecules that govern cellular responses to oxygen tension. In the fetus, smoking is associated with a reduction of weight, fat mass and most anthropometric parameters and as in the placenta with alterations in protein metabolism and enzyme activity. These alterations are the results of a direct toxic effect on the fetal cells or an indirect effect through damage to, and/or functional disturbances of the placenta. In particular, smoking interferes strongly with the fetal brain and pancreas biological parameters and induces chromosomal instability, which is associated with an increase in the risk of cancer, especially childhood malignancies.

Introduction

Chronic exposure of the fetus to the effects of tobacco smoke is recognized as the most important preventable risk factor for a complicated pregnancy outcome in all developed, and an increasing number of developing, countries. Active maternal cigarette smoking has a damaging effect in every trimester of pregnancy (Table 1). There is undisputed evidence from large epidemiological studies that maternal smoking is associated with fetal growth restriction (FGR), and with increased risks of stillbirth, preterm birth and placental abruption [1], [2], [3], [4]. Smoking around the time of implantation and establishment of the placenta is generally associated with an increased risk of miscarriage, ectopic pregnancies, and placenta previa [4], [5], [6], [7], [8], [9]. Maternal smoking can also be a risk factor for orofacial clefts, particularly among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals [10], [11]. Epidemiological studies have also indicated that passive maternal smoking can have a negative impact on fetal growth [12], [13].

Cigarette smoke contains scores of toxins, including cyanide, sulphides, cadmium, carcinogenic hydrocarbons and nicotine, all of which are capable of inducing direct cellular damage [14]. Most tobacco toxins have a low molecular weight and high water solubility, and therefore readily cross the placenta [15], [16], [17]. In particular, nicotine and cotinine pass freely across to the fetus, which as a result is exposed to relatively higher nicotine concentrations than its mother. Although placental xenobiotic-metabolizing enzymes can detoxify foreign chemicals, tobacco constituents exert direct effects on the villous cytotrophoblast proliferation and differentiation [18], [19]. These can explain the negative effects of smoking on placentation and formation of the placental membranes, and on feto-placental growth and development.

We have reviewed the effects of chronic maternal exposure to tobacco smoke on feto-placental development and the associated impact on fetal organ biology.