Elsevier

Placenta

Volume 26, Supplement, April 2005, Pages S81-S86
Placenta

The adverse effects of maternal smoking on the human placenta: A review

https://doi.org/10.1016/j.placenta.2005.02.003Get rights and content

Studies of placental pathologies associated with maternal cigarette smoking have led to many interesting observations. For example, maternal smoking impairs human placental development by changing the balance between cytotrophoblast (CTB) proliferation and differentiation. It is likely that chronic exposure to tobacco constituents in early pregnancy can affect placental development directly or indirectly by reducing blood flow, which creates a pathologically hypoxic environment. To understand this process at a molecular level, tissue samples from non-smoking and smoking mothers were studied to determine whether active and/or passive cigarette smoke exposure affects CTB expression of molecules that govern cellular responses to oxygen tension: the von Hippel-Lindau tumor suppressor protein (pVHL), hypoxia-inducible transcription factors (HIFs) and vascular endothelial growth factor-A (VEGF). The results show that maternal smoking dysregulates CTB expression of all three types of molecules. In addition, cell columns and proliferating cells were reduced while there was a corresponding increase in cell islands. All three phenomena were most obvious in the placentas of heavy smokers. Interestingly, a subset of the aforementioned effects can be detected in samples obtained from women who were passively exposed to cigarette smoke during pregnancy. These observations suggest that tobacco constituents exert direct effects on CTB proliferation and differentiation and help to explain the mechanisms by which smoking negatively effects human pregnancy outcome.

Introduction

Human reproduction is very inefficient. All stages of the process, from implantation to birth, are fraught with difficulties that lower fecundity. The inherent problems are compounded when women smoke. Epidemiological studies provide indirect but compelling evidence that maternal cigarette smoking has serious negative consequences on all aspects of human reproduction. Additionally, a strong association between maternal smoking and infertility or poor pregnancy outcome has been shown cf. Refs. [1], [2]. With regard to impaired fertility, several studies have reported the effects of maternal smoking on the success rate of in vitro fertilization and gamete intrafallopian transfer procedures. In addition to decreased rates of oocyte production and fertilization [3], [4], [5], [6], [7], other studies have reported decreased pregnancy rates [1], [8], [9], [10], [11] and increased numbers of miscarriages [7], [12]. Once pregnancy is established, smoking substantially increases a woman's risk of a number of serious complications [13], including abruption [14], [15] and preterm delivery [16]. Finally, infants of mothers who smoke have a dramatically lower birth weight, on average 200 g less than gestation-matched controls [17]; a more recent study reports a 377-g decrease [18]. Reductions in birth weight have serious consequences, as they are strongly associated with infant morbidity and mortality [19]. Thus, maternal smoking continues to be the leading preventable cause of pregnancy complications in otherwise low-risk women.

At first glance, the wide variety of adverse pregnancy outcomes that are associated with maternal smoking would appear to have an equally diverse etiology. But results from our group and many other investigators suggest that abnormal placentation could be a unifying theme e.g., Refs. [2], [20], [21], [22], [23], [24], [25], [26]. The information summarized below supports this hypothesis.

Section snippets

Smoking impairs placental structure and function

Placentation is an explosive process that occurs, by necessity, in advance of embryonic development, which ultimately depends on placental function [27]. Initially, the progenitor population of embryonic cytotrophoblasts (CTBs) forms a polarized epithelium attached to a basement membrane that forms around the stromal cores containing the intrinsic vasculature of the placenta. Subsequent development gives rise to specialized subpopulations of chorionic villi. In floating villi, the CTBs fuse to

Smoking alters cytotrophoblast differentiation and proliferation

The hypothesis that maternal smoking fundamentally alters placental development by influencing the differentiation of CTBs has been directly investigated in detail. The in vitro (nicotine and hypoxia) and in vivo (maternal cigarette smoking) variables examined all changed the relationship between CTB proliferation and differentiation [23], [38], [44]. The results suggested that maternal smoking leads to decreased CTB proliferation as well as abnormal differentiation, particularly of cells

Are some of the adverse effects of smoking on the placenta mediated by pathological hypoxia?

Important regulators of CTB differentiation include physiological parameters such as oxygen tension, which triggers either progenitor cell proliferation in hypoxia or differentiation/invasion as the cells encounter higher oxygen levels inside the uterine wall. The paradoxical effects of oxygen in controlling the balance between CTB proliferation and differentiation prompted experiments designed to find a molecular explanation. The von Hippel-Lindau tumor suppressor protein (pVHL), which

Does cigarette smoking protect women from preeclampsia?

Finally, many placental biologists have had a long-standing interest in understanding the enigmatic finding, replicated in numerous studies [15], [57], [58], that maternal smoking protects women from developing the dangerous pregnancy complication preeclampsia. This syndrome is associated with altered maternal vascular function and impairs fetal growth cf. Ref. [59]. Maternal smoking greatly enhances expression of VEGF ligands, previously shown [55] to be important regulators of CTB survival

Conclusions

Although it has been clear for decades that maternal cigarette smoking is associated with poor pregnancy outcome, the reasons have remained enigmatic. During the last several years, plausible mechanisms based on impaired placental functions have been proposed (Figure 2). It is now known that nicotine exposure has profound effects on the specialized cells of the placenta – CTBs, which perform critical functions including generation of the syncytiotrophoblastic layer of transport epithelium and

Acknowledgments

This work was supported by grant 12RT-0059 from The University of California Tobacco-Related Disease Research Program.

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