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Pregnancy complications and chemokine expression in smokers

Institution: University of California, San Francisco
Investigator(s): Penelope Drake,
Award Cycle: 1999 (Cycle 8) Grant #: 8DT-0176 Award: $24,543
Subject Area: General Biomedical Science
Award Type: Dissertation Awards

Initial Award Abstract
Smoking during pregnancy greatly increases the risk of pregnancy complications. While many negative pregnancy outcomes occur as the result of smoking, the two most common complications are spontaneous abortion (miscarriage) and intra-uterine growth retardation, a condition in which the fetus does not grow rapidly enough during gestation and, as a result, is born very small. These low birth weight babies have multiple health problems because of their small size, and many are transferred to neonatal intensive care units immediately after birth. Perinatal (during the last half of pregnancy) and neonatal (the first 28 days after birth) deaths are increased 33% in children of smoking mothers (Lambers and Clark, 1996). This increase in the death rate is probably directly attributable to the increased incidence of low birth weight babies born to smoking mothers. Population studies suggest that in the United States 20-30% of low birth weights are caused by maternal cigarette use (Kleinman et al., 1987).

The biological basis for this increase in spontaneous abortions and intra-uterine growth retardation among smoking mothers is the toxic effect of cigarette smoke on an organ unique to pregnancy - the placenta. The placenta is a transient organ that develops from fetal tissues during pregnancy. It performs tasks that are vital for the maintenance of pregnancy and for the correct growth and development of the fetus. For example, pregnancy begins when placental cells attach the embryo to the mother's uterus. Once pregnancy is established, a child must develop in the uterus for many months before its organ systems can function on their own. During this time the placenta carries out, for the child, the roles played by many important organs including the heart, lungs, digestive system and kidneys. Thus, throughout this critical period, toxic substances that harm the placenta likewise harm the developing child.

Previous studies from the Fisher lab have shown that the placenta is vulnerable to the toxic effects of maternal tobacco use. Smoking interferes with the way placental cells attach to the uterus, and subsequently, with the way they function. This application focuses on the effects of cigarette smoking on a particular function of placental cells, their ability to recruit maternal immune cells to the pregnant uterus. In non-smoking pregnancies, the uterus is infiltrated by many maternal immune cells, and evidence suggests that these cells support the proper development and growth of the placenta. It is possible that in smoking mothers this cooperation between the placenta and the maternal immune system is disrupted.

In spite of the severe negative consequences of maternal smoking on pregnancy outcome, studies suggest that approximately 20-30% of pregnant women in this country smoke (CDC, 1991; Overpeck and Moss, 1991). We envision that the results of our investigation could be used in cessation programs to help women quit smoking during pregnancy. Data suggest that pregnancy is an ideal time to intervene, since many women reduce or stop cigarette consumption upon learning that Lhey are pregnant (O'Campo et al., 1995). However, the effectiveness of cessation programs in this population is greatly enhanced when pregnancy specific materials are available for use as counseling tools (Dolan-Mullen et al., 1994). It is likely that a subset of mothers who smoke during pregnancy will be more likely to quit if they better understand the added risk their infants incur as a result of their cigarette use. A simple explanation of how smoking harms the conceptus, one possible outcome of our work, could be an important part of these specially designed materials.

Final Report
Smoking during pregnancy is associated with several complications. The most prevalent of these are spontaneous abortion (miscarriage) and intra-uterine growth retardation (IUGR). IUGR is a condition in which the fetus grows too slowly and thus is born very small. This small size puts the baby at great risk for numerous health problems, both immediate and longterm. Interestingly, these pregnancy complications related to maternal smoking occur under apparently very different conditions in the mouse. In this case, the mouse mother lacks a particular type of immune cell known as a natural killer (NK) cell. Pregnant mice deficient in NK cells have a high rate of spontaneous abortion and IUGR. However, when these mothers are artificially supplied with NK cells through a bone marrow transplant, these problems are relieved. During a normal pregnancy in humans as well as mice, NK cells infiltrate the uterus in large numbers. Intrigued by the correlation between pregnancy in women who smoke and pregnancy in mice lacking NK cells, we hypothesized that smoking impairs the ability of the placenta to attract NK cells to the uterus, and that the resulting deficiency in these immune cells leads to spontaneous abortion and IUGR. Migration of immune cells in the body is regulated largely by a family of molecules called chemokines, named for their ability to induce migration (chemotaxis) of target cells. Therefore, to find out how immune cells are attracted to the pregnant uterus, we first assessed the presence of these molecules in the placenta and uterine wall during normal pregnancy.

At the time we applied for this grant, we had evidence suggesting that chemokine production by the placenta was an important mechanism for attracting NK cells during pregnancy. During the funding period, we concluded these studies, the results of which are summarized in three articles (one published, two in preparation). The first article documents our findings that a particular type of placental cell, called cytotrophoblast, attracts NK cells and monocytes (another type of immune cell) with the chemokine MIP-la. The articles in preparation describe the production of several chemokines in the placenta and pregnant uterus, and the reciprocal production of receptors for these chemokines by local immune cells. In general, production patterns were consistent throughout pregnancy and between placental samples from different individuals. We think that significant variation from these production patterns may reflect underlying abnormalities-including that resulting from maternal smoking. We are currently testing the hypothesis that smoking during pregnancy alters chemokine production. Preliminary evidence suggests that smoking does have this effect in some placentas. We have begun large-scale experiments to address this question, and results should be available in late June and early July.

We envision that our results could be used in tobacco cessation studies to help women quit smoking during pregnancy. Research suggests that pregnancy is an ideal time to intervene, since many pregnant women reduce or stop cigarette consumption. However, the effectiveness of cessation programs for this group is greatly enhanced when they use materials that are specific to pregnant women. A simple explanation of how smoking harms a child before birth, information our work will provide, could be an important part of these specially designed materials.

Human placental cytotrophoblasts attract monocytes and CD56bright NK cells via the actions of MIP-1 alpha
Periodical: Journal of Experimental Medicine Index Medicus:
Authors: Drake P, Gunn M, Charo I, et al ART
Yr: 2001 Vol: 193 Nbr: Abs: Pg: 1199-1212