Clinical Laboratory Strategies: November 29, 2007

Looking at Maternal Lipid Levels
Does Low Cholesterol Play a Role in Preterm Delivery?
By Deborah Levenson

Recent research has uncovered a link between low total cholesterol levels in pregnant women and heightened risk for preterm delivery. Because preterm birth is the single largest factor involved in infant mortality and morbidity worldwide and its incidence has increased dramatically in developed countries over the past two decades, the findings prompt questions about the intricate biochemical mechanisms at work in early pregnancy and —if validated—might someday help identify high-risk women who could benefit from early intervention. This issue of Strategies examines the study, and what lab directors should know about it.

Maternal cholesterol has long been considered an essential building block in early pregnancy. It is converted into progesterone, the hormone that rapidly transforms the uterine lining to enable implantation of the embryo and development of the placenta. Cholesterol is present in the membrane of each new cell that forms as pregnancy progresses, so that the rapid growth of the placenta and of the embryo itself depend on an abundant supply of this building block. Previous research has suggested that preterm delivery may be caused by inadequate development of the placenta in early pregnancy, leading some investigators to believe that preterm birth is associated with alterations in maternal lipoprotein concentrations. Now, a retrospective pilot study that examined preterm delivery suggests that low total cholesterol may play a major role in preterm delivery (Pediatrics 2007; 120: 723-733).

Investigators from the National Institutes of Health, Howard University in Washington, D.C. and Greenwood (S.C.) Genetics Center selected 118 women with low total cholesterol, below the 10th population percentile or a value of below 159 mg/dL at mean gestational age of 17.6 weeks, and 940 women with higher values from among 9,938 women who were referred to South Carolina prenatal clinics for routine second-semester serum screenings. With multivariate regression models to compare rates of preterm delivery, fetal growth parameters, and congenital abnormalities between women with low total cholesterol and control subjects with total cholesterol above 10th percentile but below the 90th percentile, the investigators found that 12.7% of women with low total cholesterol had preterm deliveries, compared to just 5.0% of the other women. Infants born at term to mothers with low total cholesterol levels weighed, on average, 150g less than those born to higher levels.

Total cholesterol isn’t a preterm delivery prediction tool that clinicians and labs will see any time soon, investigators agreed. “These are provocative early findings that may be shown to have substantial clinical significance. Among other questions, we want to know to what extent cholesterol is directly linked with preterm birth or if it is a marker for other factors,” commented lead-author Robin J. Edison, MD, MPH, epidemiologist and senior research fellow at the National Human Genome Research Institute (Bethesda, Md.).

Limited Understanding of Cholesterol’s Role

Cholesterol’s role in preterm delivery is still speculative, according to the authors, who had various theories about how cholesterol is involved in preterm birth. Cholesterol may not even be the main problem. “We don’t know if cholesterol is the essential culprit here, but we’re starting with cholesterol because we can measure it and because without it, the mother may not be able to make progesterone and everything down line in pregnancy may not be built is well if cholesterol is insufficient,” explained Roger E. Stevenson, MD, director of the Greenwood Genetic Center. 

“It’s reasonable to think that if there’s not enough cholesterol, there’s not as robust a response by the uterus, and placental development is not what it should be,” Edison commented. “Low cholesterol may also be a marker for other nutritional problems and fat metabolism."

It’s believed that the fetus depends on maternal cholesterol early on, according to another research team member, Alan Remaley, MD, PhD, section chief of the Lipoprotein Metabolism Division of the National Heart, Lung, and Blood Institute and senior staff member in the Department of Laboratory Medicine at the National Institutes of Health (Bethesda, Md.). But the extent of that dependence is unknown. “It’s possible that the natural increase in maternal cholesterol that normally occurs during pregnancy may provide the developing fetus what it needs and if the mother is deficient, poor outcomes may follow.”

Validating the Results

All of the authors emphasized that their results need validation before they lead to any changes in care. Many questions must be answered before cholesterol becomes a useful tool in predicting preterm birth, Stevenson and his colleagues added. These include what type of cholesterol may be at play in the events leading to premature birth, if any genetic factors are involved, and whether cholesterol itself is the culprit, or if it masks some other cause.

A planned validation study will answer only some of these questions. The team plans to analyze data from 10,000 mothers in Wales. But getting both that data and useful results could take many years, according to Remaley.

Implications for the Future

An editorial that accompanies the paper notes that results could give rise to nutritional interventions to prevent preterm birth and suggests pathways to investigate for their role in preterm labor. “It seems likely that the highest risk group may well be those who have a combination of contributory dietary factors and a genetic predisposition to low cholesterol,” write Mario Merialdi, PhD, of the World Health Organization in Geneva, Switzerland and Jeffrey C. Murray, MD, of the University of Iowa in Iowa City. “This paper provides critical data for beginning to understand and quickly apply information on the joint genetic and environmental mechanisms causing this problem of major clinical and social importance.” 

Meanwhile, lab directors should be aware of the potential link between cholesterol and adverse pregnancy outcomes, the authors agreed. “If the results hold, that suggests that measuring the mother’s lipoproteins is useful and that there may be a greater role, in the future, for the clinical laboratory in measuring maternal cholesterol and in assessing nutritional status,” concluded Remaley.


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