Low cholesterol levels and premature babies

Amidst all the media attention on keeping our cholesterol levels low and the promotions for widespread use of statins — leading many to believe they’re as safe as aspirin — we seldom hear about studies suggesting risks associated with low cholesterol. A study published last month in the journal Pediatrics highlighted a special concern for girls and women of childbearing age and for the health of newborn babies.

JFS has looked at some of the research showing why many doctors are recommending women of child-bearing age avoid statins. Not only have such cholesterol-lowering drugs been shown to have little efficacy for preventing heart disease deaths in women, but they are beginning to be associated with incidences of birth defects. Yet, a surprising number of doctors are unaware female patients shouldn’t be on statins, said Dr. Malcolm Kendrick. “Cholesterol is essential for the development of neural tissue,” he explained. So if a mother is taking a drug that inhibits cholesterol synthesis at a time when the fetus is developing, there could be increased risks for developmental abnormalities of the brain or nervous system.

A recent University of Pittsburgh Medical Center study cautioned that many women aren’t being warned about possible risks to their unborn babies when taking certain prescription medications, such as statins, making it important for women to be proactive in seeking information.

This latest study wasn’t about statins, but tried to examine cholesterol levels themselves and the relationships to premature and underweight babies. While this was an epidemiological study and, like all such preliminary studies, its results need to be viewed with caution and confirmed in further research, compared to the avalanche of daily epidemiological studies in the news, it received surprisingly little attention, especially given its possible significance.

Researchers, led by Dr. Robin J. Edison, M.D., MPH, at the National Human Genome Research Institute of the National Institutes of Health at Bethesda, Maryland, said that optimal cholesterol levels for women of childbearing age are not known, nor are potential risks to pregnancies. What is known, they reported, is that LDL-cholesterol is the chief substrate for placental progesterone biosynthesis, that cholesterol is critical for implantation and uteroplacental vascularization, and that low cholesterol levels in mothers have been reported associated with intrauterine growth retardation in the developing fetus. They hypothesized that low maternal cholesterol levels during early pregnancy may be associated with adverse pregnancy outcomes.

They examined the health records of nearly 10,000 women who had had routine prenatal care at western South Carolina prenatal clinics during 1996-2001 and given birth to live babies. To isolate cholesterol from other known confounding factors associated with pregnancy-related problems, they excluded teens and older ages, smokers, women with serious illnesses or substance use, twins, and (pre-pregnancy) diabetics. Overall, their cohort of 1,058 women, age 21-34 years of age, was healthier, of lower risk for pregnancy-related problems, and experienced considerably fewer preterm deliveries than the general population. In excluding mothers under age 21 and smokers, they also eliminated most of those with low cholesterol levels, meaning this study’s findings are likely underestimations and cannot be generalized.

The researchers also tried to carefully isolate the mothers’ inherent cholesterol levels from the natural increases in LDL-cholesterol and total cholesterol levels that occur during the second and third trimesters. They used the mean levels at 17.6 weeks gestation and performed three levels of analysis.

Their findings?

Even among this low-risk cohort, prevalence of preterm delivery among mothers with low blood total cholesterol levels was 12.7% to 16.2% (<10th percentile and <3rd percentile, respectively) compared with 5.0% among the control group with mid-range cholesterol levels. Low serum cholesterol was associated with triple the risk for premature babies.

The risks were strikingly higher for white mothers. Prevalence of preterm babies among white mothers with low total cholesterol levels was 21% to 28.6%, compared to 5% in midrange cholesterol levels. Low cholesterol levels among white mothers was associated with nearly 6- to 8-fold higher risks for preterm babies compared to controls. [OR=5.63 for total cholesterol < 10th percentile; OR=7.69 for cholesterol levels < 3rd percentile].

The risks for preterm babies associated with the highest maternal cholesterol levels were elevated over controls, but paled in comparison to those associated with low cholesterol.

These researchers were admirably cautious and careful in their analyses, noting untenable associations. In doing so, their other hypotheses were not confirmed:

· Low cholesterol levels were consistently associated with low birthweight babies, however the risks were only statistically significant among the lowest cholesterol levels (<3rd percentile) with a nearly a 3-fold increased risk. And among the mothers with the highest cholesterol levels, there was an insignificant 10% lower risk for SGA babies. “Low maternal weight was the most significant predictor of low birthweight for gestational age,” they wrote.

· Microcephaly was over 2.5 times more prevalent among babies born to mothers with low cholesterol levels, and 3.4 times as high among the white mothers. But these findings were not confirmed statistically, they wrote. There were no increased risks at all for microcephaly among the mothers with the highest cholesterol levels. Overall, low cholesterol levels “were no more likely than control pregnancies to produce an infant with a congenital anomaly.”

They concluded that low total cholesterols were strongly associated with preterm delivery among otherwise low-risk white mothers in this pilot study. They proposed future research of questions raised in their study:

Although low serum cholesterol level is known to be correlated with poor nutritional status, there was no correlation between maternal total cholesterol and maternal weight in this cohort. However, micronutrient deficiencies may be more common among the low-total cholesterol risk group studied here and could account for the observed adverse outcomes. Many such nutritional deficiencies have been studied as predictors of preterm delivery or low birthweight. Why any of these potential mechanisms might manifest among white but not black mothers would be critical to address should these findings be replicated. By contrast, the extremely high risk ratios observed among mothers with total cholesterol below the third population percentile suggests a severe and persistent dyslipidemia, which might exert complex effects throughout pregnancy.

So, low cholesterol levels proved to be strongly associated with premature babies in this study, but these correlations don’t tell us what the real causes for low cholesterol-related risks might be. Regrettably, they made the common mistake of equating mothers' body weights with diet and nutritional status, and while they didn’t examine nutritional status or eating behaviors among the women, they did note that low cholesterol levels have been correlated to poor nutritional status in other studies. Since they didn’t explore that, let’s look at a few earlier studies that might help lead to an explanation.

Israeli researchers attempting to determine the etiology of low serum cholesterols (total, LDL and HDL-cholesterol levels) found that they were associated with chronic anemias, notably anemias with high-erythropoietic activity. While they suggested a role of genetics for these disorders, could diet-induced anemias also adversely affect cholesterol levels? Iron deficiency is one of the most common causes of anemia.

Undernutrition in American women is found among the high risk populations they excluded from their study (smokers, ill, substance abuse, etc.) and the poorest. But among low-risk populations, it’s most common among those intentionally restricting their food intake trying to lose weight, regardless of whether they’re fat or thin. Black women have generally been more accepting of their bodies and less apt to engage in dieting as much as white women, although that is beginning to change over more recent years since this study, and may perhaps explain why the Black women in their low-risk cohort had fewer preemies compared to the white women.

Iron deficiency is the most common dietary deficiency, most affecting girls and women of childbearing age. Those trying to watch their weight are at highest risk, by eating insufficient calories and avoiding iron-rich foods they believe are fattening.

A 2001 study in the Annals of Clinical & Laboratory Science examined serum lipid profiles and iron depletion among 427 teenage girls and found that total cholesterol levels in the severely anemic girls were two-fold lower than those who weren’t iron deficient. With iron supplementation, the girls’ lipid levels returned to normal.

But iron supplements can’t overcome dieting. Researchers at the Western Human Nutrition Research Center, Presidio of San Francisco, California, found that dieting itself diminishes iron status — even among obese women getting adequate iron in their foods and from supplements while dieting. They conducted a 21 week calorie-restricted diet study, where all of the foods were prepared for the obese women and the women consumed twice the U.S. Recommended Dietary Allowance for iron (half from food sources and half from an oral supplement). Despite even an iron-rich diet, restricting calories itself, and possible shortfalls of a range of nutrients, significantly reduced their iron status and hematological measures. (The women’s cognitive function and memory also significantly declined, giving further support for the mental decline seen among dieters.)

The research suggests that low cholesterol levels related to dieting and calorie-restrictive eating among women of child-bearing age and the relationship to adverse birth outcomes deserves more attention.