Critical alert for all women: Statins during pregnancy

Someone must have sent out a press release, because there was no new study... or any study at all to support the sudden appearance of this public health message... yet, news outlets across the UK and around the world all reported this story, all on the same day. Yesterday, the top news story was that statins could help pregnant women avoid caesarean sections, especially fat women blamed for raising C-section rates, with headlines announcing that all “obese pregnant mums” will now be given statins during pregnancy.

This was a false story and one that could risk women losing their babies; delivering premature babies; or having babies with limb, brain and neurological deformities. Before we get into more details, it is important that all women know: There is NO medical expert body in the world recommending statins be used by fat women or any women during pregnancy. Statins are specifically contraindicated for use by pregnant women and women trying to become pregnant.

The United States Food and Drug Administration classifies statins and all cholesterol-lowering drugs as Category X drugs [reviewed here], which identify potentially teratogenic medications.

Category X: Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant.

“All pregnant women are urged to avoid the use of cholesterol-lowering drugs such as statins,” said Dr. Karen Kuehn Howell, Ph.D., with the Maternal Substance Abuse and Child Development Project at Emory University School of Medicine.

The Australian Drug Evaluation Committee classifies statins as a Category D.

Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.

Australia recently raised statins to this category after growing reports of fetal malformations fetal malformations, including effects on the central nervous system and limb abnormalities associated with first trimester exposure to a statin. As the Australian Adverse Drug Reactions Bulletin alerted doctors and consumers, “cholesterol and other steroids are essential to fetal development including the formation of cell membranes, and the adverse effects of statin exposure during pregnancy may not be reversible.”

According to the National Health Service in the UK, NHS Drug Updates, the latest Drug and Therapeutics Bulletin, as well as the Canadian Pharmacists Association; in both the UK and Canada:

Statins should not be taken by women who are pregnant or breastfeeding. Statins are contraindicated during pregnancy and breast-feeding.

There has been NO study done to suggest statins are safe or to recommend their use during pregnancy.

Why is cholesterol important?

There are good reasons why breast milk is about 50% fat, mostly saturated and monounsaturated fats, and is high in cholesterol, and why every notable scientific review of the evidence has stressed the importance of fat through infancy and the first two years of life. Lipids are essential for the development of all tissues, most importantly the development of the central nervous system, brain, vision, hearing, etc.

During pregnancy, total cholesterol levels rise significantly, reaching a peak at 33 to 36 weeks gestation. Triglyceride levels, for example, have been shown to triple over nonpregnancy levels in women by 37 to 40 weeks. There are reasons why Mother Nature wisely does this... and why no one would suggest lowering cholesterol during pregnancy and ignoring the consequences for the health of a pregnancy and baby. It's important stuff!

As Dr. Malcolm Kendrick explained in The Great Cholesterol Con:

Why do you think that an egg yolk is full of cholesterol? Answer: because it takes one hell of a lot of cholesterol to build a healthy chicken. It also takes a lot of cholesterol to build, and maintain, a healthy human being. In fact, cholesterol is so vital that all cells, apart from neurones, can manufacture cholesterol and one of the key functions of the liver is to synthesize cholesterol.

Cholesterol appears to be essential in the development of the brain, limbs and genitals, in part due to its key role in both the biogenesis of Sonic hedgehog (Shh) and in signal transduction in Shh-responsive cells, according to researchers around the world, including at the department of Biological Structure and Center for Developmental Biology at the University of Washington in Seattle and from the Laboratoire d'Embryologie Pathologique Expérimentale, CHU Saint-Antoine in Paris.

The critical importance of cholesterol for the developing embryo is highlighted in the syndrome called Smith-Lemli-Opitz Syndrome, where there is a defect in cholesterol synthesis resulting in low cholesterol levels. As the Paris researchers emphasized, this “recessive autosomal genetic disease [is] characterized by malformations (microcephaly, corpus callosum agenesis, holoprosencephaly, and mental retardation), male pseudohermaphroditism, finger anomalies, and failure to thrive.” As Dr. Malcolm Kendrick also noted, in this syndrome, spontaneous abortions are not unusual, stillbirths have been reported, and failure to thrive is common, as are vision and hearing loss; and multiple organ system failure and death during the first weeks of life is typical for SLOS-type II.

Researchers at Vanderbilt University Medical Center recently reported that the critical developmental protein that controls patterning in the developing embryo, including proper digit patterning, requires cholesterol. Without enough cholesterol, rats also develop extra digits, as well as digits in the wrong places. “When a new mother counts her newborn’s fingers and toes, she probably doesn’t realize that cholesterol may be to thank for baby’s complete set of 20 digits,” explained Science Daily. In addition to its role in polydactyly (extra digits), Shh signaling is involved in the development of the brain and spinal cord, supporting its role in other birth defects, they reported.

No one knows what the optimal cholesterol levels are for women of childbearing age, according to researchers at the National Human Genome Research Institute of the National Institutes of Health at Bethesda, Maryland. What is known, is that LDL-cholesterol is also the chief substrate for placental progesterone biosynthesis, that cholesterol is critical for implantation of the embryo and uteroplacental vascularization needed to nourish the developing embryo, and that low cholesterol levels in mothers are associated with intrauterine growth retardation in the developing fetus.

In their recent examination of the birth records of nearly 10,000 women in South Carolina, they found that even among low-risk groups, low cholesterol levels (isolating inherent levels from the natural increases during pregnancy) were associated with triple the risk for premature babies. And research by Dr. Ricardo Uauy, of the University of Chile, Santiago, in a recent American Journal of Clinical Nutrition found that diets low in fats and animal fats resulted in significant growth stunting among infants and children.

Statins are reductase inhibitors, which means they block the entire mevalonate pathway, which relies on cholesterol synthesis, and block the production of all of those glycoproteins needed for cell identification and signaling. Animal studies have provided evidence for the teratogenic effects of statins on pregnancy outcome, which is why they are contraindicated during pregnancy, said Israeli researchers in a 2005 issue of Human Reproduction.

When the Israeli researchers studied the effects of statins on human placenta in vitro, they found that statins adversely affected a number of crucial functions of the placenta that are essential for the developing embryo. They found that statins inhibited the proliferation of human trophoblastic cells, affecting the function of those cells responsible for supporting the embryo during pregnancy, especially in the first trimester. They concluded:

These effects may contribute to failure of the implantation process and be deleterious to the growth potential of the placenta. Impaired implantation and function of the placenta in the first trimester of pregnancy can be responsible for the higher [spontaneous] abortion rate and teratogenicity that were observed in animals exposed to statins during pregnancy.

Clearly, it would be unethical to experiment on expectant mothers and unborn babies to conduct a randomized clinical trial and put half on statins and see what happened to their pregnancies and babies. Especially not, given the consistent and strong animal research, epidemiological findings, and biological plausibility suggesting that statins could put them at undue risk for harm, and that the risks far outweigh any potential benefit shown by statins for women of childbearing age.

As doctors, Beatrice Golomb M.D., Ph.D. and Michael Criqui M.D., MPH with the Statin Effects Study at the University of California, San Diego, concluded:

No study has shown statins or any other cholesterol drugs to lower overall mortality in women... indeed, lower cholesterol is linked to a slightly higher risk in some studies... Epidemiological studies show higher cholesterol to be protective, rather than harmful, in this age group, so it cannot be assumed that lowering cholesterol confers benefit exceeding risk.

Concerns about the risks of developmental defects from statins used by pregnant women were also raised by doctors Robin J. Edison, M.D., MPH, and Maximilian Muenke, M.D., senior neuroscience investigator at the National Institutes of Health. They reviewed cases of first-trimester statin exposure from FDA records from 1987 through 2001 and reported their findings in the New England Journal of Medicine. While statin use, thankfully, was low among pregnant women, they found a troubling 20 of the 52 exposed babies had been born with serious anomalies — severe brain or central nervous system defects and malformed limbs — “such very rare birth defects that one would not expect to find the number we found in a population this small,” they wrote. While the numbers are low, they suggest a rate of birth defects that rival those of thalidomide, which resulted in birth defects in 41% of fetuses exposed in utero.

While some might attempt to downplay the small numbers of cases, this report took on special significance among medical professionals, given the fact that the defects exactly fit within the known effects of inhibiting cholesterol synthesis in the fetus, according to Dr. Kendrick.

So, this is a situation where medical doctors have had to use the most scientifically credible and available data when they universally caution against the use of statins by women of childbearing age. This is the reason why statins are contraindicated for pregnant and nursing mothers. Medical professionals are trying to protect the welfare of mothers and babies, following the fundamental adage: “First, do no harm.”

Oh, what about the source for those news stories?

There was no newly published study to explain the sudden appearance of all these news reports of research on 4,000 deliveries from the University of Liverpool. There was a paper published more than a year ago in BJOG: An International Journal of Obstetrics and Gynaecology. It was a retrospective analysis of 3,913 singleton deliveries at Liverpool Women’s Hospital and the University of Liverpool in 2002, with the objective of looking for a reason why obese women have more caesarean sections.

They reported a correlation between higher maternal BMI and odds ratios (adjusted only for age, parity, smoking and labor induction) for delayed first stage labor with C-sections, with a higher odds risk only in women with normal birthweight babies. Women with large babies had less than half the risk [?] for C-sections, they reported. They concluded that higher C-sections among the obese women because of delayed first stage was likely due to poor uterine contractility. Nowhere, though, does the report reveal the actual number of C-sections to enable readers to put the odds ratios into perspective.

While the odds ratios may have sounded impressive, they were also not tenable for computer modeling-derived correlations, and the actual percentages of C-sections calculated between the obese and normal weight women differed by only 3.5% in spontaneous labors and 4.7% after inductions. Procedure rates can be a poor measure of medical necessity as they can be more reflective of policies, procedures and biases. How many doctors were also more apt to do C-sections in obese mothers simply because they believed them at higher risk for problems or slow labors? Among the factors the researchers also did not control for was gestational diabetes, social-economic status, prenatal care, general health, and the gestation of the mothers getting C-sections — any of which could play a role in the decision to perform a C-section.

This paper had been questioned by obstetricians U. Kiranaa and J. Evans, who commented last year in the October issue of the journal that the Liverpool findings were contrary to what has been reported to date and that they found the findings “unusual.” They added: “We would like to point out that successful labour is not an outcome solely based on uterine activity. Contributing factors such as birthweight, position, pelvic shape and capacity (soft and bony tissue) cannot easily be disregarded.”

In their response, the Liverpool authors reiterated their belief that obesity was related to poor uterine contractility and repeated twice that their findings show the importance of research to improve contractility with pharmaceuticals. But they didn’t explain why higher C-section rates were only found among the obese women with smaller babies in their cohort. If you read their reply closely, they did provide another possible explanation for the contractility decreases that they didn't report controlling for: “An increased incidence of postdates pregnancy also points towards increased uterine quiescence because of poor myometrial contractility...”

To evaluate contractility, the Liverpool study also took 73 biopsies from women undergoing elective C-sections. “The indications for the caesarean section in the pregnant women were previous caesarean section (24 women), fetal malpresentation (15 women), previous traumatic delivery (6 women), fetal reason (14 women) and maternal reason (14 women).” They did basic laboratory in vitro studies of calcium signaling and muscle contractility and found that the tissue samples taken from the “obese” women had less force and [Ca(2+)] flux — disregarding the fact that the “obese” women in their sample were considerably older and more likely to be multi-parous. Neither factor can be blamed on their body weight!

So, while the news reported that their story was based on research from the University of Liverpool done on 4,000 women, the published Liverpool research showed nothing to support the use of statins in pregnancy.

Digging deeper looking for cholesterol-related research from the University finds other earlier studies on the effects of cholesterol manipulation on contractility and calcium signaling in in vitro studies of myometrium, speculating that elevated cholesterol levels might affect contractility in “obese” women with high cholesterol levels.

It quickly becomes puzzling why the focus is only on cholesterol’s relationships to uterine contractility, while ignoring the affects on critical developmental pathways that could jeopardize the mother and baby in so many other ways. Equally concerning, is that even in looking at cholesterol’s role in uterine contractility, the focus is only on one side of the coin (high cholesterol).

When the University of Liverpool researchers reported the results of their studies on 12 pregnant rats in the 2004 issue of the American Journal of Physiology Cell Physiology, they concluded their “novel finding” was that cholesterol could be to blame for less forceful uterine contractions during labor in “obese” women. This study, however, didn’t examine or find any link between cholesterol and fat women. They said: “Our data suggests that if cholesterol levels are elevated in obese women, the ability of the labouring uterus to contract may be compromised.” But even that wasn’t the full story.

The importance of lipids to the developing fetus and potential risks for lowering those lipid levels was recognized early on by these researchers. Their 2004 study reported that they found serious potential risks to the developing fetus from low cholesterol levels, in inadequate nutrients to the fetus and for premature deliveries:

As mentioned above, there are significant elevation in serum cholesterol and triglycerides in pregnant women. These changes in lipid metabolism have been suggested to help maintain adequate supply of nutrients to the growing fetus. Our data suggest that another effect and possible benefit from these changes is uterine quiescence. If our results, from in vitro pregnant rats can be applied to women, they would indicate that those women with low cholesterol levels might be at risk from increased uterine activity and possibly premature labour.

Media responsibility

Public health messages like this scare me to death. Yesterday’s news stories were not responsibly reporting helpful public health messages. The news stories were not based on any credible evaluation of the medical research and body of evidence. Their suggestions were not grounded in any risk-benefit analysis for mothers and babies, nor were they reporting the conclusions of any body of medical experts. This was not news women could use.

Risking the survival of every developing fetus, putting every baby at risk for serious developmental defects and at risk of being born prematurely, and impacting their futures — all to potentially save 3.5% in costs of C-sections. Is this what public health and health care cost containment has come down to actually considering?

More disturbing was the focus on putting all fat women on statins, putting their pregnancies and babies at particular risk. Is this where fat prejudices and the myths of obesity are taking us?

For your protection, women, especially fat women, the only sound conclusion that can be taken from the news anymore is the importance of stop listening to the media. Just stop. Period. It is not a source of helpful, healthful or credible medical information that you can or should use to base any health decision.

© 2008 Sandy Szwarc