For many years, women were generally advised to avoid statins during pregnancy. The concern was that these cholesterol-lowering medicines might interfere with foetal development and increase the risk of birth defects. However, evidence from human studies has gradually challenged that assumption. An updated systematic review and meta-analysis have now brought together data from 21 studies involving more than 3.1 million pregnancies to take another look at the safety of statin exposure during pregnancy. The findings are broadly reassuring: the researchers did not find an increased risk of congenital malformations among women who were exposed to statins during pregnancy. But the findings also suggest that the question is more complicated than simply deciding whether statins are “safe” or “unsafe” during pregnancy. “Our updated systematic review and meta-analysis provide considerable reassurance on this question, but it should not be interpreted as a reason to prescribe statins routinely during pregnancy,” says Dr Saptarshi Bhattacharya, senior endocrinologist, Apollo Hospital, Delhi, who was in the review team of endocrinologists. Why does statin use during pregnancy matter? Statins are commonly prescribed to lower bad cholesterol and reduce the risk of cardiovascular disease. This is important for women who already have significant heart disease or other cardiovascular risk factors. Pregnancy itself places additional demands on the cardiovascular system. Changes in blood flow, blood vessels and the body’s tendency to form clots can create additional challenges for women who already have cardiovascular disease. Historically, concerns about possible foetal harm meant that statins were generally stopped during pregnancy. But stopping cardiovascular medications is not necessarily risk-free for every woman. When the mother’s cardiovascular risk is high, could continuing treatment sometimes provide important benefits? What did the researchers examine? “We analysed 21 studies, including six randomised trials, involving 9,016 pregnancies exposed to statins and more than 3.1 million without statin exposure. Overall, statin use was not associated with an increased risk of congenital malformations. The odds ratio was 1.05, with the confidence interval ranging from 0.92 to 1.21. There was also no signal for specific organ malformations,” says Dr Bhattacharya. How reassuring are these findings? The size of the dataset makes the absence of an overall increase in congenital malformations reassuring. Importantly, the findings were consistent across different analyses, including randomised trials and observational studies. But “no evidence of increased risk” should not be interpreted as proof of zero risk. “Statin exposure during pregnancy remains relatively uncommon and some individual statins have been studied much less extensively than others. A very small increase in risk, or a rare specific foetal abnormality, could therefore escape detection. We still need larger trials,” says Dr Bhattacharya. What about the signal for low birth weight? Statin exposure was not associated with a significant increase in low birth weight. “However, when we looked specifically at cohort studies, low birth weight was more frequent among statin-exposed pregnancies. The signal was largely seen with a particular type, what we call non-pravastatin statins (as opposed to pravastatin, which is a low-to-moderate intensity statin). There are biological reasons why pravastatin has attracted particular interest in pregnancy, including its relatively water-soluble nature. It has also been studied specifically in pregnancy complications such as pre-eclampsia. However, the available evidence is not sufficient to conclude that pravastatin is definitively safer than other statins. “Comparisons between individual drugs are based on smaller numbers and are influenced by why each statin was prescribed,” explains Dr Bhattacharya. He is also cautious because women taking statins may already have diabetes, hypertension, vascular disease or other metabolic problems that themselves influence foetal growth. This is known as confounding by indication: the reason a woman needs treatment may partly explain the outcome attributed to the treatment. What did the study find about premature birth? The analysis also did not find a statistically significant increase in preterm delivery among women exposed to statins. What’s the gap that needs to be addressed? Women who require statins are different from women who do not. “In our analysis, they were older and more likely to have diabetes, hypertension, cardiovascular disease and a history of smoking. Separating the effect of the drug from that of the underlying disease is therefore difficult, particularly in observational studies,” says Dr Bhattacharya Should a woman with heart disease stop her statin? For most women taking statins for primary prevention or uncomplicated high cholesterol, stopping treatment during pregnancy remains reasonable. Pregnancy is a limited period, and the immediate cardiovascular consequences of temporarily withholding therapy are generally small. “But the equation may be very different for a woman with established cardiovascular disease or very severe inherited hypercholesterolaemia. For a woman at very high cardiovascular risk, stopping effective lipid-lowering treatment for pregnancy and breastfeeding may not always be harmless,” Dr Bhattacharya. The decision, he feels, should balance two risks: the uncertain foetal risk of continuing treatment against the maternal cardiovascular risk of stopping it. “Our results provide reassurance for situations in which continued statin therapy is considered necessary, rather than supporting routine statin treatment during pregnancy,” he says. What do we still need to know? The major unanswered question is no longer simply whether statins cause birth defects. “We need better information on which women may benefit from continuing treatment, which statin should be used, at what dose and during which part of pregnancy. Large prospective studies should examine individual statins separately and carefully document the timing and duration of exposure. They should also evaluate foetal growth, preterm delivery, placental outcomes and longer-term development of children exposed in utero,” says Dr Bhattacharya. As of now, the review just challenges the older assumption that they must invariably be avoided in every pregnant woman.
