The short-circuit evidence on lipid-lowering drugs use in pregnancy.

The harmonized guidelines of the European Society of Cardiology (ESC) and the European Society of Atherosclerosis (EAS) for the management of dyslipidemia recommend that women discontinue lipid-lowering drugs from pregnancy planning to the end of breastfeeding [[1]Authors/task force members; ESC Committee for practice guidelines (CPG); ESC national cardiac societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Atherosclerosis. 2019 Nov; 290: 140-205https://doi.org/10.1016/j.atherosclerosis.2019.08.014Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar]. These recommendations are cautious by necessity, mainly due to the difficulties of assessing the teratogenic risk associated with these drugs [[2]Vahedian-Azimi A. Bianconi V. Makvandi S. Banach M. Mohammadi S.M. Pirro M. Sahebkar A. A systematic review and meta-analysis on the effects of statins on pregnancy outcomes.Atherosclerosis. 2021 Nov; 336: 1-11https://doi.org/10.1016/j.atherosclerosis.2021.09.010Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. Even though the relative lipids increase during pregnancy is similar between women with and without a history of hypercholesterolemia, women with familial hypercholesterolemia (FH) usually experience a higher absolute increase in atherogenic lipoprotein fractions than comparators [[3]Amundsen A.L. Khoury J. Iversen P.O. Bergei C. Ose L. Tonstad S. Retterstøl K. Marked changes in plasma lipids and lipoproteins during pregnancy in women with familial hypercholesterolemia.Atherosclerosis. 2006 Dec; 189: 451-457https://doi.org/10.1016/j.atherosclerosis.2006.01.002Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. It follows that atherosclerosis dependent placental dysfunction is a matter of concerns in patients with particularly severe forms of FH, such as homozygous FH (HoFH) [[4]Ogura M. Makino H. Kamiya C. Yoshimatsu J. Soran H. Eatough R. Perrone G. Harada-Shiba M. Stefanutti C. Lipoprotein apheresis is essential for managing pregnancies in patients with homozygous familial hypercholesterolemia: seven case series and discussion.Atherosclerosis. 2016 Nov; 254: 179-183https://doi.org/10.1016/j.atherosclerosis.2016.10.018Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar,[5]Botha T.C. Pilcher G.J. Wolmarans K. Blom D.J. Raal F.J. Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.Atherosclerosis. 2018 Oct; 277: 502-507https://doi.org/10.1016/j.atherosclerosis.2018.05.038Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. In this context, lipoprotein apheresis (LA) has been currently regarded as the most effective lipid-lowering intervention in pregnancy, being empirically able not only to reduce lipoproteins and circulating inflammatory cytokines, but also to down-regulate adhesion molecules [[4]Ogura M. Makino H. Kamiya C. Yoshimatsu J. Soran H. Eatough R. Perrone G. Harada-Shiba M. Stefanutti C. Lipoprotein apheresis is essential for managing pregnancies in patients with homozygous familial hypercholesterolemia: seven case series and discussion.Atherosclerosis. 2016 Nov; 254: 179-183https://doi.org/10.1016/j.atherosclerosis.2016.10.018Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. According to the most recent evidence, the pregnancy-related off-statin period in women with FH can reach up to 14 years that is quite a long period of time for the purpose of cardiovascular disease prevention [[6]Klevmoen M. Bogsrud M.P. Retterstøl K. Svilaas T. Vesterbekkmo E.K. Hovland A. Berge C. Roeters van Lennep J. Holven K.B. Loss of statin treatment years during pregnancy and breastfeeding periods in women with familial hypercholesterolemia.Atherosclerosis. 2021 Oct; 335: 8-15https://doi.org/10.1016/j.atherosclerosis.2021.09.003Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Of course, observational data show that women with FH breastfeed to a lesser extent than other women, in order to restart statin treatment as soon as possible [[6]Klevmoen M. Bogsrud M.P. Retterstøl K. Svilaas T. Vesterbekkmo E.K. Hovland A. Berge C. Roeters van Lennep J. Holven K.B. Loss of statin treatment years during pregnancy and breastfeeding periods in women with familial hypercholesterolemia.Atherosclerosis. 2021 Oct; 335: 8-15https://doi.org/10.1016/j.atherosclerosis.2021.09.003Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. However, it should be pointed out that, to date, there are no specific guidelines on breastfeeding for women with severe hypercholesterolemia. Until quite recently, women have been consistently underrepresented in clinical trials testing lipid-lowering drugs [[7]Fogacci F. Gori D. Cicero A.F.G. Representativity of women and racial/ethnic minorities in randomized clinical trials on bempedoic acid: positive efforts and lacking data.Eur. J. Intern. Med. 2022 Feb; 96: 122-123https://doi.org/10.1016/j.ejim.2021.11.006Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar,[8]Khan S.U. Khan M.Z. Raghu Subramanian C. Riaz H. Khan M.U. Lone A.N. Khan M.S. Benson E.M. Alkhouli M. Blaha M.J. Blumenthal R.S. Gulati M. Michos E.D. Participation of women and older participants in randomized clinical trials of lipid-lowering therapies: a systematic review.JAMA Netw. Open. 2020 May 1; 3e205202https://doi.org/10.1001/jamanetworkopen.2020.5202Crossref Scopus (53) Google Scholar], and they have been usually required to be compliant with effective contraception to be enrolled. Historically, before the last pandemic and the vaccine rush began, pregnant women had always been excluded from clinical trials for non-obstetric conditions due to several factors, including ethical concerns about fetal exposure, liability risk and complex regulations [[9]Smith D.D. Pippen J.L. Adesomo A.A. Rood K.M. Landon M.B. Costantine M.M. Exclusion of pregnant women from clinical trials during the Coronavirus disease 2019 pandemic: a review of international registries.Am. J. Perinatol. 2020 Jun; 37: 792-799https://doi.org/10.1055/s-0040-1712103Crossref PubMed Scopus (58) Google Scholar,[10]Blehar M.C. Spong C. Grady C. Goldkind S.F. Sahin L. Clayton J.A. Enrolling pregnant women: issues in clinical research.Wom. Health Issues. 2013 Jan; 23: e39-e45https://doi.org/10.1016/j.whi.2012.10.003Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar]. It follows that observational studies have gained great importance over the time, as only few and partial information on this topic could be derived from randomized controlled clinical trials. In this issue of Atherosclerosis, Christensen and colleagues describe the use of statins and other lipid-lowering medications for all pregnancies in Norway from 2005 to 2018, using nationwide linked electronic health care registries [[11]Christensen J.J. Bogsrud M.P. Holven K.B. Retterstøl K. Veierød M.B. Nordeng H. Use of statins and other lipid-modifying agents across pregnancy: a nationwide drug utilization study in Norway in 2005-2018.Atherosclerosis. 2022 Dec 6; https://doi.org/10.1016/j.atherosclerosis.2022.11.022Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. Pooling data from 503,723 women and 822,071 pregnancies, the authors observed that the use of statins during pregnancy increased from 2005 to 2018 (passing from ∼0.11% to ∼0.29% across the time). In particular, statin use appears to be more common in women with higher age, higher weight, smoking habit, and in women with comorbidities such as hypertension and diabetes mellitus (which often still require pharmacological treatment). According to the authors' observations, even though lipid-lowering agents are increasingly being used by pregnant women, these drugs are mostly discontinued during the first trimester of gestation, as it is expected to occur based on the latest ESC/EAS recommendations [[1]Authors/task force members; ESC Committee for practice guidelines (CPG); ESC national cardiac societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Atherosclerosis. 2019 Nov; 290: 140-205https://doi.org/10.1016/j.atherosclerosis.2019.08.014Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar]. The authors conclude that pregnancy-related statin use should be monitored, and that drug safety analyses for maternal and offspring health outcomes are needed. The ‘knowledge gap’ concerning safety and efficacy of several pharmacological interventions in pregnant women may ultimately result in an ‘ethical paradox’, as the use of cardioprotective drugs that may reduce the incidence of adverse outcomes (APOs) in high-risk pregnant or lactating patients is often discouraged because these medications have never been tested in clinical trials with the same purpose. Of course, the study by Christensen and colleagues has some limitations that need to be addressed and that could serve as guidance for future research directions. For example, the study design cannot provide causal insight into the risk of poor pregnancy outcomes and their determinants in women exposed to statin treatment. Moreover, authors' observations are not generalizable to lower income countries, where women experience less access to both education and affordable high-quality health care. Finally, the risk of treatment dropout after the end of lactation period has not been investigated and properly quantified, but this is also a critical issue with potentially relevant consequences for women's health in the long term. Most of the Western countries have seen the average age of women at childbirth increase by 2 and 5 years between 1970 and 2020 [[12]Vignoli D. Tocchioni V. Mattei A. The impact of job uncertainty on first-birth postponement.Adv. Life Course Res. 2020 Sep; 45100308https://doi.org/10.1016/j.alcr.2019.100308Crossref PubMed Scopus (32) Google Scholar]. It is also for this reason that is increasingly common for pregnant women to have a greater exposure to cardiovascular risk factors such as high body mass index, insulin resistance, high blood pressure and increased levels of plasma lipids. In this context, further evidence is needed to clarify how delay in risk factors management has to be considered as ‘acceptable’ in these patients, and define the best cardiovascular prevention strategy for women in the long term. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.