Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC 5GvYxmLfyzpZvHyxm4c6n8F S0066-782X2022000700001 abc.20220413 10.36660/abc.20220413 Editorial Estatinas na Gestação – Novas Recomendações do Food and Drug Administration 0000-0002-3711-1754 Bittencourt Marcio Sommer 1 University of Pittsburgh Medical Center Division of Cardiology Department of Medicine Pittsburgh EUA Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh – EUA Correspondência: Marcio Sommer Bittencourt • UPMC Presbyterian Hospital – 200 Lothrop Street | Suite A-429 Pittsburgh, PA 15213 E-mail: bittencourtms@upmc.edu 11 07 2022 07 2022 119 1 1 2 This is an open-access article distributed under the terms of the Creative Commons Attribution License Palavras-chave Inibidores de Hidroximetilglutaril-CoA Redutases Gestação Dislipidemias

O Food and Drug Administration (FDA), orgão responsável pelo controle de segurança e eficácia de medicações nos Estados Unidos, tradicionalmente utiliza uma classificação do nível de risco para o uso de medicações durante a gestação. Nesta classificação, as estatinas eram consideradas da categoria X, o que indica um risco demonstrado de anormalidades fetais acima do benefício do seu uso. No entanto, em julho de 2021, o FDA retirou esta recomendação.1

Antes da mudança, a recomendação americana era de que as estatinas fossem suspensas desde o início das tentativas de concepção até o término do aleitamento materno. A presente mudança tem embasamento científico adequado. A recomendação prévia de risco fetal associado ao uso de estatinas vem de literatura de estudos experimentais em animais com doses muito mais altas que as utilizadas em humanos.4 Já estudos mais recentes e com dados em humanos não demonstram o mesmo risco identificado nos estudos experimentais. Em um estudo observacional recente o uso de estatinas não se associou a maior risco de malformações fetais. No entanto, seu uso associou-se a baixo peso ao nascer e parto prematuro. Ainda, uma metánalise de 5 estudos de coorte publicada recentemente corroborou tais achados.5 É importante destacar que o uso de estatinas está associado a maior número de comorbidades que podem levar a baixo peso ao nascer ou parto prematuro. Logo, é possível que estas complicações estejam associadas a comorbidades e não ao uso de estatinas.

Mesmo com o uso seletivo, pesando os riscos e benefícios, esta mudança do FDA tem vários outros desdobramentos. Dentre eles, o principal é facilitar a execução de estudos clínicos com estatinas no periodo pré-concepção, gestacional e durante a amamentação. Além de avaliar o benefício de redução do risco cardiovascular nestes períodos, estudos mais recentes têm investigado outros efeitos potenciais das estatinas. Um estudo publicado neste ano avaliou o impacto da estatina nos resultados de fertilização in vitro de pacientes com dislipidemia a infertilidade. Apesar de limitações importantes, o estudo sugere que pravastatina pode melhorar a eficácia do tratamento com fertilizações in vitro nesta população. No entanto, estudos adicionais são necessários antes de qualquer implementação clínica.

Da mesma forma, diversos estudos têm avaliado o uso de estatinas na prevenção de pré-eclampsia. O racional destes estudos é que as estatinas poderiam reverter o desbalanço entre angiogenese e antiangiogenese que ocorre antes da apresentação clínica da pré-eclampsia. Apesar de diversos estudos realizados, este efeito das estatinas na pré-eclampsia, ainda é controverso. Estudos menores sugeriram benefício, mas estudos randomizados recentes foram negativos.6 Até a realização de estudos adicionais, deve-se considerar o benefício da estatina nestes cenários como incerto.

Apesar de um pequeno passo, a mudança de linguagem e recomendação proposta pelo FDA tem vários desdobramentos clínicos importantes e implicações científicas futuras. Por hora, a simples flexibilização do uso de estatinas durante o período pré-concepção e durante a gestação já terá grande impacto na prática clínica rotineira para mulheres com alto risco cardiovascular e doença aterosclerótica estabelecida, que estejam em idade fértil e desejem engravidar.

Referências Food and Drug Administration [Internet] Rockville The U.S. Food and Drug Administration 2022 [cited 14 Jun 2022] Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy 1 Food and Drug Administration [Internet]. Rockville: The U.S. Food and Drug Administration; 2022 [cited 14 Jun 2022]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy. Klevmoen M Bogsrud MP Retterstøl K Svilaas T Vesterbekkmo EK Hovland A Loss of Statin Treatment Years During Pregnancy and Breastfeeding Periods in Women with Familial Hypercholesterolemia Atherosclerosis 2021 335 8 15 10.1016/j.atherosclerosis.2021.09.003 2 Klevmoen M, Bogsrud MP, Retterstøl K, Svilaas T, Vesterbekkmo EK, Hovland A, et al. Loss of Statin Treatment Years During Pregnancy and Breastfeeding Periods in Women with Familial Hypercholesterolemia. Atherosclerosis. 2021;335:8-15. doi: 10.1016/j.atherosclerosis.2021.09.003. Eisenberg ML Thoma ME Li S McLain AC Trends in Time-to-Pregnancy in the USA: 2002 to 2017 Hum Reprod 2021 36 8 2331 2338 10.1093/humrep/deab107 3 Eisenberg ML, Thoma ME, Li S, McLain AC. Trends in Time-to-Pregnancy in the USA: 2002 to 2017. Hum Reprod. 2021;36(8):2331-8. doi: 10.1093/humrep/deab107. Edison RJ Muenke M Mechanistic and Epidemiologic Considerations in the Evaluation of Adverse Birth Outcomes Following Gestational Exposure to Statins Am J Med Genet A 2004 131 3 287 298 10.1002/ajmg.a.30386 4 Edison RJ, Muenke M. Mechanistic and Epidemiologic Considerations in the Evaluation of Adverse Birth Outcomes Following Gestational Exposure to Statins. Am J Med Genet A. 2004;131(3):287-98. doi: 10.1002/ajmg.a.30386. Karadas B Uysal N Erol H Acar S Koc M Kaya-Temiz T Pregnancy Outcomes Following Maternal Exposure to Statins: A Systematic Review and Meta-Analysis Br J Clin Pharmacol 2022 Ahead of print 10.1111/bcp.15423 5 Karadas B, Uysal N, Erol H, Acar S, Koc M, Kaya-Temiz T, et al. Pregnancy Outcomes Following Maternal Exposure to Statins: A Systematic Review and Meta-Analysis. Br J Clin Pharmacol. 2022. Ahead of print. doi: 10.1111/bcp.15423. Döbert M Varouxaki AN Mu AC Syngelaki A Ciobanu A Akolekar R Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia Circulation 2021 144 9 670 679 10.1161/CIRCULATIONAHA.121.053963 6 Döbert M, Varouxaki AN, Mu AC, Syngelaki A, Ciobanu A, Akolekar R, et al. Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia. Circulation. 2021;144(9):670-9. doi: 10.1161/CIRCULATIONAHA.121.053963. Editorial Statins and Pregnancy – New FDA Recommendations 0000-0002-3711-1754 Bittencourt Marcio Sommer 1 Pittsburgh USA Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh – USA Mailing Address: Marcio Sommer Bittencourt • UPMC Presbyterian Hospital – 200 Lothrop Street | Suite A-429 Pittsburgh, PA 15213 E-mail: bittencourtms@upmc.edu Keywords Hydroxymethylglutaryl-CoA Reductase Inhibitors Pregnancy Dyslipidemias

The Food and Drug Administration (FDA), the agency responsible for controlling the safety and efficacy of drugs in the United States, has traditionally adopted a risk classification for the use of drugs during pregnancy. Statins were considered a Category X drug, which indicates that the demonstrated risk of these drugs to cause birth defects surpassed their benefits. However, in July 2021, the FDA withdrew this recommendation.1

Before this change, the FDA recommended the discontinuation of statins from conception attempts until the end of breastfeeding. In cases where dyslipidemia is not severe, statin discontinuation may confer no additional risk. However, based on this recommendation, the duration of discontinuation may be substantial. In a study with more than 100 women with familial hypercholesterolemia in Norway and Netherlands, the mean length of time without statins was longer than two years for each pregnancy.2 Although two years is a long period, it still may be a conservative estimate. In this study, the mean interval between conception planning and pregnancy was two months. Data in the literature,2 however, suggest that the median time to pregnancy is longer, probably around six months for nulliparous women.3 Also, in this study,2 mean breastfeeding duration was four months. Considering that the World Health Organization recommends exclusive breastfeeding for the first six months of life, and continued breastfeeding along with introducing complementary foods after this period, the real impact of statin discontinuation during the gestation period may be even greater than two years. Also, many women who use statins are older and may desire more than one child, which may prolong the period of time without statins for more than five years during their reproductive period.

In this context, the change of FDA's position may have a substantial impact on reproductive women willing to become pregnant. Also, the new recommendation is rather vague, as it states that statins should be discontinued by many pregnant women, albeit a shared decision-making, weighing risks and benefits, should be the routine strategy to be adopted. The FDA also advocates that the use of statins in the pre-conception period, during which women are trying to get pregnant, is safe. This change may have a particularly strong impact on 10-20% of couples that deal with infertility, and whose pre-conceptional period may be considerably long. Also, the new recommendation has an important impact on women with known cardiovascular disease who are trying to get pregnant, as data in the literature have shown that the benefit on cardiovascular events with the use of statins can be perceived even with the use of statins for periods shorter than four months in high-risk individuals.1

Despite limited data on statins in pregnancy, the new recommendation has an adequate scientific basis. The previous guidance based on the fetal risk related to statins has been constructed from data obtained from animal experimental studies with much higher doses than those usually used in humans.4 Nevertheless, more recent studies, involving humans, have not demonstrated the same risks identified in experimental studies. A recent observational study has not shown an association of statins with a higher risk of fetal malformations but did show an association with a low birth weight and premature delivery. Similar data were found in a meta-analysis of five recently published cohort studies.5 Since the use of statins has been associated with a higher number of comorbidities, it is possible that these complications are associated with comorbidities rather than with statins. Despite that, the potential residual risk of the use of statins makes the risk and benefit discussion the best strategy.

Even with a selective use of statins, considering risks and benefits, by patients with high cardiovascular risk and those with a previous history of cardiovascular disease, the FDA decision may have other ramifications. The main one consists of clinical trials with studies with women in the pre-conception, gestational and breastfeeding periods. These studies go beyond the known cardiovascular effects. One study published this year evaluated the impact of statins on results of in vitro fertilization in patients with dyslipidemia and infertility. Despite important limitations, the study suggests that pravastatin improved these results in the studied population. Further studies are needed before clinical implementation.6

Similarly, several studies have evaluated the use of statins in preeclampsia prevention. The rational of these studies is that statins could reverse the imbalance of pro- and anti-angiogenesis factors that precedes the clinical manifestations of preeclampsia. Despite numerous studies, the effect of statins, particularly pravastatin, on preeclampsia are still controversial. While small studies have suggested beneficial effects, recent randomized studies have suggested the contrary.6 Apparently, additional studies are needed to best define those patients who would most benefit from statins, as well as the best moment to initiate the drug during pregnancy and the most appropriate dose. Until then, the benefit of statins in these scenarios must be considered as uncertain.

It was a small step, but the change in the language and recommendation proposed by the FDA has had important clinical repercussions and future scientific implications. So far, the flexibility in the use of statins in the pre-conception period and during pregnancy will already have a strong effect on routine clinical practice with women of fertile age, at high cardiovascular risk and established atherosclerosis, trying to become pregnant.