Statin Use in Pregnancy: Is It Time For a Paradigm Shift?
2022; Lippincott Williams & Wilkins; Volume: 145; Issue: 7 Linguagem: Inglês
10.1161/circulationaha.121.058983
ISSN1524-4539
Autores Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoHomeCirculationVol. 145, No. 7Statin Use in Pregnancy: Is It Time For a Paradigm Shift? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBStatin Use in Pregnancy: Is It Time For a Paradigm Shift? Rina Mauricio and Amit Khera Rina MauricioRina Mauricio Correspondence to: Rina Mauricio, MD, University of Texas Southwestern Medical Center, 2001 Inwood Rd, Suite WC05.818, Dallas, TX 75390. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3556-9913 Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. and Amit KheraAmit Khera https://orcid.org/0000-0001-7255-6874 Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. Originally published14 Feb 2022https://doi.org/10.1161/CIRCULATIONAHA.121.058983Circulation. 2022;145:496–498Statins have traditionally been contraindicated in pregnancy because of a theoretical concern about potential teratogenesis and the role of cholesterol in the developing embryo. However, on July 20, 2021, the US Food and Drug Administration (FDA) requested removal of the "Pregnancy Category X" label for statins.1 This was a welcomed action given emerging data regarding the safety of statins during pregnancy, but it immediately left patients and clinicians needing to make complex clinical decisions without adequate supporting data.The FDA language was likely purposefully vague, allowing latitude in shared decision-making: "Health care professionals should discontinue statin therapy in most pregnant patients, or they can consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy." High-risk patients include women with previous atherosclerotic cardiovascular disease (ASCVD) events and those with familial hypercholesterolemia (FH) who have markedly elevated cholesterol levels from birth. The FDA now argues that "the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk patients" and "contraindicating these drugs in all pregnant women is not appropriate." ASCVD and FH are not rare; ASCVD affects ≈1.4% of all women between the ages of 20 to 39 years in the United States and FH affects 1 in every 250 women.Previously, it was recommended that women (including those at increased risk for ASCVD) discontinue statin use while trying to conceive, during pregnancy, and throughout breastfeeding. Excluding breastfeeding, this interval could range from around 12 months to longer if there is delayed conception. The FDA now states that "statins are safe to use if you are not pregnant but can become pregnant," signaling another potential change in the approach to statin use in women. The practical implications of this latest announcement by the FDA are not straightforward and create ambiguity in the already nuanced territory of cholesterol management in pregnant, breastfeeding, and reproductive-aged women.For those with ASCVD, specifically after an acute coronary syndrome, discontinuation of statins may be unacceptable, even for a short duration, given the possible benefit of statins within about 4 months after acute coronary syndrome. Statin deferral during pregnancy in those with FH is controversial, with some studies suggesting adverse vascular consequences from high cholesterol exposure during the relatively short pregnancy period. Maternal hypercholesterolemia may affect early atherosclerosis development in offspring through complex mechanisms like genetic programming. During the already stressful time of pregnancy, these women are left with difficult decisions about balancing their own health with potential risks to their children. Against this backdrop, the data regarding safety of statins in pregnancy have evolved but are still sorely lacking.Animal studies have suggested that statins may cause fetal anomalies, but these studies have been criticized for using higher statin doses than are administered to humans. The initial human reports raising concern for adverse birth outcomes with statins were derived from case reports describing intrauterine growth retardation, fetal demise, and structural abnormalities; such studies comprised a small number of cases without systematic assessment.2 The largest observational cohort study to date involving 886 996 pregnancies—1152 with statin use during the first trimester—found no increased risk of congenital abnormalities with statin use after accounting for confounding factors.3 A recent cohort study of 469 women who used statins during pregnancy, compared with 4690 matched controls, showed that statin exposure during pregnancy was not associated with an increased risk of congenital anomalies after adjusting for maternal age and comorbidities (relative risk, 1.24 [95% CI, 0.81–1.90]); however, it was associated with an increased risk of preterm birth and low birth weight.4 It is worth noting that no studies to date have evaluated the potential adverse effects of statin cessation on the long-term health of the mother.Four randomized, blinded, placebo-controlled clinical trials have evaluated statins in pregnant women to assess the potential to prevent preeclampsia. Pravastatin was used in these trials because it is hydrophilic and a substrate of the P-glycoprotein efflux pump, theoretically limiting its ability for transplacental transfer. In animal models of preeclampsia, pravastatin use improved vascular profile, lowered blood pressure, and restored angiogenic balance in the mother without negatively affecting offspring outcomes.Three of these trials were small (n=20–62), assessed pravastatin in the second and third trimesters, and demonstrated neither beneficial effects on preeclampsia nor serious maternal or neonatal adverse effects of statin treatment. Of note, maternal total cholesterol and low-density lipoprotein cholesterol levels were lower in subjects receiving pravastatin, without any difference in total cholesterol and low-density lipoprotein cholesterol levels in the umbilical cord blood in either treatment arm. In the largest study to date (n=1120), women in their third trimester took pravastatin versus placebo until delivery and were followed for up to 6 weeks postpartum. In this large study, there again were no significant between-group differences in maternal or neonatal outcomes.5 The results of these trials suggest that pravastatin started in the second to third trimester is safe in pregnant women without an increase in congenital anomalies and merits further study in larger randomized clinical trials that can provide definitive safety and efficacy data. Further, these 4 studies demonstrate that clinical trials can be conducted effectively in pregnant women and provide needed information on the safety of these interventions, not only on maternal health but also on the health of the fetus.A broader issue is the current approach to research in pregnant women, specifically the enrollment of pregnant women in clinical trials. There is an acknowledged lack of data on the safety, efficacy, and dosing of medical therapies in pregnant and lactating women, leaving the patient and healthcare provider with the undesirable choice to either discontinue therapy for a preexisting medical condition or continue treatment, without adequate data for either decision. In 2018, the Task Force on Research Specific to Pregnant Women and Lactating Women, a group established to advise the Secretary of Health and Human Services, suggested that the "trajectory of exclusion [of pregnant and lactating women] be altered to include and integrate [them] in the clinical research agenda." The FDA has recently provided guidance on clinical research on pregnant women and concluded it is "ethically justifiable to include pregnant women with a disease or medical condition requiring treatment." Failure to study the efficacy, risks, and benefits of therapies for chronic conditions that the woman had before pregnancy and will continue to have postpartum is a disservice to our pregnant patients and the fetus who is reliant on the health of the mother.The intent of the recent FDA recommendation on statins was not to approve statin use in all pregnant patients. Rather, the goal was to revise the language to reassure clinicians that in certain individuals, especially very high-risk patients, continuing statin therapy through pregnancy may be beneficial. Ultimately, the continuation of statins in these patients rests on shared decision-making between patient and clinician and should consider the nuances of the patient's history and risk factor profile. In our view, using shared decision-making, those with ASCVD events, especially recent ones, should be encouraged to continue statins during pregnancy or resume them as soon as possible if they are withheld. For those with heterozygous FH, reasonable low-density lipoprotein control before pregnancy, and no manifest vascular disease, there may be more tolerance for statin deferral during pregnancy. Last, it is important to note that the latest recommendation by the FDA acknowledges the lack of data we have on the efficacy, risks, and benefits of therapies during pregnancy, as well as the need for dedicated research to better serve our pregnant patients.Article InformationSources of FundingNone.Nonstandard Abbreviations and AcronymsASCVDatherosclerotic cardiovascular diseaseFDAUS Food and Drug AdministrationFHfamilial hypercholesterolemiaDisclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.This article is part of the Science Goes Red™ collection. Science Goes Red™ is an initiative of Go Red for Women®, the American Heart Association's global movement to end heart disease and stroke in women.For Sources of Funding and Disclosures, see page 497.Correspondence to: Rina Mauricio, MD, University of Texas Southwestern Medical Center, 2001 Inwood Rd, Suite WC05.818, Dallas, TX 75390. Email rina.mauricio@utsouthwestern.eduReferences1. US Food and Drug Administration. FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy; still advises most pregnant patients should stop taking statins. Accessed December 29, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancyGoogle Scholar2. 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; 131:287–298. doi: 10.1002/ajmg.a.30386CrossrefMedlineGoogle Scholar3. Bateman BT, Hernandez-Diaz S, Fischer MA, Seely EW, Ecker JL, Franklin JM, Desai RJ, Allen-Coleman C, Mogun H, Avorn J, et al. Statins and congenital malformations: cohort study.BMJ. 2015; 350:h1035. doi: 10.1136/bmj.h1035CrossrefMedlineGoogle Scholar4. Chang JC, Chen YJ, Chen IC, Lin WS, Chen YM, Lin CH. Perinatal outcomes after statin exposure during pregnancy.JAMA Netw Open. 2021; 4:e2141321. doi: 10.1001/jamanetworkopen.2021.41321CrossrefMedlineGoogle Scholar5. Döbert M, Varouxaki AN, Mu AC, Syngelaki A, Ciobanu A, Akolekar R, De Paco Matallana C, Cicero S, Greco E, Singh M, et al. Pravastatin versus placebo in pregnancies at high risk of term preeclampsia.Circulation. 2021; 144:670–679. doi: 10.1161/CIRCULATIONAHA.121.053963LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited BySarraju A, Zammit A, Ngo S, Witting C, Hernandez‐Boussard T and Rodriguez F (2023) Identifying Reasons for Statin Nonuse in Patients With Diabetes Using Deep Learning of Electronic Health Records, Journal of the American Heart Association, 12:7, Online publication date: 4-Apr-2023.Khan S, Brewer L, Canobbio M, Cipolla M, Grobman W, Lewey J, Michos E, Miller E, Perak A, Wei G and Gooding H (2023) Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring: A Scientific Statement From the American Heart Association, Circulation, 147:7, (e76-e91), Online publication date: 14-Feb-2023. Al-Ashwal F, Sulaiman S, Sheikh Ghadzi S, Kubas M, Halboup A and Suppiah V (2023) Physicians and pharmacists' clinical knowledge of statin therapy and monitoring parameters, and the barriers to guideline implementation in clinical practice, PLOS ONE, 10.1371/journal.pone.0280432, 18:1, (e0280432) Wray S, Arrowsmith S and Sharp A (2023) Pharmacological Interventions in Labor and Delivery, Annual Review of Pharmacology and Toxicology, 10.1146/annurev-pharmtox-051921-122822, 63:1, (471-489), Online publication date: 20-Jan-2023. Miller R and Costacou T (2022) Cardiovascular Disease in Adults with Type 1 Diabetes: Looking Beyond Glycemic Control, Current Cardiology Reports, 10.1007/s11886-022-01763-9, 24:10, (1467-1475), Online publication date: 1-Oct-2022. O'Toole T, Kelsey M, Shah N, McGarrah R and Pagidipati N (2022) Eradicating Atherosclerosis: Should We Start Statins at Younger Ages and at Lower LDL-Cs, Current Cardiology Reports, 10.1007/s11886-022-01760-y, 24:10, (1397-1406), Online publication date: 1-Oct-2022. Liu E, Bigeh A, Ledingham L and Mehta L (2022) Prevention of Coronary Artery Disease in Women, Current Cardiology Reports, 10.1007/s11886-022-01721-5, 24:8, (1041-1048), Online publication date: 1-Aug-2022. Pham A, Polic A, Nguyen L and Thompson J (2022) Statins in Pregnancy: Can We Justify Early Treatment of Reproductive Aged Women?, Current Atherosclerosis Reports, 10.1007/s11883-022-01039-1, 24:8, (663-670), Online publication date: 1-Aug-2022. February 15, 2022Vol 145, Issue 7 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.058983PMID: 35157518 Originally publishedFebruary 14, 2022 KeywordspregnancyUnited States Food and Drug Administrationcardiovascular diseaseshyperlipoproteinemia type IIPDF download Advertisement
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