2025 Volume 32 Issue 11 Pages 1464-1469
Although the risk of acute coronary syndrome increases during pregnancy and the postpartum period compared to the non-pregnant state, dyslipidemia–one of the key risk factors for atherosclerotic cardiovascular disease–is often undertreated in this population. Several lipid-lowering medications, including statin, have not been used due to concerns about their impact on the fetus. Herein, we report a pregnant woman with possible familial hypercholesterolemia (FH) and coronary artery stenosis, whose low-density lipoprotein cholesterol (LDL-C) level was managed by a combination of statin and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the secondary prevention of coronary artery disease.
A 37-year-old pregnant woman with dyslipidemia was found to have severe coronary artery stenosis. She was suspected of having FH, and her lipid control was initiated with the goal of lowering LDL-C levels to ＜100 mg/dL. Althoug ezetimibe and colestimide were administered at 14 weeks, the target LDL-C level was not achieved. Thus, treatment with pravastatin was started at 23 weeks and evolocumab at 32 weeks of gestation. With the combination of pravastatin and evolocumab, her LDL-C levels decreased to 67 mg/dL after 35 weeks of gestation. The patient delivered vaginally at 37 weeks of gestation without any cardiac events, and her baby did not present with any abnormalities. In conclusion, the combined use of statin and PCSK9 inhibitor could effectively manage LDL-C levels, and it might be a safe option during pregnancy. Nevertheless, further research is required to assess the safety and efficacy of this combination therapy during pregnancy.
Familial hypercholesterolemia (FH) is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes1). Previous research has reported ＞4,970 mutations in the low-density lipoprotein receptor gene and ＞350 mutations in the PCSK9 gene2). However, the impact of these mutations on the pathophysiology of FH has not been completely elucidated3). Statins are the most common lipid-lowering agents used for the treatment of dyslipidemia. Recently, an increasing number of reports on the safety of statin during pregnancy have led to the removal of its contraindications by the U.S. Food and Drug Administration (FDA)4). Novel therapeutic agents, including PCSK9 inhibitors, which have potent low-density lipoprotein cholesterol (LDL-C)-lowering effects and are viable treatment options, have also been developed5). However, to the best of our knowledge based on our literature review, there is one report on their use during pregnancy6). Moreover, to date, no case reports have documented the co-administration of statins and PCSK9 inhibitors during pregnancy. Herein, we report a pregnant woman with possible FH and severe coronary artery stenosis who was treated with a combination of pravastatin and evolocumab, a PCSK9 inhibitor.
A 37-year-old primiparous woman with a body mass index of 19 kg/m2 and a history of dyslipidemia with untreated LDL-C levels exceeding 180 mg/dL. Rosuvastatin calcium was prescribed when dyslipidemia was diagnosed; however, she discontinued taking it 3 years back. She had no history of smoking, hypertension, or diabetes. There were no Achilles tendon xanthomas or cutaneous nodular xanthomas, and there were no first-degree relatives who had dyslipidemia or early-onset coronary artery disease. However, in terms of family history, her paternal grandfather had dyslipidemia and presented with acute myocardial infarction (AMI) at the age of 50 years. She experienced severe chest pain and visited a nearby hospital. However, during her visit, the symptoms had subsided, and no abnormalities were detected on examinations including electrocardiogram. Subsequently, her coronary computed tomography scan showed 70% stenosis in the proximal left anterior descending artery (LAD), with a decreased fractional flow reserve (FFR) computed tomography of 0.68. She became pregnant afterward, and she was referred to our institution at 7 weeks of gestation. The exercise tolerance test did not reveal any ischemic episodes, and no ST changes were detected on the electrocardiogram. She was considered not to have any current ischemic lesions but was deemed to be at high risk of developing AMI during pregnancy and postpartum. Therefore, a medication-based treatment plan was adopted, and therapy with 100 mg of aspirin and 0.625 mg of bisoprolol was initiated. The goal of LDL-C level was ＜100 mg/dL for the secondary prevention of coronary artery disease. Her LDL-C level at 14 weeks of gestation was 103 mg/dL. In light of the suspected diagnosis of FH and the presence of coronary artery stenosis, treatment with ezetimibe was initiated. However, it was discontinued due to drug-induced liver injury. Then, her medication was switched to colestimide. However, her LDL-C level at 22 weeks of gestation was 159 mg/dL. We obtained approval from the Ethics Committee of our hospital for the use of hydrophilic statins, specifically pravastatin. After obtaining written informed consent, we initiated 10 mg of pravastatin at 23 weeks of gestation. Because her LDL-C level did not change, pravastatin dose was increased to 20 mg at 27 weeks of gestation. However, her LDL-C level persisted at 129 mg/dL. Considering the potential efficacy of evolocumab, the treatment was switched to subcutaneous injection of evolocumab at 32 weeks of gestation at a biweekly dosage of 140 mg. At that time, her genetic testing revealed a missense mutation in the PCSK9 gene (ex5 c.791C>T p. T264I hetero). Her LDL-C level decreased to 107 mg/dL after 33 weeks of gestation. However, the target goal was still not achieved. Therefore, pravastatin at a dose of 20 mg was reintroduced and combined with evolocumab starting at 35 weeks of gestation. Her LDL-C level was 83 mg/dL, which allowed her to be managed within the target range at 36 weeks of gestation. Fetal growth was normal (Fig.1). To inhibit the increase in myocardial oxygen consumption and prevent myocardial ischemia due to coronary artery stenosis, labor induction with epidural anesthesia was planned at 37 weeks. She delivered a male baby weighing 2915 g (+ 0.5 standard deviation), with Apgar scores of 9 at 1 min and 9 at 5 min after birth. The baby had no congenital abnormalities or lipid disorders. Her LDL-C level was well-controlled at 63 mg/dL in the postpartum period (Fig.2). As the patient wished to provide only colostrum, breastfeeding was discontinued following the administration of colostrum. During the breastfeeding period, pravastatin was discontinued, and evolocumab was continued. After breastfeeding cessation, the treatment was switched from evolocumab to atorvastatin. The postpartum course was also uneventful, and her LDL-C level was controlled at 76 mg/dL with 20 mg of atorvastatin 10 months after delivery.
Fetal Growth Curve
The entire alternation of LDL-C levels and LDL-C therapy
Herein, we present the case of a pregnant woman with possible FH and coronary artery stenosis who was treated with a combination of pravastatin and evolocumab, which did not result in complications in either the mother or the baby.
The patient was a young woman with a history of LDL-C levels exceeding 180 mg/dL and progressive coronary atherosclerosis, despite the absence of other coronary risk factors. In the current case, the genetic mutations have previously been classified as benign or variants of uncertain significance in ClinVar3). However, a Japanese study reported prevalence of pathogenic variants among patients classified as having definite, probable, possible, and unlikely FH was 77.1%, 28.7%, 13.0%, and 1.2%, respectively7). Accordingly, we determined that the possibility of FH could not be excluded in this case, and we prioritized the clinical presentation and implemented a treatment strategy consistent with FH. During pregnancy, heterozygous FH patients with coronary artery disease, as well as those with homozygous familial hypercholesterolemia (HoFH), need to implement strict lipid management by starting lipoprotein apheresis (LA) to prevent further progression of coronary atherosclerosis and AMI8). LA is a feasible and effective treatment option during pregnancy. In Japan, a total of 10 deliveries in 7 pregnant women with HoFH have been reported, and bradykinin-induced hypotension was noted, indicating the need for hemodynamic monitoring during the procedure9). Moreover, LA is costly, time-consuming, and high invasive, which limits its broader application. In the present case, although the patient had established coronary stenosis, the condition differed from HoFH in that the elevation of LDL-C was relatively mild and considered manageable with pharmacotherapy alone. Accordingly, the current case received intensive lipid-lowering therapy with a high-intensity statin and adjunctive evolocumab.
The target LDL-C level was set at ＜100 mg/dL. During pregnancy, physiological increases in serum cholesterol levels are thought to occur due to hormonal changes that support fetal development. Moreover, since the safety of maintaining LDL-C at 70 mg/dL during pregnancy has not been clearly established. Although the current case would ordinarily be considered a candidate for intensive lipid-lowering therapy with a target LDL-C of ＜70 mg/dL based on secondary prevention criteria, a target of ＜100 mg/dL was deemed appropriate in light of the unique physiological context of pregnancy and the fact that the patient did not strictly meet the criteria for secondary prevention of AMI. Furthermore, reports on the use of LA in pregnant patients have shown that LDL-C levels are not consistently maintained below 70 mg/dL in all cases8). This suggests that even with the introduction of LA, strict achievement of target LDL-C levels cannot be guaranteed. Based on this consideration, setting the target LDL-C level at ＜100 mg/dL was deemed appropriate.
In the present case, percutaneous coronary intervention (PCI) was not performed during pregnancy. PCI has become a viable therapeutic option for pregnant patients10). However, concerns remain regarding the risk of procedural complications. Pregnancy is associated with an increased risk of coronary artery dissection (CAD) compared to the non-pregnant state. This is thought to be due to pregnancy-related elevations in estrogen and progesterone, which induce degenerative changes in collagen and elastic fibers within the medial and adventitial layers of the arterial wall, leading to structural fragility. In addition, increased circulating blood volume and cardiac output during pregnancy impose greater mechanical stress on the coronary arteries. Several reports have described iatrogenic CAD during PCI in pregnancy, some of which were not amenable to catheter-based repair and required surgical coronary artery bypass grafting11). Therefore, in relatively stable conditions, it is essential to manage patients cautiously while avoiding invasive interventions whenever possible. In this case, although 70% stenosis of the LAD and reduced FFR were observed, no ischemic episodes were detected during exercise tolerance testing. As a result, pharmacological therapy was prioritized over PCI during pregnancy.
Currently, the only lipid-lowering medication with established safety for use during pregnancy is anion exchange resins, colestimide. Ezetimibe, a small intestine cholesterol transporter inhibitor, is generally considered safe for use during pregnancy; however, due to limited clinical data, its administration should be restricted to cases in which the potential benefits clearly outweigh the risks12). However, both options had a limited efficacy and are not ideal for comprehensive lipid management during pregnancy. In the present case, lipid-lowering therapy was initiated in the context of dyslipidemia with coronary artery stenosis, indicating a high-risk condition. Ezetimibe was chosen as the initial agent; however, it was discontinued due to the development of drug-induced liver injury, and treatment was subsequently switched to colestimide. Statins, which are HMG-CoA reductase inhibitors, are the most commonly used treatment for high LDL-C levels and can reduce cardiovascular morbidity and mortality13). However, as animal studies and case reports have shown that statins have teratogenic effects, the FDA had long not recommended the use of statins in pregnant women. Recent studies have revealed no association between statins and teratogenic risks or other adverse pregnancy outcomes, and there is a growing body of evidence suggesting that statins may be safe for both the mother and the fetus12, 14). Therefore, the FDA has recommended the use of statins during pregnancy when the benefits outweigh the risks, particularly in pregnant women with HoFH and those who have previously had a heart attack or stroke. Thus, for the secondary prevention of coronary artery disease, we decided to use a statin if the LDL-C level was not controlled by colestimide or ezetimibe. Statins are classified into lipophilic (simvastatin, fluvastatin, atorvastatin, and pitavastatin) and hydrophilic (pravastatin and rosuvastatin) types. A retrospective cohort study comparing 469 women who took statins during pregnancy and 4,690 women who did not reported an association between lipophilic statins and low-birth-weight infants15). By contrast, the hydrophilic statin pravastatin has a low permeability to the embryo and does not affect cholesterol biosynthesis, thereby making it unlikely to influence fetal development. Therefore, in this case, a hydrophilic statin was chosen as the first choice of drug. Furthermore, in the hydrophilic statin, rosuvastatin has been reported to lower testosterone levels16), so pravastatin was chosen. Pravastatin was switched to a PCSK9 inhibitor because achieving the target LDL levels was challenging with pravastatin alone. The PCSK9 protein inhibits the recycling of LDL receptors expressed on the surface of hepatocytes, leading to elevated blood LDL-C levels5). The PCSK9 inhibitor inhibits the expression of the PCSK9 protein, thereby increasing the recycling of LDL receptors and lowering LDL levels. They have a potent LDL-C-lowering effect and can be a viable option. In Japan, the use of PCSK9 inhibitors has been approved for patients with FH and those with high LDL-C levels who are at high risk of cardiovascular events, and in cases in which statins are insufficiently effective, or statin treatment is not appropriate for FH and high LDL-C levels17). In addition, a PCSK9 inhibitor, evolocumab is classified as an IgG2 subclass of humanized IgG monoclonal antibodies. Of the immunoglobulin antibodies, IgG crosses the placenta. However, among its subgroups, IgG2 has the lowest placental permeability18). Therefore, the potential for systemic exposure in the fetus is considered to be low. The use of evolocumab during breastfeeding is not currently recommended due to a lack of data in humans19). However, IgG2 monoclonal antibodies are excreted into breast milk only in minimal amounts. Moreover, even if absorbed from the breast milk, most of the IgG2 antibodies are believed to be degraded in the neonatal gastrointestinal tract20). Their administration was likely associated with minimal neonatal impact, although long-term follow-up will be required.
In the present case, ezetimibe, pravastatin and evolocumab were initiated after the second trimester. Organogenesis primarily occurs during the first trimester, particularly between 5 and 10 weeks of gestation, and the risk of teratogenicity is considered to be lower in the second and third trimesters. Although evidence regarding lipid-lowering therapy during pregnancy remains limited, the decision to initiate treatment after the second trimester was made with maternal prognosis as the highest priority. Their administration was likely associated with minimal fetal impact, although further case accumulation is necessary for validation.
In conclusion, statins and PCSK9 inhibitors could be viable alternatives for women who require strict lipid management during pregnancy. Nevertheless, further research is required to assess the safety and efficacy of this combination therapy during pregnancy.
None.
The present study was supported by the Intramural Research Fund (25-A-1) for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center and a Grant-in-Aid for Scientific Research (C; #24K11258) from the Ministry of Education, Culture, Sports, Science, and Technology.
There are no conflicts of interest to declare.
