Exposure to alirocumab during the first trimester of pregnancy: A case report

Abstract

Background Familial hypercholesterolemia can be efficiently treated with combined lipid‐lowering drugs. Lipid‐lowering drugs are usually withdrawn for pregnancy and breastfeeding, ideally preconception, followed by lipid apheresis, however, careful plans can be precipitated due to unexpected pregnancy. Case A 28‐year old woman with familial hypercholesterolemia due to heterozygous LDLR mutations had an LDL‐cholesterol level at 14.6 mmol/L and Lp(a) at 1150 mg/L. She required a three‐vessel coronary artery bypass graft, drug‐eluting stents, rosuvastatin, ezetimibe, and alirocumab at maximal dosage. Contraception was advised during the following 12 months, with a planned drug withdrawal to bridge with lipid apheresis, such as the direct adsorption of lipoproteins (DALI). However, an unplanned pregnancy required an abrupt stop of all oral medications at six gestational weeks, except for aspirin. Lipid apheresis controlled LDL‐cholesterol in the range of 4.9–7.9 mmol/L (before DALI session) to 1.2–3.2 mmol/L (after DALI session). Later, the regular pregnancy ultrasounds highlighted an isolated agenesis of the corpus callosum later confirmed by magnetic resonance imaging. Conclusions A causal link between the early pregnancy exposure to PCSK9 inhibitors (or statins and ezetimibe taken concomitantly) and the observed complete agenesis of the corpus callosum seems unlikely in this case. Guidelines do not specifically recommend preconception measures to lower fetal and/or maternal risks of patients with severe FH considering pregnancy. We argue that lipid apheresis and other measures should be discussed with women with FH and maternity project on an individual basis, until pharmacoepidemiology studies assessing the safety of PCSK9 inhibitors in pregnancy are available.

Management of familial hypercholesterolemia in pregnancy

“…Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors should be discontinued before conception. Primate studies show that evolocumab crosses the placenta and although there are no reported adverse effects in animals there are no reports of its use in human pregnancy or lactation other than in a woman taking evolocumab at the time of unplanned conception which was discontinued at 8 weeks gestation [48] and a woman who ceased rosuvastatin, ezetimibe and the PCSK9 inhibitor alirocumab at 6 weeks gestation whose baby had a likely unrelated agenesis of the corpus callosum [52].…”

Safety of Monoclonal Antibodies Inhibiting PCSK9 in Pregnancy: Disproportionality Analysis in VigiBase®

“…Similarly, the only clinical case previously published in the scientific literature does refer of exposure to alirocumab in early pregnancy (in the first 10 weeks of pregnancy) along with the occurrence of complete agenesis of the corpus callosum, for which the causal link seemed unlikely. 7 Spontaneous abortion occurred in eight out of 13 safety reports with pregnancy outcomes in addition to drug exposure in the peripregnancy period. Since spontaneous abortion generally occurs before the 20th week of pregnancy, while alirocumab and evolocumab, as monoclonal antibodies, are expected to cross the placental barrier from 20 to 22 weeks of pregnancy, 6 a causal relationship between the use of alirocumab or evolocumab in the peripregnancy period and the occurrence of spontaneous abortion is unlikely.…”

“…6 Available safety data on exposure to alirocumab and evolocumab in the peri-pregnancy period (i.e., before, during, and after pregnancy) are scarce and, to our knowledge, so far limited to only one clinical case retrievable in the scientific literature. 7 This limited information does not allow currently for risk assessment in pregnancy. Remarkably, regulatory recommendations on the use of alirocumab and evolocumab in pregnancy differ between the United States (US) and Europe.…”

“…On the other hand, just as immunoglobulin G antibodies, monoclonal antibodies inhibiting PCSK9 cross the placenta through the neonatal Fc receptor that appears only after the first 20–22 weeks of pregnancy 6 . Available safety data on exposure to alirocumab and evolocumab in the peri‐pregnancy period (i.e., before, during, and after pregnancy) are scarce and, to our knowledge, so far limited to only one clinical case retrievable in the scientific literature 7 . This limited information does not allow currently for risk assessment in pregnancy.…”

Dyslipidaemia management in pregnant patients: a 2024 update

“…However, it was suggested that a direct causal link between these factors may not exist. 37 , 80 Other available reports indicated that the administration of PCSK9 inhibitors had no effect on foetal growth and development in monkeys. Nevertheless, data from human studies remain insufficient.…”