Immunologic Agent (Antihemolysis)
PREGNANCY RECOMMENDATION: Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The human pregnancy experience with eculizumab is very limited. The animal data from one species, using a murine version of the antibody, suggest risk. However, eculizumab is indicated for paroxysmal nocturnal hemoglobinuria (PNH), a high-risk complication in pregnancy manifested by hemolytic anemia, bone marrow failure, and thrombosis (1–3). Significant morbidity and mortality have occurred from PNH-induced venous thromboembolism with maternal and perinatal mortality up to 20% and 10%, respectively (1). Supportive therapy (red blood cells and platelet transfusions) and routine prophylactic anticoagulation are recommended. Moreover, there also is a need for additional iron and folic acid supplements because of the hemolysis. In nonpregnant and the limited number of pregnant patients, the use of eculizumab, usually in combination with low-molecular-weight heparin (LMWH), has reduced the need for transfusions and the rate of hemolytic episodes and thrombosis (1–3). Thus, if indicated, the maternal benefit appears to far outweigh the unknown embryo–fetal risk.
FETAL RISK SUMMARY
Eculizumab, an anti-C5 antibody, is a recombinant humanized monoclonal IgG2/4K antibody that contains human constant regions from IgG2 and IgG4 sequences. It is given as an IV infusion once weekly for 5 weeks and then every 2 weeks. The antibody binds to the complement protein C5 to inhibit its cleavage thereby preventing terminal complement mediated intravascular hemolysis. Eculizumab is indicated for the treatment of patients with PNH to reduce hemolysis. Eculizumab increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis), so all patients must be given meningococcal vaccine at least 2 weeks before starting eculizumab therapy and revaccinated according to current medical guidelines. The half-life of the antibody is 272 hours (4).
Reproduction studies have been conducted in mice using a murine anti-C5 antibody. Mice were given doses that were about 2–4 times (low dose) or 4–8 times (high dose) the recommended human dose based on body weight (RHD). When maternal exposure occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed in the high-dose group among 230 offspring. There was no increase in fetal loss or neonatal death. When the antibody was given from implantation through weaning, male offspring had an increased risk of death (1/25 controls, 2/25 low-dose group, and 5/25 high-dose group). Surviving offspring had normal development and reproductive performance (4).
Carcinogenic and mutagenic studies have not been conducted with eculizumab. No effects on reproductive performance or fertility were observed in male and female mice given IV doses of the murine anti-C5 antibody up to 4–8 times the RHD (4).
Although the molecular weight (about 148,000) is very high, the manufacturer states that the antibody is expected to cross the human placenta (4). There are data suggesting that all IgG subtypes can potentially cross the placenta but the IgG2 sequence having the least transfer of the subtypes (3). However, in two newborns (one at term and the other at 28 weeks’), the antibody was not detected in cord blood; in two others (twins at 35 weeks’), low levels within the background level for the assay were found (see reference 8). These cases suggest that the fetus will not be exposed to clinical significant concentrations of eculizumab.
In a 2006 correspondence, brief mention was made of a woman who became pregnant during a study of eculizumab in PNH, even though pregnancy was a study exclusion (5). Eculizumab therapy was discontinued and the woman had a successful full-term birth without complications.
A 34-year-old woman with PNH was treated with eculizumab in a twin pregnancy resulting from in vitro fertilization (6). Her first pregnancy 2 years earlier had ended with a spontaneous abortion (SAB) at 6 weeks’ despite anticoagulation with LMWH. Ongoing active hemolysis before and during the current pregnancy was documented and the patient was treated with therapeutic LMWH. At 30 weeks’, eculizumab was started with the recommended induction dose of 600 mg weekly for 4 weeks, followed by 900 mg every other week and LMWH was continued. At 35 weeks’, thrombocytopenia (60,000/μL) and increasing peripheral edema were observed. One week later, a cesarean section was conducted to deliver a 2919-g male infant and a 2199-g female infant with Apgar scores of 9 and 10 and 8 and 9, respectively. The female twin had an obstructed duplicated kidney that had been diagnosed early in the pregnancy. No additional information was provided on the status of the twins (6).
A 2010 reference described the pregnancy outcomes of seven women exposed to eculizumab for the treatment of PNH (7). All of the patients were initially on the standard maintenance dose of 900 mg every 2 weeks unless specified otherwise. Five of these cases were from the 106 women enrolled in clinical trials of the antibody in PNH. In one case, the woman underwent an elective abortion (EAB) and continued on eculizumab. In three cases, eculizumab was discontinued at 4, 5, and 14 weeks’ gestation, respectively. All delivered healthy newborns without any adverse effects. The fifth patient conceived after having been on eculizumab for 5 years. She withdrew from the trial and continued the antibody combined with LMWH throughout pregnancy. Because of breakthrough hemolysis, the eculizumab dosing interval was reduced to 12 days. She gave birth vaginally at term to a healthy, 4-kg male infant. The mother had a therapeutic eculizumab concentration (116.1 mcg/mL; time from last dose not specified) at delivery but the antibody was not detected in cord blood. The sixth patient, with twins, was treated with eculizumab for 2 years before stopping therapy for embryo implantation. She was maintained on therapeutic LMWH. At 27 weeks’, eculizumab was restarted with the recommended induction regime (600 mg every week for 4 weeks, then 900 mg every 2 weeks) but, because of continued intravascular hemolysis and hemoglobinuria, the 900 mg maintenance dosing interval was shortened to once weekly. An elective cesarean section at 35 weeks’ delivered two healthy infants (sex not specified) weighing 2.4 kg and 2 kg, respectively. At delivery, the mother had a therapeutic antibody concentration (80.5 mcg/mL; time from last dose not specified). The cord blood samples from the twins had subtherapeutic eculizumab concentrations (19.2 and 14.4 mcg/mL) that were within the background level for the assay. Patient number 7 had been receiving eculizumab and warfarin for PNH before conception. She also had chronic hypertension. At 5 weeks’ gestation, warfarin was discontinued and replaced with LMWH. At 28 weeks’, preeclampsia developed and a cesarean section delivered a 900-g infant (sex not specified). The mother had a therapeutic eculizumab concentration (63.2 mcg/mL; time from last dose not specified) at delivery but the antibody was not detected in cord blood. The mother and baby were doing well (7,8).
Another 2010 report described the pregnancy outcome of a 29-year-old woman with PNH who had been treated with eculizumab for 3 years before conception (9). Although the patient had never had thrombotic complications, LMWH was added when her pregnancy was discovered. Eculizumab and LMWH were continued throughout an uneventful pregnancy. At 38 weeks’, she vaginally delivered a healthy 3.43-kg male infant with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. At 9 months of age, the infant was developing normally (9).
In a 2013 case report, a 26-year-old white woman at 17 weeks’ had a recurrence of atypical hemolytic uremic syndrome that was initially controlled with multiple plasma exchanges with fresh-frozen plasma (10). The disease recurred at 26 weeks’ and she was treated with IV eculizumab 900 mg every 14 days until a cesarean section at 38 weeks’. The healthy, 3650-g female infant had Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The infant had normal laboratory values and was discharged home after 1 week (10).
BREASTFEEDING SUMMARY
No reports describing the use of eculizumab during human lactation have been located. In a case described above where the mother received eculizumab (900 mg) at 12-day intervals and had a therapeutic serum concentration (116.1 mcg/mL) at delivery, the antibody was not detected in milk samples obtained on postpartum days 1, 2, 3, 9, and 10 (8). Neither the time of the last dose nor the detection limit of the assay was specified. Nevertheless, the findings are compatible with the high molecular weight (about 148,000) of eculizumab. However, because human IgG is found in milk, additional reports are required to confirm that eculizumab is not excreted in detectable amounts.
The manufacturer states that published data suggest that breast milk antibodies are not systemically absorbed by nursing infants in substantial amounts (4). Consequently, breastfeeding by women receiving eculizumab is probably compatible, but meningococcal infections are a serious potential risk. Moreover, nursing infants should be closely observed for the most common (>10%) adverse effects observed in adults: headache, nasopharyngitis, back pain, nausea, fatigue, and cough.
References
1.Ziakas PD, Poulou LS, Pomoni A. Thrombosis in paroxysmal nocturnal hemoglobinuria at a glance: a clinical review. Curr Vasc Pharmacol 2008;6:347–53.
2.Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009;113:6522–7.
3.Danilov AV, Brodsky RA, Craigo S, Smith H, Miller KB. Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab. Leuk Res 2010;34:566–71.
4.Product information. Solaris. Alexion Pharmaceuticals, 2009.
5.Hillmen P. Eculizumab in paroxysmal nocturnal hemoglobinuria. Author reply. N Engl J Med 2006;355:2787–8.
6.Danilov AV, Smith H, Craigo S, Feeney DM, Relias V, Miller KB. Paroxysmal nocturnal hemoglobinuria (PNH) and pregnancy in the era of eculizumab. Leuk Res 2009;33:e4–5.
7.Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Rotoli B, Risitano AM, Schubert J, Hillmen P. Successful pregnancy outcome in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Haematologica 2009;94:452 (Abstract).
8.Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Risitano AM, Schubert J, Norfolk D, Simpson N, Hillmen P. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol 2010;149:446–50.
9.Marasca R, Coluccio V, Santachiara R, Leonardi G, Torelli G, Notaro R, Luzzatto L. Pregnancy in PNH: another eculizumab baby. Br J Haematol 2010;150:707–8.
10.Ardissino G, Ossola MW, Baffero GM, Rigotti A, Cugno M. Eculizumab for atypical hemolytic uremic syndrome in pregnancy. Obstet Gynecol 2013;122:487–9.