Endocrine/Metabolic Agent (Gaucher Disease)
PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
No alglucerase-related adverse effects in embryos and fetuses have been reported in the limited data on pregnancies complicated by type I Gaucher disease. Pregnancy may exacerbate existing disease or result in new disease manifestations, but the data suggest that treatment may reduce the risk of spontaneous abortion and bleeding complications. However, systematic human or animal studies have not been conducted. The manufacturer has replaced alglucerase with imiglucerase and the last commercially available alglucerase expired in March 2011.
FETAL RISK SUMMARY
Alglucerase, an enzyme given by IV infusion, is used in the treatment of patients with type I Gaucher disease. It is in the same pharmacologic subclass as imiglucerase, taliglucerase-α, and velaglucerase-α. Alglucerase replaced the endogenous enzyme β-glucocerebrosidase. Alglucerase is prepared from pooled human placental tissue. After infusion, the terminal elimination half-life ranges from 3.6 to 10.4 minutes (1).
Reproduction studies with alglucerase have apparently not been conducted. Moreover, the carcinogenic and mutagenic potential of alglucerase has not been studied. Histopathology studies to detect effects on spermatogenesis in rats revealed no testicular changes (1).
It is not known if alglucerase crosses the human placenta. The relatively high molecular weight (about 55,600) and the short terminal half-life suggest that exposure of the embryo–fetus will be limited, if it occurs at all.
A 1996 case report and review involved a 24-year-old woman with Gaucher disease who was treated with alglucerase 40 U/kg every 2 weeks (2). She received two doses of the enzyme during the 1st trimester and then additional doses were held until 12 weeks’ gestation when therapy was reinstituted. She gave birth at term to 3.65-kg, female infant with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. No additional information on the condition of the infant was provided (2).
A 1997 report described six pregnancies exposed to alglucerase (3). In one pregnancy, a low-dose, high-frequency regimen (30 U/kg/month, administered 3 times weekly) was discontinued before conception and then restarted at 12 weeks’ gestation. At term, a normal, 2.84-kg female infant was delivered. A second pregnancy was similarly treated but with a dose of 60 U/kg/month. This patient gave birth at term to a healthy, 3.65-kg male infant. Two women were treated throughout pregnancy on the low-dose, high-frequency regimen and gave birth at term to healthy, but small-for-gestational-age, female infants (2.56 and 2.50 kg, respectively). In a fifth pregnancy, a low-dose regimen was started at 5 months’ gestation but, about 1 month later, the woman delivered a female infant who died within 24 hours. The sixth case involved a woman with symptomatic pulmonary hypertension who had been treated with alglucerase for 3 years. At 10 weeks’ gestation, the pregnancy was terminated because of the lung condition. The conceptus was normal and appropriate for gestational age (3).
Another case report described a 25-year-old woman with avascular necrosis of the femur complicating Gaucher disease (4). She conceived 4 months later while receiving alglucerase 3200 U every 2 weeks (body weight not specified). She gave birth at term to a 4.19-kg, male infant who was doing well at 6 months of age (4).
Outcomes of exposed pregnancies treated with either alglucerase or imiglucerase have been summarized from surveys gathered from international treatment centers, from reports in the literature, as well as the manufacturer’s pharmacovigilance database. The total number of exposed patients is unclear as there could be overlap between the various sources of reports. However, as reviewed in a 2010 publication, among 43–78 treated pregnancies compared with 71–388 untreated pregnancies with the same disease, the risk of spontaneous abortion, disease-related bleeding complications at delivery, and disease-related complications postpartum was reduced. No evidence of teratogenic risk was noted (5,6).
BREASTFEEDING SUMMARY
Alglucerase has been detected in breast milk even though the relatively high molecular weight (about 55,600) and the short terminal half-life (3.6–10.4 minutes) suggest that excretion will be limited.
In a woman receiving an IV infusion of 60 U/kg, milk concentrations of the enzyme ranged from 69 to 187 ng/mL above baseline for 2–48 hours postinfusion (7). A 1998 case report described successful breastfeeding in a mother being treated with alglucerase (8).
The glycoprotein is largely destroyed in the digestive tract suggesting that even if small amounts are transferred into breast milk, the enzyme is unlikely to reach the systemic circulation of a breastfed infant (1).
References
1.Product information and personal communication. Ceredase. Genzyme, 2011.
2.Rosnes JS, Sharkey MF, Jean-Claude V, Eberhard MH. Gaucher’s disease in pregnancy. Obstet Gynecol Surv 1996;51:549–58.
3.Ebstein D, Granovsky-Grisaru S, Rabinowitz R, Kanai R, Abrahamov A, Zimran A. Use of enzyme replacement therapy for Gaucher disease. Am J Obstet Gynecol 1997;177:1509–12.
4.Cleary JE, Burke WM, Baxi LV. Pregnancy after avascular necrosis of the femur complicating Gaucher’s disease. Am J Obstet Gynecol 2001;184:233–4.
5.Zimran A, Morris E, Mengel E, Kaplan P, Belmatoug N, Hughes DA, Malinova V, Heitner R, Sobreira E, Mrsic M, Granovsky-Frisaru S, Amato D, vom Dahl S. The female gaucher patient: the impact of enzyme replacement therapy around key reproductive events (menstruation, pregnancy and menopause). Blood Cells Mol Dis 2009;43:264–88.
6.Granovsky-Grisaru S, Belmatoug N, vom Dahl S, Mengel E, Morris E, Zimran A. The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Biol 2011;156:3–8.
7.Esplin J, Greenspoon JS, Cheng E, Perkins C, Westman JA, Grabowski GA. Alglucerase infusions in pregnant type 1 Gaucher patients (abstract). Blood 1993;82:509a.
8.Aporta Rodriguez R, Escobar Vedia JL, Navarro Castro AM, Aguilar Garcia G, Cabrera Torres A. Alglucerase enzyme replacement therapy used safely and effectively throughout the whole pregnancy of a Gaucher disease patient. Haematologica 1998;83:852–3.