Endocrine/Metabolic Agent (Enzyme)
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The successful use of agalsidase-β or agalsidase-α in human pregnancy has been described in a few reports. The animal data, involving only one species, suggest low risk, but the limited human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. However, Fabry disease is a debilitating condition that can be markedly improved by the use of enzyme replacement therapy. If a woman requires enzyme replacement therapy and gives informed consent, the enzyme should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Agalsidase-β, a glycoprotein, is a recombinant α-galactosidase A enzyme that has the same amino acid sequence as the endogenous enzyme. It is indicated for patients with Fabry disease, an X-linked genetic disorder of glycosphingolipid metabolism. Agalsidase-β reduces globotriaosylceramide deposition in capillary endothelium of the kidney and certain other cells. It is given as an IV infusion every 2 weeks. The terminal plasma half-life of agalsidase-β is dose-dependent with a range of 45–102 minutes (1).
Agalsidase-α is available in Europe and the United States (as an orphan drug). The α- and β-products are produced by different protein expression systems (2). Another commercial product, α-galactosidase A, also is an orphan drug in the United States that is available elsewhere. All three formulations contain the same enzyme, α-galactosidase A.
Reproduction studies have been conducted with agalsidase-β in rats. Doses up to 30 times the human dose were not associated with impaired fertility or embryo–fetal harm. Studies for carcinogenicity and mutagenicity have not been conducted (1).
It is not known if agalsidase-β crosses the human placenta. The molecular weight (about 100,000) and short elimination half-life suggest that the enzyme will not cross to the embryo or fetus.
A 2005 case report described the use of agalsidase-α throughout gestation in a 34-year-old woman (3). Fabry disease had been diagnosed at 15 years of age and treatment with the enzyme, 0.2 mg/kg every 2 weeks infused over 40 minutes, was started 18 months before pregnancy. When pregnancy was diagnosed, the patient requested continuation of the therapy. Analysis of the amniotic fluid showed normal α-galactosidase A activity so the male fetus was not expected to have Fabry disease. After an uneventful pregnancy, the woman gave birth at 37 weeks’ to a healthy, 3010-g male infant with Apgar scores of 9, 10, and 10, presumably at 1, 5, and 10 minutes, respectively. The infant’s length and head circumference were 52 and 32 cm, respectively (3). A brief 2009 report described two pregnant women with Fabry disease who were treated with agalsidase-α (4). The outcomes of both pregnancies were healthy infants.
Three reports have described successful pregnancy outcomes that were treated with agalsidase-β for Fabry disease (5–7).
BREASTFEEDING SUMMARY
No reports describing the use of agalsidase-β, agalsidase-α, or α-galactosidase A during human lactation have been located. The molecular weight of the enzyme (about 100,000) and short plasma elimination half-life (45–102 minutes) suggest that it will not be excreted into breast milk. Even if excretion does occur, the enzyme probably would be digested in the nursing infant’s gut. α-Galactosidase A is a native enzyme and should be present in the infant. Moreover, the indication for enzyme replacement therapy implies that the mother would have received it during pregnancy. Thus, the risk to a nursing infant from maternal use of any of the three formulations appears to be nil.
References
1.Product Information. Fabrazyme. Genzyme, 2007.
2.Lee K, Jin X, Zhang K, Copertino L, Andrews L, Baker-Malcolm J, Geagan L, Qiu H, Seiger K, Barngrover D, McPherson JM, Edmunds T. A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology 2003;13:305–13.
3.Wendt S, Whybra C, Kampmann C, Teichmann E, Beck M. Successful pregnancy outcome in a patient with Fabry disease receiving enzyme replacement therapy with agalsidase alfa. J Inherit Metab Dis 2005;28:787–8.
4.Kalkum G, Macchiella D, Reinke J, Kolbl H, Beck M. Enzyme replacement therapy with agalsidase alfa in pregnant women with Fabry disease. Eur J Obstet Gynecol Reprod Biol 2009;144:92–3.
5.Germain DP, Bruneval P, Tran TC, Balouet P, Richalet B, Benistan K. Uneventful pregnancy outcome after enzyme replacement therapy agalsidase beta in a heterozygous female with Fabry disease: a case report. Eur J Med Genet 2010;53:111–2.
6.Politei JM. Treatment with agalsidase beta during pregnancy in Fabry disease. J Obstet Gynaecol Res 2010;36:428–9.
7.Thurberg BL, Politei JM. Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature. Hum Pathol 2012;43:610–4.