Pregnancy Outcome after Exposure to Migalastat for Fabry Disease: A Clinical Report

Abstract

Our patient was a 37-year-old woman with Fabry disease (GLA p.R112H) with a medical history of recurrent headache, nausea, vomiting, vertigo, and tobacco use (20 cigarettes/day). Fabry disease was diagnosed in 2005 when she experienced proteinuria, preeclampsia, and hypertension (201/130 mm Hg) during pregnancy (delivered 50 cm, 3.4 kg healthy boy; GLA wild type [WT]). Enzyme replacement therapy was initiated in 2009. The patient enrolled in the phase 3 ATTRACT trial (ClinicalTrials.gov; NCT01218659) and started migalastat in May 2012 while taking hormonal contraceptives. Two years after initiating migalastat, the patient had proteinuria (2166 mg/24 h) without hypertension (131/68 mm Hg), which persisted (788 mg/24 h a month later). Kidney biopsy results were consistent with existing Fabry disease. A serum pregnancy test and ultrasound confirmed pregnancy (18 weeks' gestation). Migalastat and hormonal contraceptives were stopped; the patient continued to smoke. Fetal MRI was normal at ~29 weeks' gestation. In October 2014, at 37+ weeks' gestation, the patient delivered a 45-cm, 2.29-kg healthy girl (GLA WT). Excepting low birth weight, which may be related to the patient's smoking, pregnancy outcome was normal despite exposure to migalastat for 18 weeks. Migalastat therapy during pregnancy is not advised.

Figure 1

Pedigree analysis. The patient is indicated by the arrow. Black boxes represent males with Fabry disease; circles with black dots represent females with Fabry disease. Slash indicates deceased.

Figure 2

Time course of (a) proteinuria and albuminuria, (b) creatinine, and (c) eGFR_CKD-EPI. ACR, albumin-to-creatinine ratio; eGFR_CKD-EPI, estimated glomerular filtration rate chronic kidney disease epidemiology collaboration; PCR, protein-to-creatinine ratio.

Figure 3

Histology and transmission electron microscopy of kidney biopsy specimens obtained (a) in 2005, one month after birth of first child (second pregnancy) and (b) in 2014, during pregnancy with second child (third pregnancy). AFOG, acid fuchsin orange G; IgA, immunoglobulin A; IgG, immunoglobulin G; PAS, periodic acid-Schiff; TEM, transmission electron microscopy. (a) The first renal biopsy (2005) shows a diffuse, segmentally accentuated mesangial matrix and mesangial cell proliferation (PAS and AFOG) in >50% of the glomeruli, and segmentally obliterated capillary loops adherent to the Bowman's capsule (AFOG). There is dominant segmental C3 deposition (C3) in the absence of IgG and IgA. Podocytes show characteristic lamellar and zebroid bodies by TEM; however, the classical appearance of “foamy” podocytes was less dominant by light microscopy (PAS) due to the segmental nature of the pathological changes. (b) The second renal biopsy (2014) shows characteristic foamy macrophages (PAS and AFOG) as well as segmental mesangial matrix and mesangial cell proliferation. Dominant C3 deposits (C3) correspond to mesangial electron dense deposits (∗) by TEM (right) while almost all podocytes contain lamellar and zebroid inclusion bodies (a).

Figure 4

Fetal MRI (coronal plane) during pregnancy at 29 weeks' gestation. MRI, magnetic resonance imaging. Images presented with patient permission.