Pregnancy in patients with Fabry and Chronic Kidney Disease

A. Schmidt

Medical University Vienna Austria

Overview

• Heritability

• Fertility

• Influence of pregnancy on Fabry disease and influence of Fabry disease on pregnancy outcome

• Chronic kidney disease in female Fabry patients and pregnancy

• Medication

Heritability

• X-linked inheritance

• Phenotypic heterogeneity due to mosaicism of mutant and normal cells in females

• 70 % of females have signs of Fabry disease!

Males: none of the sons but all daughters affected

Females: 50 % risk of affected offsprings

Heritability

Heritability Prenatal diagnosis

Genetic counseling prior to pregnancy: discuss intra-familial phenotype variations, atypical late-onset variants and

availability of therapy!!!

before pregnancy: Pre-implantation diagnosis of embryos/in vitro fertilisation

Weeks 9-11 of pregnancy: Determination of foetal sex/mother`s blood sample

Week 10 of pregnancy: Enzymatic/molecular diagnosis of chorionic villi

Week 14 of pregnancy: Enzymatic/molecular diagnosis of amniotic cells

Fertility in Fabry disease

Undisturbed hormonal function and normal fertility rate in comparison with the corresponding Austrian population

(Hauser AC, et al. Int J Clin Pract. 2005)

Azoospermia of testicular and post-testicular origin (Papaxanthos-Roche A et al. Fertility and Sterility 2007)

Females affected by FD have more children (1.8 vs. 1.1) than males, but males affected by FD have more children

than men in the United States (1.1 vs. 0.9)! (Laney DA et al. JIMD Rep. 2017)

Chronic kidney disease (CKD) and fertility

CKD 1 CKD 5 Kidney transplantation

Age and fertility

%

years

fert

ility

Zebra bodies in A endothelial, B vascular smooth muscle cells and C pericytes and positive immunohistochemistry D in the placenta of an affected mother

Vedder AC, et al., J Inherit Metab Dis 29:106-11, 2006

Abortion? Miscarriage?

Pre-eclampsia? Intrauterine growth

restriction?

Pregnancy outcome in affected women (89 pregnancies) and controls (78 pregnancies)

Bouwman MG et al. J Inherit Metab Dis 2012 35:891-898

Most common symptoms of Fabry disease during pregnancy in affected women (102 pregnancies/41)

Holmes A, Laney D. JMD Reports 2014; 56-63

Pregnancy complications in women with Fabry disease in comparison to the general population

Holmes A, Laney D. JMD Reports 2014; 56-63. A retrospective survey studying the impact of Fabry disease on pregnancy

10 women with new onset of proteinuria

6 women with new onset of hypertension

CKD and pregnancy

- CKD might influence pregnancy outcome

- Pregnancy might influence kidney function

Interdisciplinary approach (nephrologist+obstetrician+neonatologist)

Proteinuria at first report - Europe (Above or below 300 mg/24h urine)

FOS data as of March 2006

Fabry disease: Progression of nephropathy

Schiffmann et al., NDT 24:2102-11, 2009

End-stage renal disease in patients enrolled in the Fabry Registry

Eng et al., J Inherit Metab Dis 30:184-92, 2007

Unspecified renal signs: 17%

Influence of chronic kidney disease (CKD) on pregnancy

Live birth rate > 90 % in modest CKD (meta-analysis)

- maternal (gestational-)hypertension pre-eclampsia / HELLP-syndrome maternal mortality (4 vs. 1%)

- foetal / neonatal preterm birth (13 vs. 6%) intrauterine growth restriction (5 vs. 0%), small-for-gestational age (14 vs. 8%) still birth (5 vs. 2%)

Risk is highest in patients with poor kidney function and

uncontrolled hypertension

Combined endpoints:

12 vs. 2%

Significant difference in pregnancy outcome already in CKD 1 versus controls:

Preterm delivery (33 vs. 5%), C-section (57 vs. 25%), NICU (18 vs. 1%)

Piccoli GB et al. CJASN 2010 Nevis IF et al. CJASN 2011

Influence of pregnancy on chronic kidney disease

An elevation of creatinine >1.5 mg/dl and hypertension are the

major risk factors

for permanent exacerbation of underlying renal disease

½ of cases: increase of proteinuria

¼ of cases: hypertension develops or worsens

during pregnancy

Hou S. AJKD 1999 Jungers P et al. Lancet 1995 Hous S. NEJM 1985 Imbiascati E et al. AJKD 2007 Jones DC et al. NEJM 1996

Influence of pregnancy on chronic kidney disease

creatinine 1.5 – 2.9 mg/dl:

- 1. half of pregnancy: moderate decline of creatinine

2. half of pregnancy: may rise above the baseline (in 40%)

- 1/3 permanent decline of kidney function

- one study: 10% ESRD

after 12 months

creatinine < 1.5 mg/dl:

- evtl. transient decline of kidney function

- 0-10% permanent decline

- after 30 years no difference in renal survival between 171 females with chronic

glomerulonephritis and pregnancy and those without pregnancy (129)

Up: proteinuria g/d GFR: glomerular filration rate ml/min/1,73

Treatment with enzyme replacement therapy (ERT) during pregnancy (n=13)

agalsidase α Wendt S et al 2005 1 m Dehout F et al 2006 1 ? Kalkum G et al 2009 2 f, m agalsidase β Germain DP et al 2010 1 m Politei JM 2010 1 m Bouwman MG 2010 1 f Tacsi ES et al 2015 2 f, f

unknown ERT

Holmes A , Dawn L 2015 4 ?

Seely EW, Ecker J. N Engl J Med 2011;365:439-446.

Common Pharmacologic Therapies for Chronic Hypertension in Pregnancy

Pain in Fabry disease/pregnancy

?

Polite JM etal, CNS Neuroscience & Therapeutics 22, 2016: 568-576

Summary Inheritance is x-linked

Prenatal diagnosis is possible

Fertility is excellent

New onset of Proteinuria and hypertension might occur during pregnancy

CKD is rare in female Fabry patients but might influence the pregnancy outcome

And pregnancy might influence the course of CKD

There are safe medications for Fabry disease in pregnancy