pregnancy in patients with fabry and chronic...
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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
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