Will your child be sick as well? Testing before pregnancy · 2017. 9. 13. · 6th EUROPEAN...

6th EUROPEAN SYMPOSIUM ON RARE ANAEMIAS 1st Dutch-Belgian meeting for patients and health professionals

21st - 22nd November 2015

Amsterdam - The Netherlands

Will your child be sick as well? Testing before pregnancy

B. Gulbis, M.D., PhD

Université Libre de Bruxelles

Brussels, Belgium

6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals

Disclosures Company name Research

support Employee

Consultant Stockholder Speakers bureau Advisory board Other


This talk is applicable for:

Definite Probable

Thalassemia’s X

Sickle cell disease X

Membrane disorders (e.g. sferocytosis)

Enzym defects (e.g. PKD, G6PD) X

PNH

Other forms of hemolytic disease X

6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 4

Plan

• Preconception – prenatal diagnosis: the procedures

– Invasive

– Non-invasive

– Future?

• How to provide those diagnostic procedures?


Will our child be sick as well?

Genetic counselling

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCKeisLill8kCFUjvFAodaJsB5w&url=http://fr.depositphotos.com/41738597/stock-photo-question-words-drawing-as-question.html&bvm=bv.107467506,d.d24&psig=AFQjCNHiucmtDI-gl1tQsw0f7T74gBDxbw&ust=1447843961094390


Invasive procedures Prenatal diagnosis

Prenatal diagnosis (Antenatal screening)


Invasive procedures Prenatal diagnosis


Amniocentesis

Fetal

Blood

Sampling

Chorionic

Villous

Sampling


Invasive procedures Prenatal diagnosis: 10 – 12 weeks


Amniocentesis

Fetal

Blood

Sampling

Chorionic

Villous

Sampling For Prenatal Diagnosis (1983: Rodeck et al; Simonini et al; Ward et al).

Safety

• Ultrasound guidance

• Fetal medicine specialists

• Not before 10 weeks of gestation

(see limb disruption defects)

• Post-procedure loss 1%


Invasive procedures Prenatal diagnosis: after 15 weeks Prenatal diagnosis (Antenatal screening)

Amniocentesis

Fetal

Blood

Sampling

Chorionic

Villous

Sampling

Safety • Ultrasound guidance • Fetal medicine specialists • Not before 15 weeks of gestation (see direct fetal injury, amniotic membrane damage, high rate of culture failure) • Post-procedure loss 0.5%


Hôpital Erasme experience Prenatal diagnosis

CVS = 40% (107/268)


CVS - Amniocentesis

CVS Amniocentesis

Timing (weeks) 10 – 11 15 -

Chance of successful sampling

99% (contamination)

99%

Miscarriage risk ± 1% ± 0.5 %

Time required for diagnosis

3 – 7 days 3 to 7 days Culture: 2 to 3 weeks

11


Preimplantation Genetic Diagnosis (PGD)

Diagnosis on day 4

Transfer on day 5

In vitro fertilisation



• PGD-PCR

– For monogenic diseases

– For HLA typing

– …



• PGD for whom?

– Infertile couples

– Previous history of termination of pregnancy

– Objection to termination of pregnancy

– Thinking of a saviour baby



• PGD with HLA-typing

– 1/4 HLA matched embryos

– Risk of no transferable embryo

– Future of non-HLA matched embryos but without the disease?



• Most frequent indications

– Cystic fibrosis (CF)

– Myotonic dystrophy (DM1)

– Huntington disease (HD)

– Haemoglobinopathies (HBB)

– Fragile-X syndrome (FraX)

– Spinal muscular atrophy (SMA)

– + HLA typing (HBB + HLA; HLA)

The ESHRE PGD Consortium: 10 years

of data collection Harper J et al. Hum. Reprod. Update 2012;humupd.dmr052

Number of cycles

DMD, Duchenne muscular dystrophy; NF1, neurofibromatosis type 1; HaemA, haemophilia A; HLA, human leukocyte antigen for acquired diseases; APC, familial adenomatous polyposis; CMT1, Charcot-Marie-Tooth disease type 1; FAP, familial amyloidotic polyneuropathy; MS, Marfan syndrome; TS, tuberous sclerosis; VHL, Von Hippel Lindau.



• Neonatal follow-up of 995 born children

– PGD= No extra risk

• Mean term

• Prematurity

• Mean birthweight

• Perinatal death

• Major malformations

• Neonatal hospitalizations

• Congenital anomalies

Desmyttere S. et al Hum. Reprod. 2012; 27:288-93.



• Up to 4 attempts per family to achieve a suitable donor sibling

• ~20% embryos diagnosed as suitable for transfer

• ~10% embryos diagnosed as suitable for transfer if + HLA-typing


PGD experience Hôpital Erasme – Fertility Clinic

• First PGD for haemoglobinopathy in 2006

• Records treated: n= 70 • 64 for sickle cell disease (3 HbSthal.; 6 HbSC)

• 6 for thal. major

• Records rejected: 9/70 - without follow-up: 16/70

• 63 cycles for 29 couples (Mean 2.2 cycle by couple)

– PGD performed on 34 cycles (54%) all for SCD


PGD experience Hôpital Erasme

• PGD failure (biopsy not obtained): n= 29 cycles

– Failure of stimulation (not enough oocytes) 48%

– To few embryos 21%

– No fecundation 14%

– Low quality of the embryos 7%

– Spontaneous pregnancy 7%



Diagnosis on day 4: 151 embryos

Affected embryos N= 33

Unaffected embryos N= 107 (71%)

?

11

Unaffected, “good quality” embryos transferred

N= 54 (50%)

Cryopreservation N= 20 (19%)

Unaffected, “poor quality” embryos

Transfer not possible N= 20 (31%)



Diagnosis on day 4: n= 151

Transfer on day 5: n= 54

Pregnancies: n= 18/54 (33%)

Failure: n= 10

16.5%

Baby n= 9 (1 twins)


Prenatal/Preimplantation genetic diagnosis

Prenatal diagnosis PGD

Accuracy of genetic analysis

99% 99%

Risks Miscarriage, fetal injury No greater risk than conventional procedures

Major drawbacks Decision of abortion for affected embryos

Technically challenging Risk of IVF Low pregnancy and birth rates Costly

23


From the technique to the patient

•Detection of couple at risk

•Genetic counselling

•Fertility team

•If failure of stimulation or no fecundation…

•Molecular diagnosis •If failure of pregnancy or transferable embryo… •If failure of HLA matching embryo…

Couples should be clearly counselled before embarking on this reproductive option


Other options?

• Non-invasive prenatal testing with cell-free DNA

– … an accurate diagnosis of the presence or absence of the paternal mutation in the fetus was not possible in all cases to make it clinically applicable.

• D'Souza E et al J Postgrad Med. 2013 Jan-Mar;59(1):15-20. doi: 10.4103/0022-3859.109483. Detection of fetal mutations causing hemoglobinopathies by non-invasive prenatal diagnosis from maternal plasma.

– … provided that a previously born child is available for testing to determine the linkage to the paternal SNPs.

• Phylipsen M Prenat Diagn. 2012 Jun;32(6):578-87. doi: 10.1002/pd.3864. Epub 2012 Apr 20.

Non-invasive prenatal diagnosis of beta-thalassemia and sickle-cell disease using pyrophosphorolysis-activated polymerization and melting curve analysis.

https://webmail.erasme.ulb.ac.be/owa/redir.aspx?C=9de160dbc38f404d843be4642a7056af&URL=http://www.ncbi.nlm.nih.gov/pubmed/22517437


Other options? • Gene therapy

–Ongoing clinical trials

6th European Symposium on Rare Anaemias - 1st Dutch-Belgian meeting for patients and health professionals 27 Training Course on Haemoglobin Disorders 2011

Other options?

• New regulators of foetal haemoglobin ?

– two SNPs - BCL11A region rs4671393 and rs11886868

– three SNPs - HBS1L-MYB region rs28384513, rs9399137 and rs4895441

Nguyen TK et al Blood Cells Mol Dis. 2010 Aug 15;45(2):124-7.


Take home message

• Availability of relatively safe procedures

– Invasive or “non-invasive”

• New trends

• Complex procedures and not only “technical”


Thank you very much for your attention

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Will your child be sick as well? Testing before pregnancy · 2017. 9. 13. · 6th EUROPEAN...

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