Ishraq Dhaifalah, MD PhD.

Medical genetic and fetal medicine dept.University hospital,

Olomouc, Czech Rep.

Ishraq_dhaifalah@yahoo.com

Prenatal diagnosis indications and

technique

Middle east ultrasound conference Dubai, 2007

• PRIMARY PREVENTION - preventing the development of the problem– The plumber, the grocer, the politician, the doctor– Maternal Nutrition– Maternal Immunization– Avoidance of environmental teratogens– Maternal Disease Management– Pre-implantation diagnosis

• Secondary prevention - preventing the problem from causing a disease, removing the cause– Pregnancy interruption after prenatal diagnosis– Inutero medical management of maternal disorders– Inutero surgical management, gene therapy

• Tertiary prevention - preventing the problem from progressing and causing disability– identification of inborn errors of metabolism– management of medical disorders– surgical management of birth defect Dubai, 2007

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Until the recent past, couples at high risk of genetic disorder have the choose of:

- taking the risk - considering other reproductive

options (long term contraception, sterilisation, termination of pregnancy or even adoption and artificial insemination)

until the 1966 when the relation of advanced maternal age and increase rate of Down syndrome was noticed, the prenatal diagnosis start to developed

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• It is not simply to detect abnormalities and allow termination

• Provide a range of informed choice to the couples at risk of having a child with abnormality

• Provide reassurance and reduce anxiety, especially among high-risk groups

• Allow couples at high risk to know that the presence or absence of the disorder could be confirmed by testing

• Allow the couples the option of appropriate management (psychological, pregnancy/delivery, postnatal)

• To enable prenatal treatment of theaffected foetus

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Less invasive techniques (screening vs. Diagnosis)

Earlier testing (first trmester vs second trimester)

Individual diagnosis to population-based screening

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• Amniocentesis• Chorionic villus sampling• Cordocentesis• Preimplantation genetic

diagnosis• Fetoscopy

• Maternal serum AFP• Maternal serum screen• Ultrasonography• Magnetic resonance • Free fetal DNA and RNA

in maternal blood

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• advanced maternal age • previous child with a

chromosomal abnormality• family history of a

chromosomal abnormality• family history of single

gene disorder

• family history of a neural tube defect

• family history of other congenital structural abnormalities

• abnormalities identified in pregnancy

• other high risk factors (consanguinity, poor Obst., history, maternal illnesses)

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• Provide information• Education• Counseling and support

- practical and emotional- decision making

• Informed choices• Offer thearpy

Counselling (Medical geneticists) Family historyRecurrence riskPrenatal screening and testingPregnancy Counselling:Pre-conceptual, consanguinity, following diagnosis of foetal abnormality or teratogenic exposure

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Maternal Age

Trisomy 21 Trisomy 18 Trisomy 13

15-19 1:1600 1:17000 1:3300020-24 1:14000 1:14000 1:2500025-29 1:1100 1:11000 1:2000030-34 1:700 1:7100 1:400035-39 1:240 1:2400 1:480040-44 1:70 1:700 1:160045-49 1:20 1:650 1:1500

Career or Motherhood: Socio-Economic Problem Increase of fetal aneuploidies12 years in school 5 years for diploma 3 years: masters 3-4 years: PhD Total: 24 years, Career????

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Previous child with Down‘s syn. due to non disjunction or unbalanced translocation will give a risk in subsequent pregnancy as of mother‘s age related risk plus 5%

If one of parents have balanced chromosomal rearrangement (translocation, inversion) causing a serious problems for a previous child due to unbalanced re-arrangement, then recurrence risk is between 1-2% and 15-20%. The risk will depend on nature of rearrangement and segment involved

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Usually no increase in risk compared to general population since most chromosomal disorders will arise as a result of disjunction than familial rearrangement. A history of Down‘s syn.However each situation should be confirmed by nature of chromosome abnormality in affected individual or urgent chromosome analysis from blood of related parents if normal, no invasive tests...

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A previous affected child Affection of one of the

parents or both Positive family history Have a 25-50% recurrence

and prenatal diagnosis should be offered as many can be diagnosed by DNA analysis or biochemical testing (Cystic fibrosis, Achondroplasia, Huntington disease, Neurofibromatosis, cystic fibrosis, haemophilia, muscular dystrophy )

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In first and second -degree relatives the risk should be determinedHigh risks were diagnosed by amniocentesis and AFP assessment MSAFP was the method of diagnosis that have been replaced by ultrasound nowadaysSmall closed neural tube defects can be missed even with the most skilled person (fortunately are not associated with serious problems)

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Evaluation of family pedigree Calculation of the risk If increased risk detailed

ultrasound can be offered between 16-18 weeks of pregnancy it will detect most of serious defects (cranial, cardiac, renal and limb deformation)

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Uncertainty of maternal serum screening and foetal anomaly scanning can make invasive procedure for the diagnosis more necessary

Poor foetal growth can be an indication for prenatal chromosome analysis as well as for confirmation of a serious and non-viable abnormality

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• Parental consanguinity leading to hereditary disorder or congenital anomalies (offer a detailed ultrasound)

• Poor Obst. history as recurrent miscarriage or still birth indicating high risk in future preg. (offer ultrasound of fetous and chromosome analysis of parents)

• Maternal illnesses as poorly controlled DM or maternal epilepsy treated with some drugs as sodium valproate (offer detailed ultrasound)

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• Amniocentesis• Chorionic villus sampling• Cordocentesis• Preimplantation genetic

diagnosis• Fetoscopy

• Maternal serum AFP• Maternal serum screen• Ultrasonography• Magnetic resonance • Fetal DNA and RNA from

maternal blood

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1st trimester (up to 14 week) 2ed trimester (18-23) 3ed trimester (after 24 week)

Improves patient satisfaction Detects twin gestations

earlier Reduces rate of induction for

postdates Provides earlier detection of

clinically unsuspected fetal malformations

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• CMA peak velocity for diagnosis of anemia as in cases of Rh isoimmunization,

• Uterine artery in pre-eclampsia• DV and AU in fetal assessment

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Fetal MRI can serve as an adjunct tool for ultrasonography for fetal screening.

Images are obtainable in any direction and have an excellent soft tissue contrastA larger visual field for easy understanding of the relation of adjacent structuresSubstituting ultrasonography in patients with oligohydramnios or obesity, especially in late trimester of pregnancyLess association between results and operatorsUltra fast MR sequences for “picture freezing” the fetus in the uterus and escaping the influence of motion artifacts

Indications:Central nervous system (CNS) (cerebral, neural tube defects, holoprosencephaly, hydranencephaly, porencephaly, schizencephaly, ventriculomegaly, AV malformations, tuberous sclerosis, intracranial hemorrhage)Cervical teratoma (mass and its relationship to the airway and neck vessels)Chest masses (congenital diaphragmatic hernia, congenital cystic adenomatoid malformations, bronchopulmonary sequestration, neuroenteric cyst, myringotracheal obstruction)Adrenal neuroblastoma.

Screeningový test DR (%) FPR (%)

MA 30 5 MA + serum βhCG a PAPP-A v 11 – 14 týdnu 60 5 MA + fetální NT v 11 – 14 týdnu 75 5 MA + fetální NT a NB v 11 – 14 týdnu 90 5 MA + fetální NT a serum βhCG a PAPP-A v 11 – 14 týdnu 90 5MA + fetální NT a NB a serum βhCG a PAPP-A v 11 – 14 týdnu 97 5MA + sérové biochemické markery v 15 – 18 týdnu 60 - 70 5

bhCG = volná podjednotka choriového gonadotropinu;DR = senzitivita; FPR = falešná pozitivita; MA = vek matky; NB = nosní kustka;NT = šíjové projasnení; PAPP-A = Pregnancy Associated Plasma Protein-A

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Rhesus factor (and most recently Kell)

Fetal gender (both sexes)

Some autosomal dominantly (through the paternal line) inherited diseases such as achondroplasia or myotonic dystrophy

Some autosomal recessively (compound heterozygotes) inherited diseases such as beta-thallassemia or cystic fibrosis.

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• Provide information• Education• Counseling and support

- practical and emotional- decision making

• Informed choices• Offer therapy

Counseling (Medical geneticists) Family historyRecurrence riskPrenatal screening and testingPregnancy Counseling:Pre-conceptual, consanguinity, following diagnosis of fetal abnormality or teratogenic exposure

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Couples should be informed of the risk, advantage and disadvanges

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Comparative genomic hybridization

Cytogenetic karyotype

PCR

FISHM- FISH

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Treat certain abnormalities of the fetus that might otherwise be fatal

Abnormalities that may be treated:

Twin/twin transfusion syndrome

Congenital diaphragmatic hernia

Urinary tract obstruction

Congenital cystic adenomatoid malformation of the lung

Sacrococcygeal teratoma

• Failure to obtain a sample or culture failure• An ambiguous chromosome result• An unexpected chromosome result

• Ultrasound soft markers• Risks of invasive tests:• Infection• premature labor and delivery, bleeding• leakage of amniotic fluid infertility • complications associated with anesthesia if used

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Prenatální diagnostika v ČR, 1994 -2005

0

200

400

600

800

1000

1200

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

ukončené neukončenépočet

rokDubai, 2007

Congenital abn.1

2005 2005 2005 1994 - 2004

terminated not terminated total total

anencefalie 26 2 28 290encefalokéla 7 0 7 69hydrocefalus 27 11 38 304spina bifida 24 2 26 261jiné vady CNS 12 7 19 115

srdeční vady 57+29 20+2 77+31 684rozštěp rtu/patra 14 20 34 143

ageneze/hypopl. ledvin

6 3 9 125

cystické ledviny 12 20 32 200

hydronefróza 10 36 46 268

jiné vady močového traktu

1 4 5 71

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Congenital abno. 2

2005 2005 2005 1994 - 2004terminated Not terminated total total

redukční deformity končetin 10 4 14 61

jiné vady končetin 6 19 25 79osteochondrodysplázie 13 5 18 126osteogenesis imperfecta 4 0 4 25brániční kýla 1 2 3 64omfalokéla 13 4 17 169gastroschíza 23 8 31 261hydrops fetalis 17 3 20 123hygroma colli 10 1 11 60mnohočetné vrozené vady 10 1 11 74

chromosomální aberace 313 110 423 2759ostatní vrozené vady 47 17 64 385celkem 663 299 962 6707

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Prenatální diagnostika v roce 2005VV nervové soustavy

12%

VV oběhové soustavy8%

VV dýchací soustavy1%

Rozštěp rtu a patra4%

VV trávicí soustavy1%

VV močové soustavy10%

Brániční hernie, rozstěp stěny břišní5%

VV sval.a koster.soustavy6%

Abnormity chromosomů44%

Jiné vroz. vady9%

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Aberace

2005 2005 2005 1994-2004ukončené neukončené celkem celkem

Downův syndrom 152 6 158 902Edwardsův syndrom 52 3 55 295Patauův syndrom 12 0 12 96jiné trisomie a derivované chromosomy

15 5 20 127

marker chromosomy 7 7 14 69triploidie a polyploidie 23 0 23 106delece (částečné monosomie) 4 1 5 68

balancované translokace 2 51 53 344inverze chromosomů 0 8 8 95Turnerův syndrom 33 10 43 275syndrom XXX 1 7 8 60Klinefelterův syndrom 9 4 13 127syndrom XYY 2 5 7 40jiné gonosomální aberace 1 3 4 55

Celkem 313 110 423 2759

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Prenatální diagnostika chromozomálních aberací v roce 2005

Downův syndrom37%

Edwardsův syndrom13%

Patauův syndrom3%

Jiné trisomie a část.trisomie5%

Marker chromosomy3%

Triploidie a polyploidie5%

Delece (část.monosomie)1%

Balanc.translokace13%

Inverze chromosomů2%

Turnerův syndrom10%

Syndrom XXX2%

Klinefelterův syndrom3%

Syndrom XYY2% Jiné gonosomální aberace

1%

Ukončené+neukončenéDubai, 2007

Prenatální diagnostika chromozomálních aberací v roce 2005

Ukončené

Downův syndrom48%

Edwardsův syndrom17%

Patauův syndrom4%

Jiné trisomie a část.trisomie5%

Marker chromosomy2%

Triploidie a polyploidie7%

Inverze chromosomů0%

Balanc.translokace1%

Delece (část.monosomie)1%

Turnerův syndrom11%

Syndrom XXX0%

Klinefelterův syndrom3%

Syndrom XYY1% Jiné gonosomální aberace

0%

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Metody prenatální diagnostiky v roce 2005

Vyš. karytoypu

44% UZ54%

Molekulárně geneticky

2%

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Invazivní prenatální diagnostika v ČR 1994 - 2005

02000400060008000

100001200014000160001800020000

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

počet

rok

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Metody prenatální diagnostiky

0%

20%

40%

60%

80%

100%

1998 1999 2000 2001 2002 2003 2004 2005

CVS CC ACRok

2,17 0,700,741,79 0,41 0,41

3,48 1,671,773,243,252,80 1,79

0,79 1,18

1,20

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Molekulárně genetická diagnostika

Cystická fibrosa; 5

Spinální muskulární atrofie; 2

DMD/BMD; 1

Smith-Lemli-Opitz syndrom; 2

Neurofibromatosis; 1

Hemofilie; 1

Myotonická dystrofie; 1

Connexin 26; 1

Kostní dsplasie; 1

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Total number of US investigations in relation to total number of invasive

tests

512 441 403 446 554

0

1000

2000

3000

4000

5000

6000

2001 2002 2003 2004 2005

total number of US investigations in the dept.

total number of invasive procedures in the dept.

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30

35

40

45

50

2001 2002 2003 2004 2005

% of US investigations

0

5

10

15

20

2001 2002 2003 2004 2005

% of invasive procedures

Percentage of prenatal diagnosis(US) in relation to the total number of investigations

Percentage of invasive tests in relation to the total number of prenatal diagnosis (US)

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05

10152025303540455055

2001 2002 2003 2004 2005

amniocentesis CVS

Percentage of pathological cases in relation to each type of invasive test: amniocentesis vs. CVS

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Type of pathological cases detected in each year

0

5

10

15

20

25

2001 2002 2003 2004 2005

total number of chrom. abnorm. trisomy 21 trisomy 18 other

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It is the field of medicine that deal with the fetus as a patient

It can be carried out by non-invasive procedures (biochemical screening, US, MRI and genetic counseling)

Invasive procedures as amniocentesis or CVS are usually required for diagnosis of chromosomal and single gene disorders

Cordocentesis is mostly used for fetal blood transfusion Invasive procedures convey small risk for miscarriage

(around 1%) The commonest indication of prenatal diagnosis is

advanced maternal age, family history of chromosome, single gene or structural abnormality and a positive screening test in pregnancy

While the significance of most prenatal diagnostic findings is clear, situations can arise in which the implications for the fetus are very difficult to predict. When this occurs the parents should be offered specialized genetic counseling

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