Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Trisomy 21

Ermos Nicolaou

Wits Maternal and Fetal Medicine Unit

Morningside Medi-Clinic

And C H Baragwanath Hospital

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

What is the big deal?

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Copenhagen Post

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Citing case law, the High Court noted that such a claim - which would require a court to determine whether a child should have been born - "goes to the heart of what it is to be human, [something that] should not be asked of the law".

Mother sues for son's suffering

Aarti J Narsee | 29 August, 2014

“Had she known the severity of the risk, she would have aborted the fetus”

A damages claim of R6-million for the "wrongful suffering" of a child born with

Down's syndrome was heard in the Constitutional Court yesterday.

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Born to die? Woman sues for “wrongful life”A controversial case is presented before South Africa’s Constitutional Court, which could affect the way people with disabilities are treated

04 Sep, 2014

The case appears to be the first of its kind in South Africa and could go into case law history.

“The applicant appealed directly to the Constitutional Court arguing that South African law should be developed to allow the claim for ‘wrongful suffering’, as it terms the claim, particularly in light of section 28 of the Constitution which enshrines children’s rights, primarily requiring courts to consider the best interests of the child, and the Children’s Act,” the court papers said.

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Constitution (Chapter 2- Section 27/28)

Everyone has right to have access to health care services

No one may be refused emergency medical treatment

(?resuscitation of a 300g infant)

The state must take reasonable legislative and other measures within its available resources to achieve progressive realisation of these rights

Child’s best interests are of paramount importance

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

However ………

Truth does not always equal justice,

nor justice truth

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

So what’s all the fuss?Chromosome abnormalities represent 15% of congenital abnormalities. Of these, about one quarter is trisomy 21.

“Private eugenics” happen every day in hospitals all over the world and by far the most common “victims” are embryos equipped with an extra chromosome 21; Matt Ridley ”Genome”

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Introduction

• Most foetuses with chromosomal abnormalities have either external or internal defects which can be recognized by detailed ultrasonographicexamination:

-Nearly all fetuses with trisomy 13

-77-100% of fetuses with trisomy 18

-50-75% of fetuses with trisomy 21

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Detection rate

False-positive rate

Unaffected

Affected

5%

FPR

2%

FPR

Screening in pregnancy

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

Calculation of Risk for Chromosomal Abnormalities

Factor(s) derived from screening test(s)

Adjusted risk =

X

Background risk

Screening & Diagnosis of Trisomy 21

Maternal age > 35y100 50% 30,000 30030%

Serum biochemistry 12w120 60% 5000 505%

Nuchal translucency 12w150 75% 5,000 505%

Serum biochemistry 16 w130 65% 5,000 505%

Ultrasound markers 20w150 75% 15,000 15015%

100,000 pregnancies

Trisomy 21

N=200Normal

Detected

FetaldeathsCVS / Amnio

Screening & Diagnosis of Trisomy 21

Maternal age > 35y100 50% 30,000 30030%

100,000 pregnancies

Trisomy 21

N=200Normal

Detected

Fetaldeaths

CVS / Amnio

Nuchal translucency 12w100 75% 5,000 505%

Fetal NT & ß-hCG & PAPP- A180 90% 5,000 505%

NT & NB & ß-hCG & PAPP- A194 97% 5,000 505%

6 3% Remaining

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

Screening for Down’s syndrome: The 1st trimester

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

• Gestation 11-14 wks

• CRL 45-84 mm

• Mid-sagittal view

• Image size: calipers 0.1mm

• Neutral position

• Away from amnion

• Maximum lucency

• Callipers on-to-on

Nuchal Translucency: The technique

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

CRL: 54 mm

Calliper placement

Risk (%)

Age (years)

30 35 40 45

100

10

1

0.1

20 25

0.01

1: 600

1: 100

1: 3,700

1.5 2.9

Nuchal Translucency: The technique

0

2

4

6

8

10

12

14

16

18

20

-3.5 -2.5 -1.5 -0.5 0.5 1.5 2.5 3.5

Free ßhCG (SD)

%20

0

2

4

6

8

10

12

14

16

18

-3.5 -2.5 -1.5 -0.5 0.5 1.5 2.5

PAPP-A (SD)

%

Sensitivity 60% ; FPR 5%Spencer et al 1999

1st trimester biochemistry

Free beta HCG: …………. DR 25% PAPP-A: ………………………. DR 42%

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

1st trimester biochemistry

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

Estimated risk for trisomy 21

High-risk (> 1 in 100)2% of the population80% of Trisomy 21

Chorionic villous sampling2.5% of population90% of Trisomy 21

First-trimester screening

Low-risk (<1 in 1000)88% of the population5% of Trisomy 21

Ultrasound scan at 22 w

Intermediate-risk (1/101 – 1/1000)10% of the population15% of Trisomy 21

Ultrasound examination for:Absent nasal bone orAbnormal ductal flow orTricuspid regurgitation orWide facial angle

Positive Negative

cfDNA Test

Modified from Nicolaides, Advances in MFM 2013, London

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

NIPT (or better NIPS)

• During pregnancy, there are fetal cells and cell-free DNA fragments (cfDNA) from the fetus in the maternal circulation: the fetal fraction of cell-free DNA in maternal blood from week 10 is about 10-15% of all cell-free DNA

• It is possible to analyze this cell-free DNA to detect fetal trisomies such trisomy 21

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

To date, there are two major bioinformatics approaches:

1. the first-generation “quantitative” or counting approach used bymostcfDNA-based tests,

2. The second-generation approach that incorporates genotypic information (SNP) (Natera).

NIPS

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

The way in which the algorithm works is that the sample itself is used as a control to detect gains or losses of chromosomes. For example:47,XXX:2 x Chr 13 ||2 x Chr 18 ||2 x Chr 21 ||3 x Chr X |||

Thus, the median ‘amount’ of each chromosome in the sample itself is two copies (which is quantified to give a particular baseline value, say 10 (where 5 comes from each copy). If the ‘amount’ of any chromosome deviates proportionately from this, it can be determined if a gain (trisomy) or loss (monosomy) is present. Thus for Chr X in this example, its quantitative value would be 3 x 5 = 15. Thus, it can be determined that this sample was 47,XXX.

NIPS

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

in the case of triploidy XXX (69,XXX), there will be three copies of every chromosome:3 x Chr 13 |||3 x Chr 18 |||3 x Chr 21 |||3 x Chr X |||

Thus for every chromosome, the inherent value for each would be a quantitative baseline value of 15. But because there are three copies of each chromosome, the quantitative algorithm estimates that every chromosome is in equal ratio (quantitative proportion) across the genome. Thus, a 69,XXX cannot be differentiated from a 46,XX.

NIPS limitations

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

Society for Maternal-Fetal Medicine (SMFM) 34th Annual MeetingFebruary 3 - 8, 2014; New Orleans, Louisiana

Currently, the American College of Obstetrics and Gynecology and other specialty organizations recommend NIPT only for high-risk women. NIPT should be used when integrated screening identifies a woman as high risk.

NIPT failed to detect 22% of abnormalities in women younger than 25 years, but this dropped to 8% for women older than 45, "whose risk is driven by the high rate of common age-related aneuploidies for trisomies 18 and 21,"

Abnormality n Percent

Other trisomies 130 4.3

Duplications or deletions 90 3.0

Mosaic sex chromosomal abnormality

63 2.1

Common mosaics (trisomies 13, 18, 21)

32 1.1

Marker 14 0.5

Unbalanced translocations 9 0.3

Pathogenic Abnormalities Not Likely to Be Detected With NIPT

Chris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine Centre

Use of biochemistry markers in the detection of Down’s

DR for T21

• Unconjucated estriol:… 4%• AFP: …………………………… 17%• HCG: …………………………… 29%• Combination of free beta HCG, AFP, E3 & MA : DR 60%

Haddow et al

Screening for Down’s syndrome: 2nd trimester 1. Biochemical screening

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Screening for Down’s syndrome: 2nd trimester 1. Biochemical screening

Variable Serum marker

Gestational age increases with GA

Weight inversely proportional to weight

IDDM uE3 and Inhibin A reduced

total/free -hCG unchanged

AFP ?significant effect

Recent bleeding variable increase in AFP

Afro-Carribean race AFP and hCG increased

Multiple pregnancy increased

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

2. “Markers”What is a marker?

• structural anomaly

• visible on ultrasound scan

• rarely of postnatal significance

but

associated with a chromosomal abnormality

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Trisomy 21 ultrasound features

Soft markers

• brachycephaly

• mild ventriculomegaly

• flattening of the face with nasal bone hypoplasia

• nuchal edema

• echogenic bowel

• mild hydronephrosis

• shortening of the limbs

• sandal gap

• clinodactyly

• mid-phalanx hypoplasia of the fifth finger

Structural (Hard) markers

• Atrioventricular septal defects,

• Duodenal atresia

• Congenital Diaphragmatic Hernia

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Abnormalities in Trisomy 21

Major defects

Cardiac (septal) defects

Duodenal atresia, CDH,

Seen in 15% T21 cases

LR for isolated marker 5x

VSD AVSD

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Factor(s) derived from screening test(s)

Adjusted risk

X

Background risk

=

Likelihood Ratio

LRNo defect 0.3 xMild hydronephrosis 1.0 x Short femur 1.5 xShort humerus 4.5 xEchogenic bowel 3.0 x Echogenic foci 1.0 xNuchal fold >6 mm 10.0 xHypoplastic nasal bone 50.0 x

Calculation of Risk for Chromosomal Abnormalities

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Detection rates for Trisomy 21 using ultrasound markers

Author Detection Rate

Sohl 1999 67.3%

Nyberg 2001 68.8%

Smith Bindman 2001 69.0%

Hobbins 2003 71.6%

Bromley 2002 80.5%

Devore 2000 91.2%

Vintzileos 1996 92.8%

Average: 77%

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Incidence of markers / defects in 2nd Trimester scan

Trisomy 21

(%)

Normal

(%)

Positive LR

(95% CI)

Negative LR

(95% CI)

LR for isolated

marker

Nuchal fold 107/319

(33.5)

59/9331

(0.6%)

53.05

(39.37-71.26)

0.67

(0.61-0.72)

9.8

Short

Humerus

102/305

(33.4)

136/9254

(1.5)

22.76

(18.04-28.56)

0.68

(0.62-0.73)

4.1

Short femur 132/319

(41.4)

486/9331

(2.6)

7.94

(6.77-9.25)

0.62

(0.56-0.67)

1.6

Hydronephrosis 56/319

(17.6)

242/9331

(2.6)

6.77

(5.16-8.80)

0.85

(5.16-8.80)

1

Echogenic

Focus

75/266

(28.2)

401/9119

(4.4)

6.41

(5.15-7.90)

0.75

(0.69-0.80)

1.1

Echogenic

Bowel

39/293

(13.3)

58/9227

(0.6)

21.17

(14.34-31.06)

0.87

(0.83-0.0.91)

3

Major

Defect

75/350

(21.4)

61/9384

(0.65)

32.96

(23.29-43.28)

0.79

(0.74-0.83)

5.2

Nyberg et al, 2001 ; Bromley et al, 2002; Nicolaides 2003

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Combination of Markers

Echo-

Foci

Mild Hydr Short

Femur

Short

Humerus

Echo-

Bowel

Nuchal

Fold

Echogenic

Foci

- X8 X15 X30 X25 X80

Mild

Hydronephrosis

X8 - X10 X30 X25 X80

Short

Femur

X15 X10 - X50 X40 X100

Short

humerus

X30 X30 X50 - X100 X300

Echogenic

Bowel

X52 X25 X40 X100 - X200

Nuchal

fold

X80 X80 X100 X300 X200 -

Nicolaides, Ultrasound Obstet Gynecol , 2003

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Nuchal Fold Thickness: LR 10

In TCD view Out-to-out >6mm

Short Humerus LR 4.1

Short Femur LR 1.6 Mild Hydronephrosis LR 1

<20wks AP 5mm

20-24 AP 7mm

25-30 AP 8mm

>30 AP 10mm

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Echogenic Focus in the heart LR 1.1 Hyperechogenic bowel LR 3

Other causesIntra-amniotic bleedFetal hypoxemiaCystic fibrosis

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

• Hypoplastic Nasal Bone

• Defined by :

- non visible nasal bone

- length BPD/NBL >10

J Ultrasound Med. 2002 Dec;21 (12):1387-94Fetal nose bone length: a marker for Down syndrome in the second trimesterBromley B, Lieberman E, Shipp TD, Benacerraf BR

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Trisomy 21 (n=21/34) 61.8%

Normal (n=12/982) 1.2%

Hypoplastic nasal bone

Screening for Trisomy 21

18-23 weeks scan

NB-hypoplastic LR 50 caucasians

NB-hypoplastic LR 20 africans

Cicero, Ultrasound in Obstet Gynecol. 2003 Jan; 21(1):15-8

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Not used in risk calculation but alerts to look for other markers!

Choroid Plexus Cysts

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Author Gestational

age (weeks)

Populati

on

Definition of

choroid plexus

cysts

Choroid

plexus

cysts n

(%)

Karyotype for isolated

choroid plexus cysts

Karyotype for choroid

plexus cysts and other

anomalies

Normal Abnormal Normal Abnormal

Clarke2 1988 16-22 2820 3-14 mm 5 (0.2%) 5 - - -

Camurri3 1989 16-20 3000 ? 10 (0.3%) 9 - - 1 T18

Ostlere4 1990 16-18 11700 ? 100

(0.9%)

97 - - 3 T18

Achiron5 1991 20 5400 8-18 mm 30 (0.6%) 28 1 T18 - 1 T18

Twining6 1991 18-20 4541 3-13 mm 19 (0.4%) 16 - 1 1 T18

1 T21

Chinn7 1991 15-24 1045 2-11 mm 38 (3.6%) 36 - 1 1 Triploidy

Howard8 1992 18-20 4765 ? 51 (1.1%) 50 1 T18 - -

Walkinshaw10

1994

17-19 15565 ? 152

(1.0%)

137 3 T18

1 T21

11 -

Gupta11 1995 16-20 151000 > 5 mm 524

(0.4%)

486 - 29 7 T18

2 T21

Reinsch*12

1997

16-20 7340 > 5 mm 71 (1.0%) 61 1 T18 6 1 T18

2 T21

Kilby13 1997 18-21 16059 ? 301

(1.9%)

263 - 35 2 T18

1 T21

Geary14 1997 20 10481 ? 79 (0.8%) 58 - 17 4 T18

Chitty 15 1998 18-20 13690 ? 84 (0.6%) 78 - 3 3 T18

Total 247406 1464

(0.6%)

1324

(90.5%)

6 T18

1 T21

(0.5%)

103

(7%)

23 T18

6 T21

1 Triploidy

(2%)

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

No soft markers present - risk reduction

If the 18-23 week scan looks normal (No defects/markers)

•No previous NT scan reduce risk x 3

•With previous NT scan reduce risk x 2

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

• Offer all women 1st Trimester screening

• No need for 2nd Trimester serum screening

• Follow up with a detailed anomaly scan 20-23 weeks

Trisomy 21 screening: Conclusion 1

ACCREDITATION strongly recommended: 34 accredited practitioners in SA, today

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

No 1st Trimester screening

1. Offer 2nd Trimester screening

2. Major defect offer karyotyping even if isolated(low prevalence, small cost implications)

Trisomy 21 screening: Conclusion 2

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

3. Women > 35 years:

Offer diagnostic tests de novo with soft markers and risk calculation

In women up to the age of 39 years, with a background risk of <1 in 100 the adjusted risk, in the absence of any markers, will reduce to >1 in 300 (reduction by a factor of three) and therefore with a risk cut-off of one in 300 they screen negative.

Trisomy 21 screening: Conclusion 3

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

4. Women >40 years (low prevalence, small cost implications)

offer diagnostic testing

In women who are older than 40 years old, with no first trimester screening and a

background risk of >1 in 70, the adjusted risk after the second trimester scan

becomes <1 in 210 and therefore still remains screen-positive for Trisomy 21.

An invasive test could be considered here.

Trisomy 21 screening: Conclusion 4

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

100,000 pregnancies

Trisomy 21

N=200Normal

Detected

Fetaldeaths

CVS / Amnio

Nuchal translucency 12w100 75% 5,000 505%

Fetal NT & ß-hCG & PAPP- A180 90% 5,000 505%

NT & NB & ß-hCG & PAPP- A194 97% 5,000 505%

6 3% Remaining

MA + NT + NB + Biochemistry + 20w soft

markers scan 197 98.5% 5000 505%

Screening & Diagnosis of Trisomy 21

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Gestation (wks)

Amniocentesis

CVS

Cordocentesis

11w 14w

16w 24w

40w

Amniocentesis CVS Cordocentesis

Diagnosis of chromosomal defects

>23w

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

Maternal Fetal

Medicine CentreChris Hani Baragwanath

Academic Hospital

WELCOME TO 12TH WORLD DOWN SYNDROME CONGRESS

19th - 21st August 2015 ITC Grand Chola, Chennai THE PANCHAYAT: PROGRAM FOR PERSONS WITH DOWN SYNDROME