south australian maternal serum …...south australian maternal serum antenatal screening (samsas...
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SOUTH AUSTRALIAN MATERNAL SERUM ANTENATAL SCREENING (SAMSAS © ) PROGRAM
Robert Cocciolone,
Head, Antenatal Screening, WCH Genetics & Molecular Pathology
Directorate, SA Pathology
www.wch.sa.gov.au/samsas.html
“ providing obstetric support”
Lyn Raniolo
Renata Bird Khoa Lam
Chris Rothe
Eva MartinGerry Slack
Robert Cocciolone
SOUTH AUSTRALIAN MATERNAL SERUM ANTENATAL SCREENING PROGRAM
(SAMSAS© ) Longest running program in Australia,
-1978 Neural Tube Defect (NTD) screening
-1990/91 Down syndrome & other pregnancy pathologies(15-20wks)
-June 2001 First Trimester Down syndrome screening (10-14wks)
-April 2009 Integrated Testing in Second Trimester (9-20wks)
Develop and manage own software and algorithms
Service SA, TAS, NT with screening service support to PMH in WA
Integrated with Neonatal Screening database
Electronic access to Cytogenetic and Ultrasound reports
Yearly audits published in the SA Birth Defects Register Report
www.wch.sa.gov.au
•Services
•A for Antenatal Screening or
•B for Birth Defects Register
•Google SAMSAS
www.wch.sa.gov.au/samsas.html
Information for
Health Professionals
about Maternal Serum Screening
MSS is offered as a program with access to pre & post test information, genetic counselling and diagnostic services – cvs, amnio & ultrasound.
SAMSAS©
Kit based fluoroimmunoassays ~ DELFIA system
Screening
“the systematic application of a test procedure to identify individuals at sufficient risk to warrant
diagnostic investigations”
• CVS 12 wks
•Amniocentesis 15+wks
•Morphology Ultrasound 18+wks
Aim is to maximise detection of affected pregnanciesand minimise false +ves
SAMSAS©
Markers;
1st Trimester 2nd Trimester Integrated TestAFP AFP
free ββββ hCG free ββββ hCG free ββββ hCGuE3 uE3
Papp-A Papp-ANuchal NuchalTranslucency Translucency
Other Markers; Maternal ageGestational age Other Variables
•Fetus must occupy 3/4 of the image
• Fetus must be in a Neutral position
•Hyperextension of fetal neck can increase the NT b y 0.6 mm
• Flexion of the neck can decrease the NT by 0.4 mm
• Umbilical cord round the fetal neck ( 5 -10% of cas es) can increase the NT by 0.8 mm
•Amniotic membrane and Nuchal membrane must be separate
• Measure the max thickness of the subcutaneous translucency
Increased nuchal translucency and exomphalos in a trisomy 18 fetus at 12 weeks of gestation
Turners syndrome - cystic hygroma
Severe asymmetrical growth restriction in a 13-week fetus with triploidy.
NUCHAL TRANSLUCENCY
- NT is an ultrasonographic feature visible in 1st Tr of
pregnancy
- NT results from an accumulation of fluid at the base of
fetal neck
-NT thickness increases with GA (0.8 to 1.6 mm)
-Non specific marker,
thickness >2.5(3.0) mm associated with an increased risk of aneuploidy, cardiovascular & pulmonary defects, skeletal dysplasia, renal, metabolic defects & congenital infections & fetal demise.
• Population Medians / MoM
•Gestational Age
•Maternal Age
•Recurrence Risk
•Singleton vs Twins
•Maternal Weight
•Ethnicity
•Diabetes
•Smoking
•Analytical Imprecision
•Risk Calculation ~ NT ~ Biochemistry ~ Combined ~ Integrated
OUTCOME
Variables
100100,,000 pregnancies000 pregnancies
Maternal age Maternal age 606030%30%
Serum biochemistry at 16 wksSerum biochemistry at 16 wks 13013065%65%
Nuchal translucency (NT) at 12 wksNuchal translucency (NT) at 12 wks 75%75% 150150
Fetal NT & Fetal NT & ßß--hCGhCG & PAPP& PAPP -- A at 12 A at 12 wkswks
180180**90%90%
Screening for Screening for trisomytrisomy 2121
Effectiveness of different methods of screeningEffectiveness of different methods of screening
Method of screeningMethod of screening Number detectedNumber detectedDetection rateDetection rate
Screen positiveScreen positive* * 5%5%
N=5,000N=5,000
Trisomy Trisomy 2121
N=200N=200
NicolaidesNicolaides KH. Fetal nuchal translucency. Am J KH. Fetal nuchal translucency. Am J ObstetObstet GynecolGynecol 20042004
* 2.5% Screen positive
Integrated Test
SAMSAS©
Procedure related fetal loss rates are difficult figures to obtain. Corrections need to be made for the background spontaneous fetal loss.
1 : 251 : 131 : 41 : 1Fetal loss per case of Down syndrome detected
81550200Amniocenteses performed per case detected
IntegratedScreening
First trimester combined screening
Second trimester
biochemical screening
Maternal Age
Screening alone
SnijdersSnijderset al 1995et al 1995
65% Trisomy 2165% Trisomy 21
00
2020
4040
6060
8080
100100
1010 1515 2020 2525 3030 3535 4040
15% Trisomy 1315% Trisomy 13
12% Trisomy 1812% Trisomy 18
<1% <1% TriploidyTriploidy
95% 47xxx/xxy/xyy95% 47xxx/xxy/xyy
20% 45x20% 45x
%%
Gestational age Gestational age
Background RiskBackground Risk
Nicolaides et al., The 11-14-week scan, London 1999
Maternal age Maternal age
Background RiskBackground Risk
0.0001
0.001
0.01
0.1
1
10
20 25 30 35 40 44
Years
Risk %
↑↑ Trisomy 21Trisomy 21
↑↑ Trisomy 18Trisomy 18
↑↑ Trisomy 13Trisomy 13
xxx/xxx/xxy/xyyxxy/xyy
45x45x
TriploidyTriploidy
SnijdersSnijderset al 1995et al 1995Nicolaides et al., The 11-14-week scan, London 1999
Assessment of RiskAssessment of Risk
Previous Chromosomal Previous Chromosomal AbnormalityAbnormality
}}45XO45XO47XXY/XXX47XXY/XXXTriploidyTriploidy
Trisomy 21 Trisomy 21 Trisomy 18Trisomy 18Trisomy 13Trisomy 13 }} ++
0.75%0.75%
Age Age RiskRisk
Marker Levels Change Significantly with Gestation
Measured levels are converted toMultiples Of the Population Median or MoM values.
1 MoM = Reference for all markers
beta hCG at 10 wks GA
Patient 120 IU/L = 2 multiples Median 60 IU/L
MoM values are independent of gestational age and concentration Units
LogMoM values are used in calculations as they exhibit a Gaussian distribution ( Mean +/- SD)
492492492N =
Unaffected 2nd Trimester
UE3_MOMBHCG_MOMSAFP_MOM
3
2
1
0490490490490N =
Unaffected 1st Trimester
PAPP_A_MoMBHCG_MOMSAFP_MOMNT_MOM
3
2
1
0
+0.75% to both odds
Previous T21 + T18/T13
+0.75% to T18 Risk odds
Previous T18/T13
+0.75% to T21 Risk odds
Previous T21
/1.67/1.86/1.9/2.10/2.13Twins
/0.96/0.81/0.94/0.94/1.03Smoker
/0.93/0.79/0.96/0.96/0.9DiabetesIDDM
/0.99/1.553/1.09/1.107/1.17RaceAfro-Caribbean
Chineses, Korean, Japanese
/1.07/1.093/1.061/1.061RaceOriental
Indian,Pakistani, Thai, Malyasian
/1.07/1.082/0.91/0.925/0.94Race SouthAsian
/1.06/0.8/0.9/0.9/1.09RaceAboriginal
Race Caucasian
/0.92/0.89/1.09/1.08IVF
Risk OddsUe3_MoM
PappA_MoMBeta_MoM2nd
Beta_MoM1st
AFP_MoM 2nd
AFP_MoM 1st
Adjustments
Maternal WeightB et a M o M 's vs W eig ht Kg
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
40 50 60 70 80 90 100 110 120
Kgs
MoM
Pappa MoM's vs Weight Kg
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
40 50 60 70 80 90 100 110 120
Kgs
MoM
Noveux 1996, Graaf/Cuckle 2000, SAMSAS/Murdoch 2002
490490490N =
Unaffected 1st Trimester
PAPP_A_MoMBHCG_MOMNT_MOM
3
2
1
0
SAMSAS©
196196196N =
Twins 1st Trimester
PAPP_A_MoMBHCG_MOMNT_MOM
MoM
5
4
3
2
1
0
Increasing Incidence of
Twins
(1990–2003) 1:70 to 1:55
* Assisted reproduction
* Rate of twinning increases with age.
>20% (2006) of pregnancies are now to women 35yrs or over, up from <9% in 1990.
Twins Management
� Screening and Chorionicity� Nuchal discordance (mono and dichorionic)� Diagnostic tests (CVS and Amniocentesis)� Selective feticide� Twin to twin transfusion� Laser ablation of vessels� Delivery
Down syndrome First Trimester
PAPP_A_MoMBHCG_MOMNT_MOM
6
5
4
3
2
1
0
Trisomy 18 First Trimester
PAPP_A_MoMBHCG_MOMNT_MOM
8
7
6
5
4
3
2
1
0
Turners syndrome First Trimester
PAPP_A_MoMBHCG_MOMNT_MOM
8
7
6
5
4
3
2
1
0
Triploidy First Trimester
PAPP_A_MoMBHCG_MOMNT_MOM
9
8
7
6
5
4
3
2
1
0
Digynic
Diandric
T18 2nd Trimester
UE3_MOMBHCG_MOMSAFP_MOM
5.0
4.0
3.0
2.0
1.0
0.0
Triploidy 2nd Trimester
UE3_MOMBHCG_MOMSAFP_MOM
5
4
3
2
1
0
T21 2nd Trimester
UE3_MOMBHCG_MOMSAFP_MOM
5
4
3
2
1
0
Turners 2nd Trimester
UE3_MOMBHCG_MOMSAFP_MOM
5
4
3
2
1
0
Diandric
Digynic
(GA Overestimate )
Anencephaly 2nd Trimester
UE3_MOMBHCG_MOMSAFP_MOM
10
9
8
7
6
5
4
3
2
1
0
Gastroschisis 2nd Trimester
UE3_MOMBHCG_MOMSAFP_MOM
10
9
8
7
6
5
4
3
2
1
0
RISKS
1. Open Neural Tube Defects (NTD) 2. Down syndrome / Aneuploidy3. Other
NTD Down syndrome / Aneuploidy
2nd Trimester 1st & 2nd Trimester↑ AFP ≥ 2 MoM ↑ Risk ≥ 1 in 300Independent of Maternal Age Age DependentMorphology scan CVS / Amnio
~ 1/30 will have a NTD ~ 1/20 or 1/40 will have DS
Other Not NTD & Not DS: AFP < 2 MoM & DS risk is < 1 in 300But
Biochemical results fall outside the Normal expected.
Not NTD & Not Downs Profiles
SAMSAS screened pregnancies N=62,563
1st Trimester N= 26,914 2nd Trimester N= 35,649
Profile
Non Downs
N= 206 (0.77%)
Profile
Not NTD Not Downs
N= 123 (0.35%)
Total N = 329 (0.53%)
OUTCOMES
NOT KNOWN
N = 25 (7.6%)
NORMAL
N = 103 (31.3%)
FETAL DEATH
N = 171 (52%)
ABNORMAL
N = 30 ( 9.1%)
9 x Triploidy, 9 x T18
3 x T15, 3 x Anenceph.1st Tr
2 x Turners, 2 x Mult. Abn.
2 x Metabolic
1st Trimester ? Fail
PAPP_A_MoMBHCG_MOMSAFP_MOM
3
2
1
0
•N= 149
•Not Known= 4
•Normal= 2 (Obese~no NT)
•Fetal Death= 137
•Abnormal= 6 (1xTriploidy,2xXO,2xT15,1xAnencephaly)
•Anomalies Found 143/145
•Odds 1/1 ( 98.6%)
Not viable at time of screen.
No NT measured
2nd Trimester ? Fail
UE3_MOMBHCG_MOMSAFP_MOM
3
2
1
0
Not viable at time of screen.
•N= 24
•Not Known= 2
•Normal= 0
•Fetal Death= 18
•Abnormal= 4(2xT18,1xAnencephaly,1xMultiple Con. Abn.)
•Anomalies Found 22/22
•Odds 1/1 (100%)
•N= 57
•Not Known= 7
•Normal= 39
•Fetal Death= 3
•Abnormal= 8 (4xTriploidy,1xT18,1xOther,1xAnencephaly,1xRenal)
•Anomalies Found 11/50
•Odds 1/4.5 ( 22%)
1st Trimester Not Downs
PAPP_A_MoMBHCG_MOMSAFP_MOMNT_MOM
3.0
2.0
1.0
0.0
Viable at time of screen.
2nd Trimester Not NTD Not Downs
UE3_MOMBHCG_MOMSAFP_MOM
3
2
1
0
•N= 99
•Not Known= 12
•Normal= 62
•Fetal Death= 13
•Abnormal= 12(4xTrip.,6xT18,1xMultiple Con. Abn.,1xMetabolic)
•Anomalies Found 25/87
•Odds 1/3.5 ( 28.6%)
Viable at time of screen.
Missed 1st Trimester Fetal Deaths
PAPP_A_MoMBHCG_MOMSAFP_MOMNT_MOM
3.0
2.5
2.0
1.5
1.0
.5
0.0
Missed 2nd Trimester Fetal Deaths
UE3_MOMBHCG_MOMSAFP_MOM
3
2
1
0
1st Trimester Not Downs
PAPP_A_MoMBHCG_MOMSAFP_MOMNT_MOM
3.0
2.0
1.0
0.0
2nd Trimester Not NTD Not Downs
UE3_MOMBHCG_MOMSAFP_MOM
3
2
1
0
Detected Detected
SAMSAS T21 & Non NTD Non Downs distributions
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
1.2
-3 -2 -1 0 1 2 3 4 5 6 7
Discriminatory variable
T21
Non NTD Non Downs
Unaffected
The best way to detect these pregnancies is through discriminatory algorithms and distributions , utilizing multiplemarkers.
False -ves
Y= 0.425*ln_beta_MoM – 0.631*ln_Papp-a_MoM +0.761*ln_NT_MoM
What does a risk report mean? % Recall % Det. ODDS
Adverse Outcome
ODDS Affected
Miss Rate
2nd Tr Raised NTD
Risk
3% >90% 1 / 8 1 / 30 1 / 10,000
2nd Tr Raised DS
Risk
5% 65% 1 / 30 1 / 50 1 / 2,500
1st Tr Raised DS
Risk
5% 90% 1 / 10 1 / 15 1 / 3,500
Not NTD Not Downs ? Viability
0.5% 75% 1 / 4 1 / 500
Summary data ~ SAMSAS yearly audits SA Birth defects Register Reports
Reassurance of ≥≥≥≥ 99.8 % & Anomaly Risk of 2.0 – 25%
DS Risk = Mat. Age Risk x LR
DS Risk = Mat. Age Risk x LR
Discriminatory Variable
3210-1-2
1.0
.8
.6
.4
.2
0.0
Unaffected Affected
Detection Rate
False -veFalse +ve’s
h1
h2
LRaff = h2/h1Y= 0.425*ln_beta_MoM – 0.631*ln_Papp-a_MoM +0.761*ln_NT_MoM
SAMSAS©
DS Risk =Mat. Age Risk × LR
• 20 yrs = 1 in 1600 × 2 = 1 in 800
• 30 yrs = 1 in 1100 × 2 = 1 in 550
• 35 yrs = 1 in 500 × 2 = 1 in 250
• 40 yrs = 1 in 156 × 2 = 1 in 78
• 45 yrs = 1 in 40 × 2 = 1 in 20
Age Specific Performance Comparison of 1st and 2nd Trimester Screening.
Maternal Age vs Recall and Detection
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
15 20 25 30 35 40 45
Maternal Age at Delivery
%
%RR 2nd %DR 2nd %RR 1st %DR 1st
RR
DR
BENEFITS OF AN EARLY SCAN
• confirms the fetus is alive
• permits accurate dating of pregnancy
• allows early diagnosis of multiple pregnancy & chorionicity
• detects major structural abnormalities and missed abortion
SAMSAS©
SAMSAS©
Why did we introduce 1st trimester combined screening into SA ?
SAMSAS© Down Syndrome
Detect Recall %≥35 %PG≥30 Age2nd Tr91-95 63% 4.9% 9% 20% 28
96-00 76.7% 6.6% 15% 30% 29
01-03 76.7% 7.4% 17% 35% 30
1st Tr 90.9% 4.9% 25% 31.3
Primigravida
IntG 90.9% 2.5% 22% 31.2
Combining first and second trimester markers for Down syndrome screening: Think twice
Robert Cocciolone, Kate Brameld, Peter O'Leary, Eric Haan, Peter Muller, Karen Shand
Aust N Z J Obstet Gynaecol 2008; 48: 492-500
• benefits of an early scan
• less false +ves & -ves
• less normal fetuses lost
• higher detection
• personal benefits to patients from earlier diagnosis
Advantages of 1st trimester screening
Disadvantages
• cost of the nuchal translucency scan
• logistically more difficult to manage
Logistical considerations?
1TR & 2TR screening will coexist.
Management of reports & requests.
How many risks, by whom and when?
Audits and ongoing programme evaluation.
How can these be addressed?
Centralised service & databasefor, - all patient demographics- biochemical results- NT measurements & providers- reporting- recalculation of risks- retrievable data for analysis
Logical software - risks linked to gestation (1TR & 2TR algorithms)
Trends in state/based Down syndrome screening and invasive prenatal testing with the introduction of first trimester combined Down syndrome, South Australia 1995-2005
Muller PR, Cocciolone R, Haan EA, et al
Am J Obstet Gynecol 2007;196:315.e1-315.e7.
Utilization of maternal serum Down syndrome screening % of all confinements
0102030405060708090
100
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Year
%
NS
69-79%
Utilization of second trimester maternal serum (∆) and first trimester combined Down syndrome
screening (□), % of all confinements
0102030405060708090
100
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Year
%
75%
25%
49%
0.8%
*
*
* P < 0.001
% confinements ≥ 35 years (•) of age vs % of confinements undergoing invasive prenatal tests (∆)
0
5
10
15
20
25
30
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Year
%
7.6%9.3%
* P < 0.001
*
Confinements ≥ 35 years of age undergoing invasive prenatal tests
% of confinements ≥ 35 years of age with invasive prenatal test
05
101520253035404550
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Year
% * 24.8%
43%
* P < 0.001
Number of invasive prenatal tests to detect one DS fetus
1/40472005
1/49342004
1/46422003
1/66442002
1/90362001
1/79372000
1/71421999
1/61461998
1/83411997
1/94321996
1/86321995
Rate of DS per invasive
procedure*
Down syndrome cases
Year
* p < 0.001*
Number of invasive prenatal tests to detect one aneuploid fetus
1/15912005
1/21652004
1/24642003
1/32552002
1/30552001
1/32562000
1/33601999
1/31651998
1/38501997
1/47461996
1/35511995
Rate of aneuploidy per
invasive procedure*Aneuploidy casesYear
*
* p < 0.001
Overall Prenatal Detected Down Syndrome cases (%)
83.0472005
88.2342004
81.0422003
65.9442002
58.3362001
70.3372000
71.4421999
73.9461998
70.7411997
81.3321996
71.9321995
Prenatal detected DS cases(%)**
Down syndrome cases
Year
** p = 0.21
••Demonstrated an improved efficiency in the Demonstrated an improved efficiency in the utilization of invasive prenatal testsutilization of invasive prenatal tests
••Despite the increase in gravid women Despite the increase in gravid women ≥≥ 35 years of 35 years of age the number of invasive prenatal tests in this age age the number of invasive prenatal tests in this age group has significantly declinedgroup has significantly declined
••Despite the significant decrease in invasive prenatal Despite the significant decrease in invasive prenatal tests the overall antenatal detection of Down tests the overall antenatal detection of Down syndrome did syndrome did notnot decrease, and appears to increase decrease, and appears to increase once the utilization of first trimester combined Down once the utilization of first trimester combined Down syndrome screening reaches > 30% of confinementssyndrome screening reaches > 30% of confinements
To review changes in the utilization and effectiveness of state/population-based antenatal screening for NTDs in South
Australia from 1986 to 2004
Utilization of MSAFP and First Trimester Screening
0
10
20
30
40
50
60
70
80
90
100
1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006Year
%
%confinements with first trimester combined DS scre ening% confinements with MSAFP
94.5 **2417,8671999-2004
88.832*19,4371992-98
864119,7141986-91
Overall antenatal detection of NTD(%)
Average NTDs/Yr
(#)
Average births/Yr
(#)
Year
** p<0.001** p<0.001
*State*State--wide educational drive on the benefits of Folic Acid wide educational drive on the benefits of Folic Acid supplementation for the reduction of supplementation for the reduction of NTDsNTDs 19941994
Despite a significant decrease in the utilization o f MSAFP screening, the population-based detection of NTDs has increased significantly in South Australia.
The decreased utilization of second trimester The decreased utilization of second trimester MSAFP represents improve clinician confidence in MSAFP represents improve clinician confidence in second trimester ultrasound for the detection of second trimester ultrasound for the detection of NTDsNTDs
SAMSAS©
….future directions
•new biochemical markers
•fetal cells in maternal circulation
•fetal DNA in maternal circulation
•complex protein profiles - mass spectrometry
•ADAM12 (A Disintegrin And Metalloprotease) is a multidomain Zn containing protein with protease, cell adhesion and signaling activity.
•Researchers focus on ADAMs has been asthma,alzheimers and cancer (breast, liver, colon)
•ADAM12 cleaves IGFBP-3 & 5 and may regulate the bioavailability of IGF (PAPP-A cleaves IGFBP-4)
•Overall, it appears that ADAMs are expressed during growth and development.
•Human placenta expresses very high levels of ADAM12
•Is it useful in MSS programs?
0.77 0.97 1.54 ADAM12 T21 Median MoM
Caucasian Adam12 RUO MoM vs maternal weight
y = 0.00009011x2 - 0.02431198x + 2.25980095
R2 = 0.20802869
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
20 30 40 50 60 70 80 90 100 110 120 130 140 150
weight
Ada
m12
MoM
ADAM12RUO_MoM Poly. (ADAM12RUO_MoM)
Ethnicity Cases UncorrectedMedian
ng/ml / MoM
Median Weight
kg
Weight correctedMedian
MoM
? 4385 597 / 0.99 68 0.98
Aboriginal 94 597 / 0.89 73 0.95
Afro-Caribbean
71 994 / 1.15 65 1.12
Caucasian 5604 562 / 0.99 68 1.0
Oriental 153 788 / 1.28 55 1.10
South Asian 419 738 / 1.12 56.5 .98
Total/Median 10726 587 / 1.0 67 1.0
1.669227Twins
0.9470493IVF
0.8670758Smoker
0.767443IDDM
ADAM12 MoM
uncorrected
Weightkg
Cases
92.5(62/67)
89.6(60/67)
79.0(53/67)
1st Tr Combined
83 – 97(N=8579)
89.6(60/67)
86.6(58/67)
74.6(50/67)
1st Tr Combined
+ADAM12
76.1(35/46)
73.9(34/46)
93.6(102/109)
95.4(104/109)
100(42/42)
100(42/42)
7%
69.6(32/46)
65(30/46)
91.7(100/109)
91.7(100/109)
97.6 (41/42)
95.2(40/42)
5%
82.6(90/109)
85.3(93/109)
95.2 (40/42)
92.9(39/42)
3%
Triple Test+
ADAM12
Triple Test1st Tr Combined
+ADAM12
1st Tr Combined
1st Tr Combined
+ADAM12
1st Tr Combined
FPR
98 – 140(N=2941)
63 – 97 (N=12227)
≤ 82 (N= 3648)
Gest’nDays
Detection Rate%(no)
Detection Rate%(no)
Second Trimester
First Trimester
All ADAMs
95.5(21/22)
95.5(21/22)
81.8(18/22)
1st Tr Combined
83 – 97(N=8579)
95.5(21/22)
95.5(21/22)
77.3(17/22)
1st Tr Combined
+ADAM12
85.7(6/7)
85.7(6/7)
97.0(32/33)
97.0(32/33)
100(11/11)
100(11/11)
7%
71.4(5/7)
57.1(4/7)
97.0(32/33)
97.0(32/33)
100 (11/11)
90.9(10/11)
5%
81.8(27/33)
81.8(27/33)
90.9 (10/11)
81.8(9/11)
3%
Triple Test+
ADAM12
Triple Test1st Tr Combined
+ADAM12
1st Tr Combined
1st Tr Combined
+ADAM12
1st Tr Combined
FPR
98 – 140(N=2941)
63 – 97 (N=12227)
≤ 82 (N= 3648)
Gest’nDays
Detection Rate%(no)
Detection Rate%(no)
Second Trimester
First Trimester
ProsADAMs
All aff 42 67 109 46
•All current publications are based on measurements from frozen samples
•Might be useful: 9-10wks, Valinen 2009, Spencer 2007
•No advantage: 11-13wks Poon 2009
•Could be considered in multi-marker combinations: 2nd Tr Donaldson 2008 ↑DR 2-3% and ↓FPR 0.9-1.7%
•Other pregnancy complications: ↓ in IUGR/SGA Cowans & Spencer 2007,
↓ in PE Laigaard 2005
? IVF Laigaard 2009
SUMMARY
•ADAM12 levels affected by mat. wt, ethnicity, IDDM, smoking, Twins, IVF
•ADAM12 levels increase with gestation in normal pregnancies
•ADAM12 med MoM increases with gestation in affected T21 pregnancies
•In T21 pregnancies ADAM12 levels are low in early 1st Tr, equivocal in mid to late 1st Tr and elevated in 2nd trimester
•9-11w ~ 2.3-2.4% ↑DR with ADAM12 at a 3-5% FPR
•12-13w+6d performance drops with ADAM12
•9-13w+6d no advantage in using ADAM12
•14-20w MSS performance improves with ADAM12
•Improved performance can be translated to either ↑DR for a fixed FPR or to ↓FPR for a fixed risk cut off
•Larger prospective studies are needed to further assess its value in MSS programs