Prenatal Diagnosis for birth defect at fetus

diagnosis birth defect at prenatal

1. Prenatal Screening and
Diagnosis

2. What is Prenatal Diagnosis?
In-utero detection of fetal anomalies
General population risk is 3-5% for any birth defect

every pregnancy has a risk of carrying an abnormal fetus
Risk of aneuploidy increases with maternal age
Options:
Maternal age
First trimester screening
Second trimester serum screen
Detailed ultrasound
Amniocentesis
Chorionic villus sampling (CVS)
Non invasive prenatal test (NIPT)

3. Aims of Prenatal Screening and
Diagnosis
Reassurance
 by reducing likelihood of fetal anomaly
Prepare parents/family/obstetrician/pediatrician
for birth of abnormal child if pregnancy
continuing
Enable rational perinatal management
Further investigations and consultations, time of delivery, mode
of delivery, location of delivery

4. Aims of Prenatal Screening and
Diagnosis
Enable couples at risk of genetic disorders to
have unaffected children
Identify potentially important intrauterine
treatment if available
Provide information about pregnancy options
available if anomaly diagnosed

5. Counseling for Prenatal Diagnosis
Baseline risk estimate of affected fetus
Nature and consequences of affected child
Outline options for prenatal diagnosis
Risks and limitations of each diagnostic and screening
technique offered
Diagnostic accuracy (sensitivity, specificity, PPV, NPV)
Time it takes for results
Possible need for repeat procedure if failed attempt/result
Pregnancy options if affected

6. Counseling for Prenatal Diagnosis
Non-directive, non-judgemental
Integral part of any screening procedure
Provide adequate information
Results of tests must be passed to couple in a
timely and sympathetic fashion
Set protocols for managing positive screen
results

7. Performance of a Screening Test
Test positive Test negative
Affected True positive False negative
Unaffected False positive True negative
Sensitivity
proportion of patients with a disease that have a positive test
False positive rate
proportion of unaffected individuals yielding a positive result
Specificity
Proportion of patients disease free that have a negative test

8. Options for Prenatal Screening and
Diagnosis
1.Maternal age
2.First trimester screening
3.Second trimester serum screen
4.Detailed ultrasound
5.Amniocentesis
6.Chorionic villus sampling (CVS)

9. Maternal Age
Developed in the 1960s
Prevalence of aneuploidy increases with
advancing maternal age
Risk of miscarriage from amnio equivalent to
risk of any chromosomal abnormality at 35 or
older.
Maternal age alone for prenatal diagnosis is
inferior to newer screening approaches.
High false + rate (whatever % are ≥ 35 in your
population)
Detects only 30% of infants with T21

11. SOGC Clinical Practice Guideline
No. 187, February 2007
“The practice of using solely the previous
cut-off of maternal age of 35 or over at
the EDD to identify at-risk pregnancies
should be abandoned”

12. SOGC Clinical Practice Guideline
No. 187, February 2007
“All pregnant women, regardless of age,
should be offered a prenatal screening
test for the most common clinically
significant fetal aneuploidies in addition to
a second trimester ultrasound for dating,
growth and anomalies”

13. Options for Prenatal Screening and
Diagnosis
1.Maternal age
2.First trimester screening
3.Second trimester serum screen
4.Detailed ultrasound
5.Amniocentesis
6.Chorionic villus sampling (CVS)

14. First Trimester Screening
Needs to be done in context of prenatal
program
Nuchal translucency

11
+0
– 13
+ 6
weeks gestational age
Biochemical markers
PAPP-A
Free β-hCG
10
+0
– 13
+ 6
weeks gestational age Not universally available
May detect impending miscarriage, cardiac
anomalies

15. Nuchal Translucency
Normal
Increased

16. Options for Prenatal Screening and
Diagnosis
1.Maternal age
2.First trimester screening
3.Second trimester serum screen
4.Detailed ultrasound
5.Amniocentesis
6.Chorionic villus sampling (CVS)

17. Second Trimester Serum Screen
15
0
-20
6
weeks gestation
4 biochemical markers in maternal blood
AFP
total hCG
µE3
dimeric inhibin A
Influenced by gestational age, race, diabetes,
number of fetuses, maternal weight

18. Second Trimester Serum Screen
Expected results
AFP µE3 ßhCG
T21   
T18   
NTD 
If risk > predetermined cutoff then invasive testing is offered

19. Screening Options
Confusing Nomenclature Simplified
1.NT
Self explainatory
2.First Trimester Screen
NT
PAPP-A, free β-hCG
3.Triple Marker Screen (TMS/MSS)
AFP, uE3, total hCG
4.Quad Screen
TMS + dimeric inhibin A

20. Screening Options
Confusing Nomenclature Simplified
5.Serum Integrated Prenatal Screen
(SIPS/IPSS)
First trimester serum screen
Either TMS or Quad Screen
6.Integrated Prenatal Screen (IPS)
SIPS + NT
7.NIPT

21. SOGC Clinical Practice Guideline
No. 187, February 2007
Minimum standards for a screening test
for all women:
2007:
75% DR
5% FPR
2008:
75% DR
3% FPR

22. Screening Performance
SOGC Clinical Practice Guideline No. 187, February 2007
Screening OptionTerm risk
cut-off
DR (%)FPR (%)
NT 1 in 15075 8.1
FTS 1 in 325 83 5.0
TMS 1 in 38571 7.2
Quad 1 in 385 77 5.2
Serum IPS 1 in 200 85 4.4
IPS (no inhibin A) 1 in 200 88 3.0
IPS 1 in 200 87 1.9

23. What do we do?
All women should be offered SIPS
IPS for women ≥ 40
Will be ≥ 35 when enough certified
NT centres

24. Options for Prenatal Screening and
Diagnosis
1.Maternal age
2.First trimester screening
3.Second trimester serum screen
4.Detailed ultrasound
5.Amniocentesis
6.Chorionic villus sampling (CVS)

25. Detailed Ultrasound
Offered to all pregnant women
18-20 weeks gestation
Looking for:
Growth and amniotic fluid volume
Major fetal anomalies
“Soft markers”
Ability to visualize anomalies depends on:
Gestational age, fetal size, position, number
Maternal body habitus

26. Detailed Ultrasound: “soft markers”
Ultrasound findings that are variants of normal
but also associated with aneuploidy
Presence of soft markers increases the risk of
aneuploidy but is not diagnostic
Individual markers vary in the degree of
association with aneuploidy, therefore each
assigned a likelihood ratio (LR)

27. Detailed Ultrasound: “soft markers”
Detection of multiple soft markers will increase
the significance of the finding, compared to a
single marker in isolation
No markers and normal scan
Negative LR = 0.5

28. Detailed ultrasound: “soft markers”
Soft Marker Likelihood Ratio
T 21 T 18
Nuchal fold 17 -
Ventriculomegaly 9 -
Short humerus 7.5 -
Echogenic bowel 6 -
Short femur 2.7 -
Echogenic cardiac focus 2 -
CPC - 7

29. Options for prenatal diagnosis
1.Maternal age
2.First trimester screening
3.Second trimester serum screen
4.Detailed ultrasound
5.Amniocentesis
6.Chorionic villus sampling (CVS)

30. SOGC Clinical Practice Guideline
No. 187, February 2007
“Amniocentesis/CVS should not be provided
without multiple marker screening results
except for women over the age of 40”

31. Invasive Procedures:
Amniocentesis
Procedure
> 15 weeks gestation
20 cc of amniotic fluid aspirated
Ultrasound guidance
Cells from fetal skin, GI and respiratory epithelium
Cultured, stopped in metaphase
Chromosomes banded, paired and counted
Only detect abnormal # of chromosomes not specific
gene defects

33. Invasive Procedures:
Amniocentesis
Procedure related risks
Miscarriage 0.5 – 1% above baseline
baseline risk is 3% at 15 weeks
Ruptured membranes
Most common complication
90% stop spontaneously
1/ 1000 times cell cultures fail to grow
2 – 3 weeks to get result

34. Invasive Procedures:
Chorionic Villus Sampling (CVS)
Procedure
10 - 13w3d gestation
Ultrasound guidance biopsy of chorionic villi

Mitotically active cells (cytotrophoblast)
Transcervical or transabdominal
2 – 3 weeks for full result

36. Invasive Procedures:
Chorionic Villus Sampling (CVS)
Risks
0.5 - 1% miscarriage rate
More post procedure vaginal bleeding than amnio
1/2000 limb reduction defect if < 10 weeks
Confined placental mosaicism 1%
Often follow-up with amnio if suspect CPM
Does not diagnose NTD
Still need serum AFP at 15-20 weeks

37. Additional Invasive Procedures
Fluorescent in situ hybridization (FISH)

Fluorescent tags for trisomy 21,13,18 and sex
chromosomes
Rapid test result 3 days
Comparative genomic hybridization
Polymerase chain reaction (PCR)
Fetal blood sampling (cordocentesis)

38. So…
you’ve diagnosed a fetal abnormality, now
what do you do?

39. Prenatal Diagnosis: Management
Options
If an abnormality is diagnosed:
<23
6
weeks gestation
Do nothing (counsel, support, provide information, consults)
In-utero therapy and management
Termination of pregnancy!!!!
>24 weeks gestation
Do nothing (counsel, support, provide information, consults)
In-utero therapy and management
Termination of pregnancy only if lethal
Preconception counseling in future pregnancies

40. Prenatal Therapy and Management
In-utero therapy:
Limited @ present
TTTS: laser of communicating vessels
Bladder outlet obstruction: bladder shunting
Management:
Consultations with specialists (SCN, peds surgery, peds
urology, peds neurology, club-foot clinic, cleft-lip and
palate clinic, social work)
Preparation of family and friends
Prenatal monitoring (e.g. growth restriction)

41. Prenatal Diagnosis: Conclusions
Goals
Options
Maternal age
First trimester screening
Second trimester serum screening
Detailed ultrasound
Amniocentesis
CVS

42. Prenatal Diagnosis: Conclusions
Counseling
Non-directive
Non-judgemental
Baseline risk
Consequence of affected fetus
Options, limitations, alternatives for diagnosis
Options for pregnancy management
Don’t forget preconception counseling for future
pregnancies