Prenatal Screening and Diagnosis

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 • 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 • Maternal age • First trimester screening • Second trimester serum screen • Detailed ultrasound • Amniocentesis • 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 • Maternal age • First trimester screening • Second trimester serum screen • Detailed ultrasound • Amniocentesis • 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 • Maternal age • First trimester screening • Second trimester serum screen • Detailed ultrasound • Amniocentesis • Chorionic villus sampling (CVS)

17. Second Trimester Serum Screen • 150 -206 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 If risk > predetermined cutoff then invasive testing is offered

19. Screening OptionsConfusing Nomenclature Simplified • NT • Self explainatory • First Trimester Screen • NT • PAPP-A, free β-hCG • Triple Marker Screen (TMS/MSS) • AFP, uE3, total hCG • Quad Screen • TMS + dimeric inhibin A

20. Screening OptionsConfusing Nomenclature Simplified • Serum Integrated Prenatal Screen (SIPS/IPSS) • First trimester serum screen • Either TMS or Quad Screen • Integrated Prenatal Screen (IPS) • SIPS + NT • 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

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 • Maternal age • First trimester screening • Second trimester serum screen • Detailed ultrasound • Amniocentesis • 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”

29. Options for prenatal diagnosis • Maternal age • First trimester screening • Second trimester serum screen • Detailed ultrasound • Amniocentesis • 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: • <236 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