Antenatal Screening

See Also

Epidemiology

Aneuploidy (chromosomal abnormalities) affect one in 150 pregnancies
1. Result in 50% of pregnancy losses
2. Children with intellectual and physical Disability
Aneuploidy risk increases with maternal age (mean maternal age has increased over time)
1. Overall risk (Trisomy 13, Trisomy 18, Trisomy 21)
  1. Age 35 year old Risk: 1 per 200 pregnancies
  2. Age 45 year old Risk: 1 per 20 pregnancies
2. Down Syndrome (Trisomy 21)
  1. Age 20 years old: 1 per 1480
  2. Age 40 years old: 1 per 85

Precautions
Counseling

See First Trimester Education
Discuss a patient's overall risk of a child with Fetal Aneuploidy
1. See Pregnancy Risk Assessment
Discuss the types of tests available (as appropriate to patient risk)
1. Give Patient Education (see resources below)
2. See testing options (below)
Review risks and benefits of testing
1. False Positive Tests
  1. False Positive tests are common, as cut-offs favor higher Test Sensitivity
  2. Associated with increased parental anxiety
  3. Risk of additional testing (e.g. Amniocentesis)
2. False Negative Tests
  1. False Negative tests are less common, as a negative test has high NPV in Aneuploidy testing
  2. However, in high risk patients (e.g. advanced maternal age), noninvasive tests may be inadequate alone
Multiple Gestation Pregnancies
1. Exercise caution for interpretation in Twin Gestation
2. Serum testing is unreliable in triplets and higher
  1. Ultrasound for Nuchal Translucency and Fetal Survey are better screening tools in this cohort

Diagnostics
Available Tests

Ultrasound
1. First Trimester Ultrasound (Nuchal Translucency)
2. Second Trimester Ultrasound (Fetal Survey)
  1. See Aneuploidy Markers on Second Trimester Ultrasound
Labs
1. Pregnancy-Associated Plasma Protein A (PAPP-A) and bHCG (Free or Total) at 10 to <14 weeks
2. Quadruple Screening (Alpha Fetoprotein, Unconjugated Estriol, Free bHCG, Inhibin A) at 15 to <23 weeks
3. Placental Cell-Free DNA (Noninvasive Prenatal Testing or NIPT) after 10 weeks gestation
  1. Screens for monogenic and subchromosomal genetic abnormalities (e.g. skeletal dysplasia, Sickle Cell Disease, Cystic Fibrosis)
  2. Associated with high False Positive Rates
    1. Unlike conditions in Aneuploidy testing (e.g. Quad Screen), subchromosomal conditions are relatively rare
    2. Order with caution and with well Informed Consent, especially in general risk pregnancies
  3. ACOG does not recommend in general risk pregnancies (2019)
    1. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2019/02/cell-free-dna-to-screen-for-single-gene-disorders
  4. References
    1. Talati (2022) Am Fam Physician 106(6): 612 [PubMed]
Invasive Tests
1. Chorionic Villus Sampling (10-13 weeks)
  1. Risk of pregnancy loss: 1 in 455 (0.2%)
2. Amniocentesis (15-18 weeks)
  1. Risk of pregnancy loss: 1 in 900 (0.1%)
Preimplantation Genetic Screening (In-Vitro Fertilization)
1. Preimplantation Genetic Screening is performed with in-vitro fertilization before Embryo implantation
2. Cell biopsy has a risk of False Positive and False Negative
  1. Occurs due to mosaicism in which Chromosomes are from pre-placental tissue no found in Embryo
  2. Does not replace antenatal Aneuploidy Screening

Approach
Testing Protocols

See Placental Cell-Free DNA
First Trimester Combined Screening (at 10 to <14 weeks)
1. Nuchal Translucency
2. Pregnancy-Associated Plasma Protein A (PAPP-A) AND
3. bHCG (Free or Total)
Second Trimester Quad Screening (at 15 to <23 weeks)
1. Alpha Fetoprotein (aFP)
2. Unconjugated Estriol (uE3)
3. Free bHCG
4. Inhibin A
Second Trimester Fetal Survey
1. See Aneuploidy Markers on Second Trimester Ultrasound
2. Trisomy 21 Test Sensitivity: 50-60%
3. Least accurate screening for Aneuploidy
  1. Follow positive Ultrasound testing with Second Trimester Quad Screening or Placental Cell-Free DNA
Integrated Screening
1. First Trimester Combined Screening (PAPP-A, bHCG, Nuchal Translucency) at 10 to <14 weeks AND
2. Second Trimester Quad Screening (aFP, uE3, bHCG, Inhibin A) at 15 to <23 weeks
3. Trisomy 21 Test Sensitivity: 96%
  1. Wald (1999) N Engl J Med 341(7): 461-7 [PubMed]
Serum Integrated Screening
1. First Trimester Combined Screening (PAPP-A, bHCG) WITHOUT Nuchal Translucency Ultrasound AND
2. Second Trimester Quad Screening (aFP, uE3, bHCG, Inhibin A) at 15 to <23 weeks
3. Trisomy 21 Test Sensitivity: 88%
Stepwise Sequential Screening
1. First Trimester Combined Screening (PAPP-A, bHCG, Nuchal Translucency) at 10 to <14 weeks
2. Screening Results in combination with Pregnancy Risk Assessment inform decision making
  1. Lower Risk
    1. Second Trimester Quad Screening (aFP, uE3, bHCG, Inhibin A) at 15 to <23 weeks
  2. Higher Risk
    1. Consider Placental Cell-Free DNA
    2. Invasive Testing (Chorionic Villus Sampling or Amniocentesis)
3. Trisomy 21 Test Sensitivity: 95%
  1. Benn (2007) Am J Obstet Gynecol 197(3): 312e1-5 [PubMed]
Contingent Sequential Screening
1. First Trimester Combined Screening (PAPP-A, bHCG, Nuchal Translucency) at 10 to <14 weeks
2. Screening Results in combination with Pregnancy Risk Assessment inform decision making
  1. Low Risk (81% of results)
    1. No further testing
  2. Intermediate Risk (18% of results)
    1. Consider Placental Cell-Free DNA
    2. Second Trimester Quad Screening (aFP, uE3, bHCG, Inhibin A) at 15 to <23 weeks
  3. High Risk (1% of results)
    1. Invasive Testing (Chorionic Villus Sampling or Amniocentesis)
3. Trisomy 21 Test Sensitivity: 85-88%
  1. Wright (2004) Prenat Diagn 24(10): 762-66 [PubMed]

Resources
Patient Education

Making decisions about screening for Down Syndrome in pregnancy
1. https://www.psychosocialresearchgroupunsw.org/decision-aids.html
Cell-Free DNA (ACOG)
1. https://www.acog.org/patient-resources/infographics/cell-free-dna-prenatal-screening-test
Prenatal Genetic Testing
1. https://www.acog.org/patient-resources/infographics/prenatal-genetic-testing-chart

References