II. Definitions

  1. Aneuploidy
    1. Presence or absence of one or more Chromosomes

III. Indication

  1. Congenital defect screening in low risk pregnancy

IV. Precautions

  1. Does not replace Amniocentesis if age 35 years or older
    1. All test protocols have positive rates approaching 5% (most are False Positives)
    2. Test Sensitivity for Aneuploidy on the best test protocols still only approaches 87%
  2. Trisomy 21 risk increases based on Multiple Pregnancy
    1. Singleton gestation: Age 35 years
    2. Twin Gestation: Age 33 years

V. Protocol: First Trimester Combined Screening

  1. Timing
    1. Performed at 10 to <14 weeks
  2. First Trimester Combined Screening for trisomy 18 and Trisomy 21
    1. Maternal age
    2. Free Beta Human chorionic gonadotropin (bHCG)
    3. Pregnancy associated plasma protein A (PAPP-A)
    4. Fetal Ultrasound (do not use without serum testing)
      1. Nuchal Translucency
        1. Test Sensitivity: 77%
        2. High False Positive Rate: >4%
      2. Nasal bone absent
        1. Test Sensitivity: 70%
        2. False Positive Rate: 1.5%
  3. Efficacy of 4 factors in predicting trisomy 18 or 21
    1. As accurate as second trimester screening
    2. Labs report 5% of tests as abnormal resulting in a high False Positive Rate
  4. Efficacy Trisomy 21
    1. Detecting Trisomy 21 (Down Syndrome) in all women
      1. Test Sensitivity: 78-89% (>90% if age over 35 years)
      2. Test Specificity: 95% (only 78-86% if age over 35 years)
    2. Efficacy decreases as Gestational age progresses
      1. Test Sensitivity at 11 weeks: 87%
      2. Test Sensitivity at 12 weeks: 85%
      3. Test Sensitivity at 13 weeks: 82%
      4. Malone (2005) N Engl J Med 353(19):2001-11 [PubMed]
  5. Efficacy Trisomy 18
    1. Test Sensitivity: 90%
    2. Test Specificity: 98%
  6. Additional findings
    1. Low levels of both markers are associated with adverse pregnancy outcomes
    2. Some protocols also use Free or Total hCG levels
  7. References
    1. Wapner (2003) N Engl J Med 349:1405-13 [PubMed]

VI. Protocol: Second trimester screening (Standard Quad Screen)

  1. Components
    1. Alpha-fetoprotein (AFP)
      1. Increased with Neural Tube Defects
      2. Decreased in Trisomy 21 and Trisomy 18
    2. Human chorionic gonadotropin (Free bHCG)
      1. Increased in Trisomy 21 and decreased in Trisomy 18
    3. Unconjugated Estriol (uE3)
      1. Decreased in Trisomy 21 and Trisomy 18
    4. Inhibin A
      1. Increased in Trisomy 21 and normal in Trisomy 18
  2. Counsel patient before screening
    1. Screening for Neural Tube Defects and Trisomy 21, 18
    2. Protocol if screening positive and diagnostic risks
    3. Accuracy and limitations of tests
  3. Timing
    1. Optimal time: 16 to 18 weeks gestation
    2. Range of testing: 15 to 22 weeks gestation
    3. Shifting to first trimester is being investigated
  4. Efficacy: Trisomy 21
    1. Test Sensitivity: 81%
    2. Negative Predictive Value >99% regardless of age
    3. False Positive Rate is 4.9% for <30 years old (and is still 3.8% even at 40 years old)
    4. Positive Predictive Value (PPV) changes significantly with advancing maternal age
      1. Age 20 years old PPV: 1.3% (Trisomy 21Prevalence 1 per 1177)
      2. Age 25 years old PPV: 1.6% (Trisomy 21Prevalence 1 per 1040)
      3. Age 30 years old PPV: 2.3% (Trisomy 21Prevalence 1 per 700)
      4. Age 35 years old PPV: 5.5% (Trisomy 21Prevalence 1 per 296)
      5. Age 40 years old PPV: 19.1% (Trisomy 21Prevalence 1 per 86)
  5. Efficacy: Amniocentesis with Quad Screen
    1. Test Sensitivity: Approaches 90%
    2. Test Specificity: 95-98%
  6. Interpretation of abnormal results
    1. As with first trimester screening, Labs report 5% of tests as abnormal resulting in a high False Positive Rate
    2. Chromosomal abnormalities suggested
      1. Findings
        1. Trisomy 21: AFP, uE3 low, hCG,Inhibin high
        2. Trisomy 18: AFP, hCG and uE3 decreased
      2. Perform Amniocentesis for chromosomal analysis
    3. Neural Tube Defects suggested (AFP increased)
      1. Ultrasound to confirm Gestational age
      2. Recalculate AFP based on ultrasound Gestational age
        1. Redraw Triple Screen if first test <15 weeks
      3. Perform diagnostics if AFP still elevated
        1. Repeat AFP level
        2. Level II Ultrasound Fetal Survey
        3. Consider Amniocentesis
          1. Amnion AFP level
          2. Amnion acetylcholinesterase level

VII. Interpretation: Quad Screen results predict pregnancy outcomes

  1. Unexplained abnormal tests confer 2 or more fold risk
  2. Unexplained increased AFP confers poor outcome risk
    1. Preeclampsia:
    2. Intrauterine Growth Retardation
    3. Intrauterine Fetal Demise
    4. Preterm Labor
    5. Low birth weight
    6. Placental Abruption
    7. Perinatal death
  3. Unexplained increased hcg confers poor outcome risk
    1. Preeclampsia
    2. Preterm Labor
    3. Low Birth Weight Infant
    4. Intrauterine Fetal Demise
  4. Unexplained decreased estriol confers poor outcome risk
    1. Associated with specific Genetic Syndromes
  5. References
    1. Dugoff (2005) Obstet Gynecol 106:260-7 [PubMed]

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Ontology: Aneuploidy (C0002938)

Definition (NCI) A chromosomal abnormality in which there is an addition or loss of chromosomes within a set (e.g., 23 + 22 or 23 + 24).
Definition (NCI_NCI-GLOSS) The occurrence of one or more extra or missing chromosomes leading to an unbalanced chromosome complement, or any chromosome number that is not an exact multiple of the haploid number (which is 46).
Definition (MSH) The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of CHROMOSOMES, chromosome pairs, or chromosome fragments. In a normally diploid cell (DIPLOIDY) the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is MONOSOMY (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is TRISOMY (symbol: 2N+1).
Definition (CSP) chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs.
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SnomedCT 80056000
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Swedish Aneuploidi
Czech aneuploidie
Finnish Aneuploidia
French Aneuploïde, Aneuploïdie
Italian Aneuploide, Aneuploidia
Russian ANEUPLOIDIIA, АНЕУПЛОИДИЯ
Spanish aneuploidía (anomalía morfológica), aneuploidia (anomalía morfológica), aneuploidía, aneuploidia, alteración del número de cromosomas, Aneuploidia
Japanese 異数性, 非正倍数性
Croatian ANEUPLOIDIJA, ANEUPLOIDIA
Norwegian Aneuplodi
Polish Aneuploidalność
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French Dépistage d'une anomalie du tube neural (AFP sérique de la mère)
German Screening auf Neuralschlauchdefekt (Mutterserum AFP)
Italian Ricerca di difetti del tubo neurale (alfa-fetoproteina sierica materna)
Portuguese Rastreio de defeito do tubo neural (AFP no soro materno)
Spanish Estudio de defecto del tubo neural (AFP en suero materno)
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