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EVALUATION OF RISK  DISORDERS OF THE MITOCHONDRIA

Maternal Serum Testing (Triple Marker)

The California Expanded AFP (XAFP) program is administered by the California DHS

Genetic Disease Branch (GDB)
2151 Berkeley Way, Annex 4
Berkely, Ca 94704
510-540-2534
FAX: 510-540-2966 or 510-540-2095

 

REFERRAL

Patients may be referred to a prenatal diagnosis center for

  • Singleton > 2.5 MoM for NTD
  • Twins with > 4.5 multiples of the median (MoM)  for NTD
  • Twin with one  demised twin where demise occurred less than 3 weeks from the time of blood collection with  > 4.5 MoM for NTD
  • Twin with one  demised twin where demise occurred greater than or equal 3 weeks at blood collection with > 2.5 MoM for NTD (same as singleton)
  • Risk for Down syndrome 1 in 190  on the XAFP screen
  • Risk for trisomy 18 (Edward syndrome)  1 in 100 on the XAFP screen
  • Risk for Smith-Lemli-Opitz syndrome 1 in 50 on the XAFP screen.
  • H/O neural tube defect (NTD):
    • Previous child with an NTD
    • sibling or half-sibling of fetus with an NTD
    • parent of a fetus with an NTD
    • Two second degree relatives of a fetus with an NTD.
  • A history of exposure to valproic acid( Depakote, Depakene) or carbamazepine (Tegretol, Carbatrol) during the first trimester or one month prior to conception.

DATING RULES

  • The computer program uses gestational date, diabetes, weight, and race to adjust the MoM.
  • The computer  uses in order of preference the ultrasound date >LMP > the exam to calculate the gestational age. For screening purposes the biparietal diameter (BPD) is preferable to a composite gestational age measurement
     
  • Screen Positive for Neural tube defect (NTD)/ Abdominal wall defect (AWD )
    • if > 14 days, must recalculate  the XAFP result
    • if 8-13 days, up to individual prenatal diagnosis center (PDC)
    • if 7 days or less, recalculation not allowed
  • Screen Positive for T21
    • if > 14 days, must recalculate XAFP result
    • if 0-13 days, up to individual PDC
  • Screen Positive for T18
    • no dating changes allowed
  • Screen positive for more than one indication
    • T21 and T18: follow the T18 redating rules
    • NTD and T8 follow the T18 redating rules
    • NTD and T21: follow the T21 rules
       

Decimal/weeks to Days Conversion

    Decimal weeks Days
    16.1 1 day
    16.2 1 day
    16.3 2 days
    16.4 3 days
    16.5 4 days
    16.6 4 days
    16.7 5 days
    16.8 6 days
    16.9 6 days

 

  • When an Expanded AFP patient redates from screen positive to negative or too early, GDB will pay for an amniocentesis when no other source of payment is available if there is at least one of the following fetal abnormalities:
    • lemon sign
    • banana sign
    • choroid plexus cysts
    • holoprosencephaly
    • spina bifida
    • encephalocele
    • ventriculomegaly
    • cerebellar hypoplasia
    • cystic hygroma
    • nuchal fold > 6mm
    • congenital heart defect
    • pleural effusion
    • omphalocele
    • gastroschisis
    • diaphragmatic hernia
    • duodenal atresia
    • marked oligohydramnios or ployhydramnios
    • non-immune hydrops fetalis
    • echogenic bowel


    The GDB does not pay for:

      • Parental cytogenetic studies
      • Any prenatal diagnosis center (PDC) service if the patient is over 24 weeks gestation at any time of her appointment, unless approved by GDB staff.
      • Amniocentesis for the following reasons:
        • isolated anencephaly
        • fetal demise with no anomalies identified
      • Fluorescence in situ hybridization (FISH) studies
      • Rhogam


    OVERALL DETECTION RATES (DR)

      Overall DR Screen Positive
    Down syndrome 66% * 5.6%
    Neural Tube Defects   1.72%
         Open Spina Bifida 80%  
         Anencephaly 97%  
    Abdominal Wall Defects 85%  
    Trisomy 18 60% 0.41%


         DOWN SYNDROME DETECTION RATE (DR) TRIPLE MARKER

Maternal Age
(at term)

Detection Rate Screen Positive
Rate
< 20 40 2.4
21 41 2.4
22 41 2.4
23 42 2.7
24 43 2.8
25 44 3.0
26 45 3.2
27 46 3.4
28 47 3.7
29 50 4.2
30 52 4.8
31 55 5.9
32 58 6.9
33 62 9.0
34 66 10.2
35 71 12.9
36 75 16.2
37 79 20
38 83 25
39 87 30
40 90 36
41 92 43
42 95 50
43 96 58
44 99 86
45 99 89
> 46 99 95

  • The most common cause of any abnormal screen is inaccurate gestational dating.
  • For twin gestations a risk estimate is given for Down syndrome, but the estimate is not as accurate as for a singleton. No risk estimate is given for trisomy 18.
  • RESULTS OF XAFP

      POSSIBLE CONDITION

      MATERNAL SERUM SCREENING PATTERN

      alpha-fetoprotein
      (AFP)

      human chorionic gonadotropin
      (hCG)

      Unconjugated estradiol
      (uE3)

      Fetal death, open spina bifida, abdominal wall defects

      high

      normal

      normal

      Anencephaly

      high

      normal

      low

      Dates more advanced

      high

      low

      high

      Fetal death , x-linked ichthyosis (placental sulfatase deficiency) congenital adrenal hypoplasia

      normal

      normal

      very low

      Down syndrome, dates less advanced, Turner syndrome with cystic hygroma 

      low 

      high

      low

      Trisomy 18 

      low 

      low 

       low 

       

      PREGNANCY COMPLICATIONS WITH UNEXPLAINED RESULTS


      MSAFP > 2.5 MoM
        Fetal/perinatal death, prematurity, growth restriction, oligohydramnios
       MSAFP > 2.5 AND hCG > 2.0 MoM
        Hypertension, preeclampsia, premature rupture of membranes, IUGR, abruptio placentae, and perinatal death.
      The combination of both has at least a 50% risk of complications.
      uE3 < 0.15 MoM
        Fetal death, x-linked ichthyosis, congenital adrenal hypoplasia, anencephaly, Smith-Lemli-Opitz syndrome.

     

    RECOMMENDATIONS FOR FOLATE

    • 400 micrograms daily for all women of childbearing age.
    • 4 milligram daily two months prior to conception and during the the first trimester for women with a previous pregnancy complicated by neural tube defect (NTD)

    REFERENCE:Expanded AFP Screening Program Prenatal Care Provider Handbook. Sacramento, CA: California Department of Health Services, Genetic Disease Branch; 1997.
     



    RECURRENCE RISK(%) FOR COMMON MULTIFACTORIAL CONDITIONS [5]

    CONDITION

    AFFECTED RELATIVE(S)

    None  One sibling or parent*   2 Siblings or one sibling  and one parent 
    Cleft lip with or without palate  0.1 4 10-11
    Cleft palate only 0.04 2-7 15
    Anencephaly 0.1 3 8
    Meningomyelocele 0.1 3 8
    Congenital heart disease any 0.3

    4-5

    10-11
    Ventricular septal defect   3-4 10
    Patent ductus arteriosus   3-4 10
    Atrial septal defects   2-3 8
    Tetralogy of Fallot   2-3 8
    Pulmonary stenosis   2-3 6
    Aortic stenosis   2-3 6
    Hypoplastic left heart   2 6

    *For congenital heart disease if the mother is the affected parent the risk is as for two sibs

    COUNSELING: For multifactorial conditions, ask the parents if they have any ideas regarding the cause of the defect. The developmental pathology of the defect should be explained to the parents . Explain that the recurrence risk for a similar defect is generally 3 to 5 % (or the square root of the population incidence) if one offspring is affected. The recurrence risk is increased if:

  • There is more than one affected relative.
  • The defect is severe.
  • The trait is more frequent in one sex than the other,and the affected person is of the sex less likely to be affected
  • There is consanguinity.
  • The risk to a second degree relative (includes half brother or sister) is closer to the population incidence.



    REFERENCES

    1. Cuckle HA, Wald NJ, Thompson SC.Estimating a woman’s risk of having a pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level. Br J Obstet Gynaecol 1987 94:387

    2. Data from (1) adjusted for 23% loss rate: Hook, EB. Chromosome abnormalities and spontaneous fetal deaths following amniocentesis:further data and associations with maternal age. Am J Hum Genet 1983 35:110-116

    3. Estimate from Foundation for Blood Research

    4. Hook EB, Cross PK, Schreinemachers DM.Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA 1983 249:2034-203

    5. Laxova R, Feldman PF. General Genetics Principles: Chromosomal, Mendelian, and Principles of Teratology.  In: ed Gleicher N Principles and Practice of Medical Therapy in Pregnancy Norwalk CT: Appleton & Lange, 1992. p143.

     

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    Updated: 2/22/07