Prenatal Screening Why?? Prenatal Screening is used to identify those pregnancies in which there is a relatively greater risk of fetal disorders as a result of chromosomal abnormalities (e.g. an atypical number of chromosomes or a structural abnormality in one or more chromosome). These are:  Down syndrome (Trisomy 21)  Edward’s syndrome (Trisomy 18)  Patau’s syndrome (Trisomy 13) Trisomy is a condition in which an extra copy of a chromosome is present in the cell which may result in severe mental/physical retardation. Down syndrome also called as Trisomy 21 is a genetic disorder that occurs in approximately 1 of 800 live births. Down syndrome is associated with mild to moderate learning disabilities, developmental delays, characteristic facial features, and low muscle tone in early infancy. Many individuals with Down syndrome also have heart defects, leukaemia, early onset Alzheimer’s disease, gastro-intestinal problems, and other health issues. Edward’s Syndrome also known as Trisomy 18 is a genetic disorder caused by the presence of all or part of an extra 18th chromosome. It is the second most common autosomal trisomy, after Down syndrome that carries to term. Edward Syndrome occurs in 1 of 6000 live births and around 80% of those affected are female. The majority of foetuses with the syndrome die before birth. The syndrome has a very low survival rate, resulting from heart abnormalities, kidney malfunctions, and other internal organ disorders. Patau Syndrome also known as Trisomy 13 or Trisomy D, is a chromosomal abnormality in which a patient has an additional chromosome due to a nondisjunction of chromosome during meiosis. The extra chromosome 13 disrupts the normal course of development, causing heart and kidney defects. Patau syndrome affects somewhere between 1 in 10000 and 1 in 21700 live births.

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Significance All couples have approximately 2% risk of having a child with a birth defect. Over 70% of Down syndrome infants are born to women under 35 years of age Mother’s Age Chances of Down syndrome 25 yrs 1 in 1250 mothers 30 yrs 1 in 840 mothers 35 yrs 1 in 356 mothers 40 yrs 1 in 94 mothers 45 yrs 1 in 24 mothers

Global Trends Countries such as USA, Canada, UK, Netherlands, Spain & France guided by national recommendations, suggest that all pregnant women should be offered a prenatal screening test, regardless of their age.

Prenatal Tests Prenatal screening can take place in the first trimester or second trimester. First Trimester Screening (FTS) is carried out between 11-13 weeks of pregnancy. The protocol consists of two procedures, an immunoassay blood screen and an ultrasound exam. The maternal blood sample undergoes analysis for two biochemical markers:  free Beta human chorionic gonadotropin (free Beta HCG)  Pregnancy associated plasma protein-A (PAPP-A) The ultrasound exam confirms gestational age and measures accumulation behind the fetus’ neck, or nuchal translucency (NT).

fluid

These combined protocols yield the most reliable risk assessment at the earliest possible time frame with a 91% detection rate for Down syndrome and a 95% detection rate for Trisomy 18 and 13. Thus the combined FTS test offers risk assessment based on age of the patient, NT measurement and biochemistry analysis of blood sample. Clinically proven and validated by 18 investigational trials and 2 NIHsponsored studies, the combined FTS (NT/PAPP-A, free Beta HCG) protocol is Page 2 of 5   

a patented methodology pioneered by NTD Labs (A PerkinElmer company), the innovator in prenatal screening since 1976. Second Trimester Screening is carried out between 14-20 weeks. This screening program includes biochemical measurement of  AFP  HCG or free HCG  uE3 Screening Test

Combined Screening Biochemistry only

Triple test

Analytes

Time of tests First Trimester Screening NT, free HCG, PAPP-A 11-13 weeks free HCG, PAPP-A 10-13 weeks Second Trimester Screening AFP, HCG (or free 14-20 HCG), uE3 weeks

Performance achieved Around 90% Around 65%

Around 60-65%

Advantages of First Trimester Combined Screening over Triple Test

 Allows early detection of an increased risk of Down syndrome and other chromosomal abnormalities during pregnancy.  Allows more time for counselling and decision making by the couple prior to when the woman is ‘showing’.  If the screening test does not indicate an increased risk, this allows some reassurance to the couple earlier in the pregnancy.  The FTS detection rate is approximately 90 to 95% (for a false positive rate of 5%). Triple marker gives a detection rate of only about 67%.  First trimester NT measurement is superior to second trimester serum screening for multiple pregnancies (e.g. twins).  National guidelines prepared in many countries such as Singapore, UK, Netherlands, Finland, Denmark, Germany, France, Spain, Vietnam, Korea favour implementation of FTS.

Screening Model offered by Suburban Diagnostics Both First trimester and Second trimester screening tests are performed on FMF (Fetal Medicine Foundation) accredited instruments and Page 3 of 5   

reagents. The instrument uses the DELFIA method which exploits the unique fluorescence properties of lanthanide chelate labels. Also, LifeCycle with Elipse (a dedicated screening management software) provides a complete support in managing an effective, high quality screening program at Suburban Diagnostics. Elipse is a fully configurable and clinically validated independent risk calculation engine, suitable for both 1st & 2nd trimester screening. Because the system has been fully validated and all the calculation methods, algorithms and values are supported by current published literature, LifeCycle provides full confidence in maternal risk assessment programs.

Behaviour of Markers associated with Fetal defects

Marker

Site of synthesis

NTD’s

AFP

Fetal liver

uE3

Fetus+Placenta

Free HCG PAPP-A

Placenta

InhibinA

Ovary

Raised 4x No value No value No value No value

Placenta

Down syndrome (T21) Lower -25% Lower -30% Raised 2x Lower -50% Raised 2x

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Edward’s syndrome (T18) Lower -35-55% Lower -35-55% Lower -50% Lower -50% No value

Patau syndrome (T13) Slightly raised Lower -30% Lower -50% Lower -50% Raised 2x

Interpretation of Prenatal Screening Low Risk: If the risk of identified chromosomal abnormalities like Down syndrome, based on patient’s age, biochemical levels & ultrasound measurements is lower than a specified cut-off (1:250 for Down syndrome), patient is considered to be at a low risk of having a Down syndrome baby. However, a low risk does not necessarily rule out the possibility of a pregnancy with chromosomal abnormalities. With a low risk report the doctor may not advice further testing. High Risk: If risk based on the screening test result is more than the specified cut-off (1:250), patient is considered to be at a relatively high risk of having a Down syndrome baby. However, a high risk result from a prenatal screening test does not confirm trisomy hence it should be followed by a confirmatory test.

Confirmatory Tests If a screening test report indicates a high risk of having a Down syndrome baby, one of the following optional tests may be advised:  Amniocentesis  Chorion Villus Sampling Confirmatory tests are invasive and they carry a slight risk of miscarriage. Screening therefore helps ensure that invasive tests are done only for the high risk patients.

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