Prenatal Diagnosis

Invasive testing AmniocentesisChorionic villus sampling

Noninvasive testing maternal serum screening for alpha-

fetoprotein and other markersultrasonography

Prenatal Diagnosis

A needle is inserted transabdominally into the amniotic cavity, and a sample of amniotic fluid (usually about 20 ml) is withdrawn by syringe for diagnostic studies (e.g., chromosome studies, enzyme measurements, or DNA analysis). Ultrasonography is routinely performed before or during the procedure.

1 in 1600 risk of inducing miscarriage above 1-2% risk for any pregnancy at 15-16 weeks of

gestation

Invasive testing: Amniocentesis

Chorionic villus sampling. Two alternative approaches are drawn:

transcervical (by means of a flexible cannula) transabdominal (with a spinal needle)

In both approaches, success and safety depend on use of ultrasound imaging (scanner)

Invasive testing: Chorionic villus sampling

1% risk of fetal loss above baseline risk of 2% to 5% in any pregnancy at 7 to 12 weeks of gestation

Noninvasive tests

maternal serum screening for alpha-fetoprotein and other markers

ultrasonography

Maternal serum AFP concentration in normal fetuses, fetuses with open neural tube defects, and fetuses

with Down syndrome.

AFPDown syndrome ↓

Open neural tube defects ↑

Maternal serum alpha-fetoprotein (AFP)

Nuchal translucency is a dark, echo-free zone beneath the skin in an ultrasonographic "sagittal section" through the fetus and is marked by two + signs connected by a dotted line. A, Nuchal translucency of 0.12 cm in a normal 11-week fetus, the average for a normal fetus at this gestational age. B, Increased nuchal translucency of 0.59 cm, which is nearly 20 standard deviations above the mean, consistent with a diagnosis of Down syndrome

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Ultrasonography: Nuchal translucency measurements at 11 weeks of gestation

Down syndrome Decreased alpha-fetoprotein

Increased nuchal translucency Open neural tube defects Increased alpha-fetoprotein

Nuchal Translu-cency

PAPP-A

Free β

hCG

uE3 Alpha-feto

protein

Free β hCG

Inhibin A

Trisomy21

↑ ↓ ↑ ↓ ↓ ↑ ↑

Trisomy18

↑ ↓ ↓ ↓ ↓ ↓ -

Trisomy13

↑ ↓ ↓ ↓ ↓ ↓ -

Neural tube

defect

- - - - ↑ - -

PAPP-A: pregnancy-associated plasma proteinβ hCG: β subunit of human chorionic gonadotropinuE3: unconjugated estriol

First and second trimester screening testFirst-trimester screen Second-trimester screen

Triple screen: alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin β subunitQuadruple screen: triple screen + inhibin A

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Sensitivity and false-positive rate of screening tests for trisomy 21

Sensitivity for trisomiy21

False-positive rate

First trimester screen

84% 5%

Second trimester screenTriple test 72% 5%Quadruple

test81% 5%

Stepwise sequential

testing95% 5%

Number of disease cases revealed by testSensitivity = -------------------------------------------------------------- Total number of disease cases

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Medical condition is the only legitimate indication for sex selection, e.g. history of X-linked disease in family

Sex selection is prohibited when it is just a parents desire to have a child only of certain sex

Sex selection

Advanced maternal age

Previous child with de novo chromosomal aneuploidy

Presence of structural chromosomal abnormality in one of the parents

Family history of genetic disorder that may be prenatally diagnosed by biochemical or DNA analysis

Family history of X-linked disorder for which there is no specific prenatal diagnostic test

Risk of a neural tube defect

Abnormal result of maternal serum screening and ultrasound examination

Principal indications for invasive testing

Advanced maternal age dramatically increases the risk of Down syndrome

from 1 in 1000 in young female to 1 in 25 in female older then 45

More data on the incidence of Down syndrome see in the table below (optional)

Maternal Age (Years) At Birth At Amniocentesis (16 Weeks)At Chorionic Villus Sampling (9-

11 Weeks)15-19 1/1250 - -20-24 1/1400 - -25-29 1/1100 - -30 1/900 - -31 1/900 - -32 1/750 - -33 1/625 1/420 1/37034 1/500 1/333 1/25035 1/385 1/250 1/25036 1/300 1/200 1/17537 1/225 1/150 1/17538 1/175 1/115 1/11539 1/140 1/90 1/9040 1/100 1/70 1/8041 1/80 1/50 1/5042 1/65 1/40 1/3043 1/50 1/30 1/2544 1/40 1/25 1/2545 and older 1/25 1/20 1/15

Previous child with de novo chromosomal aneuploidy

Although the parents of a child with chromosomal aneuploidy may have normal chromosomes themselves, in some situations there may still be an increased risk of a chromosomal abnormality in a subsequent child. For example, if a woman at 30 years of age has a child with Down syndrome, her recurrence risk for any chromosomal abnormality is about 1/100, compared with the age-related population risk of about 1/390. Parental mosaicism is one possible explanation of the increased risk, but in the majority of cases, the mechanism of the increase in risk is unknown

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Presence of structural chromosomal abnormality in one of the parents

The risk of a chromosome abnormality in a child varies according to the type of abnormality and sometimes the parent of origin. The greatest risk, 100% for Down syndrome, occurs only if either parent has a 21q21q Robertsonian translocation or isochromosome

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Family history of genetic disorder that may be prenataly diagnosed by biochemical or DNA

analysis

Most of the disorders in this group are caused by single-gene defects with 25% or 50% recurrence risks. Cases in which the parents have been diagnosed as carriers after a population screening test, rather than after the birth of an affected child, are also in this category. Even before DNA analysis became available, numerous biochemical disorders could be identified prenatally, and DNA analysis has greatly increased this number.

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Family history of X-linked disorderFor X-linked disorders, such as Duchenne muscular dystrophy and hemophilia A and B, for which prenatal diagnosis by DNA analysis is available, the fetal sex is first determined and DNA analysis is then performed if the fetus is male. For X-linked diseases for which DNA or other methods are not available, the parents of a boy affected with an X-linked disorder may use fetal sex determination to help them decide whether to continue or to terminate a subsequent pregnancy. In either of the situations mentioned, preimplantation genetic diagnosis may be an option for allowing the transfer to the uterus of only those embryos determined to be unaffected for the disorder in question.

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Risk of a neural tube defect

First-degree relatives (and second-degree relatives at some centers) of patients with neural tube defects are eligible for amniocentesis because of an increased risk of having a child with a neural tube defect; many open neural tube defects, however, can now be detected by other noninvasive tests

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Abnormal result of maternal serum screening and ultrasound examination

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The end