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ANTENATAL SCREENING TESTS AND PRENATAL DIAGNOSİS

Selçuk Özden MD, Prof

Goal of screening is to detect or define risk for disease in an

asymptomatic low risk population.

SCREENING TESTS DURING PREGNANCY

An ideal perinatal genetic screening test should:

Identify common or important fetal disorders

Be cost-effective and easy to perform

Have a high detection rate and a low false-positive rate

Be reliable and reproducible

Screen for disorders for which a diagnostic test exists

Be positive early enough in gestation to permit safe and legal options for

pregnancy termination if desired

SCREENING TESTS DURING PREGNANCY

Complete blood count

Blood typing

Fasting glucose level

Antibody screening

Pap smear

Urine analysis

Urine culture

Rubella

Hepatitis B and C

HIV

BASIC TESTS DURING PREGNANCY

Incidence of Major congenital abnormalities: 2 to 3 percent of

pregnancies.

Screening tests

Diagnostic tests

SCREENING of FETAL ANOMALIES

Screening for neural tube defects (NTD)

Screening for aneuploidies

Screening for fetal structural anomalies

SCREENING of FETAL ANOMALIES

Neural tube defects (NTDs) are the second most common class of

birth defect after cardiac anomalies

Reported frequency : ~ 0.9 per 1000 births.

SCREENING FOR NTDs

Maternal Serum Alpha-Fetoprotein (MSAFP) Screening

AFP is a glycoprotein synthesized by the fetal yolk sac and later by the fetal

gastrointestinal tract and liver.

It is the major serum protein in the embryo and fetus and is thus analogous to

albumin.

Defects in fetal integument, such as neural-tube and ventral wall defects,

permit AFP to leak into the amnionic fluid, resulting in dramatically increased

maternal serum AFP levels.

SCREENING FOR NTDs

Maternal Serum Alpha-Fetoprotein (MSAFP) Screening

Screening is generally performed from 15 through 20 weeks.

AFP is measured in nanograms per milliliter and reported as

multiples of the median (MoM) of the unaffected population.

Cut-off value: 2.0 or 2.5 MoM.

SCREENING FOR NTDs

ABNORMAL MS-AFP LEVELS

1. Maternal weight—The AFP concentration is adjusted for the maternal volume

of distribution.

2. Gestational age—The maternal serum concentration increases by

approximately 15 percent per week during the second trimester.

3. Race/ethnicity—African American women have at least 10-percent higher

serum AFP concentrations but are at lower risk for fetal NTDs.4. Diabetes—Serum levels may be 10 to 20 percent lower in women with insulin-

treated diabetes.5. Multifetal gestation—Higher screening threshold values are used in twin

pregnancies.

FACTORS INFLUENCING AFP LEVELS

Counseling ,

Diagnostic tests

Sonography

Amniocentesis

EVALUATION of ELEVATED AFP LEVEL

99 percent of fetuses with open spina bifida had one or more of

these findings

1. Frontal nothcing (Lemon sign)

2.Small biparietal diameter,

3.Ventriculomegaly

4.Obliteration of cysterna magna,

5. Banana sign

SONOGRAPHIC FINDINGS


Lemon Sıgn Banana Sıgn

Spına BifidaHidrocephaly


Encephalocele

Anencephaly

It has been replaced in most centers by targeted sonography.

If the amnionic fluid AFP level was elevated, an assay for

acetylcholinesterase was performed, and if positive, was considered

diagnostic of an NTD.

Acetylcholinesterase leaks directly from exposed neural tissue into

the amnionic fluid.

AMNIOCENTESIS

All women who present for prenatal care before 20 weeks should be

offered screening

ANEUPLOIDY SCREENING

Types of screening:

1. Maternal age screening is a poor screening test, because approximately 70

percent of Down syndrome pregnancies are in women younger than 35 years.

2. First-trimester screening at 11 to 14 weeks’ gestation, using the fetal nuchal

translucency measurement together with serum analytes,

3. The addition of other serum analytes to second-trimester screening

4. Combinations of first- and second-trimester

5. Maternal serum cell-free fetal DNA testing for trisomy 21, 18, and 13



At 11 to 14 weeks’ gestation: Fetal nuchal translucency

measurement together with serum analytes, has achieved Down

syndrome detection

• Nasal bone

FIRST TRIMESTER ANEUPLOIDY SCREENING

The most commonly used screening protocol combines the NT

measurement with serum hCG and PAPP-A (Pregnancy Associated

Protein-A).

Detection rates: 79 to 87 percent

False-positive rate: 5 percent

FIRST TRIMESTER ANEUPLOIDY SCREENING

Triple test: Between 16-20 weeks gestation

AFP hCG Unconjugated estriol:

Quadri test: AFP, hCG, estriol and 4. inhibin are measured.

Cut-off value : 1:200

Amniocentesis and cytogenetic analysis is recommended

SECOND TRIMESTER ANEUPLOIDY SCREENING

Using massively parallel sequencing or chromosome selective

sequencing to isolate cell-free fetal DNA from maternal plasma, fetal

Down syndrome and other autosomal trisomies may be detected as

early as 10 weeks’ gestation.

Detection rates for trisomies 21, 18, and 13: ~ 98%

False-positive rate: 0.5% or less.

CELL FREE FETAL DNA SCREENING

This technology has recently become clinically available as a

screening test,

It is not considered a replacement diagnostic test.

Pretest counseling is recommended.

If an abnormal result is identified, genetic counseling and invasive

prenatal diagnostic testing should be offered to confirm the results.


Test may be offered to the following groups: (ACOG 2012)

1. Women 35 years or older at delivery

2. Those with sonographic findings indicating increased risk for fetal aneuploidy

3. Those with a prior pregnancy complicated by trisomy 21, 18, or 13

4. Patient or partner carries a balanced Robertsonian translocation indicating increased risk

for fetal trisomy 21 or 13

5. Those with an abnormal first-, second-, or combined first and second-trimester screening

test result for aneuploidy.

6. The College does not recommend offering the test to women with low-risk pregnancies or

multifetal gestations


1. Structural anomalies (Hard markers)

2. Aneuploidy markers (Soft markers)

3. Other findings

SONOGRAPHIC SCREENING

Cardiac defects,

Central nervous system,

Facial anomalies,

Cystic hygroma,

Diaphragmatic hernia

Gastrointestinal,

Genitourinary anomalies

Nonimmun hydrops

Limb anomalies

STRUCTURAL ANOMALIES

Cardiac defects:

Atrioventricular septal defect

Aneoplody risk: 58%


Duoadenal atresia:

• Double-bubble

• Polyhidramnios

• Trisomy 21 risk: 1/3


Cystic hygroma:• Aneuploidy risk: 60%


Non immun hydrops fetalis: Aneoploidy risk: 16%


Diaphragmatic hernia:• Aneoploidy risk: 8-34%


Omphalocele:• Aneoploidy risk: 30-40%


Gastroschisis:

• Aneoploidy risk is not increased


Ventriculomegaly (>10 mm):

İsolated hydrocephaly: 3%

Hydrocephaly+ spina bifida: 8%

Isolated spina bifida: 33%

Dandy Walker Malformation

Aneuoploidy risk ↑

Holoprosencephaly• Risk of trisomy 13: 50-75%

CENTRAL NERVOUS SYSTEM

Holoprosencephaly

Cleft lip and palate:

• Aneuploidy ↑ (tri.13 , 18)

• Medyan cleft lip and palate: 82%

FACIAL ANOMALIES

Rocker-Bottom Foot:

• Trisomi 13, 18 ↑

Clubfoot:

• Trisomi 13 ve 18 ↑

• Sandal gap:

LIMB ANOMALIES

Clinodactily:

Clenched hand

Polydactily:

LIMB ANOMALIES

Soft markers are normal variants rather than fetal abnormalities,

In the absence of aneuploidy they do not significantly affect

prognosis.

SOFT MARKERS

• Nuchal skinfold thickening

• Echogenic intracardiac focus

• Renal pelvis dilation

• Echogenic bowel

• Short femur and humerus

• Nasal bone absence or

hypoplasia

• Single umbilical artery

• Choroid plexus cyst

• Clinodactily

• Echogenic bowel

SOFT MARKERS

• Nuchal skinfold thickening

• A measurement ≥ 6 mm is considered abnormal

Nasal bone absence

• In approximately two thirds of fetuses with Down

syndrome, the nasal bone is not visible at the 11-

to 14-week examination

SOFT MARKERS

• Echogenic fetal bowel

• it increases the risk for Down syndrome approximately sixfold

Choroid plexus cyst:

Echogenic intracardiac focus

SOFT MARKERS

• Single umbilical artery•

Renal pelvis dilation

SOFT MARKERS

Invasive procedures used in prenatal diagnosis:

Amniocentesis,

Chorionic villus sampling, and

Fetal blood sampling

Preimplantation genetic diagnosis permits similar diagnoses to be

made in oocytes or embryos before implantation.

PRENATAL DIAGNOSTIC TESTS

Is the most common invasive procedure used to diagnose fetal

aneuploidy and other genetic conditions.

It is generally performed between 15 and 20 weeks’ gestation.

The time needed for karyotyping is 7 to 10 days.

AMNIOCENTESIS

Complications

Fetal loss rate following midtrimester amniocentesis : In sigletons: 1

per 300 to 500 . In twins: 1.8%

Amnionic fluid leakage in 1 to 2 percent and

Chorioamnionitis in less than 0.1 percent

Needle injuries to the fetus are rare.

AMNIOCENTESIS

If performed between 11 and 14 weeks, amniocentesis is termed

“early.”

Sac puncture may be more challenging due to lack of membrane

fusion to the uterine wall.

Higher rates of procedure-related complications than other fetal

procedures.

ACOG recommends against the use of early amniocentesis.

EARLY AMNIOCENTESIS

CVS is generally performed between 10 and 13 weeks’ gestation.

The primary advantage of villus biopsy is that results are available

earlier in pregnancy, allowing safer pregnancy termination, if

desired.

• A full karyotype is available in 7 to 10 days.

CHORIONIC VILLUS SAMPLING (CVS)

Complications:

Fetal loss rate is comparable to that with amniocentesis (2 percent)

Limb reduction defects and oromandibular limb hypogenesis:

When performed at ≥ 10 weeks’ gestation, the incidence of limb

defects does not exceed the background rate.

Vaginal spotting is not uncommon.• Chromosomal mosaicism is identified in up to 2 percent of

specimens. Amniocentesis should be offered,

CHORIONIC VILLUS SAMPLING (CVS)

This procedure is also called cordocentesis or percutaneous

umbilical blood sampling (PUBS).

Fetal blood karyotyping can be accomplished within 24 to 48 hours.

Fetal loss rate is approximately 1.4 percent

FETAL BLOOD SAMPLING

For couples undergoing in vitro fertilization (IVF), genetic testing

performed on oocytes or embryos before implantation may provide

valuable information regarding the chromosomal complement and

single-gene disorders.

There are two separate categories of testing

1. Preimplantation genetic diagnosis (PGD)

2. Preimplantation genetic screening (PGS)

PREIMPLANTATION GENETIC TESTING

There are three techniques:

1. Polar body analysis: Sampling of first and

second polar bodies should not affect fetal

development

2. Blastomere biopsy: is done at the 6- to 8-cell

(cleavage) stage when an embryo is 3 days old

3. Trophectoderm biopsy: involves removal of 5

to 7 cells from a 5- to 6-day blastocyst

PREIMPLANTATION GENETIC TESTING

PREIMPLANTATION GENETIC DIAGNOSIS (PGD)• When either or both members of a couple are known carriers of a

specific genetic disease or a balanced chromosomal rearrangement,

preimplantation genetic diagnosis (PGD) may be performed to

determine if an oocyte or embryo has the defect.

• Only embryos without the abnormality would be implanted.

PREIMPLANTATION GENETIC DIAGNOSIS (PGD) It is used to diagnose:

single-gene disorders such as cystic fibrosis, β-thalassemia, and

hemophilia;

to determine gender in X-linked diseases;

to identify mutations such as BRCA-1 that do not cause disease but

confer significantly increased risk;

PREIMPLANTATION GENETIC SCREENING (PGS) This term is used for aneuploidy screening that is performed on

oocytes or embryos before IVF transfer. Such screening is used with

couples who are not known to have or carry a genetic abnormality.

Most commonly, FISH is used to identify the copy number of selected

chromosomes, and it is performed on a single blastomere

1. Single step approach (75 g 2 saat OGTT)

2. Two-step approach

– First step: 50 g 1 hours glucose screening

– Second step: 100 g 3 hours Oral Glucose Tolerence Test (OGTT)

GESTATIONAL DİABETES SCREENING

ACOG recommend a two-step approach to screen and diagnose

gestational diabetes

Screening should be performed between 24 and 28 weeks’ gestation

• 50-g screening test is followed by a diagnostic 100-g, 3-hour oral

glucose tolerance test (OGTT)

GESTATIONAL DİABETES SCREENING

First step: 50-g oral glucose challenge test. If plasma glucose level >140mg/dl Second step: 100-g, 3-hour oral glucose tolerance test (OGTT) Two or more of the venous plasma glucose concentrations listed

must be met or exceeded for a positive diagnosis.

GESTATIONAL DIABETES SCREENING

Measurement of cervical length by transvaginal ultrasonography:

Benefit of routin screening is not clear.

Fetal fibronectin: Benefit of routin screening is not clear.

Periodontal disease: increase the risk of preterm labor

independently. Treatment decrease the risk.

Bacterial vaginosis: is an independent risk factor of preterm labor.

SCREENING FOR PRETERM LABOR

There is no effectiv preventive measure.

Uterine artery Doppler:

Early diastolic notch • Etkili bir önlem yok• • Serum markers: are nonspecific.

SCREENING FOR PREECLAMPSIA

Group B streptococcus screening: prevent neonatal sepsis

effectively

HIV screening: ACOG recommends routin screening and treatment.

Treatment decrease perinatal transmission

Rubella, Hepatitis B, varicella screening : Immunisation is offered

according to immunoglobulin titer. After vaccination, contraception

is recommendedfor 3 months.

SCREENING FOR INFECTIOUS DISEASES

1. Williams Obstetrics 24.th edition-Cunningham et al. The McGraw-Hill

Companies-2014

2. Gabbe: Obstetrics: Normal and Problem Pregnancies, 6th ed., 2013

3. Current Obstetrics & Gyneacology , McGrawHill, LANGE, 12 th edition 2015

4. Moore KL, The Developing Human, Tenth Edition, Copyright © 2016 By

Elsevier, Inc.

5. Creasy And Resnik’s Maternal-fetal Medicine, Seventh Edition, Elsevier

Saunders, 2014

REFERENCES

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