• The objective of prenatal diagnosis is to determine whether a fetus believed to be at risk for some genetic disease is or is not actually affected.
Prenatal diagnosis is recommended in the following cases • The pregnant woman is 35 years or older at the time of delivery. • She or her parents have had a previous child with a chromosomal abnormality. • She has a history of recurrent abortions, or her husband's previous wife experienced several miscarriages. • A history of parental consanguinity is present. • The couple is known to be carriers of a chromosomal translocation. • The pregnant woman is affected with type 1 diabetes mellitus, epilepsy, or myotonic dystrophy.
Prenatal diagnosis is recommended in the following cases • Mother is exposed to viral infections, such as rubella or cytomegalovirus. • The mother is exposed to excessive medication or to environmental hazards. • In her or her spouse's family, a history of Down syndrome or some other chromosomal abnormality is present. • A history of single gene disorder is present in her or her spouse's family. • Her male relatives have Duchenne muscular dystrophy or severe hemophilia.
Prenatal diagnosis uses various noninvasive and invasive techniques
Noninvasivetechniques • Fetal visualization – – – –
Ultrasound Fetal echocardiography Magnetic resonance imaging (MRI) Radiography
• Screening for neural tube defects (NTDs) - Measuring maternal serum alpha-fetoprotein (MSAFP)
• Screening for fetal Down syndrome – Measuring MSAFP – Measuring maternal unconjugated estriol – Measuring maternal serum beta-human chorionic gonadotropin (HCG)
• Separation of fetal cells from the mother's blood
Fetal Visualization MRI
• MRI is a fetal imaging technique that uses powerful magnets and radio waves to construct images of the body. • Because of fetal movements, its application has been limited.
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Radiography
The fetal skeleton can be visualized by radiography from 10 weeks' gestation onward. This technique is used for the diagnosis of inherited skeletal dysplasias, particularly osteochondrodysplasia, in the second and third trimesters. Because of the dangers of radiography to the fetus, this technique rarely is used
Ultrasound is used to guide invasive sampling, such as amniocentesis, CVS, cordocentesis, and various fetal biopsies
Ultrasound • Ultrasound can evaluate gestational age, as well as identify twins; fetal position; placental location; fetal growth, development, and movement; and any structural birth defects. It also can assess amniotic fluid volume. • Many fetal organ systems and anatomical lesions, including some genitourinary, gastrointestinal, skeletal, and central nervous system abnormalities and congenital cardiopathies, (can be visualized by ultrasound between 16-20 weeks' gestation). •
Fetal echocardiography • performed at 15 weeks' gestation and beyond. Recommended in cases where cardiac defects are suspected: 1. Identification of an extracardiac malformation on routine ultrasound 2. Abnormality of another major organ system 3. Suspected genetic disease or fetal chromosome abnormality associated with heart defects 4. Exposure to potentially teratogenic agents 5. Family history of congenital heart defects, particularly in a parent or sibling 6. Maternal diseases, such as diabetes 7. Alcohol or drug consumption by mother during pregnancy 8. Maternal rubella infection during pregnancy
Measuring maternal serum alpha-fetoprotein (MSAFP) • AFP is produced by the yolk sac and later by the liver; it enters the amniotic fluid and then the maternal serum via fetal urine. • In open NTDs (eg, anencephaly, spina bifida) and abdominal wall defects in the fetus, AFP diffuses rapidly from exposed fetal tissues into the amniotic fluid, thus level of MSAFP • A combination of the MSAFP test and ultrasonography detects almost all cases of anencephaly and most cases of spina bifida.
Screening for neural tube defects 1. Ultrasound findings indicate NTDs. 2. A child with NTDs is already in the family. 3. A family history of NTDs exists, especially a mother with NTDs. 4. The mother has type 1 diabetes mellitus during pregnancy. 5. Maternal exposure to drugs, such as valproic acid, is associated with NTDs. 6. Elevated level of MSAFP is present.
Screening for fetal Down syndrome •
Measuring maternal serum alpha-fetoprotein level of MSAFP indicates Down syndrome or other chromosomal aneuploidy
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Measuring maternal unconjugated estriol Fetal adrenal glands (dehydroepiandrosterone (DHEA) estriol (placenta). maternal circulation maternal kidney in urine or by maternal liver in the bile. level of estriol is an indication of Down syndrome
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Measuring maternal serum beta-human chorionic gonadotropin
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The trophoblasts produce enough beta-HCG, which is an indication for pregnancy. In the middle to late second trimester. beta-HCG level coupled MSAFP level suggests Down syndrome. Use of MSAFP, hCG and estriol with routine testing over age 35 can identify 60% of pregnancies with DOWN SYNDROME
Separation of fetal cells from the mother's blood • Fetal blood cells make access to maternal circulation through the placental villi. These cells can be collected safely from approximately 18 weeks' gestation onward,. The fetal cells can be sorted out and analyzed by different techniques. 1. Fluorescent in situ hybridization (FISH) can diagnose aneuploid conditions, such as trisomies and monosomy X. • 2. In the condition of fetal infection with such viruses as rubella, cytomegalovirus, and toxoplasmosis, the viral immunoglobulin M (IgM) can be identified in fetal blood.
3. Fetal blood cells can be analyzed for the diagnosis of genetic disorders using molecular genetic techniques by isolating DNA and amplifying it by polymerase chain reaction (PCR). EX. cystic fibrosis, sickle cell anemia, and thalassemia in a fetus.
Invasive techniques • Fetal visualization – Embryoscopy – Fetoscopy
• Fetal tissue sampling – – – – –
Amniocentesis Chorionic villus sampling (CVS) Percutaneous umbilical blood sampling (PUBS) Percutaneous skin biopsy Other organ biopsies, including muscle and liver biopsy
• Preimplantation biopsy of blastocysts obtained by in vitro fertilization / Preimplantation Genetic Diagnosis(PGD)
FETOGRAPHY • Use of contrast medium which coats the vernix covered skin thus outlining the fetus • Can diagnosed neural tube defects, other ectoderm abnormalities • Limitations : * no vernix during early pregnancy, the time when information regarding fetal genetic status is helpful.
Embryoscopy • Embryoscopy is performed in the first trimester of pregnancy (up to 12 weeks’ gestation). • Technique: a rigid endoscope is inserted via the cervix in the space between the amnion and the chorion, under sterile conditions and ultrasound guidance, to visualize the embryo for the diagnosis of structural malformations.
Fetoscopy • Fetoscopy is performed during the second trimester • Uses: 1. to detect the presence of subtle structural abnormalities 2. for fetal blood and tissue sampling. • Fetoscopy is associated with a 3-5% risk of miscarriage; therefore, it is superseded by detailed ultrasound scanning
Amniocentesis During its development, the fetus sheds cells into the amniotic fluid. After 15-20 weeks of pregnancy, a small volume of this fluid can be removed (using a needle inserted through the abdominal wall).
DISORDERS THAT CAN BE DIAGNOSED BY AMNIOTIC FLUID ANALYSIS
* Chromosomal Disorders – chromosome analysis * Sex-linked Disorders – determination of fetal sex * Metabolic Disorders – measurement of specific enzyme activity, hormones, amino acids and detect abnormal metabolites. * Neural tube defect
COMPLICATIONS OF AMNIOCENTESIS MATERNAL * Spontaneous abortion *Antepartum hemorrhage
FETAL * Respiratory problems * Postural deformities * Rhesus-immunization * Purulent chorionitis * Perinatal mortality
CHORIONIC VILLUS SAMPLING ( CVS) • Done during 1st trimester (10-12 wks.) Technique: • A small amount of placental tissue is sucked out by a tube inserted through the abdominal wall or through the vagina (the latter avoiding the need for an incision).
Chorionic VillusSampling CVS Transabdominal
Transcervical
Chorionic Villus Sampling (CVS) • Advantages; 1. The fetal cells can be examined immediately without the need to culture them. 2. It can be performed earlier in pregnancy (after only 10–12 weeks) than amniocentesis. • If an abortion is to be performed, it is a simpler process early in pregnancy
CYTOGENETIC ABNORMALITIES CONFIRM BY CVS • Autosomal aneuoploidy (trisomies 21, 13,18) • Sex chromosome aneuploidy (45 XO, 47 XXY) • Chromosome Structural Defects
FETAL BLOOD SAMPLING (Cordocentesis) • Percutaneous umbilical blood sampling • Simple, safe, and 100% fetal blood
COMPLICATIONS • Fetal loss • Preterm delivery • Infection
INDICATIONS • • • • •
Hemoglobinopathy Coagulopathy Isoimmunization Cytogenetics Evaluation of congenital cytomegalovirus and rubella infection • Fetal acid – base status before/during labor • Measure glucose /insulin level in fetus of diabetic mother • Evaluation of growth retarded fetus
Screeningfor Genetic Disease
• Most of these tests can be performed on cells removed from a) the adults (maternal blood) b) the fetus c) pre-implantation embryo.
Preimplantation Genetic Diagnosis • • •
A single cell removed from the 8-cell morula in humans can be used to generate a culture of embryonic stem cells. So couples using in vitro fertilization (IVF) can take advantage of genetic screening. While the embryo is in culture, a cell can safely be removed and tested for its genotype. 1. The sex of the embryo can be determined with a probe for Yspecific DNA. This permits prospective mothers carrying a severe Xlinked trait like hemophilia A to choose a female rather than a male embryo for attempted implantation. 2. Entire karyotype of the embryo can be determined: – too much (e.g. 3 copies of #21 — trisomy Ex. Down’s Syndrome) or – too little (only a single copy of #14 — monosomy Ex. Turner’s Syndrome)
LIMITATIONS OF PRENATAL DIAGNOSIS • • • •
Not 100% accurate. Many technical problems Procedures are time consuming Complications are plenty: * Maternal: abortion, hemorrhage, peritonitis * Fetal: trauma, hematoma, pneumothorax, amnionitis, abruptio, death
Benefitsof Prenatal Diagnosis • It is helpful for couples to decide whether to continue the pregnancy. • It indicates possible complications that can arise at birth process. • It is helpful for the management of remaining weeks of pregnancy. • It prepares the couple for the birth of a child with an abnormality. • Prenatal diagnosis can be helpful for the improvement of the outcome of pregnancy using fetal treatment
Prenatal Diagnosis (the future) • The ultimate goal is treatment of the fetus to correct the defects. • With the rapid advances in genetic knowledge and technology, genetic abnormalities may not necessitate therapeutic abortion, instead definitive management could be instituted during antenatal period
FETAL SURGERY
repair of spina bifida