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Procedures for Prenatal Genetic Diagnosis

By

Jeffrey S. Dungan

, MD, Northwestern University, Feinberg School of Medicine

Reviewed/Revised Jan 2024
View PATIENT EDUCATION

Prenatal procedures that provide a definitive diagnosis of genetic disorders are invasive and involve some fetal risk. Women may choose to have prenatal procedures to know of fetal abnormalities before birth, regardless of whether they would consider pregnancy termination if testing detects a serious abnormality.

Preimplantation Genetic Testing (PGT)

Preimplantation genetic testing (PGT) is sometimes possible before implantation when in vitro fertilization In vitro fertilization (IVF) Assisted reproductive technologies (ARTs) involve manipulation of sperm and ova or embryos in vitro with the goal of producing a pregnancy. For assisted reproductive technologies, oocytes and... read more In vitro fertilization (IVF) is done; polar bodies from oocytes, blastomeres from 6- to 8-cell embryos, or a trophectoderm sample from the blastocyst is used. These tests are available only in specialized centers and are expensive. However, newer techniques may reduce costs and make such tests more widely available.

There are 3 forms of PGT:

  • PGT-M: Testing for monogenic (ie, single-gene) abnormalities

  • PGT-A: Testing for aneuploidy

  • PGT-SR: Testing for structural rearrangements such as unbalanced translocations

PGT-M is used primarily when the risk of certain mendelian disorders (eg, cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Cystic Fibrosis ) in the fetus is high. PGT-A or PGT-SR is used when chromosomal abnormalities in the fetus is a risk.

Chorionic Villus Sampling

In chorionic villus sampling (CVS), chorionic villi are aspirated into a syringe and cultured. CVS provides the same information about fetal genetic and chromosomal status as amniocentesis Amniocentesis Prenatal procedures that provide a definitive diagnosis of genetic disorders are invasive and involve some fetal risk. Women may choose to have prenatal procedures to know of fetal abnormalities... read more and has similar accuracy. However, CVS is done between 10 weeks gestation and the end of the first trimester and thus provides earlier results. Therefore, if needed, pregnancy may be terminated earlier (and more safely and simply), or if results are normal, parental anxiety may be relieved earlier.

Unlike amniocentesis, CVS does not enable clinicians to obtain amniotic fluid, and alpha-fetoprotein cannot be measured. Thus, women who have CVS should be offered maternal screening for serum alpha-fetoprotein at 16 to 18 weeks to assess risk of fetal neural tube defects Maternal serum screening for neural tube defects Noninvasive prenatal screening for genetic disorders, unlike invasive testing, has no risk of test-related complications. Noninvasive maternal screening can help women decide whether to have... read more Maternal serum screening for neural tube defects .

Depending on placental location (identified by ultrasonography), CVS can be done by passing a catheter through the cervix or by inserting a needle through the woman’s abdominal wall. After CVS, Rho(D) immune globulin 300 mcg is given to Rh-negative unsensitized women.

Errors in diagnosis due to maternal cell contamination are rare. Detection of certain chromosomal abnormalities (eg, tetraploidy) may not reflect true fetal status but rather mosaicism confined to the placenta. Confined placental mosaicism is detected in about 1% of CVS specimens. Consultation with experts familiar with these abnormalities is advised. Rarely, subsequent amniocentesis is required to obtain additional information.

Amniocentesis

In amniocentesis, a needle is inserted transabdominally, using ultrasonographic guidance, into the amniotic sac to withdraw amniotic fluid and fetal cells for testing, including measurement of chemical markers (eg, alpha-fetoprotein, acetylcholinesterase). The safest time for amniocentesis is after 14 weeks gestation. Immediately before amniocentesis, ultrasonography is done to assess fetal cardiac motion and determine gestational age, placental position, amniotic fluid location, and fetal number. If the mother has Rh-negative blood and is unsensitized, Rho (D) immune globulin 300 mcg is given after the procedure to help prevent Rh sensitization Prevention Hemolytic disease of the fetus and neonate is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal... read more .

Amniocentesis has traditionally been offered to pregnant women > 35 years because their risk of having an infant with Down syndrome Down Syndrome (Trisomy 21) Down syndrome is an abnormality of chromosome 21 that can cause intellectual disability, microcephaly, short stature, and characteristic facies. Diagnosis is suggested by physical anomalies... read more Down Syndrome (Trisomy 21) or another chromosomal abnormality is increased. However, with the widespread availability and improved safety of amniocentesis, the American College of Obstetricians and Gynecologists recommends all pregnant women be offered amniocentesis (3 References Prenatal procedures that provide a definitive diagnosis of genetic disorders are invasive and involve some fetal risk. Women may choose to have prenatal procedures to know of fetal abnormalities... read more ).

Occasionally, the amniotic fluid obtained is bloody. Usually, the blood is maternal, and amniotic cell growth is not affected; however, if the blood is fetal, it may falsely elevate amniotic fluid alpha-fetoprotein level. Dark red or brown fluid indicates previous intra-amniotic bleeding and an increased risk of fetal loss. Green fluid, which usually results from meconium staining, does not appear to indicate increased risk of fetal loss.

Amniocentesis rarely results in significant maternal morbidity (eg, symptomatic amnionitis). With experienced operators, risk of fetal loss is about 0.1 to 0.2% (4 References Prenatal procedures that provide a definitive diagnosis of genetic disorders are invasive and involve some fetal risk. Women may choose to have prenatal procedures to know of fetal abnormalities... read more ). Vaginal spotting or amniotic fluid leakage, usually self-limited, occurs in 1 to 2% of women tested. Amniocentesis done before 14 weeks gestation, particularly before 13 weeks, results in a higher rate of fetal loss and an increased risk of talipes equinovarus Talipes Equinovarus (Clubfoot) and Other Foot Abnormalities Talipes equinovarus, sometimes called clubfoot, is characterized by plantar flexion, inward tilting of the heel (from the midline of the leg), and adduction of the forefoot (medial deviation... read more Talipes Equinovarus (Clubfoot) and Other Foot Abnormalities (clubbed feet) and is rarely done.

Percutaneous Umbilical Blood Sampling

Fetal blood samples can be obtained by percutaneous puncture of the umbilical cord vein (funipuncture) using ultrasound guidance. Chromosome analysis can be completed in 48 to 72 hours. For this reason, percutaneous umbilical blood sampling (PUBS) was formerly often done when results were needed rapidly. This test was especially useful late in the third trimester, particularly if fetal abnormalities were first suspected at that time. Now, genetic analysis of amniotic fluid cells or chorionic villi via interphase fluorescent in situ hybridization (FISH) allows preliminary diagnosis (or exclusion) of more common chromosomal abnormalities within 24 to 48 hours, and PUBS is rarely done for genetic indications.

References

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