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Chapter: Obstetrics and Gynecology: Assessment of Genetic Disorders in Obstetrics and Gynecology

Prenatal Diagnosis of Genetic Disorders

Prenatal genetic diagnosis should be offered in circum-stances in which there is a definable increased risk for a fetal genetic disorder that may be diagnosed by one or more methods.



Prenatal genetic diagnosis should be offered in circum-stances in which there is a definable increased risk for a fetal genetic disorder that may be diagnosed by one or more methods. Prenatal screening or diagnosis should be voluntary and informed. In most circumstances, test results are normal and provide patients with a high degree of re-assurance that a particular disorder does not affect a fetus, although there is no guarantee that the fetus is normal and with no abnormalities. Early prenatal genetic diagnosis also affords patients the option to terminate affected preg-nancies. Alternatively, a diagnosis of a genetic disorder may allow a patient to prepare for the birth of an affected child and, in some circumstances, may be important in establish-ing a plan for care during pregnancy, labor, delivery, and the immediate neonatal period.


Carrier Testing


Individuals who have a family history of a specific genetic dis-order but who show no signs of the disorder themselves, may undergo carrier testing to determine the risk of passing the dis-order on to their offspring. In addition, individuals with certain ethnic backgrounds predisposed to genetic disorders may undergo carrier testing. For example, ACOG recommends that indi-viduals of Ashkenazi Jewish descent should be tested prior to pregnancy or early in pregnancy for Tay-Sachs disease, Canavan disease cystic fibrosis, and familial dysautonomia. There are also recommendations for other ethnic groups.


Carrier testing involves testing of cells obtained from a saliva or blood sample. Genes responsible for many diseases have been located, and direct testing for the presence of a specific mutation can be performed. Examples of diseases for which direct tests exist are Tay-Sachs disease, hemophilia A, cystic fibrosis, sickle cell disease, Canavan disease, familial dysautonomia, and thalassemia. For disorders where disease-causing mutations have not been delineated, indi-rect testing is required. Indirect testing refers to the process of determining DNA sequences of specific length that are linked to a mutation. These sequences, called restriction fragment-length polymorphisms (RFLPs),can be tested for by the Southern blot technique. Indirect testing is not as accurate as direct testing.


One partner is usually tested first. If one partner is found to be a carrier of a particular disorder, the other part-ner is tested as well. If both partners are carriers, a genetic counselor can provide more information regarding the risk of transmitting the disorder.


Fetal Diagnostic Procedures


Prenatal analysis of DNA requires fetal nucleated cells, cur-rently obtained by amniocentesis, CVS, or percutaneous umbilical blood sampling (PUBS).



Amniocentesis is the withdrawal of 20 to 40 mL of amni-otic fluid transabdominally, under concurrent ultrasound guidance, with a 20-gauge to 22-gauge needle. Traditional genetic amniocentesis is usually performed between 15 and 20 weeks’ gestation. Direct analysis of the amniotic fluid supernatant is possible for AFP and acetylcholinesterase assays; such analyses permit detection of fetal NTDs and other fetal structural defects (e.g., omphalocele, gastroschisis).


Studies have confirmed the safety of amniocentesis as well as its cytogenic diagnostic accuracy (greater than 99%). The risk ofpregnancy loss is less than 1%. Complications, which occur infrequently, include transient vaginal spotting or amniotic fluid leakage in approximately 1% to 2% of all cases, and chorioamnionitis in less than 1 in 1000 cases. The perinatal survival rate in cases of amniotic fluid leakage following midtrimester amniocentesis is greater than 90%.


Early amniocentesis performed from 11 weeks to 13 weeks of gestation has significantly higher rates of preg-nancy loss and complications than traditional amniocente-sis. For these reasons, early amniocentesis before 14 weeks of gestation should not be performed.



Chorionic villus sampling was developed to provide pre-natal diagnosis in the first trimester. CVS is performed after 10 weeks of gestation by transcervical or transabdominal aspiration of chorionic villi (immature placenta) under con-current ultrasound guidance. Recent multicenter trials have demonstrated transabdominal CVS to have similar safety and accuracy rates to that of traditional (i.e., performed at or after 15 weeks’ gestation) amniocentesis; transcervical CVS carries a higher risk of pregnancy loss. Disorders that require analysis of amniotic fluid, such as NTDs, cannot be diagnosed with CVS. There is also a significant learning curve associated with the safe performance of CVS.


The rate of pregnancy loss associated with CVS appears to approach, and may be the same as, the loss associated with midtrimester amniocentesis. The most common complicationof CVS is vaginal spotting or bleeding, which occurs in up to 32.2% of patients after transcervical CVS is performed. The incidence after transabdominal CVS is less. There have been reports that CVS performed before 10 weeks of gestation is associated with limb reduction and oro-mandibular defects. Although these associations are contro-versial, they should be discussed with the patient during counseling. Until further information is available, CVS should not be performed before 10 weeks of gestation.




Percutaneous umbilical blood sampling (PUBS), also known as cordocentesis, is usually performed after 20 weeks’ gestation and has traditionally been used to obtain fetal blood for blood component analyses (e.g., hematocrit, Rh status, platelets), as well as cytogenetic and DNA analy-ses. The indications for PUBS are declining. One major benefit of PUBS is the ability to obtain rapid (18 to 24 hours) fetal karyotypes. However, with the advent of fluorescence in situ hybridization (FISH), PUBS has obviated the need for a procedure with more potential for complications. The procedure-related pregnancy loss rate has been reported to be less than 2%. Cordocentesis is rarely needed, but may be useful to further evaluate chromosomal mosaicism dis-covered after CVS or amniocentesis is performed.


Other prenatal diagnostic procedures include fetalskin sampling, fetal tissue (muscle, liver) biopsy, and fetoscopy. These procedures are used only for the diagno-sis of rare disorders not amenable to diagnosis by less inva-sive methods.



Once fetal cells are obtained, a variety of tests and analyses can be performed. A karyotype is a photomicrograph of the chromosomes taken during metaphase, when the chro-mosomes have condensed. A separate image is made of each individual chromosome from this micrograph. The chro-mosomes are then matched to their homologue, so that the karyotype shows the chromosome pairs. Because most fetal cells in amniotic fluid specimens obtained through amnio-centesis are not in metaphase, these cells must first be cul-tured (grown) in order to perform a karyotype analysis. An advantage of CVS over amniocentesis is that CVS allows for rapid cytogenetic and DNA analyses, because cytotro-phoblasts obtained from first-trimester placentas are more likely to be in metaphase than amniotic fluid cells.


Fluorescence in situ hybridization (FISH) is a tech-nique that involves fluorescent labeling of genetic probes for specific chromosomes, most commonly 13, 18, 21, X, and Y. FISH can identify abnormalities in chromosome number, and results are usually available by 48 hours. Although FISH analysis has been shown to be accurate, false-positive and false-negative results have been reported. Therefore, clinical decision making should be based on information from FISH and either a traditional karyotype, ultrasound findings, or a positive screening test result. Spectral karyotyping (SKY) is similar to FISH, but canbe done for all chromosomes. SKY is useful in detecting translocations.


Comparative genomic hybridization (CGH) is anevolving method that identifies submicroscopic chromoso-mal deletions and duplications. This approach has proved useful in identifying abnormalities in individuals with devel-opmental delay and physical abnormalities, when results of traditional chromosomal analysis have been normal. At present, the use of CGH in prenatal diagnosis is limited because of the difficulty in interpreting which DNA alter-ations revealed through CGH may be normal population variants. Until more data are available, use of CGH for rou-tine prenatal diagnosis is not recommended.


Genetic Counseling


Many couples at increased risk for having children with genetic disorders can benefit from genetic counseling, in which the primary health care provider, a medical geneti-cist, or other trained professional provides information and options to individuals or families about genetic dis-orders and risks. Ideally, this counseling takes place before conception. The key elements in genetic counseling are accu-rate diagnosis, communication, and nondirective presentation of options. The counselor’s function is not to dictate aparticular course of action, but to provide information that will allow couples to make informative decisions. Counseling is directed at helping the patient or family in the following areas:


·            Comprehending the medical facts, including the diag-nosis, probable course of the disorder, and available management


·            Appreciating the way in which heredity contributes to the disorder and the risk of occurrence or recurrence in specific relatives


·  Understanding the options for dealing with the risk of recurrence, including prenatal genetic diagnosis Choosing the course of action that seems appropriate in view of the risk and the family’s goals and act in accor-dance with that decision


·  Making the best possible adjustment to the disorder in an affected family member and to the risk of recurrence in another family member


Genetic counseling may also involve alternative repro-ductive options (e.g., pregnancy termination, permanent sterilization, selective pregnancy reduction, or donor insemination). Patients should also understand that out-side parties, such as insurance companies, may be able to obtain the results of genetic testing.


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