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Genetic evaluation is part of routine prenatal care and is ideally done before conception. The extent of genetic evaluation a woman chooses is related to how the woman weighs factors such as
For these reasons, the decision is individual, and recommendations often cannot be generalized to all women, even those with similar risk.
A screening history is part of the evaluation. The history is summarized as a pedigree (see Fig. 1: General Principles of Medical Genetics: Symbols for constructing a family pedigree. ). Information should include the health status and presence of genetic disorders or carrier status of both parents, of 1st-degree relatives (parents, siblings, offspring), and of 2nd-degree relatives (aunts, uncles, grandparents), as well as ethnic and racial background and consanguineous matings. Outcomes of previous pregnancies are noted. If genetic disorders are suspected, relevant medical records must be reviewed.
Genetic screening tests are best done before conception. Tests are offered to parents at risk of being asymptomatic carriers for certain common mendelian disorders (see Table 1: Prenatal Genetic Counseling and Evaluation: Genetic Screening for Some Ethnic Groups ). Diagnostic tests for specific abnormalities are offered to parents when appropriate (see Table 2: Prenatal Genetic Counseling and Evaluation: Indications for Fetal Genetic Diagnostic Tests).
Pregnant women should be offered screening using multiple maternal serum markers (α-fetoprotein, β-human chorionic gonadotropin [β-hCG], estriol, inhibin A—see Prenatal Genetic Counseling and Evaluation: Maternal serum screening for chromosomal abnormalities) to detect neural tube defects, Down syndrome (and other chromosomal abnormalities), and some other birth defects. This screening is done at 15 to 20 wk of pregnancy.
Fetal genetic diagnostic tests
These tests are usually done via chorionic villus sampling, amniocentesis, or, rarely, percutaneous umbilical blood sampling. They can detect all trisomies, many other chromosomal abnormalities, and several hundred mendelian abnormalities. They are usually recommended if risk of a fetal chromosomal abnormality is increased (see Table 2: Prenatal Genetic Counseling and Evaluation: Indications for Fetal Genetic Diagnostic Tests). Fetal genetic diagnostic tests, unlike screening tests, are usually invasive and involve fetal risk. Thus, in the past, these tests were not routinely recommended for women without risk factors. However, because fetal genetic diagnostic tests are now more widely available and safety has improved, offering fetal genetic testing to all pregnant women, regardless of risk, is recommended. Preimplantation diagnosis is not commonly used because the procedure requires technical expertise and is expensive.
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Table 1
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| Genetic Screening for Some Ethnic Groups |
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Ethnic Group
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Disorder
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Parental Screening Tests
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Prenatal Diagnosis
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All
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Cystic fibrosis*
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DNA analysis of the 25 most common CFTR mutations, each of which is present in ≥ 0.1% of the US population
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CVS or amniocentesis for genotype determination†
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Ashkenazi Jews‡
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Canavan disease
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DNA analysis to detect the most common mutations
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CVS or amniocentesis for DNA analysis
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Familial dysautonomia
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DNA analysis to detect the most common mutations
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CVS or amniocentesis for DNA analysis
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Tay-Sachs disease
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Measurement of serum hexosaminidase A to check for deficiency; possibly DNA analysis
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CVS or amniocentesis for enzymatic assays or molecular analysis to check for hexosaminidase A; DNA analysis
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Blacks
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Sickle cell anemia
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Hemoglobin electrophoresis
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CVS or amniocentesis for genotype determination (direct DNA analysis)
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Cajuns
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Tay-Sachs disease
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Measurement of serum hexosaminidase A to check for deficiency; possibly DNA analysis
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CVS or amniocentesis for enzymatic assays or molecular analysis to check for hexosaminidase A
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Mediterranean people
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β-Thalassemia
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CBC; if MCV is < 80 fL, hemoglobin electrophoresis
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CVS or amniocentesis for genotype determination (direct DNA analysis or linkage analysis)
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Southeast Asians, Cambodians, Chinese, Filipinos, Laotians, Vietnamese
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α-Thalassemia
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CBC; if MCV is < 80 fL, hemoglobin electrophoresis
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CVS or amniocentesis for genotype determination (direct DNA analysis or linkage analysis)
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*The test should be offered to whites and Ashkenazi Jews and should be made available to other ethnic groups (eg, Asians, Hispanics, blacks).
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†Definitive diagnosis is not always possible; sensitivity varies by ethnic group.
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‡For Ashkenazi Jews, some experts also recommend screening for Gaucher's disease, Niemann-Pick disease type A, Fanconi syndrome group C, Bloom syndrome, and mucolipidosis IV. Most (90%) Jews are Ashkenazi; thus, Jews who do not know whether they are Ashkenazi should be screened.
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CVS = chorionic villus sampling; MCV = mean corpuscular volume.
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Table 2
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| Indications for Fetal Genetic Diagnostic Tests |
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Indication
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Comments
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Desire for testing
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Testing should be offered to all pregnant women, regardless of risk.
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Maternal age > 35 at expected delivery
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ACOG recommends all pregnant women be offered invasive testing to assess fetal karyotype, regardless of maternal age.
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Recurrent previous spontaneous abortions
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Chromosome analysis may be indicated for both parents.
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Chromosomal abnormality in a previous child
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Chromosome analysis may be indicated for both parents.
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Paternal age > 50
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Need for testing is controversial.
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Parental chromosomal disorder
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Not all parental chromosomal rearrangements are associated with risks to offspring.
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Suspected parental sex-linked mendelian disorder
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—
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Autosomal recessive mendelian disorder diagnosed or suspected in both parents
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—
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Levels of maternal serum markers* suggesting trisomy 21 or 18
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Chorionic villus sampling during the 1st trimester or amniocentesis during the 2nd trimester is done.
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Elevated maternal α-fetoprotein and indeterminate ultrasound results
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Amniocentesis is done.
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Structural abnormalities in the fetus (including increased nuchal translucency in the 1st trimester) noted during ultrasonography
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Risk of fetal chromosomal abnormality depends on specific anatomic findings.
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*Measured during the 1st or 2nd trimester.
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ACOG = American College of Obstetricians and Gynecologists.
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Procedures
All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated, or in some cases, a disorder can be treated (eg, dexamethasone to prevent virilization in a female fetus with 21-hydroxylase deficiency). Even if neither of these possibilities is anticipated, some women prefer to know of fetal abnormalities before birth.
Ultrasonography
Some experts recommend ultrasonography routinely for all pregnant women. Others use ultrasonography only for specific indications, such as checking for suspected genetic or obstetric abnormalities or helping interpret abnormal maternal serum marker levels. If ultrasonography is done by skilled operators, sensitivity for major congenital malformations is high. However, some conditions (eg, oligohydramnios, maternal obesity, fetal position) interfere with obtaining optimal images. Ultrasonography is noninvasive and has no known risks to the woman or fetus.
Basic ultrasonography is done to
Although ultrasonography provides only structural information, some structural abnormalities strongly suggest genetic abnormalities. Multiple malformations may suggest a chromosomal disorder.
Targeted ultrasonography, with high-resolution ultrasonography equipment, is available at certain referral centers and provides more detailed images than basic ultrasonography. This test may be indicated for couples with a family history of a congenital malformation (eg, congenital heart defects, cleft lip and palate, pyloric stenosis), particularly one that may be treated effectively before birth (eg, posterior urethral valves with megacystis) or at delivery (eg, diaphragmatic hernia). High-resolution ultrasonography may also be used if maternal serum marker levels are abnormal. High-resolution ultrasonography may allow detection of the following:
During the 2nd trimester, identifying structures that are statistically associated with increased risk of fetal chromosomal abnormalities helps refine risk estimate.
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, α-fetoprotein, acetylcholinesterase). The safest time for amniocentesis is after 14 wk 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, Rh0 (D) immune globulin 300 μg is given after the procedure to reduce the likelihood of sensitization (see Abnormalities of Pregnancy: Prevention).
Amniocentesis has traditionally been offered to pregnant women > 35 because their risk of having an infant with Down syndrome 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 to assess the presence of fetal chromosomal disorders.
Occasionally, the amniotic fluid obtained is bloody. Usually, the blood does not affect amniotic cell growth and is maternal; however, if the blood is fetal, it may falsely elevate amniotic fluid α-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%. Vaginal spotting or amniotic fluid leakage, usually self-limited, occurs in 1 to 2% of women tested. Amniocentesis done before 14 wk gestation, particularly before 13 wk, results in a higher rate of fetal loss and an increased risk of talipes equinovarus (clubbed feet).
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 and has similar accuracy. However, CVS is done between 10 wk gestation and the end of the 1st 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, amniotic fluid is not obtained at the time of CVS, and α-fetoprotein cannot be measured. Thus, women who have CVS should be offered maternal screening for serum α-fetoprotein at 16 to 18 wk to assess risk of fetal neural tube defects (see Prenatal Genetic Counseling and Evaluation: 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, Rh0 (D) immune globulin 300 μg 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.
Rate of fetal loss due to CVS is similar to that of amniocentesis (ie, about 0.2%). Transverse limb defects and oromandibular-limb hypogenesis have been attributed to CVS but are exceedingly rare if CVS is done after 10 wk gestation by an experienced operator.
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 h. 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 3rd 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 h, and PUBS is rarely done for genetic indications.
Procedure-related fetal loss rate with PUBS is about 1%.
Preimplantation Diagnosis
Genetic diagnosis is sometimes possible before implantation when in vitro fertilization 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 used primarily for couples with a high risk of certain mendelian disorders (eg, cystic fibrosis) or chromosomal abnormalities. Newer techniques may reduce costs and make such tests more widely available. Preimplantation genetic diagnosis to screen embryos from older women does not appear to increase the chance of successful pregnancy.
Noninvasive Maternal Screening Strategies
Noninvasive maternal screening, unlike invasive testing, has no risk of test-related complications. By more precisely assessing the risk of fetal abnormalities, particularly for women at otherwise low risk, noninvasive maternal screening can help women decide whether to have invasive testing. Noninvasive maternal screening for fetal chromosomal abnormalities should be offered to all pregnant women who have not already decided to have amniocentesis or CVS. However, if CVS is to be done, maternal serum screening should still be offered for detection of fetal neural tube defects.
Normal values vary with gestational age. Corrections for maternal weight, diabetes mellitus, race, and other factors may be necessary. Screening can be done during the 1st trimester, 2nd trimester, or both (called sequential or integrated screening). Any of the 3 approaches are acceptable. Regardless of which is done, maternal levels of α-fetoprotein should be measured during the 2nd trimester.
1st-Trimester Screening
First-trimester combined screening includes measurement of
Fetal Down syndrome is typically associated with high levels of β-hCG, low levels of PAPP-A, and presence of enlarged fetal nuchal translucency (NT). Although an enlarged NT is associated with increase in risk for fetal Down syndrome, no threshold NT value is considered diagnostic. In large prospective US trials involving women of various ages, overall sensitivity for detection of Down syndrome was about 85%, with a false-positive rate of 5%. Specialized ultrasound training and adherence to rigorous quality-assurance monitoring of NT measurements are necessary to achieve this level of screening accuracy. First-trimester screening is being used increasingly in the US, particularly in large centers. It provides information early so that a definitive diagnosis can be made with CVS. An important advantage of 1st-trimester screening is that termination of pregnancy is safer during the 1st rather than the 2nd trimester.
2nd-Trimester Screening
Second-trimester screening may include the multiple marker screening approach, which includes
Second-trimester multiple marker screening is used to help assess the risk of Down syndrome, trisomy 18, and a few rarer single-gene syndromes (eg, Smith-Lemli-Opitz syndrome). Maternal serum tests are widely available, but detection rates for Down syndrome are not as high as those obtained with 1st-trimester screening. Also, termination of pregnancy is riskier in the 2nd trimester than in the 1st trimester.
Second-trimester screening may also include
Maternal serum screening for neural tube defects
An elevated level of MSAFP may indicate a fetal malformation such as open spina bifida. Results are most accurate when the initial sample is obtained between 16 and 18 wk gestation, although screening can be done from about 15 to 20 wk. Designating a cutoff value to determine whether further testing is warranted involves weighing the risk of missed abnormalities against the risk of complications from unnecessary testing. Usually, a cutoff value in the 95th to 98th percentile or 2.0 to 2.5 times the normal pregnancy median (multiples of the median, or MOM) is used. This value is about 80% sensitive for open spina bifida and 90% sensitive for anencephaly. Closed spina bifida is usually not detected. Amniocentesis is eventually required in 1 to 2% of women originally screened. Lower cutoff values of MSAFP increase sensitivity but decrease specificity, resulting in more amniocenteses.
Ultrasonography is the next step if further testing is warranted. Targeted ultrasonography (see Prenatal Genetic Counseling and Evaluation: Targeted ultrasonography) with or without amniocentesis is done if no explanation can be determined with basic ultrasonography. Ultrasonography can confirm gestational age (which may be underestimated) or detect multifetal pregnancy, fetal death, or congenital malformations. In some women, ultrasonography cannot identify a cause for elevated α-fetoprotein levels. Some experts believe that if high-resolution ultrasonography done by an experienced operator is normal, further testing is unnecessary. However, because this test occasionally misses neural tube defects, many experts recommend further testing by amniocentesis regardless of ultrasonography results.
Amniocentesis with measurement of α-fetoprotein and acetylcholinesterase levels in amniotic fluid is done if further testing is needed. Elevated α-fetoprotein in amniotic fluid suggests
Presence of acetylcholinesterase in amniotic fluid suggests a neural tube defect or another malformation. Elevated α-fetoprotein plus presence of acetylcholinesterase in amniotic fluid is virtually 100% sensitive for anencephaly and 90 to 95% sensitive for open spina bifida. Abnormal amniotic fluid markers indicate that a malformation is likely even if high-resolution ultrasonography (which can detect most of these malformations) does not detect a malformation, and parents should be informed.
Maternal serum screening for chromosomal abnormalities
During the 2nd trimester, the most common approach to screening is with multiple serum markers. These markers, adjusted for gestational age, are used mainly to refine estimates of Down syndrome risk beyond that associated with maternal age. With triple screening (ie, α-fetoprotein, hCG, and unconjugated estriol), sensitivity for Down syndrome is about 65 to 70%, with a false-positive rate of about 5%.
Quad screening is triple screening plus measurement of inhibin A. Quad screening increases sensitivity to about 80%, with a 5% false-positive rate.
If maternal serum screening suggests Down syndrome, ultrasonography is done to confirm gestational age, and risk is recalculated if the presumed gestational age is incorrect. If the original sample was drawn too early, another one must be drawn at the appropriate time. Amniocentesis is offered particularly if risk exceeds a specific prespecified threshold (usually 1 in 270, which is about the same as risk when maternal age is > 35).
Triple screening can also assess risk of trisomy 18, indicated by low levels of all 3 serum markers. Sensitivity for trisomy 18 is 60 to 70%; the false-positive rate is about 0.5%. Combining ultrasonography and serum screening increases sensitivity to about 80%.
Targeted ultrasonography
Targeted ultrasonography is offered at some perinatal centers and is used to assess risk for chromosomal abnormalities by searching for structural features associated with fetal aneuploidy (so-called soft markers). However, no structural finding is diagnostic for a given chromosomal abnormality, and all soft markers may also be seen in fetuses that are chromosomally normal. Nonetheless, the discovery of such a marker may lead to offering the woman amniocentesis to confirm or exclude a chromosomal abnormality. If a major structural malformation is present, a fetal chromosomal abnormality is more likely. Disadvantages include unnecessary anxiety if a soft marker is detected and unnecessary amniocentesis. Several experienced centers report high sensitivity, but whether a normal ultrasound indicates a substantially reduced risk of fetal chromosomal abnormalities is unclear.
Sequential 1st- and 2nd-Trimester Screening
Noninvasive 1st-trimester and 2nd-trimester quad screening can be combined sequentially, with invasive fetal genetic testing withheld until results of 2nd-trimester screening are available—whether 1st-trimester test results are abnormal or not. Sequential screening followed by amniocentesis for high-risk patterns increases sensitivity for Down syndrome to 95%, with a false-positive rate of only 5%.
A variation of sequential screening, called contingent sequential screening, is based on the level of risk indicated by 1st-trimester screening:
Last full review/revision December 2008 by Jeffrey S. Dungan, MD; Sherman Elias, MD
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