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Genetic Evaluation

By Jeffrey S. Dungan, MD, Northwestern University, Feinberg School of Medicine

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Patient Education

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

  • The probability of a fetal abnormality based on risk factors and the results of any previous testing

  • The probability of a complication from invasive fetal testing

  • The importance of knowing the results (eg, would the pregnancy be terminated if an abnormality was diagnosed, would not knowing the results cause anxiety)

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 Figure: 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. Traditionally, tests are offered to parents at risk of being asymptomatic carriers for certain common mendelian disorders (see Table: Genetic Screening for Some Ethnic Groups). Diagnostic tests for specific abnormalities are offered to parents when appropriate (see Table: Indications for Fetal Genetic Diagnostic Tests). Because parent ethnicity is more complex and less well-defined than previously thought and because prenatal genetic testing is becoming much less expensive and quicker, some clinicians are starting to screen all potential (and expectant) parents, regardless of ethnicity (called universal carrier screening). Consensus on which disorders should be tested for does not yet exist. Increasing the amount of testing and evaluation is expected to increase the complexity of pre-test counseling.

Pregnant women should be offered screening using multiple maternal serum markers (alpha-fetoprotein, beta-human chorionic gonadotropin [beta-hCG], estriol, inhibin A—see Noninvasive Maternal Screening Strategies : 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 called analyte screening. It is done at 15 to 20 wk of pregnancy. An alternate form of screening for fetal Down syndrome or trisomy 18 is with analysis of cell-free DNA (cfDNA) in maternal plasma.

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. Submicroscopic chromosomal abnormalities are missed by traditional karyotype testing and can be identified only by microarray technologies, such as array comparative genomic hybridization and single nucleotide polymorphism (SNP)-based arrays.

Tests are usually recommended if risk of a fetal chromosomal abnormality is increased (see Table: 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. The role of array comparative genomic hybridization in prenatal testing is under study; it is most frequently used to evaluate fetuses with structural abnormalities.

Preimplantation genetic diagnosis may be available for couples who are using in vitro fertilization.

Genetic Screening for Some Ethnic Groups

Ethnic Group


Parental Screening Tests

Prenatal Diagnosis


DNA analysis of the 23 most common CFTR mutations, each of which is present in 0.1% of the US population

CVS or amniocentesis for genotype determination*

Ashkenazi Jews

Canavan disease

DNA analysis to detect the most common mutations

CVS or amniocentesis for DNA analysis

Familial dysautonomia

DNA analysis to detect the most common mutations

CVS or amniocentesis for DNA analysis

Measurement of serum hexosaminidase A to check for deficiency; possibly DNA analysis

CVS or amniocentesis for enzymatic assays or molecular analysis to check for hexosaminidase A; DNA analysis


Hemoglobin electrophoresis

CVS or amniocentesis for genotype determination (direct DNA analysis)


Tay-Sachs disease

Measurement of serum hexosaminidase A to check for deficiency; possibly DNA analysis

CVS or amniocentesis for enzymatic assays or molecular analysis to check for hexosaminidase A

Southeast Asians, Asian Indians, Africans, people from the Mediterranean region and the Middle East

CBC; if MCV is <80 fL, hemoglobin electrophoresis

CVS or amniocentesis for genotype determination (direct DNA analysis or linkage analysis)

Southeast Asians, Cambodians, Chinese, Filipinos, Laotians, Vietnamese

CBC; if MCV is <80 fL, hemoglobin electrophoresis

CVS or amniocentesis for genotype determination (direct DNA analysis or linkage analysis)

*Definitive diagnosis is not always possible; sensitivity varies by ethnic group.

For Ashkenazi Jews, some experts also recommend screening for Gaucher 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.

CFTR = cystic fibrosis transmembrane conductance regulator; CVS = chorionic villus sampling; MCV = mean corpuscular volume.

Indications for Fetal Genetic Diagnostic Tests



Desire for testing

Testing should be offered to all pregnant women, regardless of risk.

Maternal age > 35 at expected delivery

ACOG recommends that all pregnant women be offered invasive testing to assess fetal karyotype, regardless of maternal age.

Recurrent previous spontaneous abortions

Chromosome analysis may be indicated for both parents.

Chromosomal abnormality in a previous child

Chromosome analysis may be indicated for both parents.

Paternal age >50

Need for testing is controversial.

Parental chromosomal disorder

Not all parental chromosomal rearrangements are associated with risks to offspring.

Suspected parental sex-linked mendelian disorder

Autosomal recessive mendelian disorder diagnosed or suspected in both parents

Levels of maternal serum markers* suggesting trisomy 21 or trisomy 18

Chorionic villus sampling during the 1st trimester or amniocentesis during the 2nd trimester is done.

Abnormal cell-free DNA analysis from maternal plasma

Chorionic villus sampling during the 1st trimester or amniocentesis during the 2nd trimester is done.

Elevated maternal alpha-fetoprotein and indeterminate ultrasound results

Amniocentesis is done.

Structural abnormalities in the fetus (including increased nuchal translucency in the 1st trimester) noted during ultrasonography

Risk of fetal chromosomal abnormality depends on specific anatomic findings.

*Measured during the 1st or 2nd trimester.

ACOG = American College of Obstetricians and Gynecologists.


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, fetal surgery to repair spina bifida). Even if neither of these possibilities is anticipated, some women prefer to know of fetal abnormalities before birth.

Prenatal 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

  • Confirm gestational age

  • Determine fetal viability

  • Detect a multifetal pregnancy

  • During the 2nd or 3rd trimester, possibly identify major malformations in the fetal intracranial structures, spine, heart, bladder, kidneys, stomach, thorax, abdominal wall, long bones, and umbilical cord

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.


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 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 mcg is given after the procedure to reduce the likelihood of sensitization (see Erythroblastosis Fetalis : 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 risk of fetal chromosomal disorders.

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%. 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, 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 wk to assess risk of fetal 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 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.

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 Genetic Testing (PGT)

Preimplantation genetic testing 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 expensive. However, newer techniques may reduce costs and make such tests more widely available. Preimplantation genetic diagnosis (PGD) which checks for specific hereditary disorders is used primarily for couples with a high risk of certain mendelian disorders (eg, cystic fibrosis) or chromosomal abnormalities. Preimplantation genetic screening (PGS) which screens for aneuploidy is used primarily for embryos from older women but 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, 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, even if CVS is to be done, maternal serum screening should still be offered to check for 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 is acceptable. Maternal levels of alpha-fetoprotein should be measured during the 2nd trimester to check for neural tube defects.

Pearls & Pitfalls

  • Measure maternal levels of alpha-fetoprotein during the 2nd trimester to check for neural tube defects regardless of other tests planned and the timing of those tests.

1st-Trimester Screening

Traditionally, 1st-trimester combined screening includes measurement of

  • Maternal serum beta-hCG (total or free)

  • Pregnancy-associated plasma protein A (PAPP-A)

  • Fetal nuchal translucency (by ultrasonography)

Fetal Down syndrome is typically associated with high levels of beta-hCG, low levels of PAPP-A, and enlarged fetal nuchal translucency (NT). Although enlarged NT is associated with increased risk of 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 should be offered to all pregnant women. 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.

Cell-free fetal nucleic acid testing

An increasingly used approach, called noninvasive prenatal screening or cell-free DNA (cfDNA) screening, can identify fetal chromosomal abnormalities in singleton pregnancies by analyzing circulating cell-free fetal nucleic acids in a maternal blood sample. This test can be done as early as 10 gestational wk and may replace traditional 1st- and 2nd-trimester noninvasive screening.

Cell-free fetal nucleic acids, most commonly DNA fragments, are shed into the maternal circulation during normal breakdown of placental trophoblast cells. Variation in amounts of fragments from particular chromosomes predicts fetal chromosomal abnormalities with higher accuracy than traditional 1st- and 2nd-trimester combined screening using serum analytes and ultrasound. Also, sex chromosomal abnormalities (X, XXX, XYY, and XXY) can be identified in singleton pregnancies, although with somewhat lower accuracy. Early validation trials reported > 99% sensitivity and specificity for the identification of Down syndrome (trisomy 21) and trisomy 18 in high-risk pregnancies. Trisomy 13 can also be detected, although the sensitivity and specificity have not been precisely determined (1).

Cell-free DNA (cfDNA) screening is currently recommended for women with pre-existing risk factors for fetal trisomy. However, in a recent large multicenter trial that studied the effectiveness of cfDNA screening in a low-risk population, sensitivity for detection of fetal Down syndrome was equivalent to that in a high-risk population. Given the lower incidence of fetal Down syndrome in younger pregnant women, the specificity and positive predictive value were lower than if screening only high-risk women. However, cfDNA screening was superior to traditional analyte screening in low-risk women in overall performance. Cell-free DNA screening has largely replaced serum analyte screening in high-risk women, but screening approaches in low-risk women still rely primarily on traditional, and less expensive, 1st- and 2nd-trimester combined screening with serum analytes and ultrasound (1).

Abnormal results from cfDNA screening should be confirmed with diagnostic karyotyping using fetal specimens obtained through invasive techniques. Negative results from cfDNA screening will likely reduce the use of routine invasive testing.


2nd-Trimester Screening

Second-trimester screening may include cfDNA or the multiple marker screening approach, which includes

  • Maternal levels of serum alpha-fetoprotein (MSAFP): MSAFP may be used independently as a screen for neural tube defects only, not for risk of Down syndrome. An elevated level suggests open spina bifida, anencephaly, or abdominal wall defects. Unexplained elevations in MSAFP may be associated with increased risk of later pregnancy complications, such as stillbirth or intrauterine growth retardation.

  • Maternal levels of beta-hCG, unconjugated estriol, alpha-fetoprotein, and sometimes inhibin A: This screening may be used as an alternative or adjunct to 1st-trimester screening.

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 or with cfDNA. Also, termination of pregnancy is riskier in the 2nd trimester than in the 1st trimester.

Second-trimester screening may also include

  • Targeted ultrasonography

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. Women who have been screened for fetal chromosome disorders by cfDNA should have serum screening with MSAFP alone, not with multiple marker screening.

Ultrasonography is the next step if further testing is warranted. 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 alpha-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 alpha-fetoprotein and acetylcholinesterase levels in amniotic fluid is done if further testing is needed. Elevated alpha-fetoprotein in amniotic fluid suggests

  • A neural tube defect

  • Another malformation (eg, omphalocele, congenital nephrosis, cystic hygroma, gastroschisis, upper GI atresia)

  • Contamination of the sample with fetal blood

Presence of acetylcholinesterase in amniotic fluid suggests

  • A neural tube defect

  • Another malformation

Elevated alpha-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 cfDNA or 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, alpha-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%.

Analysis of cfDNA does not depend on gestational age and thus is not prone to dating errors.

Targeted ultrasonography

Targeted ultrasonography is offered at some perinatal centers and is used to assess risk of 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:

  • High risk: Invasive testing is offered without doing 2nd-trimester screening.

  • Intermediate risk: 2nd-trimester screening is offered.

  • Low risk (eg, < 1 in 1500): 2nd-trimester screening for Down syndrome is not offered because the 1st-trimester risk is so low.

Patients with abnormal 1st-trimester, 2nd-trimester, or sequential screening may choose to pursue further testing for fetal trisomy with cfDNA (cell free DNA) analysis. Results of cfDNA testing may indicate low risk and be reassuring but are not definitive. Also, cfDNA testing may be inordinately expensive, and awaiting results of cfDNA testing delays definitive testing such as CVS or amniocentesis (1).


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* This is the Professional Version. *