Genetic Evaluation

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 Overview of Congenital Cardiovascular Anomalies Congenital heart disease is the most common congenital anomaly, occurring in almost 1% of live births ( 1). Among birth defects, congenital heart disease is the leading cause of infant mortality... read more , cleft lip and palate Cleft Lip and Cleft Palate Cleft lip, cleft lip and palate, and isolated cleft palate, are collectively termed oral clefts (OCs). OCs are the most common congenital anomalies of the head and the neck with a total prevalence... read more , pyloric stenosis Hypertrophic Pyloric Stenosis Hypertrophic pyloric stenosis is obstruction of the pyloric lumen due to pyloric muscular hypertrophy. Diagnosis is by abdominal ultrasonography. Treatment is surgical. Hypertrophic pyloric... read more ), particularly one that may be treated effectively before birth (eg, posterior urethral valves with megacystis) or at delivery (eg, diaphragmatic hernia Diaphragmatic Hernia Diaphragmatic hernia is protrusion of abdominal contents into the thorax through a defect in the diaphragm. Lung compression may cause persistent pulmonary hypertension. Diagnosis is by chest... read more ). 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 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 Erythroblastosis fetalis is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal red blood cells.... read more .

Amniocentesis has traditionally been offered to pregnant women > 35 because their risk of having an infant with Down syndrome Down Syndrome (Trisomy 21) Down syndrome is an anomaly of chromosome 21 that can cause intellectual disability, microcephaly, short stature, and characteristic facies. Diagnosis is suggested by physical anomalies and... read more 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 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 (clubbed feet) and is rarely done.

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 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... read more and has similar accuracy. However, CVS is done between 10 weeks 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 weeks to assess risk of fetal neural tube defects Maternal serum screening for neural tube defects 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... read more .

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.

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 weeks gestation by an experienced operator.

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 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 hours, and PUBS is rarely done for genetic indications.

Procedure-related fetal loss rate with PUBS is about 1%.

Preimplantation genetic testing (PGT) is sometimes possible before implantation when in vitro fertilization In vitro fertilization (IVF) Assisted reproductive techniques (ARTs) involve manipulation of sperm and ova or embryos in vitro with the goal of producing a pregnancy. ARTs may result in multifetal pregnancy, but risk is... read more 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 is used primarily for couples 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 ) in the fetus is high. PGT-A or PGT-SR is used for couples when chromosomal abnormalities in the fetus is a risk.

PGT-A is used primarily for embryos from older women, but routine use is controversial ( 1 Preimplantation genetic testing reference 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... read more ).

Traditionally, 1st-trimester combined screening includes measurement of

Fetal Down syndrome is typically associated with high levels of beta-hCG, low levels of PAPP-A, and enlarged fetal nuchal translucency. Although enlarged nuchal translucency is associated with increased risk of fetal Down syndrome Down Syndrome (Trisomy 21) Down syndrome is an anomaly of chromosome 21 that can cause intellectual disability, microcephaly, short stature, and characteristic facies. Diagnosis is suggested by physical anomalies and... read more , no threshold value for nuchal translucency 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 nuchal translucency 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.

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

Second-trimester multiple marker screening is used to help assess the risk of Down syndrome, trisomy 18 Trisomy 18 Trisomy 18 is caused by an extra chromosome 18 and is usually associated with intellectual disability, small birth size, and various congenital anomalies, including severe microcephaly, heart... read more , 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

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:

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 chorionic villus sampling or amniocentesis ( 1 Sequential 1st- and 2nd trimester screening reference 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... read more ).