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 Spina Bifida Spina bifida is defective closure of the vertebral column. Although the cause is often unknown, low folate levels during pregnancy increase risk. Some children are asymptomatic, and others have... read more ). Even if neither of these possibilities is anticipated, some women prefer to know of fetal abnormalities before birth.
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 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 An oral-facial cleft is a birth defect in which the lip, the roof of the mouth, or both do not close in the midline and remain open, creating a cleft lip and/or cleft palate. These defects are... 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:
Renal malformations (eg, renal agenesis Renal agenesis The urinary tract is a common location for congenital anomalies of varying significance. Many anomalies are asymptomatic and diagnosed via prenatal ultrasonography or part of a routine evaluation... read more [Potter syndrome], polycystic kidney disease Autosomal Dominant Polycystic Kidney Disease (ADPKD) Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more )
Lethal forms of short-limbed skeletal dysplasias (eg, thanatophoric skeletal dysplasia, achondrogenesis)
Gut malformations (eg, obstruction)
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 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 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 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.
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 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... 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 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... 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.
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 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)
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. For assisted reproductive techniques, oocytes and sperm... 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: 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 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 references 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... read more ). In a large multicenter randomized trial, ongoing pregnancy rates using frozen-thawed single embryo transfer after PGT-A or after morphologic evaluation did not differ significantly (2 Preimplantation genetic testing references 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... read more ).
Preimplantation genetic testing references
1. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology: The use of preimplantation genetic testing for aneuploidy (PGT-A): A committee opinion. Fertil Steril 109 (3):429–436, 2018. doi: 10.1016/j.fertnstert.2018.01.002
2. Munné S, Kaplan B, Frattarelli JL, et al: Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: A multicenter randomized clinical trial. Fertil Steril 112 (6):1071–1079.e7, 2019. doi: 10.1016/j.fertnstert.2019.07.1346