Maternal serum screening can be performed to identify individuals who need further diagnostic evaluation for fetal anomalies such as neural tube defects (NTDs), trisomy 21/Down syndrome, and trisomy 18. NTDs result from failure of fusion of the neural plate and failure of complete covering by the 27th day post conception. The extent and location of neural tissue exposed indicates the severity of the defect (ie, anencephaly, meningomyelocele, and encephalocele). The result of a NTD is a direct communication of the amniotic fluid with fetal plasma proteins, and release of alpha-fetoprotein (AFP) into amniotic fluid and maternal serum. Rates of NTDs have decreased due to the addition of folic acid to grain, as well as initiation of recommendations for folic acid supplementation prior to conception. Trisomy 21 or Down syndrome is caused by an extra copy of chromosome 21 and is the most frequent chromosomal disorder among live-born children (1/600 to 1/800 live births). Risk factors for Down syndrome include advanced maternal age, the birth of a previously affected child, and balanced parental structural rearrangement of chromosome 21. Affected children suffer from mental retardation, hypotonia, congenital heart defects, and a flat facial profile. The main phenotypic features of trisomy 18 include hypertonia, prominent occiput, small mouth, micrognathia, short sternum, and horseshoe kidney.
Maternal serum screening can be performed to identify individuals who need further diagnostic evaluation for fetal anomalies such as neural tube defects (NTDs), trisomy 21/Down syndrome, and trisomy 18.
An additional discussion of maternal screening for Down syndrome is found in Chapter 7.
Screening for NTDs is done at 15 to 22 weeks gestation by measurement of serum AFP that is expressed as a multiple of the median population (MoM). MoMs greater than 2 or 2.5 are considered abnormal and should be followed up by high-resolution ultrasound or measurement of amniotic fluid AFP and acetylcholinesterase.
Sequential serum screening is performed to screen for trisomies and combines first- and second-trimester testing. First-trimester testing is performed between 10 and 14 weeks and includes measurement of hCG and pregnancy-associated plasma protein-A (PAPP-A) as well as an ultrasound measurement for infant nuchal translucency (NT). Specific training is required of operators for determination of NT. This procedure is highly operator dependent. Free beta hCG testing is more accurate than intact hCG testing in the first trimester and is used instead of intact hCG for the first-trimester screen. PAPA-A is a protein produced by the placenta. Elevated hCG, decreased PAPP-A, and increased NT are seen in pregnancies affected by trisomy 21.
In the sequential screen, first-trimester screening is followed up with second-trimester screening at 15 to 22 weeks, with measurement of serum AFP, hCG, estriol, and inhibin A (ie, the quad screen). AFP is the most abundant serum protein in the fetal circulation. Maternal serum AFP is detectable at 10 weeks and peaks at 15 to 20 weeks. Estriol is the predominant estrogen of pregnancy and also the most difficult to measure because of low concentration and limited stability. Inhibin A, secreted by the ovaries and placenta, is a glycoprotein that inhibits FSH. Concentrations of individual analytes from the first- and second-trimester screens and NT measurements are combined into a risk assessment algorithm that adjusts for gestational age, maternal weight, number of fetuses, and presence or absence of diabetes mellitus. The most frequent causes of abnormal results include incorrect dating, the presence of twins, and fetal demise. For this reason, an ultrasound confirming gestational age is the first line of testing in a patient with apparently increased risk. Fetal karyotyping is necessary to confirm chromosomal abnormalities.
Second trimester-only testing can be done and should utilize the quad screen. Elevated hCG, increased inhibin A, decreased estriol, and decreased AFP are seen in pregnancies affected by trisomy 21, while all 4 analytes in the quad screen are decreased in pregnancies affected by trisomy 18. Patients at risk should undergo further diagnostic evaluation as described with sequential screen.
Recently, new methods have been developed for trisomy 21 screening using circulating fetal DNA. These methods utilize “massively parallel genomic sequencing” (MPGS). DNA fragments are isolated from a sample of maternal blood, which contains a mixture of maternal DNA and infant DNA. The DNA fragments are amplified and then sequenced. The number of sequences that originate from a particular chromosome is counted and tabulated for each chromosome. If a fetus has an extra chromosome, then the percentage of DNA fragments from that chromosome is higher than expected. These tests have been shown to have excellent detection rates (~99%) with very low false-positive rates (~0.2%). Currently, MPGS is only validated for the detection of Down syndrome and not other fetal aneuploidies such as trisomy 18 or trisomy 13. The test does have the capability of detecting these disorders and, if they are detected, the results are reported. However, because the test has not been thoroughly investigated for detecting trisomy 18 or trisomy 13, a negative result does not rule out their presence. Also, the test does not detect open NTDs (eg, spina bifida), for which screening usually involves biochemical (not genetic) screening tests.
The American College of Obstetricians and Gynecologists (ACOG) cautions that these tests are screening tests, not diagnostic tests. They also recommend that DNA-based screening tests be performed only on women who are at increased risk of having a fetus with aneuploidy, including women with: maternal age 35 years or older at delivery, fetal ultrasound findings suggesting aneuploidy, a previous aneuploid pregnancy, or abnormal biochemical screening test results.