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Prenatal screening for Down syndrome and trisomy 18
Prenatal screening for neural tube defects: (this is only applicable to Part 2 [second trimester] of the test)
-Part 2 (second trimester): alpha-fetoprotein
Maternal serum screening has historically been used in obstetric care to identify pregnancies that may have an increased risk for certain birth defects, such as Down syndrome and trisomy 18. Screening in the second trimester has been available in some version (eg, alpha fetoprotein [AFP] test, triple screen, quad screen) for decades. Screening in the first trimester became an established alternative over the last decade.
More recently, sequential screening, which has an improved detection rate as compared to either first- or second-trimester screening, has become a standard option. Sequential screening has a higher detection rate because information about a pregnancy is collected in both trimesters, which provides a greater opportunity for detecting problems.
Sequential Maternal Screening, Part 1, Serum involves an ultrasound and a blood draw. The ultrasound measurement is of the back of the fetal neck, where fluid tends to accumulate in babies who have chromosome conditions, heart conditions, and other health problems. This measurement, referred to as the nuchal translucency (NT), is difficult to perform accurately. Therefore, NT data is accepted only from NT-certified sonographers. Along with the NT measurement, a maternal serum specimen is drawn and 1 pregnancy-related marker is measured (pregnancy-associated plasma protein A: PAPP-A). The results of the ultrasound measurement and blood work are then entered with the maternal age and demographic information into a mathematical model that calculates Down syndrome and trisomy 18 risk estimates.
If the result from Part 1 indicates a risk for Down syndrome that is higher than the screen cutoff, the screen is completed and a report is issued. In that event, the patient is typically offered counseling and diagnostic testing (either chorionic villus sampling or amniocentesis). When the screen is completed after Sequential Maternal Screening Part 1, Serum, a neural tube defect (NTD) risk is not provided. For a stand-alone NTD-risk assessment, order MAFP / Alpha-Fetoprotein (AFP), Single Marker Screen, Maternal, Serum.
If the risk from the first trimester is below the established cutoff, an additional serum specimen is drawn in the second trimester for Sequential Maternal Screening, Part 2, Serum. Once that specimen is processed, information from both trimesters is combined and a report is issued. If results are positive, the patient is typically offered counseling and diagnostic testing (ie, amniocentesis).
AFP is a fetal protein that is initially produced in the fetal yolk sac and liver. A small amount also is produced by the gastrointestinal tract. By the end of the first trimester, nearly all of the AFP is produced by the fetal liver. The concentration of AFP peaks in fetal serum between 10 to 13 weeks. Fetal AFP diffuses across the placental barrier into the maternal circulation. A small amount also is transported from the amniotic cavity.
The AFP concentration in maternal serum rises throughout pregnancy, from a nonpregnancy level of 0.2 to about 250 ng/mL at 32-weeks gestation. If the fetus has an open neural tube defect (NTD), AFP is thought to leak directly into the amniotic fluid causing high concentrations of AFP. Subsequently, the AFP reaches the maternal circulation, thus producing elevated serum levels. Other fetal abnormalities such as omphalocele, gastroschisis, congenital renal disease, esophageal atresia, and other fetal-distress situations such as threatened abortion and fetal demise, also may show AFP elevations. Increased maternal serum AFP values also may be seen in multiple pregnancies and in unaffected singleton pregnancies in which the gestational age has been underestimated. Lower values have been associated with an increased risk for genetic conditions such as trisomy 21 (Down syndrome) and trisomy 18.
Unconjugated Estriol (uE3):
Estriol, the principal circulatory estrogen hormone in the blood during pregnancy, is synthesized by the intact feto-placental unit. Estriol exists in maternal blood as a mixture of the unconjugated form and a number of conjugates. The half-life of uE3 in the maternal blood system is 20 to 30 minutes because the maternal liver quickly conjugates estriol to make it more water soluble for urinary excretion. Estriol levels increase during the course of pregnancy. Decreased uE3 has been shown to be a marker for Down syndrome and trisomy 18. Low levels of estriol also have been associated with overestimation of gestation, pregnancy loss, Smith-Lemli-Opitz, and X-linked ichthyosis (placental sulfatase deficiency).
Human Chorionic Gonadotropin (hCG):
hCG is a glycoprotein consisting of 2 noncovalently bound subunits. The alpha subunit is identical to the alpha subunits of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH), while the beta subunit has significant homology to the beta subunit of LH and limited similarity to the FSH and TSH beta subunits. The beta subunit determines the unique physiological, biochemical, and immunological properties of hCG.
The CGA gene (glycoprotein hormones, alpha polypeptide) is thought to have developed through gene duplication from the LH gene in a limited number of mammalian species. hCG only plays an important physiological role in primates (including humans), where it is synthesized by placental cells, starting very early in pregnancy, and serves to maintain the corpus luteum and, hence, progesterone production, during the first trimester. Thereafter, the concentration of hCG begins to fall as the placenta begins to produce steroid hormones and the role of the corpus luteum in maintaining pregnancy diminishes.
Increased total beta hCG levels are associated with Down syndrome, while decreased levels may be seen in trisomy 18. Elevations of hCG also can be seen in multiple pregnancies, unaffected singleton pregnancies in which the gestational age has been overestimated, triploidy, fetal loss, and hydrops fetalis.
Inhibins are a family of heterodimeric glycoproteins that consist of disulfide-linked alpha and beta subunits, primarily secreted by ovarian granulosa cells and testicular Sertoli cells. While the alpha subunits are identical in all inhibins, the beta subunits exist in 2 major forms, termed A and B, each of which can occur in different isoforms. Depending on whether an inhibin heterodimer contains a beta-A or a beta-B chain, they are designated as inhibin A or inhibin B, respectively. Together with the related activins, which are homodimers or heterodimers of beta-A and beta-B chains, the inhibins are involved in gonadal-pituitary feedback and in paracrine regulation of germ cell growth and maturation. During pregnancy, inhibins and activins are produced by the feto-placental unit in increasing quantities, mirroring fetal growth. Their physiological role during pregnancy is uncertain. They are secreted into the coelomic and amniotic fluid, but only inhibin A is found in appreciable quantities in the maternal circulation during the first and second trimesters.
Maternal inhibin A levels are correlated with maternal hCG levels and are abnormal in the same conditions that are associated with abnormal hCG levels (eg, inhibin A levels are typically higher in Down syndrome pregnancies). However, despite their similar behavior, measuring maternal serum inhibin A concentrations in addition to maternal serum hCG concentrations further improves the sensitivity and specificity of maternal multiple marker screening for Down syndrome.
An interpretive report will be provided. See Interpretation section for more details.
Maternal screens provide an estimation of risk, not a diagnosis. A negative result indicates that the estimated risk falls below the screen cutoff. A positive result indicates that the estimated risk exceeds the screen cutoff.
Neural Tube Defect (NTD):
Screen-negative results indicate that the alpha-fetoprotein (AFP) multiple of the median (MoM) falls below the screen cutoff of 2.50 MoM (5.33 MoM for twins). A negative screen does not guarantee the absence of an NTD.
Screen-positive results indicate that the calculated AFP MoM is > or =2.50 MoM (5.33 MoM for twins). Positive results may indicate an increased risk for an open NTD. The actual risk depends on the level of AFP and the individual's pretest risk of having a child with an NTD based on variables including family history, geographical location, maternal conditions such as diabetes and epilepsy, and use of folate prior to conception. A screen-positive result does not infer a definitive diagnosis of a NTD, but indicates that further evaluation should be considered. Approximately 80% of pregnancies affected with open NTDs have AFP MoM values >2.5.
Sequential Maternal Screening, Part 2, Serum results are negative when the calculated risk is below 1/270 (0.37%). Negative results mean that the risk is less than the established cutoff; they do not guarantee the absence of Down syndrome.
Results are positive when the risk is greater than the established cutoff (> or =1/270 in Sequential Maternal Screening, Part 2, Serum). Positive results are not diagnostic.
When both Sequential Maternal Screening Part 1 and Part 2 are performed with a screen cutoff of 1/270, the combination of maternal age, nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A), AFP, unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A has an overall detection rate of approximately 90% with a false-positive rate of approximately 3% to 4%. In practice, both the detection rate and false-positive rate vary with maternal age.
In Part 2, the screen cutoff for trisomy 18 is 1 in 100 (1%). Risks that are > or =1% are screen-positive; positive results are not diagnostic. Risks <1% are screen-negative; negative results do not guarantee the absence of trisomy 18.
Use caution when revising positive results with earlier dating. Babies with trisomy 18 tend to be small, which can lead to underestimation of gestational age and an increased risk of missing a true-positive.
When both Sequential Maternal Screening Part 1 and Part 2 of sequential screening are performed with a screen cutoff of 1/100, the combination of maternal age, PAPP-A, AFP, uE3, and hCG, has an overall detection rate of approximately 90% with a false-positive rate of approximately 0.1%.
Verify that all information used in the risk calculation is correct (maternal date of birth, gestational dating, etc). If any information is erroneous, contact the laboratory for a revision.
Screen-negative results typically do not warrant further evaluation.
If the results are positive, the patient is typically offered counseling, ultrasound, diagnostic testing, and, possibly, a referral to genetics counseling or a high-risk clinic.
Nuchal translucency (NT) measurements must be obtained from NT-certified sonographers. NT-measurement quality indicators will be monitored on a regular basis. Sonographers will be contacted if there is ongoing deviation in the quality indicators.
Incorrect or incomplete information may significantly alter results.
A negative screen does not guarantee the absence of fetal defects.
A positive screen does not provide a diagnosis, but indicates that diagnostic testing should be considered (an unaffected fetus may have a screen-positive result for unknown reasons).
The use of these markers to screen for Down syndrome or trisomy 18 is not an approved FDA procedure.
Maternal serum alpha-fetoprotein (AFP) should not be measured after amniocentesis because maternal-fetal transfusion may occur, which would falsely increase the serum AFP.
In twin pregnancies, the risk for Down syndrome is approximated, using twin-adjusted medians. A specific risk for trisomy 18 cannot be calculated. In cases where one twin has demised, results may be unreliable.
Results are not available for triplets or higher-multiple pregnancies.
Each center offering maternal serum screening to patients should establish a standard screening protocol, which provides pre- and post-screening education and appropriate follow-up for screen-positive results.
1. Malone FD, Canick JA, Ball RH, et al: First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005 Nov 10;353(19):2001-2011
2. Screening for fetal chromosomal abnormalities. ACOG Practice Bulletin No. 77. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:217-227
3. Wald NJ, Rodeck C, Hackshaw AK, et al: SURUSS in Perspective. Semin Perinatol 2005;29:225-235
4. Palomaki GE, Steinort K, Knight GJ, et al: Comparing three screening strategies for combining first- and second-trimester Down syndrome markers. Obstet Gynecol 2006 Feb;107(2 Pt 1): 367-375
5. Palomaki GE, Neveux LM, Knight GJ, et al: Maternal serum-integrated screening for trisomy 18 using both first- and second-trimester markers. Prenat Diagn 2003 Mar;23(3):243-247