Maternal Serum Alpha-fetoprotein Screening Research Articles

A-321 Rethinking the Role of Race in Prenatal AFP Screening for Open Neural Tube Defects

Abstract Background The quantification of alpha-fetoprotein (AFP) in maternal serum is commonly used in prenatal screening to estimate the risk of fetal open neural tube defects (ONTDs). This involves comparing a patient’s measured AFP concentration to the median AFP for women of similar gestational age and weight, reported in AFP multiples of the median (MoM). Current guidelines recommend establishing population medians separately grouped by patients’ race, based on historical reports documenting differences in median AFP concentrations across different populations. We aimed to reevaluate this practice of race based ONTD risk stratification given the limited and questionable historical evidence as well as the small observed differences in AFP concentrations in our practice and in a recent report. Methods We collected maternal serum AFP screening data for patients between 12/30/19 and 2/9/24. Informed by the statistical methods used for clinical risk stratification, we developed two log-linear multiple variable regression models for estimating AFP: gestational age (GA), weight, and interaction terms (Model 1) and Model 1 predictors, race, and interaction terms (Model 2). AFP MoMs were calculated by dividing the measured AFP concentration by the model-estimated AFP. Results We analyzed maternal ONTD screening for 7,702 patients with singleton pregnancies. The current clinical process uses race and ethnicity as documented in the electronic health record, which was categorized as Black (N = 2,360), White (N = 3,734), Hispanic (N = 209), Asian (N = 641), and Other (N = 758). The addition of race in Model 2 included statistically significant predictors (p < 0.001) for Black (β = 0.2), Asian (β = 0.05), and Black:weight interaction (β = -5.9 x 10-4). Between Model 1 and Model 2, the mean change in AFP MoMs was -0.05, +0.03, 0.0, -0.02, and +0.01 for Black, White, Hispanic, Asian, and Other patients, respectively. 95% of Black patients had a change < 0.12 in AFP MoM and > 99% of all other patients had a change < 0.1. Using the clinical interpretative threshold, 56 (0.7%) results were considered elevated in both models, 4 (0.05%) elevated in Model 1 only (3 Black, 1 Other), and 4 (0.05%) elevated in Model 2 only (3 White, 1 Hispanic). Chart review of the 8 discordant interpretations showed small changes in MoMs (mean absolute difference = 0.09) and no cases of ONTDs. Conclusions In our health system’s population, maternal race appears to have a small statistically significant association with maternal AFP concentration, even after adjustment for weight and maternal GA. However, preliminary analyses indicate that this difference has a small impact on the clinical interpretation of these studies, with most patients classified similarly when race is not accounted for in the calculation. Further investigation is needed to clarify whether this small impact on estimation of risk warrants the continued inclusion of race in NTD screening, as well as whether other clinical, social, or community factors available for inclusion in this clinical risk stratification model would be better predictors than the poorly defined and discriminatory concept of race.

Limited Role of MSAFP Screening for Prenatal Omphalocele Detection.

Although serum screening for aneuploidies has become less prevalent, maternal-serum alpha-fetoprotein (MSAFP) screening for body-wall defects remains widespread. We explored whether MSAFP screening is associated with earlier omphalocele detection than ultrasound alone. This is a retrospective cohort study of prenatally detected omphalocele cases at our center from 2007 to 2023. We explored the association between MSAFP screening, gestational age at omphalocele detection, and clinical outcomes. Among 101 pregnancies with prenatally diagnosed omphalocele, 27 (26.7%) had MSAFP screening. The median gestational age at MSAFP screening was 17 weeks 4 days. Of those who received MSAFP screening, 11 (41%) had values ≥2.5 multiples of the median (MoM) and 16 (59%) were not elevated. MSAFP results did not correlate with omphalocele size and were not associated with prenatal or postnatal outcomes. MSAFP screening did not result in earlier suspicion for or confirmation of omphalocele (P = .97 and P = .87, respectively). In contrast, first-trimester ultrasound screening was associated with earlier suspicion for and confirmation of omphalocele (P < .01 and P = .01, respectively). There were no clinical or demographic differences between those who received MSAFP screening and those who did not (including body mass index or commute distance to an urban center). MSAFP screening is not associated with earlier omphalocele detection. Furthermore, in pregnancies with prenatally diagnosed omphalocele, the results of MSAFP screening are not predictive of clinical outcomes.

Reconsidering Race Adjustment in Prenatal Alpha-Fetoprotein Screening.

Black racial designation is the only race for which adjustment is recommended for maternal prenatal serum alpha-fetoprotein (AFP) screening. The objective of this study is to reevaluate the relationship between maternal race and maternal serum AFP values in prenatal analyte screening. This was a single-center retrospective analysis of patients who underwent prenatal analyte screening between January 2007 and December 2020. Nomograms for raw maternal serum AFP values by gestational age were created and compared between patients identified as "Black" and "non-Black" on the laboratory requisition. Multivariable linear regression models were created to evaluate the relationship among gestational age, maternal weight, and maternal race on maternal serum AFP levels. The new models were compared with the laboratory-derived calculations, which used historically determined race adjustments. A total of 43,997 patients underwent analyte screening, and 27,710 patients had complete data for analysis. Of these, 6% were identified as Black. Black patients had laboratory blood draws at a mean gestational age of 123 days, compared with 120 days in non-Black patients ( P <.001), and had higher maternal weight (mean 170 vs 161 lbs, P <.001). Nomograms for raw maternal serum AFP values did not differ between Black and non-Black patients ( P =.065). When adjusted for gestational age and maternal weight, no difference in maternal serum AFP values was identified between Black and non-Black individuals ( P =.81). No difference in maternal serum AFP values was identified between Black and non-Black pregnant individuals when adjusted by maternal weight and gestational age at blood draw. These findings suggest that routine race-based adjustment of maternal serum AFP screening should be discontinued.

The clinical value of serum alpha-fetoprotein

Alpha fetoprotein (AFP) is a major fetal serum globulin structurally and functionally related to albumin. During fetal development, AFP is produced sequentially by the fetal yolk sac, gastrointestinal tract, and liver. Thus normal production of AFP is unique to fetal development, making it an ideal marker for early fetal evaluation. Since its introduction into obstetric practice, maternal serum alpha-fetoprotein (MSAFP) screening has become the earliest non-invasive biochemical test to provide information regarding the fetus, thereby promoting access to earlier diagnosis, enabling families to make informed reproductive choices, and designing appropriate strategies for prenatal care and delivery. Normally, fetal AFP concentration levels continue to decrease through infantile stage (0 to 2 years), down to adult levels (0 – 8ng/ml). However, AFP is frequently re-expressed in patients affected by hepatocellular carcinoma (HCC) and yolk-sac tumors (YST) therefore used in clinical practice as a tumor marker. To improve the specificity of AFP, glycoforms of AFP are determined and used in the differential/early diagnosis, follow up of treatment and prognostication of patients with AFP secreting tumors. Alpha-fetoprotein is also used as a biochemical diagnostic and prognostic marker for prolonged jaundice in newborns.

Impact on spina bifida screening of shifting prenatal Down syndrome maternal serum screening from the second trimester to the first.

Shifting screening for trisomy 21 to the first trimester has resulted in the loss of maternal serum alpha-fetoprotein screening for spina bifida. The aim of this study was to study the impact on open spina bifida prenatal screening. We reviewed prenatally diagnosed cases of spina bifida over three years: 2009 (only second-trimester screening, MSM2T), 2010 (transient period) and 2011 (majority first-trimester screening, MSM1T). Cases were assigned to three groups based on maternal serum markers (MSM2T, MSM1T and 'not performed'). Gestational age at diagnosis of spina bifida was compared between these three groups and between the years 2009 and 2011. Median gestational ages at diagnosis of the 742 spina bifida cases between the three groups were 22weeks [18+6 -23], 22+1 weeks [21+3 -23] and 21+4 weeks [14+1 -23], respectively (P<0.005). The diagnosis was made at 14-20weeks in 34.7% for MSM2T group versus 8.5% for MSM1T (P<0.001). Spina bifida diagnosis at 14-20weeks declined from 38.8% in 2009 to 13.3% in 2011 (P<0.001). Loss of maternal serum alpha-fetoprotein had a tangible effect on the gestational age at diagnosis of spina bifida and resulted in a decrease of 25% of cases of spina bifida detected before 20weeks. © 2017 John Wiley & Sons, Ltd.

Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy.

Noninvasive prenatal screening that uses cell-free DNA from the plasma of pregnant women offers tremendous potential as a screening method for fetal aneuploidy. A number of laboratories have validated different techniques for the use of cell-free DNA as a screening test for fetal aneuploidy. All tests have a high sensitivity and specificity for trisomy 18 and trisomy 21, regardless of which molecular technique is used. Women whose results are not reported, indeterminate, or uninterpretable (a "no call" test result) from cell-free DNA screening should receive further genetic counseling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy. Patients should be counseled that cell-free DNA screening does not replace the precision obtained with diagnostic tests, such as chorionic villus sampling or amniocentesis and, therefore, is limited in its ability to identify all chromosome abnormalities. Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects. Patients who are undergoing cell-free DNA screening should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment. The cell-free DNA screening test should not be considered in isolation from other clinical findings and test results. Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone. Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy. Given the performance of conventional screening methods, the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population.

Committee Opinion Summary No. 640: Cell-Free DNA Screening For Fetal Aneuploidy.

Noninvasive prenatal screening that uses cell-free DNA from the plasma of pregnant women offers tremendous potential as a screening method for fetal aneuploidy. A number of laboratories have validated different techniques for the use of cell-free DNA as a screening test for fetal aneuploidy. All tests have a high sensitivity and specificity for trisomy 18 and trisomy 21, regardless of which molecular technique is used. Women whose results are not reported, indeterminate, or uninterpretable (a "no call" test result) from cell-free DNA screening should receive further genetic counseling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy. Patients should be counseled that cell-free DNA screening does not replace the precision obtained with diagnostic tests, such as chorionic villus sampling or amniocentesis and, therefore, is limited in its ability to identify all chromosome abnormalities. Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects. Patients who are undergoing cell-free DNA screening should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment. The cell-free DNA screening test should not be considered in isolation from other clinical findings and test results. Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone. Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy. Given the performance of conventional screening methods, the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population.

Committee Opinion No. 640

Noninvasive prenatal screening that uses cell-free DNA from the plasma of pregnant women offers tremendous potential as a screening method for fetal aneuploidy. A number of laboratories have validated different techniques for the use of cell-free DNA as a screening test for fetal aneuploidy. All tests have a high sensitivity and specificity for trisomy 18 and trisomy 21, regardless of which molecular technique is used. Women whose results are not reported, indeterminate, or uninterpretable (a “no call” test result) from cell-free DNA screening should receive further genetic counseling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy. Patients should be counseled that cell-free DNA screening does not replace the precision obtained with diagnostic tests, such as chorionic villus sampling or amniocentesis and, therefore, is limited in its ability to identify all chromosome abnormalities. Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects. Patients who are undergoing cell-free DNA screening should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment. The cell-free DNA screening test should not be considered in isolation from other clinical findings and test results. Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone. Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy. Given the performance of conventional screening methods, the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population.

Committee Opinion No. 640

Noninvasive prenatal screening that uses cell-free DNA from the plasma of pregnant women offers tremendous potential as a screening method for fetal aneuploidy. A number of laboratories have validated different techniques for the use of cell-free DNA as a screening test for fetal aneuploidy. All tests have a high sensitivity and specificity for trisomy 18 and trisomy 21, regardless of which molecular technique is used. Women whose results are not reported, indeterminate, or uninterpretable (a "no call" test result) from cell-free DNA screening should receive further genetic counseling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy. Patients should be counseled that cell-free DNA screening does not replace the precision obtained with diagnostic tests, such as chorionic villus sampling or amniocentesis and, therefore, is limited in its ability to identify all chromosome abnormalities. Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects. Patients who are undergoing cell-free DNA screening should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment. The cell-free DNA screening test should not be considered in isolation from other clinical findings and test results. Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone. Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy. Given the performance of conventional screening methods, the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population.

The effectiveness of prenatal serum biomarker screening for neural tube defects in second trimester pregnant women: a meta‐analysis

Neural tube defects (NTDs) are common and serious birth defects all over the world. Prenatal screening for NTDs using maternal serum alpha-fetoprotein (MSAFP) during the second trimester of pregnancy has been widely used, but its effectiveness remains unclear. We evaluated the studies published in the English and Chinese on MSAFP screening for NTDs. The homogeneity of the studies was evaluated by the forest graph. Meta-analysis was applied to calculate the combined effect values and their 95% confidence intervals. As many as 22 articles were selected according to the criteria and were included in the meta-analysis, for a total of 684,140 pregnant women screened during the second trimester. All the studies selected were homogenous according to the forest graph (chi(2) = 25.17, P > 0.10). The combined relative risk estimate was 0.25 and its 95% confidence interval was 0.21 to 0.29. The combined protective rate was 75%. The sensitivity and specificity of MSAFP screening were 75.1 and 97.7%, respectively. Use of MSAFP during the second trimester in pregnant women is an effective measure for the screening of NTDs.

Twin Pregnancy with Gastroschisis in Both Twins

Gastroschisis is a congenital malformation characterized by an abdominal wall defect located laterally to a normal umbilicus. The cause of gastroschisis is unknown, but most authors consider it exogenous. We describe the case of a woman with a twin pregnancy in which both twins had gastroschisis. A 17-year-old primiparous female was referred to our institution because of a twin pregnancy, with one twin diagnosed with gastroschisis at 34 weeks of gestation. Unfortunately, gastroschisis was noted in both twins, but no other anomalies were observed under level II sonographic evaluation. The twins were delivered by cesarean section at 36+ weeks of gestation because of preterm labor and breech presentation of one fetus. Both twins presented with a 3-cm abdominal wall defect located to the right side of the umbilicus and a large portion of the bowel protruding that was not covered by membrane. Histopathology of the placenta revealed that the twins were diamniotic monochorionic. Chromosomal analysis of cord blood showed normal karyotype (46,XX) in both newborns. The cause of gastroschisis is unknown, although possible exogenous causes have been studied. The diagnosis of gastroschisis in twin pregnancy is always in late gestation. Therefore, maternal serum alpha fetoprotein screening and a detailed prenatal ultrasound evaluation are recommended in multifetal pregnancies.

Screening for neural tube defects.

The birth prevalence of neural tube defects fell by 95% in England and Wales between 1970 and 1990 largely as a result of antenatal screening, subsequent diagnosis and selective abortion of affected pregnancies. Anencephaly can be diagnosed using ultrasound, whereas both amniotic fluid biochemistry and ultrasound are required for the diagnosis of spina bifida. Both methods have a false-positive rate of about two per 1000 when carried out in high-risk pregnancies. The diagnostic results are likely to be better if the two methods are used in parallel. Maternal serum alpha-fetoprotein screening at 16-18 weeks gestation can detect about 75% of pregnancies affected by spina bifida. Routine ultrasound anomaly screening, usually performed at 18-20 weeks gestation, can detect a similar proportion. New developments indicate that earlier, more accurate detection may be possible but more research will be needed before this can be established.

Neural tube defects in the sample of genetic counselling

This study was conducted to evaluate the major demographic details, diagnostical and clinical features, as well as the risk of recurrence of cases with the major types of neural tube defects (NTD). We also examined the efficiency of ultrasonography based on autopsy examinations during 26 years. The investigations were made into the sample of 743 NTD diagnosed between 1 January 1976 and 31 December 2002. A computerized database was used to sum up the available information about the individual cases; in addition to surveying the couples' major demographic details, we also had the opportunity to collect detailed information about the history, diagnostics (ultrasound) and outcome of the pregnancies as well as the results of the autopsies during the investigation. In the 743 cases of NTD, maternal and paternal median ages turned out to be 23.7 years (+/-5.22 years) and 28.7 years (+/-5.81 years), respectively. The male:female ratio was 0.78. Comparable samples of anencephaly and spina bifida allowed for the conclusion that a positive genetic history was equally often found while a positive obstetrical history was almost twice as common in anencephaly. The sensitivity of the maternal serum-alpha fetoprotein (AFP) screening test is the highest in anencephaly and lowest in encephalocele. While the majority of cases of anencephaly were diagnosed before the 24th gestational week, examples of diagnosing spina bifida and encephalocele at a later time could also be found. Among the associated malformations other than those of the central nervous system special mentioning should be made of fetal pyelectasia, cleft palate as well as diaphragmatic herniation. No pathological karyotypes were found in association with encephalocele or spina bifida, but anencephaly was accompanied with trisomy 21 and trisomy 18 in one case each. Anencephaly was found to have the highest risk of recurrence in both nervous system malformations and malformations other than those of the nervous system. Sonography proved to be the most reliable method in cases of enecephalocele. The respective median values of maternal and paternal age show that aetas has no role in the occurrence of NTDs. NTDs are more common among girls. Positive genetic, obstetrical and medical findings are of great importance in the incidence of NTDs. Although reliable to only a limited extent, maternal serum-AFP tests are considered to be useful and necessary in screening NTDs, while sonography is the gold standard method in recognizing these frequent malformations. The knowledge of the eventual associated malformations is mainly important in certain cases of spina bifida, which may also yield a good post-natal prognosis. Our data obtained from the sample of 26 years also confirm that the periconceptional administration of folic acid reduces the incidence and risk of recurrence of NTDs.

Maternal Serum Alpha-Fetoprotein Level during Pregnancy and Isolated Cryptorchidism in Male Offspring

Cryptorchidism is thought to result from a disruption of the androgen-estrogen balance in utero. Alpha-fetoprotein (AFP) interacts with and may modulate fetal responses to estrogens. Using a cohort of boys born to women participating in a Danish maternal serum AFP screening program between 1980 and 1994, the authors explored whether AFP levels (as reflected by maternal serum AFP levels in gestational weeks 14-22) were associated with the risk of isolated cryptorchidism in male offspring. Cryptorchidism diagnoses and covariate information were obtained from Denmark's national health registries. Risk ratios for cryptorchidism by maternal serum AFP multiples of the median were estimated by use of log-linear binomial regression. Of 25,418 boys, 663 (2.6%) were diagnosed with cryptorchidism. After adjustment for confounders, boys with maternal serum AFP levels greater than or equal to 2.5 times the median had a 63% (95% confidence interval: -2, 172) greater risk of cryptorchidism than did boys with maternal serum AFP levels within 25% of the median. High fetal AFP levels may contribute directly to events producing cryptorchidism; alternatively, elevated maternal serum AFP levels may reflect placental dysfunction, some aspect of which contributes to cryptorchidism.

1123: Prenatal diagnosis of ventral wall defects

Ventral wall defects are a common group of fetal anomalies and a wide variety of ventral wall defects are diagnosed. And there are various options for perinatal management of fetal ventral wall defects, which range from termination of pregnancy to normal term delivery with postnatal surgery, depending on the type and severity of the lesion and probability of associated structural and chromosomal abnormalities. The routine fetal ultrasonography with widespread use of maternal serum alpha fetoprotein (AFP) screening allows the majority of ventral wall defects to be identified prenatally. But confusion arises when the ventral wall defect is complex or has other associated abnormalities. The accurate prenatal diagnosis of ventral wall defects is important because it affects patient management and prognosis. This lecture reviews the characteristic sonographic findings with possible pathological correlation, the associated structural and/or chromosomal abnormalities and outcome of simple and complicated types of ventral wall defects, which were diagnosed on our hospital over a 10-y period.

Recovery of Genomic DNA from Residual Frozen Archival Blood Clots Suitable for Amplification and Use in Genotyping Assays

A greatly neglected source of DNA potentially useful for genetic or forensic studies is the clot remaining from blood samples collected for serum chemistry measurements. We have investigated the utility of residual clots remaining from venipunctures collected for California's Expanded Maternal Serum Alpha-Fetoprotein Screening Program. We report a protocol based on the salting out method for the extraction of DNA from samples which have been archived and frozen for up to 2.5 years. As much as 57 microg of high-quality DNA can be obtained from a 2-ml clot as determined by PicoGreen (Molecular Probes, Inc., Eugene, OR) fluorescence measurements. Quality of the purified DNA was evaluated by its ability to serve as template in polymerase chain reaction (PCR) amplifications, using primers that flank the polymorphic regions of six genes of pharmacogenetic interest distributed throughout the human genome. Sizes of the gene regions successfully amplified range from 215 bp to 2064 bp, using as little as 10 ng of template DNA. Because many genotyping protocols routinely recommend the design of amplicons in the 100-200 bp range, and 10-50 ng of template, we conclude that the clot remaining after serum has been removed from blood collected for serum chemistry measurements can serve as a reliable source of DNA for genotyping studies.

Routine Ultrasonography Compared With Maternal Serum Alpha-fetoprotein for Neural Tube Defect Screening

This study was done to estimate the value of prenatal maternal serum alpha-fetoprotein (MSAFP) screening compared with that of routine ultrasonography in the diagnosis of neural tube defects (NTDs). An integrated database was used retrospectively to identify cases of NTDs among 219,000 consecutive pregnancy outcomes observed during a 7-year period at 40 Kaiser Permanente facilities in Northern California. We specifically examined types of NTD and the tests used to diagnose cases. We identified 189 NTD cases, 102 of which had received MSAFP screening. Results of MSAFP testing were negative in 25 (25%) of these 102 cases. Without other testing, these 25 NTD diagnoses would have been missed. These included 15 (38%) of the 40 spina bifida cases screened, 6 (67%) of the 9 encephalocele cases screened, and 4 (8%) of the 53 anencephaly cases screened. Of the 186 NTD cases diagnosed prenatally, 115 (62%) were initially detected by routine ultrasonography administered during the second trimester without knowledge of MSAFP values; 69 (37%) were diagnosed by targeted ultrasonography after MSAFP screening indicated a higher risk for NTD; and 2 (1%) were diagnosed by pathology examination after miscarriage. Compared with MSAFP performed alone for screening, routine second-trimester ultrasonography was more likely to discover an NTD.

Technical standards and guidelines: Prenatal screening for open neural tube defects: This new section on “Prenatal Screening for Open Neural Tube Defects,” together with the new section on “Prenatal Screening for Down Syndrome,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories

Technical standards and guidelines: Prenatal screening for open neural tube defects: This new section on “Prenatal Screening for Open Neural Tube Defects,” together with the new section on “Prenatal Screening for Down Syndrome,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories *

Ultrasound screening of fetuses at increased risk for Down syndrome: how many missed diagnoses?

To determine the number of Down syndrome (DS) fetuses identified, amniocenteses performed, and procedure-related losses incurred when second-trimester ultrasound is used to screen high-risk patients in order to determine who should undergo an amniocentesis. A decision analytic model was designed for women at increased risk for a DS fetus due to either advanced maternal age (AMA) or a positive expanded maternal serum alpha fetoprotein (MSAFP) screening test, also known as a triple screen (+triple) test. The model compared: (1) the current standard of offering all at-risk women amniocentesis to (2) a policy of performing amniocentesis only when sonographic markers of DS are seen on ultrasound. Baseline assumptions included a sensitivity of 60.6% for targeted ultrasound and a screen-positive rate of 16.2%. If targeted ultrasound is used to determine whether high-risk patients should undergo amniocentesis, 56% (3933/7025) of all DS fetuses are missed. The diagnosis of DS is missed most frequently among women at highest risk for DS (AMA and +triple). In this subgroup of patients, there are 3152 DS fetuses in the second trimester, of which 2815 (89%) are identified by triple screen test. When an ultrasound screen is added, only 1709 (54%) of DS fetuses will be identified. Substantially fewer DS fetuses will be detected when targeted ultrasound is used as a screen among already identified high-risk patients.

Historical Perspectives

This month’s Historical Perspectives is in a slightly different format, but should be of considerable interest to readers of NeoReviews. Professor Nicholas Wald is an epidemiologist who has evaluated and written about a variety of topics, but he is best known for his work on screening methods, particularly in the area of maternal serum alpha-fetoprotein (AFP) and fetal abnormalities. Because of his continuing heavy commitments and to minimize the disruption of his schedule, I posed a number of questions to him, to which he responded with detailed answers. Before moving to his responses, some background information seems in order. Shortly before publication of the article highlighted this month, evaluation of amniotic fluid in cases of open spina bifida and other neural tube defects had shown increased levels of AFP. (1) Somewhat later, it was shown that abdominal wall defects, as well as neural tube defects, could contribute to increased levels of amniotic fluid AFP. (2) In his responses, Professor Wald documents the sequence of events that followed, noting that Professor David Brock in Edinburgh described the association of increased levels of maternal serum alpha-fetoprotein (MSAFP) with fetal anencephaly, which triggered the idea that this also might be true of open spina bifida. Thus, MSAFP was used as a screening tool for the detection of neural tube and abdominal wall defects. Elevated MSAFP levels were noted in other “at-risk” pregnancies (3) and twin pregnancies. (4) To provide better standardization, Professor Wald introduced the concept of “multiples of the median” (MoM) at different gestational ages. Approximately a decade passed before the association was made between low MoMs for AFP and chromosomal defects, particularly Down syndrome. Soon thereafter, several other serum markers for Down syndrome were described, and by linking them to maternal age, screening became increasingly valuable. In the early 1980s, Dr …