Is maternal plasma DNA testing impacting serum-based screening for aneuploidy in the United States?

Purpose: We sought to determine whether tests for fetal aneuploidy based on next-generation sequencing of cell-free DNA in maternal circulation have had an impact on routine serum-based screening in the general pregnant population.

Methods: We compared results from laboratory surveys in 2011 and 2014 that reported types of prenatal serum screening tests and numbers of tests performed. Testing records from two prenatal serum screening laboratories examined temporal trends in the proportion of screened women 35 years of age and older from 2008 (or 2009) to 2014.

Screening for down syndrome in the United States: results of surveys in 2011 and 2012.

Context: Participants in a College of American Pathologists external proficiency testing program for first and second trimester Down syndrome screening.

Objectives: To determine the number of women screened for Down syndrome in the United States, along with the type of test received and to compare those results to earlier surveys in 1988 and 1992.

Design: Questionnaires regarding the type and number of Down syndrome tests performed per month were completed by participants in early 2011 and again in early 2012.

Four years' experience with an interlaboratory comparison program involving first-trimester markers of Down syndrome.

Context: We initiated a voluntary, self-funded interlaboratory comparison program in the fall of 2005 because no proficiency testing program was available to laboratories in North America offering first-trimester, combined serum and ultrasound, Down syndrome screening. Objectives.-To evaluate the first 4 years of the interlaboratory comparison program against stated goals, to identify areas of concern, and to create new initiatives as indicated.

Second and first trimester estimation of risk for Down syndrome: implementation and performance in the SAFER study.

Objectives: Document patient choices and screening performance (false positive and detection rates) when three improved Down syndrome screening protocols were introduced coincidentally.

Method: Second-trimester 'triple marker' screening was expanded by adding second-trimester dimeric inhibin-A (four-marker), with or without first-trimester pregnancy-associated plasma protein-A (five-marker). Nuchal translucency (NT) measurements were included when available from accredited sonographers (six-marker).

Estimating first-trimester combined screening performance for Down syndrome in dried blood spots versus fresh sera.

Purpose: The study purpose was to examine the consequences of using dried blood spots rather than fresh sera in first-trimester Down syndrome screening.

Methods: We collected and compared human chorionic gonadotropin and pregnancy-associated plasma protein-A results from clients providing dried blood spots (Cohort 1) and from other clients providing fresh sera (Cohort 2). Inclusion and exclusion criteria aimed at ensuring the two cohorts were similar.

Repeated measurement of pregnancy-associated plasma protein-A (PAPP-A) in Down syndrome screening: a validation study.

Objectives: To confirm that measuring pregnancy-associated plasma protein-A (PAPP-A) in both first- and second-trimester serum samples improves Down syndrome screening.

Methods: We selected paired first- and second-trimester stored serum samples from 34 Down syndrome pregnancies (cases) and 514 unaffected pregnancies (controls) and tested the second-trimester samples for PAPP-A and dimeric inhibin-A (DIA). First-trimester PAPP-A measurements were already available, as were second-trimester measurements of alpha-fetoprotein, unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG).

Comparing three screening strategies for combining first- and second-trimester Down syndrome markers.

Objective: To describe the choices and tradeoffs inherent in 3 published strategies that combine first- and second-trimester markers for Down syndrome screening.

Methods: Published marker distributions for Down syndrome and unaffected pregnancies in the first and second trimesters were combined with a maternal age distribution and age-associated Down syndrome risk in a statistical model to compare sequential, contingent, and integrated screening.

Results: Sequential and contingent screening strategies are always less efficient (higher false-positive rate for a given detection rate) than integrated screening, but the reduction in efficiency is dependent on the combination of risk cutoffs chosen.

Integrated serum screening for Down syndrome in primary obstetric practice.

Objectives: Integrated serum screening for Down syndrome is potentially more effective than current second-trimester screening. We report results of an intervention trial of integrated serum screening that involved 229 primary prenatal care practitioners throughout Maine.

Methods: Women provided a first-trimester serum (for PAPP-A) followed by a second-trimester serum (for AFP, uE3, hCG, and DIA).

Patient and health professional acceptance of integrated serum screening for Down syndrome.

Integrated testing for Down syndrome combines first trimester maternal serum and nuchal translucency (NT) measurements with second trimester maternal serum measurements into a single second trimester Down syndrome risk. A variant of integrated testing, the integrated serum test, requires only the serum measurements and may be more suitable for widespread use in the general pregnancy population. Concern has been voiced that women will find the delay associated with waiting for screening results unacceptable for either fully integrated (including NT measurements) or integrated serum testing.

Maternal serum invasive trophoblast antigen and first-trimester Down syndrome screening.

Background: In the United States, Down syndrome screening is still performed mainly in the second trimester, using 3 or 4 markers. Moving screening into the first trimester has the advantage of earlier diagnosis. Currently, first-trimester screening typically includes maternal serum pregnancy-associated plasma protein-A (PAPP-A), the free beta-subunit of human chorionic gonadotropin (free beta), and ultrasound measurement of nuchal translucency thickness (NT).

A comparison of human chorionic gonadotropin- related components in fresh frozen serum with the proficiency testing material used by the College of American Pathologists.

Context: As part of a College of American Pathologists (CAP) proficiency testing survey, a comparison is made between human chorionic gonadotropin (hCG) results from an actual patient pool and a similarly targeted artificial sample. The goal is to gain insight into the possible source(s) of bias attributable to the proficiency testing material (PTM) with a view toward creating more appropriate survey materials.

Objective: To compare hCG and related variants in a pool of fresh frozen sera (FFS) with that found in PTM.

Maternal serum invasive trophoblast antigen (hyperglycosylated hCG) as a screening marker for Down syndrome during the second trimester.

Background: Approximately two million pregnancies in the United States are screened for Down syndrome annually by use of second-trimester maternal serum markers. At present, a combination of four markers can identify 75% of affected pregnancies when 5% of screened women are classified as candidates for amniocentesis. Although not currently included in screening panels, invasive trophoblast antigen (ITA) is a promising screening marker in serum or urine in both the second and first trimesters.

Invasive trophoblast antigen (hyperglycosylated human chorionic gonadotropin) in second-trimester maternal urine as a marker for down syndrome: preliminary results of an observational study on fresh samples.

Background: Down syndrome screening is commonly performed in the US using maternal age and three or four second-trimester maternal serum markers that can identify up to 75% of affected pregnancies by offering diagnostic studies to 5% of women. Invasive trophoblast antigen [ITA; hyperglycosylated human chorionic gonadotropin (hCG)] is a promising marker that can be measured in urine or serum in the first or second trimester. We report preliminary results for urinary ITA in an ongoing observational study.

Epidemiologic monitoring of prenatal screening for neural tube defects and Down syndrome.

Achieving and maintaining the proper balance between detecting fetuses with open spina bifida or Down syndrome while maintaining an acceptably low screen-positive rate requires careful, ongoing monitoring of screening performance indicators along with specific procedures aimed at taking rapid and effective corrective actions when warranted. The process of epidemiologic monitoring, which uses data generated from the screened population, has been developed as an extended quality assurance measure for this purpose. The primary indicators used include the percentage of women with a screen-positive result and the grand multiple of the median.

Maternal serum-integrated screening for trisomy 18 using both first- and second-trimester markers.

Objectives: To estimate the prenatal screening performance of an integrated serum test for detecting trisomy 18, which combines measurements of first- and second-trimester markers with maternal age to assign patient-specific risks.

Methods: Published and new observations of maternal serum marker levels in trisomy 18 and unaffected pregnancies are used to derive population parameters. These parameters are then combined in a multivariate Gaussian model to assign patient-specific risks for trisomy 18.