Positive Serum Screening Research Articles

62 Multicenter prospective study of SNP-based cfDNA screening for aneuploidy with genetic confirmation in 18,496 pregnancies

To evaluate performance of single nucleotide polymorphism (SNP)-based cell-free DNA (cfDNA) screening for detection of trisomies 13, 18, and 21 in a large unselected cohort with genetic confirmation. We hypothesized that performance in all risk groups is equivalent to published studies without genetic confirmation. Unselected pregnant women who had SNP-based cfDNA for T13, T18 and T21 were recruited at 21 centers in 6 countries. Genetic confirmation was obtained for all pregnancies from prenatal or newborn DNA samples. Sensitivity, specificity, PPV and test failure (no call) rates were calculated and compared between women at low and high prior risk for aneuploidy. High risk was defined as having positive serum screening, nuchal translucency >3mm, major fetal anomaly on ultrasound or >35 years old with no prior screening. Performance of an updated cfDNA algorithm, blinded to pregnancy outcome, was also assessed. Of 20,887 women enrolled, 18,496 (88.5%) had genetic confirmation and comprised the study cohort. Mean gestational age at enrollment was 13.2 weeks. 133 (0.72%) cases of trisomy were identified: n=100 T21, n=18 T18 and n=15 T13. 18,205 women received a cfDNA result while 291 (1.57%) were no call. Screen positive rate was lower in low vs high risk cases (0.26% vs 2.1%, p<.0001). Sensitivity and specificity were similar between risk groups. (Table) PPV for all trisomies combined was lower in low risk women (74.3% vs 94.1%, p=.003), while it was not different for any specific trisomy. Performance of the updated algorithm was not different than in the prospective cohort but had lower no call rate after both the first (1.46% vs. 3.3%, p<.0001) and second draw (0.60% vs 1.57%, p<.0001). Based on genetic confirmation in an unselected cohort of 18,496 pregnancies, SNP-based cfDNA high sensitivity and specificity for the common trisomies was corroborated in all risk groups. The PPVs in women that are low risk for aneuploidy are >50% for all trisomies. An updated algorithm decreased the no-call rate while maintaining performance.

Anti NMDA receptor encephalitis: a potentially treatable encephalitis

Anti NMDA receptor encephalitis is autoimmune encephalitis where antibodies are directed against NMDA receptor subunit. It represents a new category of immune-mediated disorder that is often paraneoplastic, presenting with neuropsychiatric symptoms, which is treatable and can be diagnosed serologically affecting both children and adults. Patient can have variable clinical presentation ranging from prodromal illness, neuropsychiatric symptoms, seizures, autonomic instability, hyperkinesias, catatonia, hypoventilation and with or without an associated teratoma. A positive serum or CSF sample screening for antibodies to the NMDA receptor subunit is confirmative. Supportive findings include CSF study, EEG and MRI Brain. The first-line therapies includes IVIG, corticosteroids or plasma exchange. Second line immunotherapy is rituximab or cyclophosphamide or both. Given the high mortality rate (up to 25%), the likelihood of presentation across the age range and the potential for treatment, a high index of suspicion is warranted by clinicians. Authors report a case of a 5 year old child with anti NMDA receptor encephalitis who responded well to IVIG therapy.

Impact of cell-free fetal DNA on early invasive prenatal diagnosis at a Chinese reference maternal medicine center

Purpose The aim of this study is to evaluate the impact of the utility of maternal cell-free DNA (cfDNA) on the number of chorionic villus sampling (CVS) at a mainland Chinese maternal hospital. Methods This was a retrospective cohort study conducted in consecutive singleton pregnancies that underwent CVS between the 11th and 14th gestational weeks at a Chinese maternal hospital during a nine-year period. The indications, complications and prenatal diagnosis results were evaluated. Results This study consisted of 5108 CVS procedures, including 2000 performed for fetal karyotyping, and 3108 performed for fetal single-gene genotyping. During the period with the introduction of cfDNA, the proportion of the number of CVS procedures for the indication of positive serum screening declined significantly, and abnormal ultrasound was the main indication for CVS performed for fetal karyotyping. Thalassemia was always the main indication for CVS, accounting for 50.5% of all CVS cases. Conclusions cfDNA has changed the spectrum of CVS indications. CVS is now the invasive procedure performed for patients with a fetus having a very high risk of fetal genetic defects, including fetuses having major abnormal ultrasound or having a risk of single-gene disorder inherited from their parents.

Indications of percutaneous umbilical cord blood sampling in prenatal diagnosis

Objective To investigate the tendency and safety of percutaneous umbilical cord blood sampling (PUBS) in prenatal screening and diagnosis, and the possibilities of avoiding unnecessary PUBS. Methods This was a retrospective study of pregnant women who underwent PUBS for prenatal diagnosis in Peking University First Hospital from January 2015 to December 2017. Clinical indications, timing of PUBS, further investigations (chromosome karyotype, molecular genetics and pathogen testing), results, and pregnancy outcomes were collected and analyzed. One-way analysis of variance (ANOVA), Chi-square test for linear trend, Fisher's exact probability test/Cochran-Armitage analysis and Cruskal-Wallis rank-sum test were used for statistical analysis. Results (1) A total of 412 singleton pregnancies underwent PUBS at 20-38 gestational weeks during the study period, and 379 (92.2%) of them received PUBS before 34 gestational weeks. The positive test results accounted for 10.4% (43/412). There were six (1.5%) miscarriages after PUBS. In vitro cell culture failure occurred in two cases, one in 2015 and the other in 2016. (2) Among the 412 cases, 304 (73.8%) had only one indication. Fourteen cases could be identified as high risk in the first trimester, such as advanced maternal age (AMA, >35 years), pregnant history with chromosomal abnormal fetus and one of the couples carrying abnormal genes. There were four, zero and one case receiving PUBS only for AMA in 2015, 2016 and 2017, respectively. Indications, including high risk suggested by serum screening and fetal abnormality found by ultrasound were identified in 290 cases (70.4%) in the second or third trimester. Other than AMA, there were no statistically significant differences in single indicators. The proportion PUBS with double indicators increased from 2015 to 2017 but without significant difference. AMA and positive serum screening as indicators of aneuploidy screening accounted for 7.6% (8/105) in double-indicator group and 1.9% (8/412) in all. (3) There were 363 PUBS (88.1%) performed for ultrasound abnormalities. Among them, 76.9% (280/363) only had abnormal ultrasound findings, and the percentage was decreased year by year. The other 83 cases (80 with double indicators and three with triple indicators) also presented with other indicators, including AMA, adverse pregnancy history and positive serum screening. The proportion of PUBS performed with the presence of multiple indicators tended to increase recently, but no statistically significant difference was found. All the 18 cases with abnormality diagnosed by molecular genetic testing had abnormal ultrasound findings. Conclusions Although PUBS's complications are rare, it carries some risks. The constitution of single indication has been declined every year. With the improvement of prenatal screening system and application of molecular karyotyping, the necessity of invasive prenatal diagnosis with PUBS is greatly reduced. An improvement in reasonable and standardized application of PUBS needs to be achieved. Key words: Prenatal diagnosis; Phlebotomy; Blood specimen collection; Umbilical veins

Over a Half Million Noninvasive Prenatal Tests: A Clinical Laboratory Experience [31R

INTRODUCTION: We describe the clinical laboratory experience with the MaterniT® 21 PLUS test, including autosomal/sex aneuploidies and select subchromosomal deletions. METHODS: Over 500,000 samples from pregnant patients were submitted for NIPT at our CLIA-certified, CAP-accredited, appropriately state-licensed clinical laboratories in Morrisville, NC and San Diego, CA using genome-wide sequencing. The test includes aneuploidies for chromosomes 13, 18, 21, X, Y and selected subchromosomal events. Statistical analysis of this large patient cohort was undertaken. RESULTS: The predominant indication for testing in this large cohort was advanced maternal age, followed by ultrasound findings and positive serum screening. Overall positivity rates were 1.25%, 0.40%, and 0.20% for trisomies of chromosomes 21, 18, and 13, respectively. More than 22,000 cases (∼4.2%) were multifetal pregnancies. In 2015 the average turnaround time was 5.4 calendar days, and the test had a total non-reportable rate, including quantity of DNA not sufficient and technical failures, of 1.75%. Estimated performance based on ad hoc clinical outcome showed that sensitivity and specificity met or exceeded the original clinical validation studies. Additionally, positive predictive values (PPV) of subchromosomal findings for all events ranged from 65.3% - 100%. CONCLUSION: MaterniT® 21 PLUS offers pregnant patients accurate and reliable information about fetal aneuploidy status. This laboratory developed test has demonstrated positivity rates for trisomy 21, 18 and 13 that mirror those found in large studies on populations that underwent invasive testing. The addition of subchromosomal events has been shown to perform well, with high PPVs. Operational performance met or exceeded performance from the original clinical validation studies.

Cell-free DNA screening in clinical practice: abnormal autosomal aneuploidy and microdeletion results

Since its commercial release in 2011 cell-free DNA screening has been rapidly adopted as a routine prenatal genetic test. However, little is known about its performance in actual clinical practice. We sought to investigate factors associated with the accuracy of abnormal autosomal cell-free DNA results. We conducted a retrospective cohort study of 121 patients with abnormal cell-free DNA results from a referral maternal-fetal medicine practice from March 2013 through July 2015. Patients were included if cell-free DNA results for trisomy 21, trisomy 18, trisomy 13, or microdeletions (if reported by the laboratory) were positive or nonreportable. The primary outcome was confirmed aneuploidy or microarray abnormality on either prenatal or postnatal karyotype or microarray. Secondary outcomes were identifiable associations with invitro fertilization, twins, ultrasound findings, testing platform, and testing laboratory. Kruskal-Wallis or Fisher exact tests were used as appropriate. A total of 121 patients had abnormal cell-free DNA results for trisomy 21, trisomy 18, trisomy 13, and/or microdeletions. In all, 105 patients had abnormal cell-free DNA results for trisomy 21, trisomy 18, and trisomy 13. Of these, 92 (87.6%) were positive and 13 (12.4%) were nonreportable. The results of the 92 positive cell-free DNA were for trisomy 21 (48, 52.2%), trisomy 18 (22, 23.9%), trisomy 13 (17, 18.5%), triploidy (2, 2.2%), and positive for >1 parameter (3, 3.3%). Overall, the positive predictive value of cell-free DNA was 73.5% (61/83; 95% confidence interval, 63-82%) for all trisomies (by chromosome: trisomy 21, 83.0% [39/47; 95% confidence interval, 69-92%], trisomy 18, 65.0% [13/20; 95% confidence interval, 41-84%], and trisomy 13, 43.8% [7/16; 95% confidence interval, 21-70%]). Abnormal cell-free DNA results were associated with positive serum screening (by group: trisomy 21 [17/48, 70.8%]; trisomy 18 [7/22, 77.8%]; trisomy 13 [3/17, 37.5%]; nonreportable [2/13, 16.7%]; P= .004), and abnormal first-trimester ultrasound (trisomy 21 [25/45, 55.6%]; trisomy 18 [13/20, 65%]; trisomy 13 [6/14, 42.9%]; nonreportable [1/13, 7.7%]; P= .003). There was no association between false-positive rates and testing platform, but there was a difference between the 4 laboratories (P= .018). In all, 26 patients had positive (n= 9) or nonreportable (n= 17) microdeletion results. Seven of 9 screens positive for microdeletions underwent confirmatory testing; all were false positives. The positive predictive value of 73.5% for cell-free DNA screening for autosomal aneuploidy is lower than reported. The positive predictive value for microdeletion testing was 0%. Diagnostic testing is needed to confirm abnormal cell-free DNA results for aneuploidy and microdeletions.

AB109. Noninvasive prenatal testing (NIPT): differences in testing indications between the US and Southeast Asia

Background and objective Cell-free DNA-based noninvasive prenatal testing (NIPT) has been validated as a screening test for certain fetal aneuploidy in high-risk women. High-risk indications include advanced maternal age (AMA), positive serum screen result, abnormal fetal ultrasound findings, and a previous affected pregnancy. However, recent studies show the effectiveness of NIPT in all pregnant women, regardless of risk. Determine if there are global differences in NIPT implementation between centers in Southeast Asia and the United States (US).

Chromosome abnormalities diagnosed in utero: a Japanese study of 28 983 amniotic fluid specimens collected before 22 weeks gestations.

To investigate the frequency and type of abnormal karyotype in Japan by amniocentesis before 22 weeks of gestation. We performed a retrospective analysis of 28 983 amniotic fluid specimens in a local population collected before 22 weeks gestations for fetal karyotyping. The incidence of abnormal karyotype was 6.0%. The main indication was advanced maternal age (AMA) of 35 years and older, which represented over half of the clinical indications. Abnormal karyotype was most frequently reported among the referrals for abnormal ultrasound findings (21.8%), followed by positive maternal serum screen results (5.3%). Three-fourths of abnormal karyotype was either autosomal aneuploidy (64.0%) or sex chromosome aneuploidy (11.6%). Abnormal karyotype was detected in 2.8% of pregnant women referred for AMA. Clinically significant abnormal karyotype increased with advancing maternal age. The frequency and type of abnormal karyotype detected by amniocentesis for various indications were determined. Amniocentesis was mainly performed among the referrals for AMA, which is a characteristic distribution of indications of Japan.

Maternal plasma DNA testing: experience of women counseled at a prenatal diagnosis center.

To evaluate the early introduction of circulating cell-free (ccf) DNA testing in a prenatal diagnosis center serving a statewide population. A retrospective chart review of patients at high aneuploidy risk counseled during the two 10-week periods that documents indication, risk, maternal age, insurance coverage, decisions, and reasoning behind that decision. Among the 299 included women, indication was advanced maternal age (17% with and 56% without an additional indication), positive serum screen (15%), and abnormal ultrasound (12%). Uptake increased from 10% to 17%, as did patient awareness of the test (4% to 14%). Women with lower copayments were more likely to complete testing (23% vs. 5%, p<0.001). Most women completing testing (75%) wanted to avoid an invasive procedure, while those declining cited testing would not change anything (47%), preferred diagnostic testing (16%), negative follow-up testing (20%), and cost/insurance issues (9%). One of 42 tests was positive (trisomy 21). Individual patient follow-up allows us to document ccfDNA-related patient decision-making. Nearly half of the women did not want further testing and one in seven preferred immediate diagnostic testing. Patient costs were a barrier to testing that, if avoided, could increase test uptake by 50% or more.

599: Uptake of cell free fetal DNA testing in women with positive serum screening

women with positive serum screening Shilpa Chetty, Joanne Taylor, Louanne Hudgins, Mary Norton Stanford University/Lucile Packard Children’s Hospital, Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Stanford, CA, Stanford University/Lucile Packard Children’s Hospital, Department of Pediatrics, Division of Medical Genetics, Stanford, CA OBJECTIVE: To investigate how the additional option of cell free fetal DNA (cffDNA) testing impacted women’s testing choices following a positive serum screening result STUDY DESIGN: Beginning in March 2012, all women referred to our Prenatal Diagnosis Center following a positive serum screening result were offered cffDNA as an alternative to invasive prenatal diagnosis. A query of the genetic counseling database was performed to identify all such patients and to determine follow up testing decisions. Results were compared to testing decisions during the prior year (March 2011 through March 2012). Outcomes were grouped into 4 categories: 1. CVS/amniocentesis; 2. cffDNA; 3. CVS/amniocentesis and cffDNA and 4. no follow up testing. Information regarding race/ethnicity was obtained. RESULTS: Between March and June 2012, there were 113 women with positive serum screening results who were offered cffDNA testing. CVS/amniocentesis was pursued by 39% (n 44), compared to 46% (301/639) of screen positive patients the previous year (p 0.15). cffDNA was chosen by 44% (50/113). Of patients who had cffDNA testing, 2 pursued amniocentesis despite cffDNA indicating low risk result for T13, T18 or T21; both had normal karyotypes. Two patients underwent amniocentesis confirmation following cffDNA results indicated a high risk for T21; both confirmed T21. From March to June 2012, 16% (18/113) declined all testing; as compared to 53% (338/ 639) who declined follow up testing the previous year when cffDNA was not available (p 0.05). Patients that declined all testing prior to cffDNA and following introduction of cffDNA were predominantly Hispanic (56% and 62% respectively). CONCLUSION: The introduction of cffDNA testing did not result in a significant decrease in the number of women who opted for invasive testing, perhaps due to small numbers. However, fewer women declined all follow up testing when a noninvasive option was available.

Maternal serum second trimester screening for chromosomal disorders and neural tube defects in a government hospital of North India

Down syndrome (DS) has major resource implications especially in developing countries being third most important cause of mental handicap. Maternal serum screening for chromosomal aneuploidies and neural tube defects (NTDs) is practiced worldwide in many countries and has been integrated into mainstream health care, while it is gradually gaining momentum in Asian countries. This prospective cohort study was carried out in pregnant women undergoing triple screening test between January 2007 and December 2010 after informed consent. Biomarkers alpha-fetoprotein, human-chorionic-gonadotropin and unconjugated-estriol were tested, and risk of pregnancy being affected with DS, Edward's syndrome or NTDs were calculated. Screen-positive patients were referred for detailed ultrasonography and confirmatory amniocentesis. Follow-up record was maintained until delivery. Of 7400 pregnant women enrolled, 419(5.7%) were screen-positive, including 339 positive for DS, two for trisomy 18, and 62 for NTDs. Total eight cases of DS were eventually diagnosed in the population (prevalence of DS = 1 : 925), seven of which were detected in utero following diagnostic evaluation for positive serum screen (DR of DS screen = 87.5%). Total five cases of NTD were observed, yielding NTD prevalence of 0.67/1000. Triple screening in the second trimester is reasonably effective for the detection of major chromosomal defects and NTDs, and can be implemented successfully also in India.

Distal villous hypoplasia

Distal villous hypoplasia is a form of placental villous maldevelopment that has the potential to cause significant intrauterine growth restriction with adverse consequences for fetal viability, neurodevelopmental outcome and adult cardiovascular health. It is characterized by a sparse, poorly developed distal villous tree with abnormally shaped, elongated, slender villi and widening of the intervillous space. Generally, villi show widespread trophoblast abnormalities with thinning of the villous trophoblast layer, reduction in cytotrophoblast numbers, evidence of a widespread increase in syncytiotrophoblast nuclear senescence and wave-like syncytial knots. Investigation of pregnancies with false positive serum screening tests for fetal aneuploidy/structural defects can help identify pregnancies at risk of placental insufficiency, particularly when combined with ultrasound assessment of placental morphology at 19–22 weeks. Identification of pregnancies with multiple abnormal tests of placental function permits high-risk specialist referral to optimize maternal-fetal outcome.

Chorionic villus sampling for abnormal screening compared to historical indications: prevalence of abnormal karyotypes

Objective: To determine the prevalence of abnormal karyotype results in women undergoing chorionic villus sampling (CVS) for abnormal first trimester screening compared to CVS for historical indications (advanced maternal age (AMA) or prior aneuploidy). Methods: Retrospective cohort of all patients undergoing CVS at Oregon Health & Science University from January 2006 to June 2010. Patients were separated based on CVS indication: (1) positive ultrasound (U/S) or serum screening; or (2) AMA or prior aneuploidy with normal or no screening. Prevalence of abnormal karyotype results were compared between groups. Results: Fetal karyotyping was successful in 500 of 506 CVS procedures performed. 203 CVS were performed for positive screening with 69 abnormal karyotypes (34.0%). 264 CVS were performed for historical indications with 11 abnormal karyotypes (4.2%). This difference was statistically significant (χ2 71.9, p < 0.001; OR 11.8 [95% CI 5.8, 24.6]). There were two age-related aneuplodies in AMA women without positive screening. 42 out of 44 AMA women diagnosed with aneuploidy (95.5%) had abnormal U/S and/or serum screening (35 U/S, 4 serum, 3 U/S and serum). Conclusions: Combined ultrasound and serum screening should be recommended to all women, including AMA women, prior to undergoing invasive testing to improve risk-based counseling and minimize morbidity.

715: Structural chromosome rearrangements identified through positive prenatal serum screen

Prenatal serum screening for trisomy 21 and/or trisomy 18 has identified pregnancies affected with other chromosomal aneuploidies. Less studied are the structural chromosome rearrangements that are also identified, which this project aims to describe.

The significance of a positive second trimester serum screen for trisomy 18

Objectives. We designed this study to estimate the proportion of fetuses in pregnancies with positive second trimester serum screens for trisomy 18 who actually have trisomy 18, to estimate the proportion of women with trisomy 18 who have a negative serum screen, and to assess the role of ultrasound in the diagnosis of trisomy 18.Methods. Retrospective study of two cohorts of pregnant women in 2004 and 2005: (1) those with a second trimester serum screen positive for trisomy 18 and (2) those with fetuses having trisomy 18.Results. There were 93 women with positive serum screens for trisomy 18. Of these, only three had a fetus with trisomy 18. There were five other cases of trisomy 18, three of which had a negative second trimester serum screen for trisomy 18. All fetuses with trisomy 18 had multiple major structural abnormalities detected on targeted genetic sonography.Conclusions. A positive second trimester serum screen has a poor sensitivity and poor prediction for trisomy 18. Trisomy 18 is highly unlikely if a woman with a positive screen for trisomy 18 has no fetal abnormalities detected on targeted genetic sonography. Women with a positive second trimester serum screen for trisomy 18 should be offered genetic sonography, and the practice of routine amniocentesis for all women with a positive screen should be discouraged when targeted genetic sonography is available.

Maternal Serum Screening: Results Disclosure, Anxiety, and Risk Perception

Although increased maternal anxiety following the disclosure of positive second-trimester maternal serum screen (MSS) results has been well documented, how this anxiety correlates with the method of results disclosure has not been well defined. This pilot study aimed to determine how abnormal second-trimester MSS results are disclosed, the level of anxiety experienced by women as a result of this disclosure, and the accuracy of their risk perception. Women referred for prenatal genetic counseling were asked to complete a questionnaire including demographics, standardized Spielberger State-Trait Anxiety Inventory, results disclosure information, and perceived risk. Of the 561 questionnaires distributed, 388 (69.2%) women chose to participate. Of the 136 participants referred for an abnormal MSS, 125 (91.9%) were aware of this indication and elected to complete the results disclosure portion of the questionnaire. The average anxiety level was not significantly different based on the method of results disclosure or who reported the results. We did not identify a definite cause for the anxiety experienced by women receiving abnormal MSS results; however, this study illustrates the need for further research to identify factors that contribute to the elevated anxiety experienced by these women.

Prenatal screening for Down's syndrome: editorial responsibilities

On Sept 16, UK television's Channel 4 News featured an “exclusive” and “shocking” report that, after positive serum or ultrasound screening for Down's syndrome, diagnostic testing by amniocentesis or chorionic villus sampling results in two healthy babies being miscarried for every three Down's syndrome births prevented.1 The findings (published early online to coincide with the broadcast) are from an editorial by Frank Buckley and Sue Buckley, Chief Executive and Chief Scientist of Down Syndrome Education International (DSEI), respectively, in Down Syndrome Research and Practice.

Sotos syndrome: Antenatal presentation

There is little published information regarding the clinical presentation of Sotos syndrome in pregnancy. In this report, we describe the antenatal presentation of a child subsequently diagnosed with Sotos syndrome by molecular analysis. The pregnancy was complicated by a positive maternal serum screen and abnormal ultrasound findings including macrocephaly, polyhydramnios and decreased fetal movements. This is the first report of an elevated Down syndrome risk in a pregnancy with confirmed Sotos syndrome. Sotos syndrome should be included in the differential diagnosis of newborns with a normal karyotype where the pregnancy has demonstrated an increased risk for Down syndrome by maternal serum screening, especially in the presence of supportive ultrasound findings.

Évaluation de la pratique de l’amniocentèse sur le réseau sud-ouest francilien pendant l’année 2003

To assess amniocentesis practice of a network during one year. In a retrospective multicenter study of the south-west Francilian network, we have enrolled 2400 patients who underwent amniocentesis, from 1 January 2003 to 31 December 2003. The rate of amniocentesis was 9.5%. The most frequent indication was a positive maternal serum screening test result (44%). The rate of global fetal losses (spontaneous miscarriage and intrauterine death) was 1.4%. Once the fetuses with aneuploidy and lethal pathology excluded, the rate of global fetal losses potentially related to amniocentesis was 1.21%. The rate of premature rupture of the membranes was 1.12% and prematurity affected 6.5% of the living births. Our study has highlighted several practices of amniocentesis within the network. Overall, amniocentesis potentially induces 1.12% of fetal losses. Screening tests are currently used sequentially, which leads to an increase number of amniocentesis and to an increase number of losses of "a priori" healthy fetus. Only the use of a combined screening could lower the frequency of amniocentesis without decreasing the detection rate of chromosome abnormalities.

Combining fetal nuchal fold thickness with second‐trimester biochemistry to screen for trisomy 21

To assess second-trimester screening for trisomy 21 by combining ultrasound nuchal fold (NF) measurement with maternal serum biochemistry. NF, maternal serum alpha-fetoprotein (AFP) and free beta-human chorionic gonadotropin (beta-hCG) were determined concurrently at 14-19 weeks' gestation in a study population comprising 1813 women with singleton pregnancies, including 1257 unselected women undergoing serum screening for trisomy 21 (1999-2002), and 556 high-risk pregnancies prior to amniocentesis (2003-2005), 402 of whom had positive serum screening tests. The results were expressed in multiples of the gestation-specific normal median (MoMs). There were 1799 unaffected singleton pregnancies, and their NF values approximately fitted a log Gaussian distribution over a wide range. There was a weak but statistically significant correlation between log NF and log AFP (r = - 0.069, P < 0.005) and the correlation coefficient between log NF and log free beta-hCG was even smaller and not statistically significant (r = 0.038, P = 0.11). Among the seven trisomy 21 pregnancies, the median NF level was 1.53 MoM (geometric mean 1.75 MoM), a highly statistically significant increase compared with unaffected pregnancies (P < 0.0001, one-tail Wilcoxon Rank Sum Test). In pregnancies referred because of positive serum screening tests (391 unaffected, seven cases of trisomy 21, one of monosomy X and three other chromosomal anomalies) the use of NF to modify the serum screening risk would have reduced the invasive procedures in unaffected pregnancies by 46% without affecting the detection rate of trisomy 21 or other anomalies. Statistical modeling predicted that adding NF to AFP and free beta-hCG would increase detection more than would adding unconjugated estriol as well as inhibin-A, an analyte that is difficult to measure with precision. The addition of NF measurement to second-trimester biochemical markers improves screening performance, and could overcome drawbacks in the implementation of inhibin-A assay in clinical practice.