Limited additional value of karyotyping cultured amniotic fluid cell colonies in addition to microarray on uncultured cells for confirmation of abnormal non-invasive prenatal testing results.

OBJECTIVES: Non-invasive prenatal testing (NIPT) allows the detection of placental chromosome aberrations. To verify whether the fetus also has the chromosome aberration, diagnostic follow-up testing is required. The aim of this retrospective study was to assess the added value of analyzing amniotic fluid (AF) cell cultures in addition to uncultured AF cells for the detection of fetal mosaicism. METHOD: NIPT was performed as part of the Dutch TRIDENT study. Cytogenetic studies in uncultured AF were performed using single nucleotide polymorphism (SNP)-array. Cultured AF cell colonies (in situ method) were investigated with fluorescent in situ hybridization and/or karyotyping. Clinical outcome data were collected in cases with discordant results. RESULTS: Between April 2014 and December 2021, 368 amniocenteses were performed after a chromosomal aberration was detected with NIPT. Excluding 134 cases of common aneuploidies (confirmed by quantitative fluorescence polymerase chain reaction), 29 cases with investigation of uncultured cells only and 1 case without informed consent, 204 cases were eligible for this study. In 196 (96%) cases, the results in uncultured and cultured cells were concordant normal, abnormal or mosaic. Five cases (2%) showed mosaicism in cultured AF cells, whereas uncultured AF cells were normal. Two (1%) of these, one mosaic trisomy 13 and one mosaic trisomy 16, were considered true fetal mosaics. CONCLUSION: The added value of investigating AF cell cultures in addition to uncultured cells is limited to two of 204 (1%) cases in which true fetal mosaicsm would otherwise be missed. The clinical relevance of one (trisomy 13) remained unknown and the other case also showed ultrasound anomalies, which determined pregnancy management. This seems to justify limiting prenatal cytogenetic confirmatory testing to SNP arrays on uncultured AF cells, considerably shortening the reporting time.

What proportion of couples with a history of recurrent pregnancy loss and with a balanced rearrangement in one parent can potentially be identified through cell-free DNA genotyping?

BACKGROUND: Balanced chromosome aberrations are reported in about 1:30 couples with recurrent pregnancy loss (RPL). Karyotyping of both parents is necessary to identify these aberrations. Genome-wide non-invasive prenatal testing (NIPT) in case of recurrent pregnancy loss could be a more efficient way to identify couples at increased risk for carrying a balanced chromosome rearrangement. The aim of this study was to evaluate whether the potential fetal imbalances caused by parental balanced aberrations detected in our center are large enough to be detectable by genome-wide non-invasive prenatal testing (NIPT). MATERIAL AND METHODS: From January 1970 until May 2020 our laboratory received 30,863 unique requests for karyotyping due to RPL. We have identified 16,045 couples and evaluated all abnormal cytogenetic results to assess the minimal size of the involved chromosomal segments in potential unbalanced products of the rearrangements. RESULTS: In the presented cohort we detected 277 aberrant balanced translocations/inversions in females and 185 in males amongst 16,045 couples with RPL, which can be translated to a risk of 1:35 (2.9%, 95% CI 2.6-3.2%). Our study showed that the vast majority (98.7%, 95% CI 97.1-99.5%) of these balanced aberrations will potentially cause a fetal imbalance > 10 Mb, which is detectable with genome-wide NIPT if it was performed during one of the miscarriages. CONCLUSIONS: Our study suggests that genome-wide NIPT is able to reveal most unbalanced products of balanced chromosomal rearrangements carried by couples with RPL and therefore can potentially identify balanced chromosomal aberration carriers. Moreover, our data suggest that these couples can be offered NIPT in case they decline invasive testing in future pregnancies.

Prenatal ultrasound finding of atypical genitalia: Counseling, genetic testing and outcomes.

OBJECTIVE: To report uptake of genetic counseling (GC) and prenatal genetic testing after the finding of atypical genitalia on prenatal ultrasound (US) and the clinical and genetic findings of these pregnancies. METHODS: A retrospective cohort study (2017-2019) of atypical fetal genitalia in a large expert center for disorders/differences of sex development. We describe counseling aspects, invasive prenatal testing, genetic and clinical outcome of fetuses apparently without [group 1, n = 22 (38%)] or with [group 2, n = 36 (62%)] additional anomalies on US. RESULTS: In group 1, 86% of parents opted for GC versus 72% in group 2, and respectively 58% and 15% of these parents refrained from invasive testing. Atypical genitalia were postnatally confirmed in 91% (group 1) and 64% (group 2), indicating a high rate of false positive US diagnosis of ambiguous genitalia. Four genetic diagnoses were established in group 1 (18%) and 10 in group 2 (28%). The total genetic diagnostic yield was 24%. No terminations of pregnancy occurred in group 1. CONCLUSIONS: For optimal care, referral for an expert fetal US scan, GC and invasive diagnostics including broad testing should be offered after prenatal detection of isolated atypical genitalia.

Biallelic KIF24 Variants Are Responsible for a Spectrum of Skeletal Disorders Ranging From Lethal Skeletal Ciliopathy to Severe Acromesomelic Dysplasia.

Skeletal dysplasias comprise a large spectrum of mostly monogenic disorders affecting bone growth, patterning, and homeostasis, and ranging in severity from lethal to mild phenotypes. This study aimed to underpin the genetic cause of skeletal dysplasia in three unrelated families with variable skeletal manifestations. The six affected individuals from three families had severe short stature with extreme shortening of forelimbs, short long-bones, and metatarsals, and brachydactyly (family 1); mild short stature, platyspondyly, and metaphyseal irregularities (family 2); or a prenatally lethal skeletal dysplasia with kidney features suggestive of a ciliopathy (family 3). Genetic studies by whole genome, whole exome, and ciliome panel sequencing identified in all affected individuals biallelic missense variants in KIF24, which encodes a kinesin family member controlling ciliogenesis. In families 1 and 3, with the more severe phenotype, the affected subjects harbored homozygous variants (c.1457A>G; p.(Ile486Val) and c.1565A>G; p.(Asn522Ser), respectively) in the motor domain which plays a crucial role in KIF24 function. In family 2, compound heterozygous variants (c.1697C>T; p.(Ser566Phe)/c.1811C>T; p.(Thr604Met)) were found C-terminal to the motor domain, in agreement with a genotype-phenotype correlation. In vitro experiments performed on amnioblasts of one affected fetus from family 3 showed that primary cilia assembly was severely impaired, and that cytokinesis was also affected. In conclusion, our study describes novel forms of skeletal dysplasia associated with biallelic variants in KIF24. To our knowledge this is the first report implicating KIF24 variants as the cause of a skeletal dysplasia, thereby extending the genetic heterogeneity and the phenotypic spectrum of rare bone disorders and underscoring the wide range of monogenetic skeletal ciliopathies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing: Follow-up results of the TRIDENT-2 study.

In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings.

Factors associated with poor outcome in fetuses prenatally diagnosed with sacrococcygeal teratoma.

AIM OF THE STUDY: Outcome of fetuses, prenatally diagnosed with sacrococcygeal teratoma (SCT), is still poorly documented. This study assesses the incidence and prenatal predictors of outcome in all fetuses prenatally diagnosed with SCT. METHODS: This is a retrospective study on all fetuses prenatally diagnosed with SCT from 1998 to 2018 in the Netherlands. Poor outcome was defined as terminations of pregnancy (TOP) because of expected unfavorable outcome, intrauterine fetal death, or early neonatal death. Potential risk factors for poor outcome were analyzed. MAIN RESULTS: Eighty-four fetuses were included. Sixteen (19.0%) TOPs were excluded from statistical analysis. Eleven of the remaining 68 fetuses had poor outcome. Overall mortality was 32.1%, with a mortality excluding TOPs of 13.1%. Thirteen fetal interventions were performed in 11 (13.1%) fetuses. Potential risk factors for poor outcome were the presence of fetal hydrops (OR: 21.0, CI: 2.6-275.1, p = 0.012) and cardiomegaly (OR: 10.3, CI: 1.9-55.8, p = 0.011). CONCLUSIONS: The overall mortality of fetuses prenatally diagnosed with SCTs including tTOP was 32.1%. This high mortality rate was mainly due to termination of pregnancy. Mortality excluding TOP was 13.1%. Potential risk factors for poor outcome were fetal hydrops and cardiomegaly.

Patient-friendly integrated first trimester screening by NIPT and fetal anomaly scan.

Many major structural fetal anomalies can be diagnosed by first trimester fetal anomaly scan. NIPT can accurately detect aneuploidies and large chromosomal aberrations in cfDNA in maternal blood plasma. This study shows how a patient-friendly first trimester screening for both chromosomal and structural fetal anomalies in only two outpatient visits can be provided. Genotype-first approach assures not only the earliest diagnosis of trisomy 21 (the most prevalent chromosome aberration), but also completion of the screening at 12-14 weeks. To ensure proper management and avoid unnecessary anxiety abnormal NIPT different from trisomy 21, 18 and 13 should be referred for genetic counseling.

The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies.

INTRODUCTION: The aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results. MATERIAL AND METHODS: In the period 2013-2016, 391 pregnant women with fetal ultrasound anomalies who received normal chromosomal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre- and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (prenatal or postnatal). RESULTS: In 76 of 391 fetuses (19.4%, 95% CI 15.8%-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, 73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis. CONCLUSIONS: Our retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increase the diagnostic yield in fetuses with ultrasound anomalies and would allow early diagnosis of a genetic disorder irrespective of the (incomplete) fetal phenotype.

An unwanted pregnancy and language proficiency level are associated with first antenatal visit after the first trimester: Results from a prospective cohort study.

OBJECTIVE: To study the association between the reasons for a 'late' first antenatal visit and the influence of several maternal determinants and practical limitations on the timing of the first antenatal visit. DESIGN: A prospective cohort study. SETTING: Southwest region of The Netherlands, mainly characterised by large urban and suburban areas. PARTICIPANTS: Women receiving information and counselling about prenatal screening between April 2010 and December 2010 were included (n = 9,268). MEASUREMENTS AND FINDINGS: Timing of first antenatal visit, categorised as: 'in time' (<12+0 weeks of gestation), 'late' (≥12-23+6 weeks of gestation) and 'very late' (≥24 weeks of gestation). An unplanned or unwanted pregnancy was the most frequently reported reason for delay of the first antenatal visit (30.7%) especially in Surinamese women (79%), and women younger than 20 years (63%) or older than 40 years (50.0%). Compared to women who timed their first antenatal visit 'in time', women with a delay in their first visit were more often younger than 20 or older than 40 years of age, high order multiparous (P ≥3), with a previous miscarriage, and had an absent Dutch language proficiency level. The latter showed the strongest association with a 'very late' first antenatal visit (OR 4.96, 95%CI 2.45-10.05). KEY CONCLUSIONS: Language proficiency level was highly associated with a delay in the timing of the first antenatal visit. When women timed their first antenatal visit late, having an unplanned or unwanted pregnancy was the most frequently reported reason for this delay. IMPLICATIONS FOR PRACTICE: Findings from this study can be used to inform and develop interventions to improve timely antenatal care use.

Nuchal translucency of 3.0-3.4 mm an indication for NIPT or microarray? Cohort analysis and literature review.

INTRODUCTION: Currently fetal nuchal translucency (NT) ≥3.5 mm is an indication for invasive testing often followed by chromosomal microarray. The aim of this study was to assess the risks for chromosomal aberrations in fetuses with an NT 3.0-3.4 mm, to determine whether invasive prenatal testing would be relevant in these cases and to assess the residual risks in fetuses with normal non-invasive prenatal test (NIPT) results. MATERIAL AND METHODS: A retrospective study and meta-analysis of literature cases with NT between 3.0 and 3.4 mm and 2 cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed: Rotterdam region (with a risk >1:200 and NT between 3.0 and 3.4 mm) tested in the period July 2012 to June 2019 and Central Denmark region (with a risk >1:300 and NT between 3.0 and 3.4 mm) tested between September 2015 and December 2018. RESULTS: A total of 522 fetuses were referred for invasive testing and chromosomal microarray. Meta-analysis indicated that in 1:7.4 (13.5% [95% CI 8.2%-21.5%]) fetuses a chromosomal aberration was diagnosed. Of these aberrant cases, 47/68 (69%) involved trisomy 21, 18, and 13 and would potentially be detected by all NIPT approaches. The residual risk for missing a (sub)microscopic chromosome aberration depends on the NIPT approach and is highest if NIPT was performed only for common trisomies-1:21 (4.8% [95% CI 3.2%-7.3%]). However, it may be substantially lowered if a genome-wide 10-Mb resolution NIPT test was offered (~1:464). CONCLUSIONS: Based on these data, we suggest that the NT cut-off for invasive testing could be 3.0 mm (instead of 3.5 mm) because of the high risk of 1:7.4 for a chromosomal aberration. If women were offered NIPT first, there would be a significant diagnostic delay because all abnormal NIPT results need to be confirmed by diagnostic testing. If the woman had already received a normal NIPT result, the residual risk of 1:21 to 1:464 for chromosome aberrations other than common trisomies, dependent on the NIPT approach, should be raised. If a pregnant woman declines invasive testing, but still wants a test with a broader coverage of clinically significant conditions then the genome-wide >10-Mb resolution NIPT test, which detects most aberrations, could be proposed.

Under-reported aspects of diagnosis and treatment addressed in the Dutch-Flemish guideline for comprehensive diagnostics in disorders/differences of sex development.

We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles. Recent initiatives striving for uniform high-quality care across Europe, and beyond, such as the completed COST action 1303 and the European Reference Network for rare endocrine conditions (EndoERN), have generated several excellent papers covering nearly all aspects of DSD. The Dutch-Flemish guideline follows these international consensus papers and covers a number of other topics relevant to daily practice. For instance, although next-generation sequencing (NGS)-based molecular diagnostics are becoming the gold standard for genetic evaluation, it can be difficult to prove variant causality or relate the genotype to the clinical presentation. Network formation and centralisation are essential to promote functional studies that assess the effects of genetic variants and to the correct histological assessment of gonadal material from DSD patients, as well as allowing for maximisation of expertise and possible cost reductions. The Dutch-Flemish guidelines uniquely address three aspects of DSD. First, we propose an algorithm for counselling and diagnostic evaluation when a DSD is suspected prenatally, a clinical situation that is becoming more common. Referral to ultrasound sonographers and obstetricians who are part of a DSD team is increasingly important here. Second, we pay special attention to healthcare professionals not working within a DSD centre as they are often the first to diagnose or suspect a DSD, but are not regularly exposed to DSDs and may have limited experience. Their thoughtful communication to patients, carers and colleagues, and the accessibility of protocols for first-line management and efficient referral are essential. Careful communication in the prenatal to neonatal period and the adolescent to adult transition are equally important and relatively under-reported in the literature. Third, we discuss the timing of (NGS-based) molecular diagnostics in the initial workup of new patients and in people with a diagnosis made solely on clinical grounds or those who had earlier genetic testing that is not compatible with current state-of-the-art diagnostics.

Social and medical need for whole genome high resolution NIPT.

BACKGROUND: Two technological innovations in the last decade significantly influenced the diagnostic yield of prenatal cytogenetic testing: genomic microarray allowing high resolution analysis and noninvasive prenatal testing (NIPT) focusing on aneuploidy. To anticipate future trends in prenatal screening and diagnosis, we evaluated the number of invasive tests in our center and the number of aberrant cases diagnosed in the last decade. METHODS: We retrospectively analyzed fetal chromosomal aberrations diagnosed in 2009-2018 in 8,608 pregnancies without ultrasound anomalies. RESULTS: The introduction of NIPT as the first-tier test led to a substantial decrease in the number of invasive tests and a substantially increased diagnostic yield of aneuploidies in the first trimester. However, we have also noted a decreased detection of submicroscopic aberrations, since the number of invasive tests substantially decreased. We have observed that pregnant women were interested in broader scope of prenatal screening and diagnosis than detection of common trisomies. CONCLUSION: Since the frequency of syndromic disorders caused by microdeletions/microduplications is substantial and current routine NIPT and ultrasound investigations are not able to detect them, we suggest that a noninvasive test with resolution comparable to microarrays should be developed, which will also meet patient's needs.

TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

[Incidental detection of maternal malignancy in non-invasive prenatal test]. / Maligniteit als nevenbevinding bij de niet-invasieve prenatale test.

Since 2017, the non-invasive prenatal test (NIPT) has been offered to all pregnant woman in the Netherlands in the context of the TRIDENT-2 study, which has been implemented as a trial within the Dutch national screening programme for Down's, Edwards' and Patau's syndrome. The NIPT examines cell-free DNA in maternal blood. A small proportion of this DNA is of placental origin, but a vast proportion originates from the expectant mother. Findings other than the aforementioned syndromes are considered incidental. Occasionally, maternal malignancy is suspected in asymptomatic women as a result of aberrant NIPT results. In this case series, we present three patients with suspected malignancy based on NIPT results. We recommend the implementation of clinical guidelines for when this situation arises.

Unexpected finding of uniparental disomy mosaicism in term placentas: Is it a common feature in trisomic placentas?

OBJECTIVE: Non-invasive prenatal testing (NIPT) detects placental chromosome aberrations. When amniocentesis reveals a normal karyotype, confined placental mosaicism (CPM) may be assumed. In order to confirm this, placental cytogenetic studies were performed. METHOD: NIPT was conducted in the course of the Dutch TRIDENT study. Placentas of 10 cases with NIPT results indicating an autosomal trisomy and showing a normal (N = 9) or low mosaic karyotype (N = 1) in amniotic fluid (AF) were investigated. The cytotrophoblast as well as the mesenchymal core of two to four placental chorionic villi biopsies were studied with single nucleotide polymorphism (SNP) array. Clinical outcome data were collected. RESULTS: In 10/10 cases, CPM was proven. In 3/10 cases trisomy/uniparental disomy (UPD)/biparental disomy (BPD) mosaicism was discovered. In 2/3 cases, all three cell lines were present in the placenta, whereas BPD was found in AF. In 1/3 cases trisomy 22/UPD22 was present in AF while trisomy 22/BPD22 mosaicism was found in the placenta. Five of 10 pregnancies were affected with pre-eclampsia, low birth weight, preterm delivery, and/or congenital malformations. CONCLUSION: The presence of trisomy/UPD/BPD mosaicism in 3/10 cases that we investigated proves that trisomic zygote rescue may involve multiple rescue events during early embryogenesis. UPD mosaicism, when present in crucial fetal tissues, may explain the abnormal phenotype in undiagnosed cases.

Ethnicity and Language Proficiency Differences in the Provision of and Intention to Use Prenatal Screening for Down's Syndrome and Congenital Anomalies. A Prospective, Non-selected, Register-Based Study in the Netherlands.

Objective We aimed to conduct an analysis of the associations between the information provision procedure of prenatal screening for Down's syndrome and congenital anomalies and the intention to participate in prenatal screening (PS) of ethnicity groups and Dutch language proficiency groups. Design Using a prospective web-based registration form, we asked counselors (midwives, general practitioners, nurses and gynecologists) to report whether and how they offered information about PS to pregnant women. Duration The study was conducted from 2008 to 2010. Participants We collected data on the characteristics of the women who received an information offer about PS from counselors. Measurements Measures included socio-demographic and language proficiency level (LPL) characteristics, key elements of the provision procedure of PS, and intentional participation in PS. Findings The dataset represents 37% of the total population in the study area. Women with a non-native Dutch background and/or insufficient Dutch LPL received fewer information offers about PS, faced a reduced chance of receiving counseling, and showed lower intentional participation rates for PS. Key Conclusions Women with a non-native Dutch background and/or with an insufficient LPL are underserved in the Dutch PS program. These findings present evidence indicating that the fundamental principle of the Dutch Population Screening Act, namely, equal access to PS for all pregnant women, is not being realized. Implications for Practice Therefore, the study findings are important for national and international healthcare, policy makers and governmental professionals to allow ethnic and LPL-related differences in the provision and intentional uptake of PS.

Inequalities in uptake of prenatal screening according to ethnicity and socio-economic status in the four largest cities of the Netherlands (2011-2013).

OBJECTIVES: In the Netherlands, all women are claimed to have equal access to prenatal screening (PS). Prior research demonstrated substantial inequalities in PS uptake associated with socioeconomic status (SES) and ethnic background. The suggested pathway was a lack of intention to participate in PS among these subgroups. We studied the background of inequalities in PS participation, challenging intention heterogeneity as the single explanation. METHODS: Multivariable logistic regression analyses of the national PS registry, focusing on the four largest cities in the Netherlands (n = 4578, years 2011-2013), stratified by SES. OUTCOME MEASURES: (1) any uptake of PS (yes/no) and (2) uptake (one/two tests) for women who intended to participate in two tests. Determinants included intention, ethnicity, practice, and age. RESULTS: Of non-Western women, 85.7% were screened versus 89.7% of Western women. Intention was an important explanatory factor in all models. However, after correction for intention, ethnicity remained a significant determinant for differences in uptake. Ethnicity and SES also interacted, indicating that non-Western women in low SES areas had the lowest uptake (corrected for intention). CONCLUSIONS FOR PRACTICE: Socioeconomic status and ethnicity related inequalities in PS uptake are only partially explained by intention heterogeneity; other pathways, in particular provider-related determinants, may play a role. © 2017 John Wiley & Sons, Ltd.

The influence of SNP-based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies.

Prenatal diagnostics has been impacted by technological changes in the past decade, which have affected the diagnostic yield. The aim of this study was to evaluate the impact of SNP array and noninvasive prenatal testing (NIPT) on the diagnostic yield and the number of invasive tests in our center. The frequency of pathogenic fetal unbalanced chromosome aberrations was studied in 10,005 cases referred for prenatal testing in 2009-2015. Chromosomal SNP microarray analysis replaced karyotyping in all invasively tested pregnancies and since 2014 a choice between NIPT and diagnostic testing with microarray was offered to women with an increased risk for common aneuploidy. The introduction of microarray led to an additional yield of submicroscopic pathogenic chromosome aberrations: 3.6% in fetuses with ultrasound anomalies and 1.9% in fetuses without ultrasound anomalies. The introduction of NIPT led to a decrease of invasive tests and of diagnostic yield. Moreover, a diagnostic delay in about 1:350 cases was observed. Since 20%-33% of pathogenic fetal chromosome aberrations are different from the common aneuploidies and triploidy, whole-genome analysis should be offered after invasive sampling. Because NIPT (as a second screening) has led to a decreased diagnostic yield, it should be accompanied by an appropriate pretest counseling.

An Audit of Second-Trimester Fetal Anomaly Scans Based on a Novel Image-Scoring Method in the Southwest Region of the Netherlands.

OBJECTIVES: Since 2007 the second-trimester fetal anomaly scan is offered to all pregnant women as part of the national prenatal screening program in the Netherlands. Dutch population-based screening programs generally have a well-described system to achieve quality assurance. Because of the absence of a uniform system to monitor the actual performance of the fetal anomaly scan in 2012, we developed a standardized image-scoring method. The aim of this study was to evaluate the scanning performance of all sonographers in the southwestern region of the Netherlands using this image-scoring method. METHODS: Each sonographer was requested to set up a digital portfolio. A portfolio consists of five logbooks from five different pregnant women, each containing 25 fetal anatomical structures and six biometric measures of randomly selected fetal anomaly scans. RESULTS: During the study period, 425 logbooks of 85 sonographers were assessed as part of the audit process. Seventy-three out of 85 sonographers (86%) met the criteria in the primary audit, and 12 sonographers required individual hands-on training. A successful assessment was achieved for 11 sonographers in the re-audit and one sonographer ceased her contract. Moreover, 2.1% of the required images were not digitally stored and therefore could not be reviewed. CONCLUSIONS: Quality assessment using the image-scoring method demonstrated that most of the sonographers met the expectations of the audit process, but those who had subpar performance met the expectations after retraining.