Effect of prenatal screening on trends in perinatal mortality associated with congenital anomalies before and after the introduction of prenatal screening:A population-based study in the Northern Netherlands

BACKGROUND: Perinatal mortality in foetuses/children with congenital anomalies remains high. Prenatal diagnosis, essential for risk assessment and organisation of perinatal/postnatal care, offers parents the opportunity to consider the termination of pregnancy. In times of quick changes in prenatal screening programmes, it is relevant to evaluate the effect of prenatal screening on perinatal mortality rates. OBJECTIVES: The objective of this study was to study trends in early foetal and perinatal mortality associated with congenital anomalies before/after the introduction of the Dutch prenatal screening programme. METHODS: This population‐based cohort study included 8535 foetuses/neonates with congenital anomalies born in the Northern Netherlands between 2001 and 2017. Total deaths were defined as sum of early foetal (before 24 weeks’ gestation) and perinatal deaths (from 24 weeks’ gestation till day 7 post‐partum). Foetal deaths were categorised into spontaneous or elective termination of pregnancy for foetal anomalies (TOPFA). Trends in total mortality as well as early foetal and perinatal mortality were studied. Joinpoint regression was used to calculate the average annual percentage chance (AAPC) and identify linear trends in mortality within subperiods. RESULTS: Total and perinatal mortality were 17% and 4%. Total mortality was higher in abnormal karyotype and central nervous system anomalies. We observed an increase in total mortality over time: 11.9% in 2001 versus 21.9% in 2017 (AAPC 2.6, 95% confidence interval [CI] 1.5, 3.7), caused by an increase in early foetal mortality from 5.5% to 19.2% (AAPC 8.7, 95% CI 4.7, 12.9) and a decrease in perinatal mortality from 6.4% to 2.7% (AAPC −5.6, 95% CI −10.0, −1.0). The increase in early foetal mortality reflects an increase in TOPFA from 3.6% to 16.9% (AAPC 8.3, 95% CI 4.2, 12.7), mostly occurring at 13–14 and 20–23 weeks’ gestation. CONCLUSIONS: The introduction of the prenatal screening programme led to a decrease in perinatal mortality among foetuses and neonates with congenital anomalies and a marked increase in early foetal mortality before 24 weeks’ gestation due to higher rates of TOPFA

The impact of national prenatal screening on the time of diagnosis and outcome of pregnancies affected with common trisomies, a cohort study in the Northern Netherlands

Background: To evaluate the impact of the introduction of prenatal screening on time of detection and pregnancy outcome for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13). Methods: We performed a retrospective, population-based cohort study in the Northern Netherlands including 503 trisomy cases born between 2005 and 2012. Screening tests and invasive procedures, timing of diagnosis and pregnancy outcome were compared between the period before (2005-2006) and after introduction (2007-2012) using chi(2) tests. Results: There was an increase in proportion of women who had a prenatal screening and/or invasive test, from 62% in 2005-2006 to 84% in 2010-2012 (p 35 years (p <0.01). More T13/T18 cases were diagnosed <24 weeks after introduction (62% vs 84%; p <0.01). In T13/T18 intra-uterine death decreased (26% vs 15%), while terminations increased: 55% vs 72%. Conclusion: The introduction of prenatal screening had limited impact on the time of detection and outcome of the most common trisomies. The introduction of the 20-week anomaly scan has resulted in more trisomy cases diagnosed <24 weeks and a shift from fetal death to terminations

Parental experiences of rapid exome sequencing in cases with major ultrasound anomalies during pregnancy

BACKGROUND: Adding rapid Exome Sequencing (rES) to conventional genetic tests improves the diagnostic yield of pregnancies showing ultrasound abnormalities but also carries a higher chance of unsolicited findings. We evaluated how rES, including pre- and post-test counseling, was experienced by parents investigating its impact on decision-making and experienced levels of anxiety. METHODS: A mixed-methods approach was adopted. Participating couples (n=46) were asked to fill in two surveys (pre-test and post-test counseling) and 11 couples were approached for an additional interview. RESULTS: All couples accepted the rES test-offer with the most important reason for testing emphasizing their hope of finding an underlying diagnosis that would aid decision-making. The actual impact on decision-making was low, however, since most parents decided to terminate the pregnancy based on the major and multiple fetal ultrasound anomalies and did not wait for their rES results. Anxiety was elevated for most participants and decreased over time. CONCLUSION: Major congenital anomalies detected on ultrasound seem to have more impact on prenatal parental decision-making and anxiety then the offer and results of rES. However, the impact of rES on reproductive decision-making and experienced anxiety requires further investigation, especially in pregnancies where less (severe) fetal anomalies are detected on ultrasound. This article is protected by copyright. All rights reserved

Stillbirth and neonatal mortality in pregnancies complicated by major congenital anomalies:Findings from a large European cohort

Objective: To provide prognostic information to help parents to reach an informed decision about termination or continuation of the pregnancy and to shape peripartum policy based on a large European cohort. Method: Thirteen registries from the European Surveillance of Congenital Anomalies (EUROCAT) network contributed data from January 1, 1998, to December 31, 2011. Terminations for fetal anomalies were excluded. Chromosomal anomalies, syndromes and isolated anomaly groups were distinguished according to EUROCAT guidelines. Perinatal mortality, stillbirths, and early and late neonatal mortality rates (NMRs) were analyzed by anomaly group and gestational age. Results: Among 73337 cases, perinatal mortality associated with congenital anomaly was 1.27 per 1000 births (95% confidence interval, 1.23-1.31). Average stillbirth rate was 2.68% (range 0%-51.2%). Early and late NMR were 2.75% (range 0%-46.7%) and 0.97% (range 0%-17.9%), respectively. Chromosomal anomalies and syndromes, and most isolated anomalies, had significant differences regarding timing of fetal demise compared to the general population. Chromosomal and central nervous system anomalies had higher term stillbirth rates. Conclusions: We found relevant differences between anomalies regarding rates of stillbirth, NMR, and timing by gestational age. Our data can help parents to decide about their unborn child with a congenital anomaly and help inform maternal-fetal medicine specialists regarding peripartum management

NIPTRIC:an online tool for clinical interpretation of non-invasive prenatal testing (NIPT) results

To properly interpret the result of a pregnant woman's non-invasive prenatal test (NIPT), her a priori risk must be taken into account in order to obtain her personalised a posteriori risk (PPR), which more accurately expresses her true likelihood of carrying a foetus with trisomy. Our aim was to develop a tool for laboratories and clinicians to calculate easily the PPR for genome-wide NIPT results, using diploid samples as a control group. The tool takes the a priori risk and Z-score into account. Foetal DNA percentage and coefficient of variation can be given default settings, but actual values should be used if known. We tested the tool on 209 samples from pregnant women undergoing NIPT. For Z-scores <5, the PPR is considerably higher at a high a priori risk than at a low a priori risk, for NIPT results with the same Z-score, foetal DNA percentage and coefficient of variation. However, the PPR is effectively independent under all conditions for Z-scores above 6. A high PPR for low a priori risks can only be reached at Z-scores > 5. Our online tool can assist clinicians in understanding NIPT results and conveying their true clinical implication to pregnant women, because the PPR is crucial for individual counselling and decision-making

Noninvasive Prenatal Test Results Indicative of Maternal Malignancies:A Nationwide Genetic and Clinical Follow-Up Study

PURPOSE: Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA derived from maternal plasma can incidentally raise suspicion for cancer. Diagnostic routing after malignancy suspicious-NIPT faces many challenges. Here, we detail malignancy suspicious-NIPT cases, and describe the clinical characteristics, chromosomal aberrations, and diagnostic routing of the patients with a confirmed malignancy. Clinical lessons can be learned from our experience. METHODS: Patients with NIPT results indicative of a malignancy referred for tumor screening between April 2017 and April 2020 were retrospectively included from a Dutch nationwide NIPT implementation study, TRIDENT-2. NIPT profiles from patients with confirmed malignancies were reviewed, and the pattern of chromosomal aberrations related to tumor type was analyzed. We evaluated the diagnostic contribution of clinical and genetic examinations. RESULTS: Malignancy suspicious-NIPT results were reported in 0.03% after genome-wide NIPT, and malignancies confirmed in 16 patients (16/48, 33.3%). Multiple chromosomal aberrations were seen in 23 of 48 patients with genome-wide NIPT, and a malignancy was confirmed in 16 patients (16/23, 69.6%). After targeted NIPT, 0.005% malignancy suspicious-NIPT results were reported, in 2/3 patients a malignancy was confirmed. Different tumor types and stages were diagnosed, predominantly hematologic malignancies (12/18). NIPT data showed recurrent gains and losses in primary mediastinal B-cell lymphomas and classic Hodgkin lymphomas. Magnetic resonance imaging and computed tomography were most informative in diagnosing the malignancy. CONCLUSION: In 231,896 pregnant women, a low percentage (0.02%) of NIPT results were assessed as indicative of a maternal malignancy. However, when multiple chromosomal aberrations were found, the risk of a confirmed malignancy was considerably high. Referral for extensive oncologic examination is recommended, and may be guided by tumor-specific hallmarks in the NIPT profile

Multiplex ligation-dependent probe amplification versus karyotyping in prenatal diagnosis: the M.A.K.E. study

Abstract BACKGROUND: In the past 30 years karyotyping was the gold standard for prenatal diagnosis of chromosomal aberrations in the fetus. Traditional karyotyping (TKT) has a high accuracy and reliability. However, it is labor intensive, the results take 14-21 days, the costs are high and unwanted findings such as abnormalities with unknown clinical relevance are not uncommon. These disadvantages challenged the practice of karyotyping. Multiplex ligation-dependent probe amplification (MLPA) is a new molecular genetic technique in prenatal diagnosis. Previous preclinical evidence suggests equivalence of MLPA and traditional karyotyping (TKT) regarding test performance. METHODS/DESIGN: The proposed study is a multicentre diagnostic substitute study among pregnant women, who choose to have amniocentesis for the indication advanced maternal age and/or increased risk following prenatal screening test. In all subjects, both MLPA and karyotyping will be performed on the amniotic fluid sample. The primary outcome is diagnostic accuracy. Secondary outcomes will be maternal quality of life, women's preferences and costs. Analysis will be intention to treat and per protocol analysis. Quality of life analysis will be carried out within the study population. The study aims to include 4500 women. DISCUSSION: The study results are expected to help decide whether MLPA can replace traditional karyotyping for 'low-risk' pregnancies in terms of diagnostic accuracy, quality of life and women's preferences. This will be the first clinical study to report on all relevant aspects of the potential replacement

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 weigh