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Contains fulltext : 251979.pdf (Publisher’s version ) (Open Access) 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

Contains fulltext : 294339.pdf (Publisher’s version ) (Open Access) OBJECTIVES: First-trimester ultrasound screening is increasingly performed to detect fetal anomalies early in pregnancy, aiming to enhance reproductive autonomy for future parents. This study aims to display the current practice of first-trimester ultrasound screening in developed countries. METHOD: An online survey among 47 prenatal screening experts in developed countries. RESULTS: First-trimester structural anomaly screening is available in 30 of the 33 countries and is mostly offered to all women with generally high uptakes. National protocols are available in 23/30 (76.7%) countries, but the extent of anatomy assessment varies. Monitoring of scan quality occurs in 43.3% of the countries. 23/43 (53.5%) of the respondents considered the quality of first-trimester ultrasound screening unequal in different regions of their country. CONCLUSIONS: First-trimester screening for structural fetal anomalies is widely offered in developed countries, but large differences are reported in availability and use of screening protocols, the extent of anatomy assessment, training and experience of sonographers and quality monitoring systems. Consequently, this results in an unequal offer to parents in developed countries, sometimes even within the same country. Furthermore, as offer and execution differ widely, this has to be taken into account when results of screening policies are scientifically published or compared. 01 juni 2023

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.

Contains fulltext : 154468.pdf (Publisher’s version ) (Closed access) OBJECTIVE: This study evaluates pregnant women's and healthcare professionals' preferences regarding specific prenatal screening and diagnostic test characteristics. METHOD: A discrete choice experiment was developed to assess preferences for prenatal tests that differed in seven attributes: minimal gestational age, time to test results, level of information, detection rate, false positive rate, miscarriage risk and costs. RESULTS: The questionnaire was completed by 596 (70.2%) pregnant women and 297 (51.7%) healthcare professionals, of whom 507 (85.1%) and 283 (95.3%), respectively, were included in further analyses as their choice behavior indicated prenatal testing was an option to them. Comparison of results showed differences in relative importance attached to attributes, further reflected by differences in willingness to trade between attributes. Pregnant women are willing to accept a less accurate test to obtain more information on fetal chromosomal status or to exclude the risk of procedure-related miscarriage. Healthcare professionals consider level of information and miscarriage risk to be most important as well but put more emphasis on timing and accuracy. CONCLUSION: Pregnant women and healthcare professionals differ significantly in their preferences regarding prenatal test characteristics. Healthcare professionals should take these differences into consideration when counseling pregnant women on prenatal testing. (c) 2015 John Wiley & Sons, Ltd.

Item does not contain fulltext This overview provides insight into the underlying genetic mechanism of the high incidence of cardiac defects in fetuses with increased nuchal translucency (NT). Nuchal edema, the morphological equivalent of increased NT, is likely to result from abnormal lymphatic development and is strongly related to cardiac defects. The underlying genetic pathways are, however, unknown. This study aims to present a systematic overview of genes involved in both cardiac and lymphatic development in mouse embryos. A search of PubMed and the Mammalian Phenotype Browser was performed. Fifteen candidate genes involved in both cardiac and lymphatic development were identified: Adrenomedullin; Chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TFII); Cyp51; Ephrin-B2; Forkhead box protein C2 (Foxc2); Nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1); Neurofibromatosis type 1 (Nf1); Phosphoinositide 3-kinase encoding isoform p110alpha (Pik3ca); Podoplanin; Prospero-related homeobox 1 (Prox1); T-box 1 (Tbx1); Tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains 1 (Tie1); vascular endothelial growth factor (Vegf)-A; Vegf receptor-3 (Vegfr-3); and Vascular endothelial zinc finger 1 (Vezf1). Mutations in all but one gene (Pik3ca) resulted in both a cardiac defect and nuchal edema. Candidate genes - mainly encoding for endothelium - are involved in both cardiac and lymphatic development. Alterations in candidate genes are associated with the strong relation between increased NT and cardiac defects. (c) 2015 John Wiley & Sons, Ltd.

Item does not contain fulltext OBJECTIVE: Increased nuchal translucency originates from disturbed lymphatic development. Abnormal neural crest cell (NCC) migration may be involved in lymphatic development. Because both neuronal and lymphatic development share retinoic acid (RA) as a common factor, this study investigated the involvement of NCCs and RA in specific steps in lymphatic endothelial cell (LEC) differentiation and nuchal edema, which is the morphological equivalent of increased nuchal translucency. METHODS: Mouse embryos in which all NCCs were fluorescently labeled (Wnt1-Cre;Rosa26(eYfp) ), reporter embryos for in vivo RA activity (DR5-luciferase) and embryos with absent (Raldh2(-/-) ) or in utero inhibition of RA signaling (BMS493) were investigated. Immunofluorescence using markers for blood vessels, lymphatic endothelium and neurons was applied. Flow cytometry was performed to measure specific LEC populations. RESULTS: Cranial nerves were consistently close to the jugular lymph sac (JLS), in which NCCs were identified. In the absence of RA synthesis, enlarged JLS and nuchal edema were observed. Inhibiting RA signaling in utero resulted in a significantly higher amount of precursor-LECs at the expense of mature LECs and caused nuchal edema. CONCLUSIONS: Neural crest cells are involved in lymphatic development. RA is required for differentiation into mature LECs. Blocking RA signaling in mouse embryos results in abnormal lymphatic development and nuchal edema. (c) 2014 John Wiley & Sons, Ltd.

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Item does not contain fulltext OBJECTIVES: To analyze the outcomes of fetuses referred because of short femur length. METHODS: This was a retrospective study of all singleton pregnancies referred to a tertiary care referral hospital with a femur length below the 5(th) percentile. All ultrasound scan reports, including Doppler, fetal karyotyping, pregnancy outcome and neonatal data were analyzed. RESULTS: In 112 patients, 87 (78%) had an isolated short femur and 25 (22%) had a non-isolated short femur. The non-isolated cases consisted of chromosomal disorders (n = 6), skeletal abnormalities (n = 6), multiple abnormalities (n = 12) and 1 genetic disorder. In the isolated group 37 cases (43%) were intrauterine growth restricted (positive likelihood ratio 1.20, negative likelihood ratio 0.45). In 33 cases the short femur was unexplained and 17 referrals were considered false-positive. The growth restricted group had significant more abnormal Doppler measurements (p = 0.01), caesarean deliveries (p = 0.043) and admissions to the neonatal intensive care unit (p = 0.001). CONCLUSION: An isolated short femur is associated with intrauterine growth restriction and adverse pregnancy outcome.

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Item does not contain fulltext OBJECTIVE: Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60-70% of the Noonan syndrome cases, a gene mutation can be demonstrated. Previous research showed that aneuploid fetuses with increased nuchal translucency (NT) demonstrate an aberrant lymphatic endothelial differentiation. METHOD: Fetuses with increased NT and normal karyotype (n = 7) were compared with euploid controls having normal NT (n = 5). A Noonan syndrome gene mutation was found in three out of seven fetuses with increased NT. Endothelial differentiation was evaluated by immunohistochemistry using lymphatic markers (PROX-1, Podoplanin, LYVE-1) and blood vessel markers vascular endothelial growth factor-A (VEGF-A), Neuropilin-1 (NP-1), Sonic hedgehog, von Willebrand factor, and the smooth muscle cell marker, smooth muscle actin. RESULTS: Nuchal edema and enlarged jugular lymphatic sacs (JLSs) were observed in fetuses with increased NT, together with abnormal lymphatic endothelial differentiation i.e. the presence of blood vessel characteristics, including high levels of VEGF-A and NP-1 expression. The enlarged JLSs contained erythrocytes and were surrounded by smooth muscle cells. CONCLUSION: This study shows an aberrant lymphatic endothelial differentiation in fetuses with increased NT and a normal karyotype (including Noonan syndrome fetuses), as was previously reported before in aneuploid fetuses. 01 februari 2011

Objective. The purpose of this study was to evaluate ductus venosus flow velocities and a possible relationship with the type of cardiac defect in fetuses with increased nuchal translucency (NT). Methods. Seventy-two fetuses with normal NT and 137 fetuses with increased NT (>95th percentile) were evaluated. The ductus venosus pulsatility index for veins (Ply), late diastolic velocity (velocity during atrial contraction [a-V]), and intracardiac velocities were evaluated. In cases of pregnancy termination, a postmortem examination was performed. Cardiac defects were grouped into septal defects, left and right inflow obstruction, left and right outflow obstruction, and other defects. Data were evaluated by multilevel analysis. Results. A cardiac defect was found in 45 fetuses with increased NT. Fetuses with increased NT showed a higher ductus venosus PIV and a lower a-V compared to fetuses with normal NT (P < .05). Within the group of fetuses with increased NT, a higher PIV and a lower a-V were found in cases with a cardiac defect compared to cases with a normal heart (P < .001). No differences in PIV and a-V were found between the types of cardiac defects. Intracardiac velocities showed no differences between fetuses with normal and increased NT, irrespective of the presence of a cardiac defect. Conclusions. Ductus venosus flow velocities in fetuses with increased NT are not related to a certain type of cardiac defect. This indicates that the altered ductus venosus flow velocities found in fetuses with increased NT cannot be explained by cardiac failure due to a specific altered cardiac anatomy.

Our healthcare system is under increasing pressure, both in terms of financial and human capacity, which forces us into difficult choices. Value-based healthcare offers a theory in which the outcomes of care that matter to patients, relative to the costs incurred, are leading in these choices. Important principles of value-based healthcare are organizing care around the patient and gaining insight into care outcomes that matter to patients. In perinatal care, collaboration around the pregnant woman (integrated maternity care) is already underway, but relatively little insight exists into care results from the patient's perspective. In this thesis, we investigated how structured questionnaires on patient-reported outcomes of perinatal care, such as breastfeeding or incontinence, and experiences, such as satisfaction or autonomy, can contribute to improved care. In clinic, we saw that discussing answers individually as part of regular care contacts helped to identify complaints and personalize care, provided that the questionnaires were properly aligned with the care path. At group level, the insight into outcome data gave healthcare providers motivation for quality improvement. Translating the data into recognizable personas helped to achieve substantive discussion and improvement actions. The network-wide approach to measuring and improving outcomes ensured patient-centeredness but hindered implementation. The iterative, context-specific approach of action research helped to achieve change. The findings in this thesis provide direction for the implementation and application of patient-reported measures around pregnancy and childbirth to strengthen the development towards a healthcare system driven by value for patients.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare but potentially life threatening disease that can lead to intracranial haemorrhage (ICH) in babies during fetal development and the neonatal period. ICH is associated with perinatal mortality and can lead to long-term neurodevelopmental impairment. If pregnancies at risk for FNAIT are identified upon antenatal screening, timely intervention could prevent the occurrence of fetal ICH. Implementation of population-based screening to prevent FNAIT is hampered by the lack of knowledge on the natural history, whom to treat and costs of case finding. We performed a large nationwide screening study and provide new evidence on the incidence of FNAIT. In addition, we confirm the value of risk factors for immunisation and severe disease. We describe current postnatal treatment strategies and the long-term outcome of cases that were affected by FNAIT. Based on these studies, we conducted a cost-effectiveness analysis comparing the situation with antenatal screening to the current situation without screening. In the general discussion, we evaluate the knowledge gained in this thesis and in the available literature guided by the principles from Wilson and Junger. We conclude that knowledge is available to all principles and nationwide screening for FNAIT during pregnancy seems warranted.

Around 10% of pregnancies in the Netherlands are complicated by different obstetric complications. Follow up of these pregnancies need extra surveillance with weekly visits or antenatal hospital admission. This thesis describes the use of digital health in pregnancy to replace hospital care to home care for antenatal follow up of complicated pregnancies. Hypertension in pregnancy is increasingly common, and an important cause of maternal and neonatal morbidity and mortality, at short as well as long term. Frequent monitoring of blood pressure (BP), fetal growth, blood and urine during pregnancy is recommended to early identify and monitor hypertensive disease. Interfering with daily life, (un)planned visits and hospitalization pose a substantial burden to patients and care resources. From our SAFE@HOME studies, we found that telemonitoring of blood pressure and symptoms can be of added value in antenatal care. We developed a digital care platform for daily monitoring of home-measurements. In case of good test results, there is no need for (unplanned) hospital visits. In care of a rise in blood pressure, extra visits can be planned. Telemonitoring was associated with a decrease in health care consumption (visits, ultrasounds and hypertension-related hospital admission), without negative effects on maternal and neonatal outcomes. Moreover, home blood pressure monitoring gave pregnant women more insight into their own health and helped (shared) decision making in pregnancy care. In the second part of the thesis, our research focused on pregnant women with established complications requiring daily fetal and maternal monitoring. To compare standard hospital admission with telemonitoring of cardiotocography and blood pressure from home, we performed different studies in order to increase knowledge of this use of digital health for complicated pregnancies. From our work, fetal telemonitoring is feasible for use in the Netherlands. The results from this thesis suggest that use of digital health in pregnancy has the potential to profoundly change antenatal care.

Item does not contain fulltext RU Radboud Universiteit, 05 juli 2016 Promotor : Vugt, J.M.G. van Co-promotores : Bekker, M.N., Faas, B.H.W.