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... Show moreThe 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. Show less
Palen, R.L.F. van der; Zee, C. van der; Vink, A.S.; Knobbe, I.; Jurgens, S.J.; Leeuwen, E. van; ... ; Clur, S.A.B. 2019
Purpose: Exome sequencing (ES) is an efficient tool to diagnose genetic disorders postnatally. Recent studies show that it may have a considerable diagnostic yield in fetuses with structural... Show morePurpose: Exome sequencing (ES) is an efficient tool to diagnose genetic disorders postnatally. Recent studies show that it may have a considerable diagnostic yield in fetuses with structural anomalies on ultrasound. We report on the clinical impact of the implementation of prenatal ES (pES) for ongoing pregnancies in routine care.Methods: We retrospectively analyzed the impact of pES on pregnancy outcome and pre-or perinatal management in the first 22 patients counseled for pES because of one or more structural anomalies on fetal ultrasound.Results: In two cases, a diagnosis was made by chromosomal microarray analysis after ES counseling. The remaining 20 cases were divided in three groups: (1) pES to aid parental decision making (n = 12), (2) pES in the context of late pregnancy termination requests (n = 5), and (3) pES to guide pre-or perinatal management (n = 3). pES had a clinical impact in 75% (9/12), 40% (2/5), and 100% (3/3) respectively, showing an overall clinical impact of pES of 70% (14/20).Conclusion: We show that clinical implementation of pES is feasible and affects parental decision making or pre- and perinatal management supporting further implementation of ES in the prenatal setting. Show less
Introduction: Congenital heart defects are associated with neurodevelopmental delay. It is hypothesized that fetuses affected by congenital heart defect have altered cerebral oxygen perfusion and... Show moreIntroduction: Congenital heart defects are associated with neurodevelopmental delay. It is hypothesized that fetuses affected by congenital heart defect have altered cerebral oxygen perfusion and are therefore prone to delay in cortical maturation. The aim of this study was to determine the difference in fetal brain age between consecutive congenital heart defect cases and controls in the second and third trimester using ultrasound.Material and methods: Since 2014, we have included 90 isolated severe congenital heart defect cases in the Heart And Neurodevelopment (HAND)-study. Every 4 weeks, detailed neurosonography was performed in these fetuses, including the recording of a 3D volume of the fetal brain, from 20 weeks onwards. In all, 75 healthy fetuses underwent the same protocol to serve as a control group. The volumes were analyzed by automated age prediction software which determines gestational age by the assessment of cortical maturation.Results: In total, 477 volumes were analyzed using the age prediction software (199 volumes of 90 congenital heart defect cases; 278 volumes of 75 controls). Of these, 16 (3.2%) volume recordings were excluded because of imaging quality. The age distribution was 19-33 weeks. Mixed model analysis showed that the age predicted by brain maturation was 3 days delayed compared with the control group (P = .002).Conclusions: This study shows that fetuses with isolated cases of congenital heart defects show some delay in cortical maturation as compared with healthy control cases. The clinical relevance of this small difference is debatable. This finding was consistent throughout pregnancy and did not progress during the third trimester.Keywords: congenital heart defects; fetus; malformations of cortical development; neurodevelopmental outcome; ultrasonography. Show less
Lifelong health is thought to be partially set during intrauterine life by persistent epigenetic changes induced by the prenatal environment. To evaluate this hypothesis, we initiated a prospective... Show moreLifelong health is thought to be partially set during intrauterine life by persistent epigenetic changes induced by the prenatal environment. To evaluate this hypothesis, we initiated a prospective longitudinal study in monochorionic (MC) twins: the TwinLIFE study. MC twins are monozygotic, thus in origin genetically identical, and share a single placenta. Although MC twins have many environmental factors in common, in one-third of the MC twin pairs, one fetus has significantly less access to nutrients and resources during pregnancy than its co-twin often resulting in a significant discordance in prenatal growth. Hence, MC twins constitute a unique natural experiment to study the influence of the prenatal environment on health. In TwinLIFE, we will chart intrapair differences in DNA methylation focusing on mesenchymal stromal cells isolated from cord as an advanced proxy of epigenetic dysregulation relevant for long-term health consequences. Next, we will follow up the MC twins for growth, cardiovascular and neurodevelopmental outcomes during childhood and evaluate the impact of an epigenetic signature at birth on future health. The current target is to include 100 MC twin pairs, but we aim to continue enrollment after procuring additional funding. TwinLIFE will not only address an unmet clinical need in the high-risk group of MC twins, but may also advance early-life strategies to prevent adverse growth, cardiovascular and neurodevelopmental outcomes in the general population. Show less
OBJECTIVE: To assess the effectiveness of amnioinfusion in women with second-trimester preterm prelabor rupture of membranes. METHODS: We performed a nationwide, multicenter, open-label, randomized... Show moreOBJECTIVE: To assess the effectiveness of amnioinfusion in women with second-trimester preterm prelabor rupture of membranes. METHODS: We performed a nationwide, multicenter, open-label, randomized controlled trial, the PPROM: Expectant Management versus Induction of Labor-III (PPROMEXIL-III) trial, in women with singleton pregnancies and preterm prelabor rupture of membranes at 16 0/7 to 24 0/7 weeks of gestation with oligohydramnios (single deepest pocket less than 20 mm). Participants were allocated to transabdominal amnioinfusion or no intervention in a oneto- one ratio by a web-based system. If the single deepest pocket was less than 20 mm on follow-up visits, amnioinfusion was repeated weekly until 28 0/7 weeks of gestation. The primary outcome was perinatal mortality. We needed 56 women to show a reduction in perinatal mortality from 70% to 35% (b error 0.20, two-sided a error 0.05). RESULTS: Between June 15, 2012, and January 13, 2016, we randomized 28 women to amnioinfusion and 28 to no intervention. One woman was enrolled before the trial registration date (June 19, 2012). Perinatal mortality rates were 18 of 28 (64%) in the amnioinfusion group vs 21 of 28 (75%) in the no intervention group (relative risk 0.86, 95% CI 0.601.22, P5.39). CONCLUSION: In women with second-trimester preterm prelabor rupture of membranes and oligohydramnios, we found no reduction in perinatal mortality after amnioinfusion. Show less
We report a case of a monochorionic diamniotic twin diagnosed with twin-twin transfusion syndrome (TTTS; stage 3) with co-existing severe cerebral damage in the donor twin at 18 + 4 weeks'... Show moreWe report a case of a monochorionic diamniotic twin diagnosed with twin-twin transfusion syndrome (TTTS; stage 3) with co-existing severe cerebral damage in the donor twin at 18 + 4 weeks' gestation. After counselling, the parents opted for selective foeticide of the donor twin. For the procedure, radiofrequency ablation (RFA) was used. Serial ultrasound examinations at 20 + 1 and 21 + 1 weeks' gestation showed good recovery of the ex-recipient, after which the patient was sent back to the referring hospital. At 29 + 5 weeks' gestation, an unexpected foetal death was diagnosed. On macroscopic placental examination, (iatrogenic) monoamnionicity was detected. In addition, the umbilical cord of the recipient was found to be constricted by the macerated umbilical cord of the ex-donor. This case demonstrates that iatrogenic monoamnionicity can be a serious complication of RFA in monochorionic twins complicated by TTTS, with a subsequent risk for cord entanglement leading to a fatal outcome for the remaining co-twin. Although the actual incidence of iatrogenic monoamnionicity after RFA remains unknown, increased attention to the intactness of the inter-twin membrane even weeks after the RFA may be required. Show less
