Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

Maternal and neonatal antibody levels on pertussis vaccination in pregnant women on immune-modulating therapy for rheumatic disease.

OBJECTIVES: While protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In this pilot study, we explored whether treatment with tumour necrosis factor alpha inhibitors (TNFis) in pregnant patients with rheumatic disease interferes with Tdap vaccine responses and affects maternal anti-pertussis IgG antibody levels in newborns. METHODS: Patients were included by a rheumatologist during pregnancy in case they received maternal Tdap vaccination in the late-second or early-third trimester of pregnancy. Blood samples were obtained from mothers during the first pregnancy trimester, 3 months after delivery and from the umbilical cord. IgG antibody levels against Tdap-included antigens were measured using a bead-based multiplex immunoassay. Findings on patients exposed to TNFis were compared with those from TNFi-unexposed patients and with data from a historical comparator study among healthy Tdap vaccinated mother-infant pairs (n=53). RESULTS: 66 patients (46 exposed and 20 unexposed to TNFIs) were enrolled. No major differences in IgG antibody levels were observed between TNFi-exposed and unexposed mothers before maternal Tdap vaccination and 3 months after delivery. In cord sera, however, antibody levels against pertussis toxin were significantly lower after TNFi-treatment (35.94 IU/mL, 95% CI 20.68 to 62.45) compared with no TNFi-treatment of mothers with rheumatic disease (94.61 IU/mL, 95% CI 48.89 to 183.07) and lower compared with a cohort of healthy mothers (125.12 IU/mL, 95% CI 90.75 to 172.50). We observed similar differences for filamentous haemagglutinin, pertactin, tetanus toxoid and diphtheria toxoid. CONCLUSION: These preliminary data indicate no major differences in IgG antibody levels on maternal Tdap vaccination in pregnant women with or without immune-modulating treatment, although our findings suggest that TNFis during pregnancy induce lower maternal anti-pertussis-specific protective antibody levels in newborns.

Monoclonal antibodies effectively potentiate complement activation and phagocytosis of Staphylococcus epidermidis in neonatal human plasma.

Central line associated bloodstream infections (CLABSI) with Staphylococcus epidermidis are a major cause of morbidity in neonates, who have an increased risk of infection because of their immature immune system. As especially preterm neonates suffer from antibody deficiency, clinical studies into preventive therapies have thus far focused on antibody supplementation with pooled intravenous immunoglobulins from healthy donors (IVIG) but with little success. Here we study the potential of monoclonal antibodies (mAbs) against S. epidermidis to induce phagocytic killing by human neutrophils. Nine different mAbs recognizing Staphylococcal surface components were cloned and expressed as human IgG1s. In binding assays, clones rF1, CR5133 and CR6453 showed the strongest binding to S. epidermidis ATCC14990 and CR5133 and CR6453 bound the majority of clinical isolates from neonatal sepsis (19 out of 20). To study the immune-activating potential of rF1, CR5133 and CR6453, bacteria were opsonized with mAbs in the presence or absence of complement. We observed that activation of the complement system is essential to induce efficient phagocytosis of S. epidermidis. Complement activation and phagocytic killing could be enhanced by Fc-mutations that improve IgG1 hexamerization on cellular surfaces. Finally, we studied the ability of the mAbs to activate complement in r-Hirudin neonatal plasma conditions. We show that classical pathway complement activity in plasma isolated from neonatal cord blood is comparable to adult levels. Furthermore, mAbs could greatly enhance phagocytosis of S. epidermidis in neonatal plasma. Altogether, our findings provide insights that are crucial for optimizing anti-S. epidermidis mAbs as prophylactic agents for neonatal CLABSI.

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.

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. METHODS AND FINDINGS: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. CONCLUSIONS: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. TRIAL REGISTRATION: Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

Associations between periconceptional lifestyle behaviours and adverse pregnancy outcomes.

BACKGROUND: While the potential adverse outcomes of prenatal exposure to unhealthy lifestyle are widely evidenced, little is known about these exposures in the periconception period. We investigated the associations between lifestyle behaviours and adverse pregnancy outcomes with a unique distinction between preconceptional- and prenatal lifestyle behaviours. METHODS: A secondary analysis took place within a prospective multicentre cohort study in the Netherlands, including 3,684 pregnant women. Baseline characteristics and preconceptional and first trimester lifestyle behaviours were assessed through a self-administered questionnaire in the first trimester. Adverse pregnancy outcomes (hypertensive disorders in pregnancy (HDP), small for gestational age (SGA), gestational diabetes (GDM) and spontaneous preterm birth (sPTB)) were reported by healthcare professionals. Data were collected between 2012 and 2014 and analysed using multivariate logistic regression. RESULTS: Women who are overweight, and especially obese, have the highest odds of developing any adverse pregnancy outcome (adjusted odds ratio (aOR) 1.61 (95 % Confidence Interval (CI) 1.31-1.99) and aOR 2.85 (95 %CI 2.20-3.68), respectively), particularly HDP and GDM. Women who prenatally continued smoking attained higher odds for SGA (aOR 1.91 (95 %CI 1.05-1.15)) compared to the reference group, but these odds decreased when women prenatally quit smoking (aOR 1.14 (95 %CI 0.59-2.21)). Women who did not use folic acid supplements tended to have a higher odds of developing adverse pregnancy outcomes (aOR 1.28 (95 %CI 0.97-1.69)), while women who prenatally started folic acid supplements did not (aOR 1.01 (95 %CI 0.82-1.25)). CONCLUSIONS: Our results indicate that smoking cessation, having a normal body mass index (BMI) and initiating folic acid supplements preconceptionally may decrease the risk of adverse pregnancy outcomes. Therefore, intervening as early as the preconception period could benefit the health of future generations.

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.

Implementation of a first-trimester prognostic model to improve screening for gestational diabetes mellitus.

BACKGROUND: Improvement in the accuracy of identifying women who are at risk to develop gestational diabetes mellitus (GDM) is warranted, since timely diagnosis and treatment improves the outcomes of this common pregnancy disorder. Although prognostic models for GDM are externally validated and outperform current risk factor based selective approaches, there is little known about the impact of such models in day-to-day obstetric care. METHODS: A prognostic model was implemented as a directive clinical prediction rule, classifying women as low- or high-risk for GDM, with subsequent distinctive care pathways including selective midpregnancy testing for GDM in high-risk women in a prospective multicenter birth cohort comprising 1073 pregnant women without pre-existing diabetes and 60 obstetric healthcare professionals included in nine independent midwifery practices and three hospitals in the Netherlands (effectiveness-implementation hybrid type 2 study). Model performance (c-statistic) and implementation outcomes (acceptability, adoption, appropriateness, feasibility, fidelity, penetration, sustainability) were evaluated after 6 months by indicators and implementation instruments (NoMAD; MIDI). RESULTS: The adherence to the prognostic model (c-statistic 0.85 (95%CI 0.81-0.90)) was 95% (n = 1021). Healthcare professionals scored 3.7 (IQR 3.3-4.0) on implementation instruments on a 5-point Likert scale. Important facilitators were knowledge, willingness and confidence to use the model, client cooperation and opportunities for reconfiguration. Identified barriers mostly related to operational and organizational issues. Regardless of risk-status, pregnant women appreciated first-trimester information on GDM risk-status and lifestyle advice to achieve risk reduction, respectively 89% (n = 556) and 90% (n = 564)). CONCLUSIONS: The prognostic model was successfully implemented and well received by healthcare professionals and pregnant women. Prognostic models should be recommended for adoption in guidelines.

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.

eHealth as the Next-Generation Perinatal Care: An Overview of the Literature.

BACKGROUND: Unrestricted by time and place, electronic health (eHealth) provides solutions for patient empowerment and value-based health care. Women in the reproductive age are particularly frequent users of internet, social media, and smartphone apps. Therefore, the pregnant patient seems to be a prime candidate for eHealth-supported health care with telemedicine for fetal and maternal conditions. OBJECTIVE: This study aims to review the current literature on eHealth developments in pregnancy to assess this new generation of perinatal care. METHODS: We conducted a systematic literature search of studies on eHealth technology in perinatal care in PubMed and EMBASE in June 2017. Studies reporting the use of eHealth during prenatal, perinatal, and postnatal care were included. Given the heterogeneity in study methods, used technologies, and outcome measurements, results were analyzed and presented in a narrative overview of the literature. RESULTS: The literature search provided 71 studies of interest. These studies were categorized in 6 domains: information and eHealth use, lifestyle (gestational weight gain, exercise, and smoking cessation), gestational diabetes, mental health, low- and middle-income countries, and telemonitoring and teleconsulting. Most studies in gestational diabetes and mental health show that eHealth applications are good alternatives to standard practice. Examples are interactive blood glucose management with remote care using smartphones, telephone screening for postnatal depression, and Web-based cognitive behavioral therapy. Apps and exercise programs show a direction toward less gestational weight gain, increase in step count, and increase in smoking abstinence. Multiple studies describe novel systems to enable home fetal monitoring with cardiotocography and uterine activity. However, only few studies assess outcomes in terms of fetal monitoring safety and efficacy in high-risk pregnancy. Patients and clinicians report good overall satisfaction with new strategies that enable the shift from hospital-centered to patient-centered care. CONCLUSIONS: This review showed that eHealth interventions have a very broad, multilevel field of application focused on perinatal care in all its aspects. Most of the reviewed 71 articles were published after 2013, suggesting this novel type of care is an important topic of clinical and scientific relevance. Despite the promising preliminary results as presented, we accentuate the need for evidence for health outcomes, patient satisfaction, and the impact on costs of the possibilities of eHealth interventions in perinatal care. In general, the combination of increased patient empowerment and home pregnancy care could lead to more satisfaction and efficiency. Despite the challenges of privacy, liability, and costs, eHealth is very likely to disperse globally in the next decade, and it has the potential to deliver a revolution in perinatal care.

Pessary or Progesterone to Prevent Preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial.

BACKGROUND: Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments. METHODS/DESIGN: The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs. DISCUSSION: This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples. TRIAL REGISTRATION: Trial registration number: NTR 4414 . Date of registration January 29th 2014.

Cardiac defects, nuchal edema and abnormal lymphatic development are not associated with morphological changes in the ductus venosus.

BACKGROUND: In human fetuses with cardiac defects and increased nuchal translucency, abnormal ductus venosus flow velocity waveforms are observed. It is unknown whether abnormal ductus venosus flow velocity waveforms in fetuses with increased nuchal translucency are a reflection of altered cardiac function or are caused by local morphological alterations in the ductus venosus. AIM: The aim of this study was to investigate if the observed increased nuchal translucency, cardiac defects and abnormal lymphatic development in the examined mouse models are associated with local changes in ductus venosus morphology. STUDY DESIGN: Mouse embryos with anomalous lymphatic development and nuchal edema (Ccbe1(-/-) embryos), mouse embryos with cardiac defects and nuchal edema (Fkbp12(-/-), Tbx1(-/-), Chd7(fl/fl);Mesp1Cre, Jarid2(-/-NE+) embryos) and mouse embryos with cardiac defects without nuchal edema (Tbx2(-/-), Fgf10(-/-), Jarid2(-/-NE-) embryos) were examined. Embryos were analyzed from embryonic day (E) 11.5 to 15.5 using markers for endothelium, smooth muscle actin, nerve tissue and elastic fibers. RESULTS: All mutant and wild-type mouse embryos showed similar, positive endothelial and smooth muscle cell expression in the ductus venosus at E11.5-15.5. Nerve marker and elastic fiber expression were not identified in the ductus venosus in all investigated mutant and wild-type embryos. Local morphology and expression of the used markers were similar in the ductus venosus in all examined mutant and wild-type embryos. CONCLUSIONS: Cardiac defects, nuchal edema and abnormal lymphatic development are not associated with morphological changes in the ductus venosus. Ductus venosus flow velocity waveforms most probably reflect intracardiac pressure.

Why increased nuchal translucency is associated with congenital heart disease: a systematic review on genetic mechanisms.

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 p110α (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.

The consequences of implementing non-invasive prenatal testing in Dutch national health care: a cost-effectiveness analysis.

OBJECTIVE: Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy. Clinical trials have shown high sensitivity and specificity for trisomy 21 (T21) in both high-risk and average-risk populations. Although its great potential for prenatal medicine is evident, more information regarding the consequences of implementing NIPT in a national programme for prenatal screening is required. STUDY DESIGN: A decision-analytic model was developed to compare costs and outcomes of current clinical practice in The Netherlands using conventional screening only, with two alternatives: implementing NIPT as an optional secondary screening test for those pregnancies complicated by a high risk for T21, and implementing NIPT as primary screening test, replacing conventional screening. Probability estimates were derived from a systematic review of international literature. Costs were determined from a health-care perspective. Data were analysed to obtain outcomes, total costs, relative costs and incremental cost-effectiveness ratios (ICERs) for the different strategies. Sensitivity analysis was used to assess the impact of assumptions on model results. RESULTS: Implementing NIPT as an optional secondary, or as primary screening test will increase T21 detection rate by 36% (from 46.8% to 63.5%) and 54% (from 46.8% to 72.0%), simultaneously decreasing the average risk of procedure-related miscarriage by 44% (from 0.0168% to 0.0094% per pregnant woman) and 62% (from 0.0168% to 0.0064% per pregnant woman), respectively. None of the strategies clearly dominated: current clinical practice is the least costly, whereas implementing NIPT will cause total costs of the programme to increase by 21% (from €257.09 to €311.74 per pregnant woman), leading to an ICER of k€94 per detected case of T21, when utilised as an optional secondary screening test and by 157% (from €257.09 to €660.94 per pregnant woman), leading to an ICER of k€460 per detected case of T21, when utilised as primary screening test. However, implementing NIPT as triage test did result in the lowest expected relative costs per case of T21 diagnosed (k€141). CONCLUSION: NIPT should be implemented in national health care as an optional secondary screening test for those pregnancies complicated by a high risk for T21.

Positive predictive values for detection of trisomies 21, 18 and 13 and termination of pregnancy rates after referral for advanced maternal age, first trimester combined test or ultrasound abnormalities in a national screening programme (2007-2009).

OBJECTIVE: The objective of this article is to analyse the positive predictive value (PPV) of trisomies 21, 18 and 13 after referral for advanced maternal age (AMA), first trimester combined test or ultrasound findings to suggest improvements for clinical practice. METHODS: Data (48 457 combined tests, 134 000 fetal anomaly scans and 24 379 invasive prenatal tests) were combined to calculate PPV and termination of pregnancy rates. RESULTS: For referral for AMA, the PPV for T21 was 1.0% and 1.8% for amniocentesis and chorionic villus biopsy, respectively; for the combined test at a maternal age ≥36 years, these percentages were 4.9% and 12.5%, respectively and for maternal age <36 years, 4.4% and 8.1%, respectively. For ultrasound findings, the PPV was 5.3% and 14.8%, respectively. Termination of pregnancy rate upon trisomy 21 diagnosis was >90% unless detected after referral for ultrasound findings (71.5-85.9%). About 50% of pregnant women with a high combined test risk chose not to have invasive testing. CONCLUSIONS: Advanced MA is still a large contributor to invasive testing but should be abandoned (low PPV, high fetal loss rate) and be replaced by reimbursable combined test screening for all women. Patient information on second trimester ultrasound screening should indicate that abnormal ultrasound findings are associated with high trisomy rate.

Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency.

OBJECTIVE: Previous research in fetuses with increased nuchal translucency (NT) showed abnormal lymphatic endothelial differentiation characteristics, including increased vascular endothelial growth factor (VEGF)-A expression, and aberrant smooth muscle cells (SMCs) surrounding enlarged jugular lymphatic sacs (JLS). We hypothesized that abnormal Sonic hedgehog (Shh) expression would result in altered VEGF-A signaling in the lymphatic endothelial cells of the JLS and that aberrant acquisition of SMCs could be caused by downregulation of forkhead transcription factor FOXC2 and upregulation of platelet-derived growth factor (PDGF)-B in the lymphatic endothelial cells of the JLS. METHODS: Five trisomy 21 fetuses and four controls were investigated using immunohistochemistry for Shh, VEGF-A, FOXC2 and PDGF-B expression in the lymphatic endothelial cells of the JLS. RESULTS: An increased Shh, VEGF-A and PDGF-B expression, and decreased FOXC2 expression were shown in the lymphatic endothelial cells of the JLS of the trisomic fetuses. CONCLUSIONS: Increased Shh and VEGF-A expression is correlated with an aberrant lymphatic endothelial differentiation in trisomy 21 fetuses. The SMCs surrounding the JLS can possibly be explained by an increase of PDGF-B-induced SMC recruitment and/or differentiation. This underscores earlier findings that indicate the loss of lymphatic identity in trisomy 21 fetuses and a shift towards a blood vessel wall phenotype.

Persistence of nuchal edema and distended jugular lymphatic sacs in Noonan syndrome.

OBJECTIVE: Noonan syndrome is one of the most common genetic syndromes manifesting at birth. Still, it is diagnosed late, often during infancy. Diagnosis is difficult because prenatal ultrasound findings are unspecific and the dysmorphias after birth can be subtle. CASES: Two women were referred to our university hospital because of an increased nuchal translucency in the first trimester of pregnancy. Further ultrasound examination showed the bilateral presence of distended jugular lymph sacs. Karyotyping revealed euploidy in both fetuses. The second trimester ultrasound scan showed a persistence of the jugular lymph sacs together with a nuchal fold, indicating a disturbed lymphatic development. There were no other anomalies. In 1 case the jugular lymph sacs containing newly formed lymph node tissue remained visible until 35 weeks' gestation. Both newborns were diagnosed with Noonan syndrome after birth. Postnatal echocardiography revealed a mild pulmonary stenosis. CONCLUSION: Distension of the jugular lymph sacs is known to cause nuchal edema and normally resolves after the first trimester. In case of persistence of the jugular lymphatic sacs beyond the second trimester of pregnancy, the diagnosis of Noonan syndrome and subsequent DNA testing should be considered.

Nuchal edema and venous-lymphatic phenotype disturbance in human fetuses and mouse embryos with aneuploidy.

OBJECTIVE: Nuchal edema (NE) is a clinical indicator for aneuploidy, cardiovascular anomalies, and several genetic syndromes. Its etiology, however, is unknown. In the nuchal area, the endothelium of the jugular lymphatic sacs (JLS) develops by budding from the blood vascular endothelium of the cardinal veins. Abnormal distension of the jugular sacs is associated with NE. We hypothesize that a disturbed lymphatic endothelial differentiation and sac formation causes NE. We investigated endothelial differentiation of the jugular lymphatic system in human and mouse species with NE. METHODS: Aneuploid human fetuses (trisomy 21; trisomy 18) were compared with euploid controls (gestational age 12 to 18 weeks). Trisomy 16 mouse embryos were compared with wild type controls (embryonic day 10 to 18). Trisomy 16 mice are considered an animal model for human trisomy 21. Endothelial differentiation was investigated by immunohistochemistry using lymphatic markers (prox-1, podoplanin, lymphatic vessel endothelial hyaluronan receptor [LYVE]-1) and en blood vessel markers (neuropilin [NP]-1 and ligand vascular endothelial growth factor [VEGF]-A). Smooth muscle actin (SMA) was included as a smooth muscle cell marker. RESULTS: We report a disturbed venous-lymphatic phenotype in aneuploid human fetuses and mouse embryos with enlarged jugular sacs and NE. Our results show absent or diminished expression of the lymphatic markers Prox-1 and podoplanin in the enlarged jugular sac, while LYVE-1 expression was normal. Additionally, the enlarged JLS showed blood vessel characteristics, including increased NP-1 and VEGF-A expression. The lumen contained blood cells and smooth muscle cells lined the wall. CONCLUSION: A loss of lymphatic identity seems to be the underlying cause for clinical NE. Also, abnormal endothelial differentiation provides a link to the cardiovascular anomalies associated with NE.