From lymphatic development to nuchal translucency

De “nuchal translucency” (NT), in de volksmond ook wel nekplooi genoemd, is een kleine transoniteit in de nekregio van de foetus in het eerste trimester van de zwangerschap. Normaliter verdwijnt deze transoniteit na 14 weken zwangerschapsduur. Een verdikte NT bestaat uit oedeem en is geassocieerd met aneuploidie. De echoscopische NT meting tussen 10 en 14 weken zwangerschapsduur is, samen met de maternale leeftijd en een serumtest, een bewezen sensitieve en effectieve methode om chromosomale afwijkingen in het eerste trimester van de zwangerschap op te sporen. Deze methode, de zogenaamde combinatietest,wordt wereldwijd op grote schaal toegepast. De meest frequent gediagnosticeerde afwijking is trisomie 21, gevolgd door trisomie 13, trisomie 18 en monosomie X. Echter, een foetus met een verdikte NT en een normaal karyogram heeft nog steeds een verhoogd risico op een wijd scala aan structurele afwijkingen, genetische afwijkingen en syndromen. Niettemin heeft een deel van de foetussen met een verdikte NT een normale uitkomst van de zwangerschap. De oorzaak van de verdikte NT en de relatie met het grote spectrum aan aangeboren afwijkingen is nog altijd onbekend. Recentelijk is een abnormale lymfeontwikkeling gesuggereerd als mogelijke oorzaak voor de verdikte NT. Deze suggestie is gebaseerd op de ontdekking van vergrote jugulaire lymfezakken bij trisomie 16 muisembryo’s met een verdikte NT. Deze trisomie 16 muisembryo’s zijn een geaccepteerd diermodel voor humaan trisomie 21. De ontwikkeling van het lymfesysteem in de nek start met de formatie van de jugulaire lymfezakken. Deze zakken worden gevormd door een groep endotheelcellen die vanuit de wand van de primaire halsvene, de vena cardinalis, ontspringen en tot lymfe-endotheel differentiëren. Vanaf 10 weken zwangerschapsduur reorganiseren deze lymfezakken zich tot lymfeklieren. De ontwikkeling wordt voltooid door de ingroei van de ductus thoracicus in de linker lymfezak, waardoor een verbinding met de lymfevaten van de rest van het lichaam tot stand wordt gebracht. Door de connectie tussen de ductus thoracicus en de vena jugularis interna vindt drainage van het lymfevocht naar de veneuze circulatie plaats. Het doel van dit proefschrift is om de relatie tussen de jugulaire lymfeontwikkeling en nekoedeem te bestuderen, om meer inzicht te krijgen in de etiologie van de verdikte NT. In hoofdstuk 1 wordt een korte introductie gegeven over de NT. Daarnaast wordt de opbouw van dit proefschrift uiteengezet. Hoofdstuk 2 bevat een overzicht van de verschillende hypothesen over de etiologie van de verdikte NT. De verscheidenheid aan theorieën kan worden ingedeeld in drie hoofdstromen. Ten eerste wordt hartfalen gesuggereerd als etiologische factor vanwege de verhoogde incidentie van cardiovasculaire afwijkingen en het optreden van afwijkende doorstromingsprofielen van de ductus venosus bij foetussen met een verdikte NT. Ten tweede zijn verschillen in de samenstelling van de extracellulaire matrix beschreven in de nek van foetussen met een aneuploidie. Deze veranderingen in de extracellulaire matrix zouden kunnen leiden tot accumulatie van vocht. Als laatste is een verstoorde lymfeontwikkeling aangetoond bij foetussen met nekoedeem. Wij concluderen dat de vele hypotheses over de etiologie van de verdikte NT veelal berusten op associaties. Zowel hartfalen en extracellulaire matrix veranderingen verklaren het tijdelijke en lokale karakter van de vergrote NT niet. Een vertraagde organisatie en verbinding met de veneuze circulatie van de jugulaire lymfezakken zouden deze eigenschappen wellicht wel kunnen verklaren. In hoofdstuk 3 wordt de aanwezigheid van verwijde jugulaire lymfezakken bij foetussen met een normale en een verdikte NT prospectief onderzocht door middel van transvaginale echoscopie. Wij vonden een relatie tussen de aanwezigheid van nekoedeem en een verwijding van het jugulaire lymfesysteem op de eerste trimester echo. Onder normale omstandigheden zijn de jugulaire lymfezakken niet zichtbaar. In 22 van de 26 (85%) foetussen met een verdikte NT waren vergrote lymfezakken zichtbaar, in tegenstelling tot 2 van de 137 (1,5%) van de foetussen met een normale NT. De vergrote lymfezakken waren aanwezig ongeacht het karyotype van de foetus. Daarnaast, was een dikkere NT geassocieerd met een hogere kans op distensie van de jugulaire lymfezakken. Een associatie tussen vergrote lymfezakken en de aanwezigheid van een verdikte NT betekent echter niet dat er ook een causaal verband is tussen beide entiteiten. Daarom, wordt in hoofdstuk 4 een longitudinale analyse verricht in foetussen met een verdikte NT, waarbij de ontwikkeling van het nekoedeem en de jugulaire lymfezakken wordt geanalyseerd met voortschrijden van de zwangerschap. In deze studie werden 74 foetussen tussen 11 en 17 weken zwangerschapsduur wekelijks onderzocht door middel van echoscopie.Gittenberger-de Groot, A.C. [Promotor]Vugt, J.M.G. van [Promotor

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 (48457 combined tests, 134000 fetal anomaly scans and 24379 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 ≥36years, these percentages were 4.9% and 12.5%, respectively and for maternal age 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

Home-Based Monitoring and Telemonitoring of Complicated Pregnancies: Nationwide Cross-Sectional Survey of Current Practice in the Netherlands

Background: Daily monitoring of fetal and maternal conditions in complicated pregnancies leads to recurrent outpatient visits or (prolonged) hospitalization. Alternatives for hospital admissions include home-based monitoring with home visits by professionals or telemonitoring with self-measurements performed by pregnant women and uploaded for in-clinic assessment. For both alternatives, cardiotocography and blood pressure measurement can be performed at home. It is unknown to what extent, for which reasons, and for which pregnancy complications these strategies are used. Objective: This study aims to assess the current practice and attitudes concerning home-based monitoring (with daily home visits by professionals) and telemonitoring (using devices and the internet for daily self-recorded measurements) in high-risk pregnancies requiring maternal and fetal monitoring in the Netherlands. Methods: This nationwide cross-sectional study involved sending a web-based survey to the obstetrics departments of all 73 hospitals in the Netherlands to be answered by 1 representative dedicated to pregnancy monitoring per hospital. The primary outcome was the provision of home-based monitoring or telemonitoring using cardiotocography between 1995 and 2018. The survey further addressed perspectives regarding the use of home-based monitoring and telemonitoring, including (contra)indications, advantages, and disadvantages for pregnant women and clinicians. Results: The response rate for the provision of either home-based monitoring or telemonitoring was 100%. In 2018, 38% (28/73) of centers in the Netherl

Implementation of a standard outcome set in perinatal care: a qualitative analysis of barriers and facilitators from all stakeholder perspectives

Background: To improve their quality, healthcare systems are increasingly focused on value delivered to patients. For perinatal care, the International Consortium for Health Outcomes Measurement (ICHOM) proposed a patient-centred outcome set with both clinical and patient-reported measures for pregnancy and childbirth (PCB set). This study aimed to identify factors that affect the implementation of the PCB set at the pre-implementation stage, using the consolidated framework for implementation research (CFIR). Methods: In this qualitative study, we conducted semi-structured interviews amongst a purposive sample of key stakeholders within an obste

A feasibility study of implementing a patient-centered outcome set for pregnancy and childbirth

Background and Aims: Patient-reported outcome and experience measures (PROM and PREM) can facilitate shared decision making and hold potential to improve healthcare quality. However, their adoption in perinatal care is still limited. The International Consortium for Health Outcomes Measurement (ICHOM) developed a Pregnancy and Childbirth (PCB) outcome set, including PROM and PREM questionnaires. We studied the feasibility to use these PROMs/PREMs in Dutch perinatal care, addressing both women's and professionals' perspective. Methods: Patients and professionals in primary and hospital care participated. Women under care at one of five timepoints for PROM/PREM collection of the PCB set (2 during pregnancy, 3 postpartum) were e-mailed a questionnaire and discussed their answers with their obstetric professional the next regular visit. Compliance was recorded. After discussing the PROMs/PREMs, usability and experience were assessed with separate surveys amongst women and professionals. Results: Of 26 women approached, 21 completed and discussed their PROM/PREM questionnaire. Mean questionnaire completion rate was 97%. Average reported time completing the questionnaires was 10 minutes; most women (90%) stated this was acceptable. Women preferred completing questionnaires digitally and discuss their answers with an obstetric professional rather than othe

Prognostic models versus single risk factor approach in first-trimester selective screening for gestational diabetes mellitus: a prospective population-based multicentre cohort study

Objectives: To evaluate whether (1) first-trimester prognostic models for gestational diabetes mellitus (GDM) outperform the currently used single risk factor approach, and (2) a first-trimester random venous glucose measurement improves model performance. Design: Prospective population-based multicentre cohort. Setting: Thirty-one independent midwifery practices and six hospitals in the Netherlands. Population: Women recruited before 14 weeks of gestation without pre-existing diabetes. Methods: The single risk factor approach (presence of at least one risk factor: BMI ≥30 kg/m2, previous macrosomia, history of GDM, positive first-degree family history of diabetes, non-western ethnicity) was compared with the four best performing models in our previously published external validation study (Gabbay-Benziv 2014, Nanda 2011, Teede 2011, van Leeuwen 2010) with and without the addition of glucose. Main outcome measures: Discrimination was assessed by c-statistics, calibration by calibration plots, added value of glucose by the likelihood ratio chi-square test, net benefit by decision curve analysis and reclassification by reclassification plots. Results: Of the 3723 women included, a total of 181 (4.9%) developed GDM. The c-statistics of the prognostic models were higher, ranging from 0.74 to 0.78 without glucose and from 0.78 to 0.80 with glucose, compared with

SAFE@HOME: Digital health platform facilitating a new care path for women at increased risk of preeclampsia – A case-control study

Objective: In women at risk of developing preeclampsia, we evaluated the use of a digital health platform for telemonitoring blood pressure and symptoms combined with a minimal antenatal visit schedule. Study design: A case-control study for women with chronic hypertension, history of preeclampsia, or maternal cardiac or kidney disease. A care path was designed with reduced visits enhanced with a digital platform (SAFE@HOME) for daily blood pressure and symptom monitoring starting from 16 weeks of gestation. Homemeasurements were monitored in-hospital by obstetric professionals, taking actions upon alarming results. This prospective SAFE@HOME group was compared to a retrospective control group managed without self-monitoring. Main outcome measures: Primary: healthcare consumption (number of antenatal visits, ultrasounds, admissions and diagnostics), user experiences of the platform. Secondary: mate

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

Objectives: To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities. Methods: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected. Results: In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95th and 99th percentile and 62% for fetuses with NT≥99th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively. Conclusion: Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement

Low dose aspirin in the prevention of recurrent spontaneous preterm labour - the APRIL study: A multicenter randomized placebo controlled trial

Background: Preterm birth (birth before 37 weeks of gestation) is a major problem in obstetrics and affects an estimated 15 million pregnancies worldwide annually. A history of previous preterm birth is the strongest risk factor for preterm birth, and recurrent spontaneous preterm birth affects more than 2.5 million pregnancies each year. A recent meta-analysis showed possible benefits of the use of low dose aspirin in the prevention of recurrent spontaneous preterm birth. We will assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in the prevention of recurrent spontaneous preterm birth in a randomized clinical trial. Methods/design: Women with a singleton pregnancy and a history of spontaneous preterm birth in a singleton pregnancy (22-37 weeks of gestation) will be asked to participate in a multicenter, randomized, double blinded, placebo controlled trial. Women will be randomized to low dose aspirin (80 mg once daily) or placebo, initiated from 8 to 16 weeks up to maximal 36 weeks of gestation. The primary outcome measure will be preterm birth, defined as birth at a gestational age (GA) < 37 weeks. Secondary outcomes will be a composite of adverse neonatal outcome and maternal outcomes, including subgroups of prematurity, as well as intrauterine growth restriction (IUGR) and costs from a healthcare perspective. Preterm birth will be analyzed as a group, as well as separately for spontaneous or indicated onset. Analysis will be performed by intention to treat. In total, 406 pregnant women have to be randomized to show a reduction of 35% in preterm birth from 36 to 23%. If aspirin is effective in preventing preterm birth, we expect that there will be cost savings, because of the low costs of aspirin. To evaluate this, a cost-effectiveness analysis will be performed comparing preventive treatment with aspirin with placebo. Discussion: This trial will provide evidence as to whether or not low dose aspirin is (cost-) effective in reducing recurrence of spontaneous preterm birth. Trial registration: Clinical trial registration number of the Dutch Trial Register: NTR 5675. EudraCT-registration number: 2015-003220-31