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.

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.

Perspectives of pregnant women on broadening the scope of noninvasive prenatal testing from screening for foetal aneuploidies to prediction of adverse pregnancy outcomes: A qualitative study.

OBJECTIVE: To explore the perspectives of pregnant women on broadening the scope of noninvasive prenatal testing (NIPT) from screening for foetal aneuploidies to prediction of adverse pregnancy outcomes. METHODS: Four online focus groups (n = 23 participants) and 14 individual semi-structured interviews were conducted. Participants included pregnant women with and without a history of adverse pregnancy outcomes. RESULTS: Both women at low and high risk of adverse pregnancy outcomes had a positive attitude towards using NIPT to predict adverse pregnancy outcomes. Perceived benefits included the possibility to potentially improve maternal and foetal outcomes by taking risk-reducing measures and/or intensified monitoring during pregnancy and the ability to mentally prepare for the potential adverse outcome. Perceived concerns included anxiety and stress caused by a high-risk test result, a false sense of control over pregnancy, and potential false reassurance. Additionally, women reasoned that broadening the scope of NIPT could increase the complexity of prenatal screening and raised concerns on the combined screening aims in one test (prediction of adverse pregnancy outcomes to improve foetal and maternal health vs. screening for foetal aneuploidies to increase reproductive autonomy). On a societal level, considerations on the risk of medicalising pregnancy and overall pressure to opt for NIPT were mentioned. CONCLUSION: In general, pregnant women have a positive attitude towards broadening the scope of NIPT to the prediction of pregnancy outcomes, although some concerns are acknowledged.

Variability in Fetal Fraction Estimation: Comparing Fetal Fractions Reported by Noninvasive Prenatal Testing Providers Globally.

BACKGROUND: Fetal fraction (FF) measurement is considered important for reliable noninvasive prenatal testing (NIPT). Using minimal FF threshold as a quality parameter is under debate. We evaluated the variability in reported FFs of individual samples between providers and laboratories and within a single laboratory. METHODS: Genomic quality assessment and European Molecular Genetics Quality Network provide joint proficiency testing for NIPT. We compared reported FFs across all laboratories and stratified according to test methodologies. A single sample was sequenced repeatedly and FF estimated by 2 bioinformatics methods: Veriseq2 and SeqFF. Finally, we compared FFs by Veriseq and SeqFF in 87 351 NIPT samples. RESULTS: For each proficiency test sample we observed a large variability in reported FF, SDs and CVs ranging from 1.7 to 3.6 and 17.0 to 35.8, respectively. FF measurements reported by single nucleotide polymorphism-based methods had smaller SDs (0.5 to 2.4) compared to whole genome sequencing-based methods (1.8 to 2.9). In the internal quality assessment, SDs were similar between SeqFF (SD 1.0) and Veriseq v2 (SD 0.9), but mean FF by Veriseq v2 was higher compared to SeqFF (9.0 vs 6.4, P 0.001). In patient samples, reported FFs were on average 1.12-points higher in Veriseq than in SeqFF (P 0.001). CONCLUSIONS: Current methods do not allow for a reliable and consistent FF estimation. Our data show estimated FF should be regarded as a laboratory-specific range, rather than a precise number. Applying strict universal minimum thresholds might result in unnecessary test failures and should be used with caution.

Fetal fraction of cell-free DNA in noninvasive prenatal testing and adverse pregnancy outcomes: a nationwide retrospective cohort study of 56,110 pregnant women.

BACKGROUND: Noninvasive prenatal testing by cell-free DNA analysis is offered to pregnant women worldwide to screen for fetal aneuploidies. In noninvasive prenatal testing, the fetal fraction of cell-free DNA in the maternal circulation is measured as a quality control parameter. Given that fetal cell-free DNA originates from the placenta, the fetal fraction might also reflect placental health and maternal pregnancy adaptation. OBJECTIVE: This study aimed to assess the association between the fetal fraction and adverse pregnancy outcomes. STUDY DESIGN: We performed a retrospective cohort study of women with singleton pregnancies opting for noninvasive prenatal testing between June 2018 and June 2019 within the Dutch nationwide implementation study (Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing [TRIDENT]-2). Multivariable logistic regression analysis was used to assess associations between fetal fraction and adverse pregnancy outcomes. Fetal fraction was assessed as a continuous variable and as <10th percentile, corresponding to a fetal fraction <2.5%. RESULTS: The cohort comprised 56,110 pregnancies. In the analysis of fetal fraction as a continuous variable, a decrease in fetal fraction was associated with increased risk of hypertensive disorders of pregnancy (adjusted odds ratio, 2.27 [95% confidence interval, 1.89-2.78]), small for gestational age neonates <10th percentile (adjusted odds ratio, 1.37 [1.28-1.45]) and <2.3rd percentile (adjusted odds ratio, 2.63 [1.96-3.57]), and spontaneous preterm birth from 24 to 37 weeks of gestation (adjusted odds ratio, 1.02 [1.01-1.03]). No association was found for fetal congenital anomalies (adjusted odds ratio, 1.02 [1.00-1.04]), stillbirth (adjusted odds ratio, 1.02 [0.96-1.08]), or neonatal death (adjusted odds ratio, 1.02 [0.96-1.08]). Similar associations were found for adverse pregnancy outcomes when fetal fraction was <10th percentile. CONCLUSION: In early pregnancy, a low fetal fraction is associated with increased risk of adverse pregnancy outcomes. These findings can be used to expand the potential of noninvasive prenatal testing in the future, enabling the prediction of pregnancy complications and facilitating tailored pregnancy management through intensified monitoring or preventive measures.

Non-invasive prenatal testing (NIPT) in twin pregnancies affected by early single fetal demise: A systematic review of NIPT and vanishing twins.

The screening performance of non-invasive prenatal testing (NIPT) in vanishing twin (VT) pregnancies is relatively unknown. To close this knowledge gap, we conducted a systematic review of the available literature. Studies describing the test performance of NIPT for trisomy 21, 18, 13, sex chromosomes and additional findings in pregnancies with a VT were retrieved from a literature search with a publication date until October 4, 2022. The methodological quality of the studies was assessed with the quality assessment tool for diagnostic accuracy studies-2 (QUADAS-2). The screen positive rate of the pooled data and the pooled positive predictive value (PPV) were calculated using a random effects model. Seven studies, with cohort sizes ranging from 5 to 767, were included. The screen positive rate of the pooled data for trisomy 21 was 35/1592 (2.2%), with a PPV of 20% (confirmation in 7/35 cases [95% CI 9.8%-36%]). For trisomy 18, the screen positive rate was 13/1592 (0.91%) and the pooled PPV 25% [95% CI 1.3%-90%]. The screen positive rate for trisomy 13 was 7/1592 (0.44%) and confirmed in 0/7 cases (pooled PPV 0% [95% CI 0%-100%]). The screen positive rate for additional findings was 23/767 (2.9%), of which none could be confirmed. No discordant negative results were reported. There is insufficient data to fully evaluate NIPT performance in pregnancies with a VT. However, existing studies suggest that NIPT can successfully detect common autosomal aneuploidies in pregnancies affected by a VT but with a higher false positive rate. Further studies are needed to determine the optimal timing of NIPT in VT pregnancies.

Association between low fetal fraction in cell-free DNA screening and fetal chromosomal aberrations: A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of the available literature on low fetal fraction (LFF) in cell-free DNA (cfDNA) screening and the risk of fetal chromosomal aberrations. METHOD: We searched articles published between January 2010 and May 2021 in PubMed and EMBASE databases. Risk of bias was assessed using QUADAS-2. RESULTS: Twenty-seven studies met the inclusion criteria, comprising data of 243,700 singleton pregnancies. Compared to normal fetal fraction, LFF was associated with a higher risk of trisomy 13 (OR 5.99 [3.61-9.95], I 2 of heterogeneity = 0%, n = 22 studies), trisomy 18 (OR 4.46 [3.07-6.47], I 2  = 0%, n = 22 studies), monosomy X (OR 5.88 [2.34-14.78], I 2  = 18%, n = 10 studies), and triploidy (OR 36.39 [9.83-134.68], I 2  = 61%, n = 6 studies), but not trisomy 21 (OR 1.25 [0.76-2.03], I 2  = 36%, n = 23 studies). LFF was also associated with a higher risk of various other types of fetal chromosomal aberrations (OR 4.00 [1.78-9.00], I 2  = 2%, n = 11 studies). Meta-analysis of proportions showed that absolute rates of fetal chromosomal aberrations ranged between 1% and 2% in women with LFF. A limitation of this review is the potential risk of ascertainment bias because of differences in outcome assessment between pregnancies with LFF and those with normal fetal fraction. Heterogeneity in population characteristics or applied technologies across included studies may not have been fully addressed. CONCLUSION: An LFF test result in cfDNA screening is associated with an increased risk of fetal trisomy 13, trisomy 18, monosomy X, and triploidy, but not trisomy 21. Further research is needed to assess the association between LFF and other specific types of fetal chromosomal aberrations.

Current practice of first-trimester ultrasound screening for structural fetal anomalies in developed countries.

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.

A cross-country comparison of pregnant women's decision-making and perspectives when opting for non-invasive prenatal testing in the Netherlands and Belgium.

BACKGROUND: The Netherlands and Belgium have been among the first countries to offer non-invasive prenatal testing (NIPT) as a first-tier screening test. Despite similarities, differences exist in counseling modalities and test uptake. This study explored decision-making and perspectives of pregnant women who opted for NIPT in both countries. METHODS: A questionnaire study was performed among pregnant women in the Netherlands (NL) (n = 587) and Belgium (BE) (n = 444) opting for NIPT, including measures on informed choice, personal and societal perspectives on trisomy 21, 18 and 13 and pregnancy termination. RESULTS: Differences between Dutch and Belgian women were shown in the level of informed choice (NL: 83% vs. BE: 59%, p < 0.001), intention to terminate the pregnancy in case of confirmed trisomy 21 (NL: 51% vs. BE: 62%, p = 0.003) and trisomy 13/18 (NL: 80% vs. BE: 73%, p = 0.020). More Belgian women considered trisomy 21 a severe condition (NL: 64% vs. BE: 81%, p < 0.001). Belgian women more frequently indicated that they believed parents are judged for having a child with trisomy 21 (BE: 42% vs. NL: 16%, p < 0.001) and were less positive about quality of care and support for children with trisomy 21 (BE: 23% vs. NL: 62%, p < 0.001). CONCLUSION: Differences in women's decision-making regarding NIPT and the conditions screened for may be influenced by counseling aspects and country-specific societal and cultural contexts.

Informed choice and routinization of the second-trimester anomaly scan: a national cohort study in the Netherlands.

BACKGROUND: Since 2007 all pregnant women in the Netherlands are offered the second-trimester anomaly scan (SAS) in a nationwide prenatal screening program. This study aims to assess the level of informed choice of women opting for the SAS and to evaluate the presence of routinization 16 years after its implementation. It further explores decisional conflict and women's decision making. METHODS: This prospective national survey study consisted of an online questionnaire which was completed after prenatal counseling and before undergoing the SAS. Informed choice was measured by the adapted multidimensional measure of informed choice (MMIC) and was defined in case women were classified as value-consistent, if their decision for the SAS was deliberated and made with sufficient knowledge. RESULTS: A total of 894/1167 (76.6%) women completed the questionnaire. Overall, 54.8% made an informed choice, 89.6% had good knowledge, 59.8% had deliberated their choice and 92.7% held a positive attitude towards the SAS. Women with low educational attainment (p=0.004) or respondents of non-Western descent (p=0.038) were less likely to make an informed choice. Decisional conflict was low, with a significantly lower decisional conflict score in women that made an informed choice (p<0.001). Most respondents (97.9%) did not perceive pressure to undergo the SAS. CONCLUSIONS: Our study showed a relatively low rate of informed choice for the SAS, due to absence of deliberation. Therefore, some routinization seem to be present in the Netherlands. However, most women had sufficient knowledge, did not perceive pressure and experienced low decisional conflict.

Maternal vaccination against pertussis as part of the national immunization program: a qualitative evaluation among obstetric care providers one year after the implementation in December 2019.

BACKGROUND: Immunization of pregnant women with a tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccine is an effective and safe way to protect infants from pertussis before their primary vaccinations. Vaccine uptake among pregnant women is influenced by their care providers' attitudes toward maternal vaccination. This qualitative study aimed to evaluate the implementation of the maternal Tdap vaccination under the National Immunization Program of the Netherlands from the perspective of obstetric care providers. METHODS: In this qualitative and explorative study, we conducted in-depth interviews by telephone with obstetric care providers who were selected from a pool of respondents (convenience sampling) to a questionnaire in a previous study. The interviews were based on a semi-structured interview guide that covered three aspects of the implementation strategy: providers' overall experience with the implementation of maternal Tdap vaccination in the Netherlands; implementation logistics and counseling, and pregnant women referrals to municipal Youth Healthcare Centers. The interviews were recorded, pseudonymized and transcribed verbatim. Transcripts were analyzed according to the Thematic Analysis approach by two researchers independently in two phases of iterative coding, categorizing, reviewing and redefining until ultimately, emergent themes regarding maternal Tdap vaccination implementation were identified. RESULTS: Interviews with 11 midwives and 5 OB-GYN physicians yielded 5 major themes regarding the Tdap vaccination implementation strategy: challenges throughout the implementation process, views on maternal Tdap vaccination, general versus tailored counseling, provider responsibilities in vaccine promotion, and impact of materials for information delivery. Participants indicated that to improve provider attitudes toward Tdap vaccination, its implementation requires clear and transparent information about what is entailed, i.e., what is expected from obstetric care providers, how they can obtain information, and when their actions must be initiated. Participants demanded involvement throughout the implementation planning process. They preferred tailored communication with pregnant women over a generalized approach. CONCLUSION: This study emphasized the importance of involving all relevant healthcare professionals in planning the implementation of maternal Tdap vaccination. Possible barriers perceived by these professionals should be taken into account in order to improve their attitudes toward vaccination, thus to increase uptake among pregnant women.

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.

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.

Additional value of advanced ultrasonography in pregnancies with two inconclusive cell-free DNA draws.

OBJECTIVE: We aimed to evaluate the additional value of advanced fetal anatomical assessment by ultrasound in pregnancies with twice inconclusive noninvasive testing (NIPT) due to low fetal fraction (FF). METHODS: We performed a multicenter-retrospective study between 2017 and 2020 including 311 pregnancies with twice inconclusive NIPT due to low FF ≤ 1%. Women were offered invasive testing and advanced fetal anatomical assessment at ≤18 weeks' gestation. Ultrasound findings, genetic testing, and pregnancy/postnatal outcomes were evaluated. RESULTS: Ninety-two/311 (29.6%) women underwent invasive testing. Structural anomalies were diagnosed in 13/311 (4.2%) pregnancies (nine at the first scan and four at follow-up). In 6/13 (46.2%) cases, genetic aberrations were confirmed (one case of Trisomy 13 (detectable by NIPT), two of Triploidy, one of 16q12-deletion, HCN4-mutation and UPD(16) (nondetectable by NIPT). Genetic aberrations were found in 4/298 (1.3%) structurallynormal pregnancies (one 47XYY, two microscopic aberrations, one monogenic disorder found postpartum). Structural anomalies in genetically normal fetuses (2.0%) were not more prevalent compared to the general pregnant population (OR 1.0 [0.4-2.2]). CONCLUSION: In pregnancies with twice inconclusive NIPT due to low FF, fetal structural anomalies are not more prevalent than in the general obstetric population. The detailed anatomical assessment has the added value to detect phenotypical features suggestive of chromosomal/genetic aberrations and identify pregnancies where advanced genetic testing may be indicated.

Telemonitoring for COVID-19 positive pregnant women; feasibility and user experience of SAFE@home Corona: prospective pilot study.

BACKGROUND: COVID-19 has catalysed digital innovations enabling remote healthcare. Pregnant women are at increased risk for severe course of COVID-19 infection. Also, the pandemic has a negative emotional impact on pregnant women as they worry about their own health and the health of their unborn child. We developed a telemonitoring platform called SAFE@home-corona consisting of a pulse oximeter and an app with symptom checklist. The aim of this study was to examine the feasibility, defined by compliance to the platform and by monitoring the course of COVID-19, patient satisfaction and user experience of a telemonitoring platform in COVID-19 positive pregnant women in the Netherlands. METHODS: We conducted a prospective pilot study among Dutch-speaking COVID-19 symptomatic pregnant women. Women were asked to monitor their oxygen-saturation with a pulse oximeter and COVID-related complaints with an in-app questionnaire daily. Oxygen-saturation and complaints were monitored by the Medical Management Centre with triage protocol. COVID-19, pregnancy, and user experience data were collected. To assess feasibility, compliance of daily self-monitoring and compliance of all intended measurements were calculated. Severity of COVID-19 was assessed via the platform and medical record. Patient satisfaction and user experience were measured through a self-developed questionnaire. RESULTS: Twenty-eight women were eligible of which 27 (93.1%) completed the study. Compliance of daily measurement and all intended measurements was high with 98.9 and 93.9%, respectively. Six women were hospitalized, of whom one to the intensive care unit. Overall, women indicated high satisfaction scores, varying from 8 to 10/10. Women were more concerned for the health of their unborn child or family then for themselves (66.7%). They stated that the platform offered reassurance. Patients would highly recommend the platform to pregnant peers during COVID infection. CONCLUSIONS: This pilot study demonstrated feasibility of the SAFE@home-corona platform for self-monitoring COVID-19 course in pregnant women. Patients were satisfied, it offered reassurance, women would recommend use to peers. Upscaling the platform is needed to draw conclusions from the early signalling abilities and to keep evaluating patient satisfaction. The platform has great potential for self-monitoring of COVID-19 and possibly other pulmonary infections in pregnant women.

Patient-Reported Outcome and Experience Measures in Perinatal Care to Guide Clinical Practice: Prospective Observational Study.

BACKGROUND: The International Consortium for Health Outcomes Measurement has published a set of patient-centered outcome measures for pregnancy and childbirth (PCB set), including patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs). To establish value-based pregnancy and childbirth care, the PCB set was implemented in the Netherlands, using the outcomes on the patient level for shared decision-making and on an aggregated level for quality improvement. OBJECTIVE: This study aims to report first outcomes, experiences, and practice insights of implementing the PCB set in clinical practice. METHODS: In total, 7 obstetric care networks across the Netherlands, each consisting of 1 or 2 hospitals and multiple community midwifery practices (ranging in number from 2 to 18), implemented the PROM and PREM domains of the PCB set as part of clinical routine. This observational study included all women participating in the clinical project. PROMs and PREMs were assessed with questionnaires at 5 time points: 2 during pregnancy and 3 post partum. Clinical threshold values (alerts) supported care professionals interpreting the answers, indicating possibly alarming outcomes per domain. Data collection took place from February 2020 to September 2021. Data analysis included missing (pattern) analysis, sum scores, alert rates, and sensitivity analysis. RESULTS: In total, 1923 questionnaires were collected across the 5 time points: 816 (42.43%) at T1 (first trimester), 793 (41.23%) at T2 (early third trimester), 125 (6.5%) at T3 (maternity week), 170 (8.84%) at T4 (6 weeks post partum), and 19 (1%) at T5 (6 months post partum). Of these, 84% (1615/1923) were filled out completely. Missing items per domain ranged from 0% to 13%, with the highest missing rates for depression, pain with intercourse, and experience with pain relief at birth. No notable missing patterns were found. For the PROM domains, relatively high alert rates were found both in pregnancy and post partum for incontinence (469/1798, 26.08%), pain with intercourse (229/1005, 22.79%), breastfeeding self-efficacy (175/765, 22.88%), and mother-child bonding (122/288, 42.36%). Regarding the PREM domains, the highest alert rates were found for birth experience (37/170, 21.76%), shared decision-making (101/982, 10.29%), and discussing pain relief ante partum (310/793, 39.09%). Some domains showed very little clinical variation; for example, role of the mother and satisfaction with care. CONCLUSIONS: The PCB set is a useful tool to assess patient-reported outcomes and experiences that need to be addressed over the whole course of pregnancy and childbirth. Our results provide opportunities to improve and personalize perinatal care. Furthermore, we could propose several recommendations regarding methods and timeline of measurements based on our findings. This study supports the implementation of the PCB set in clinical practice, thereby advancing the transformation toward patient-centered, value-based health care for pregnancy and childbirth.

Digital decision aid for prenatal counseling in imminent extreme premature labor: development and pilot testing.

BACKGROUND: In case of extreme premature delivery at 24 weeks of gestation, both early intensive care and palliative comfort care for the neonate are considered treatment options. Prenatal counseling, preferably using shared decision making, is needed to agree on the treatment option in case labor progresses. This article described the development of a digital decision aid (DA) to support pregnant women, partners and clinicians in prenatal counseling for imminent extreme premature labor. METHODS: This DA is developed following the International Patient Decision Aid Standards. The Dutch treatment guideline and the Dutch recommendations for prenatal counseling in extreme prematurity were used as basis. Development of the first prototype was done by expert clinicians and patients, further improvements were done after alpha testing with involved clinicians, patients and other experts (n = 12), and beta testing with non-involved clinicians and patients (n = 15). RESULTS: The final version includes information, probabilities and figures depending on users' preferences. Furthermore, it elicits patient values and provides guidance to aid parents and professionals in making a decision for either early intensive care or palliative comfort care in threatening extreme premature delivery. CONCLUSION: A decision aid was developed to support prenatal counseling regarding the decision on early intensive care versus palliative comfort care in case of extreme premature delivery at 24 weeks gestation. It was well accepted by parents and healthcare professionals. Our multimedia, digital DA is openly available online to support prenatal counseling and personalized, shared decision-making in imminent extreme premature labor.

Study protocol of the PIMPI-project, a cohort study on acceptance, tolerability and immunogenicity of second trimester maternal pertussis immunization in relation to term and preterm infants.

BACKGROUND: Maternal immunization confers passive immunity to the fetus by transplacental antibody transfer. Infants may be better protected against pertussis if the mother received a diphtheriae, tetanus and acellular pertussis (Tdap) vaccination in the second trimester of pregnancy compared to the third trimester. This study evaluates IgG antibody concentrations in term and preterm infants at birth and 2 months after birth after maternal Tdap-vaccination between 200 and 240 w of gestation vs third trimester Tdap-vaccination. Further aims are assessing the determinants that underlie acceptance of second trimester maternal Tdap-vaccination as well as the tolerability of vaccination. METHODS: This prospective cohort study consists of two parts. In the acceptance part, pregnant women complete a questionnaire on determinants that underlie acceptance of a second trimester Tdap-vaccination, which is offered subsequently between 200 and 240 w of gestation. Vaccinated women complete an additional questionnaire on vaccination tolerability. Vaccinated women may also participate in the immunogenicity part, in which blood is drawn from mother at delivery and from infant at birth and 2 months after birth. Women are also eligible for the immunogenicity part if they received a Tdap-vaccination between 200 and 240 w of gestation via the national immunization program and get hospitalized for an imminent preterm delivery. Blood sampling continues until 60 term and 60 preterm mother-infant-pairs have been included. Pertussis-specific IgG antibody concentrations are determined in serum using a fluorescent bead-based multiplex immunoassay. For term infants, non-inferiority in IgG antibody concentrations against pertussis toxin (anti-PT) will be assessed referred to a historical control group in which mothers were Tdap-vaccinated between 300 and 320 w of gestation. For preterm infants, non-inferiority of anti-PT IgG concentrations is referred to as 85% of infants having ≥ 20 international units/mL at 2 months after birth. DISCUSSION: This study investigates acceptance, tolerability and immunogenicity regarding maternal Tdap-immunization between 200 and 240 w of gestation. Its results provide insight into the effects of second trimester Tdap-vaccination on IgG antibody concentrations in term and preterm infants before primary infant vaccinations. Results on acceptance and tolerability guide antenatal care providers in communication with pregnant women and maintain the safety of second trimester Tdap-vaccination. TRIAL REGISTRATION: EU Clinical Trials Register, 2018-002976-41, retrospectively registered 24 July 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-002976-41 .

Non-invasive prenatal test uptake in socioeconomically disadvantaged neighborhoods.

OBJECTIVE: Non-Invasive Prenatal Testing (NIPT) is increasingly being implemented worldwide. In public health programs, equitable access to healthcare is a fundamental principle which also applies to fetal aneuploidy screening. However, the out-of-pocket costs of NIPT may lead to sociodemographic disparities in uptake of screening. This study assessed whether there is a difference in the uptake of NIPT in socioeconomically disadvantaged neighborhoods compared to all other neighborhoods in the Netherlands, where NIPT is implemented in a national screening program (TRIDENT-2 study). METHOD: NIPT uptake, postal code and age of 156,562 pregnant women who received pre-test counselling for prenatal screening in 2018 were retrieved from the national prenatal screening database. Postal codes were used as a proxy to categorize neighborhoods as being either socioeconomically disadvantaged or other. The out-of-pocket costs for NIPT were €175. RESULTS: NIPT uptake in socioeconomically disadvantaged neighborhoods was 20.3% whereas uptake in all other neighborhoods was 47.6% (p < 0.001). The difference in NIPT uptake between socioeconomic disadvantaged neighborhoods and other areas was smaller for the youngest maternal age-group (≤25 years) compared to other age-groups. CONCLUSION: The variation in uptake suggest underlying disparities in NIPT uptake, which undermines the goals of a national fetal aneuploidy screening program of providing reproductive autonomy and equitable access. This has ethical and policy implications for ensuring fair and responsible implementation of fetal aneuploidy screening.

Association between low fetal fraction in cell-free DNA testing and adverse pregnancy outcome: A systematic review.

OBJECTIVE: Low fetal fraction (LFF) in prenatal cell-free DNA (cfDNA) testing is an important cause of test failure and no-call results. LFF might reflect early abnormal placentation and therefore be associated with adverse pregnancy outcome. Here, we review the available literature on the relationship between LFF in cfDNA testing and adverse pregnancy outcome. METHOD: A systematic literature search was conducted in MEDLINE and EMBASE up to November 1, 2020. RESULTS: Five studies met the criteria for inclusion; all were retrospective observational cohort studies. The cohort sizes ranged from 370 to 6375 pregnancies, with all tests performed in the first trimester or early second trimester. A 4% cutoff for LFF was used in two studies, two studies used the 5th and 25th percentiles, respectively, and one study used a variety of cutoff values for LFF. LFF in prenatal cfDNA testing was observed to be associated with hypertensive disease of pregnancy, small for gestational age neonates, and preterm birth. Conflicting results were found regarding the association between LFF and gestational diabetes mellitus. CONCLUSIONS: LFF in cfDNA testing is associated with adverse pregnancy outcome,specifically pregnancy-related hypertensive disorders, preterm birth, and impaired fetal growth related to placental dysfunction. Since the available evidence is limited, a large prospective cohort study on the relationship between fetal fraction and pregnancy outcomes is needed.