Cardiac adaptation and malformation in twin-twin transfusion syndrome and selective fetal growth restriction: A systematic review.

OBJECTIVES: This systematic review explores cardiac adaptation in monochorionic (MC) twins with twin-twin transfusion syndrome (TTTS) or selective fetal growth restriction (sFGR) and assesses the risk of congenital heart defects (CHDs). METHODS: Adhering to PRISMA guidelines, 63 studies were reviewed (49 on cardiac adaptation, 13 on CHD, one on both). A narrative synthesis of cardiac adaptation patterns was performed. Additionally, a meta-analysis compared the livebirth prevalence of CHD in TTTS and sFGR against uncomplicated MC twins. RESULTS: In TTTS recipients, cardiac function may be impaired for diastolic, systolic, as well as global functions, while in donors, cardiac function is generally preserved. In sFGR, large twins may show hypertrophic cardiomyopathy, and small twins may show impaired systolic function. Co-occurrence of TTTS and sFGR magnifies cardiac impact but is often underreported. Meta-analysis for CHD prevalence revealed a relative risk ratio of 3.5 (95% CI: 2.5-4.9) for TTTS and 2.2 (95%CI: 1.3-3.5) for sFGR compared with uncomplicated MC twins. CONCLUSIONS: This study highlights the well-documented cardiac adaptation in TTTS, contrasting with limited understanding in sFGR. Elevated CHD risks were observed in both conditions. Enhanced cardiovascular surveillance is warranted in complicated MC twin pregnancies. Future research should explore cardiac adaptation in sFGR and its long-term consequences.

Suppression of Hb Bart's to improve tissue oxygenation and fetal development in homozygous alpha-thalassemia.

Intra-uterine reduction of Hb Bart's only reached with exchange transfusions.

Changing epidemiology of parvovirus B19 in the Netherlands since 1990, including its re-emergence after the COVID-19 pandemic.

Parvovirus B19V (B19V) infection during pregnancy can be complicated by potentially life-threatening fetal hydrops, which can be managed by intrauterine transfusion (IUT). This study investigates the long-term temporal patterns in the epidemiology of B19V and evaluates the impact on fetal hydrops, by combining data on B19V infections from the Dutch Sentinel Surveillance system in the period 1990 to 2023, Dutch blood banking data and hospital data on fetal hydrops. Using wavelet analysis, we identified annual epidemic cycles in the Netherlands in the period 1990-2019 and we identified superimposed multiannual cycles in the period 1990-2009. After 2009, no multiannual cycle could be identified, although the incidence fluctuated and correlates with number of IUT performed. As of 2020, weekly reports of B19V infection demonstrated a historically low incidence and B19V-DNA positive blood donors were nearly absent. From May 2020 to May 2023, no IUT for B19V-related hydrops was performed. In the spring of 2023, B19V infections re-emerged, reaching pre-pandemic epidemic levels. Due to the changes in B19V epidemiology over the last 30 years and the near-absence of B19V during the COVID-19 pandemic, the resulting low immunity levels may lead to rebound outbreaks. Alertness to severe complications such as fetal hydrops is warranted.

Artery-to-vein anastomoses in unequally divided placentas and their association with birthweight discordance.

INTRODUCTION: This study investigated the impact of the shared intertwin circulation in unequally divided monochorionic (MC) placentas on fetal growth. METHODS: This retrospective analysis included color-dyed, unequally shared placentas from two tertiary centers. Exclusions included twin-twin transfusion syndrome, twin anemia polycythemia sequence, and lethal anomalies. Measurement of the external diameters and areas of the artery-to-artery (AA), artery-to-vein (AV), and vein-to-vein (VV) anastomoses was performed. The ratio of the shared circulation (AV ratio) was determined by comparing the areas of the summed venous components of shared AV anastomoses to those in the individual AV anastomoses of the smaller placental part. The birth weight ratio/placental ratio (BWR/PR), total AV size areas and net AV transfusion were calculated. Univariable and multivariable linear regressions were performed to assess the relationship between BWR/PR, the AV ratio, the areas of the different anastomoses and cord insertion discordance. RESULTS: Among 352 placentas, 97 % (340) had intertwin AV anastomoses, and 50 % (176) were from pregnancies with selective growth restriction. The AV ratio, AA, VV, total AV areas, and cord insertion discordance negatively correlated with BWR/PR. Multivariable linear regression confirmed the independent negative association between BWR/PR and the AV ratio, suggesting that a larger shared circulation benefits the twin with the smaller placental part. Type III sFGR placentas exhibited the highest AV ratio, resulting in the lowest BWR/PR. DISCUSSION: A larger shared circulation mitigates the impact of an unequally divided placenta on fetal growth. This effect surpasses the influence of AA and VV diameters and is most prominent in Type III sFGR placentas.

Severity of haemolytic disease of the fetus and newborn in patients with a history of intrauterine transfusions in a previous pregnancy: A nationwide retrospective cohort study.

OBJECTIVE: Pregnant women who received at least one intrauterine transfusion (IUT) for haemolytic disease of the fetus and newborn (HDFN) in the preceding pregnancy are presumed to have a high likelihood of requiring IUTs again, often starting at an earlier gestational age. Our aim was to quantify these risks in a large national cohort. DESIGN: Retrospective cohort study of a nationwide Dutch database. SETTING: The Netherlands. POPULATION: All women treated in The Netherlands with IUTs for Rhesus D (RhD)- or Kell-mediated HDFN between 1999 and 2017 and their follow-up pregnancies were included. Pregnancies with an antigen-negative fetus were excluded. METHODS: Electronic patient files were searched for the number and gestational age of each IUT, and analysed using descriptive statistics and linear regression. MAIN OUTCOME MEASURES: Percentage of women requiring one or more IUTs again in the subsequent pregnancy, and gestational age at first IUT in both pregnancies. RESULTS: Of the 321 women in our study population, 21% (69) had a subsequent ongoing pregnancy at risk. IUTs were administered in 86% (59/69) of cases. In subsequent pregnancies, the median gestational age at first IUT was 3 weeks earlier (interquartile range -6.8 to 0.4) than in the preceding pregnancy. CONCLUSIONS: Our study shows that pregnant women with a history of IUTs in the previous pregnancy are highly likely to require IUTs again, and on average 3 weeks earlier. Clinicians need to be aware of these risks and ensure timely referral, and close surveillance from early pregnancy onwards. Additionally, for women with a history of IUT and their caregivers, this information is essential to enable adequate preconception counselling.

Perspectives of extremely prematurely born adults on what to consider in prenatal decision-making: a qualitative focus group study.

OBJECTIVE: A shared decision-making (SDM) approach is recommended for prenatal decisions at the limit of viability, with a guiding role for parental values. People born extremely premature experience the consequences of the decision made, but information about their perspectives on prenatal decisions is lacking. Therefore, this study aims to describe their perspectives on what is important in decision-making at the limit of viability. DESIGN: Semi-structured focus group discussions were conducted, recorded and transcribed verbatim. The data were independently analysed by two researchers in Atlas.ti. RESULTS: Four focus groups were conducted in the Netherlands, with five to six participants each, born between 240/7 and 300/7 weeks gestation in the period between 1965 and 2002. Considering their personal life experiences and how their extremely premature birth affected their families, the participants reflected on decision-making at the limit of viability. Various considerations were discussed and summarised into the following themes: anticipated parental regret, the wish to look at the baby directly after birth, to give the infant a chance at survival, quality of life, long-term outcomes for the infant and the family, and religious or spiritual considerations. CONCLUSIONS: Insights into the perspectives of adults born extremely premature deepened our understanding of values considered in decision-making at the limit of viability. Results point out the need for a more individualised prediction of the prognosis and more extensive information on the lifelong impact of an extremely premature birth on both the infant and the family. This could help future parents and healthcare professionals in value-laden decision-making.

Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial.

BACKGROUND: Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn. METHODS: We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 µg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed. FINDINGS: Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study. INTERPRETATION: Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn. FUNDING: Sanquin Blood Supply. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Opportunities and Challenges of Prognostic Models for Extremely Preterm Infants.

Predicting the short- and long-term outcomes of extremely preterm infants remains a challenge. Multivariable prognostic models might be valuable tools for clinicians, parents, and policymakers for providing accurate outcome estimates. In this perspective, we discuss the opportunities and challenges of using prognostic models in extremely preterm infants at population and individual levels. At a population level, these models could support the development of guidelines for decisions about treatment limits and may support policy processes such as benchmarking and resource allocation. At an individual level, these models may enhance prenatal counselling conversations by considering multiple variables and improving transparency about expected outcomes. Furthermore, they may improve consistency in projections shared with parents. For the development of prognostic models, we discuss important considerations such as predictor and outcome measure selection, clinical impact assessment, and generalizability. Lastly, future recommendations for developing and using prognostic models are suggested. Importantly, the purpose of a prognostic model should be clearly defined, and integrating these models into prenatal counselling requires thoughtful consideration.

Adults born prematurely prefer a periviability guideline that considers multiple prognostic factors beyond gestational age.

AIM: The aim of the study was to explore the perspectives of adults born prematurely on guidelines for management at extreme premature birth and personalisation at the limit of viability. METHODS: We conducted four 2-h online focus group interviews in the Netherlands. RESULTS: Twenty-three participants born prematurely were included in this study, ranging in age from 19 to 56 years and representing a variety of health outcomes. Participants shared their perspectives on different types of guidelines for managing extremely premature birth. They agreed that a guideline was necessary to prevent arbitrary treatment decisions and to avoid physician bias. All participants favoured a guideline that is based upon multiple prognostic factors beyond gestational age. They emphasised the importance of discretion, regardless of the type of guideline used. Discussions centred mainly on the heterogeneity of value judgements about outcomes after extreme premature birth. Participants defined personalisation as 'not just looking at numbers and statistics'. They associated personalisation mainly with information provision and decision-making. Participants stressed the importance of involving families in decision-making and taking their care needs seriously. CONCLUSION: Adults born prematurely prefer a periviability guideline that considers multiple prognostic factors and allows for discretion.

Perinatal outcome after selective fetal reduction in monochorionic twin pregnancies: A comparison of techniques over a 20-year period.

OBJECTIVE: To assess the perinatal outcome after fetal reduction in complicated monochorionic (MC) twin pregnancies by comparing different techniques. METHODS: A retrospective cohort study at a national referral center comparing data between four techniques: interstitial laser coagulation, radiofrequency ablation (RFA), fetoscopic laser coagulation (FLC) and bipolar cord coagulation (BCC). The primary outcome was the mortality of the co-twins. Secondary outcomes were preterm pre-labor rupture of membranes (PPROM), gestational age at delivery and neonatal morbidity. RESULTS: 259 MC twin pregnancies underwent selective fetal reduction: 29 IL, 64 RFA, 85 FLC and 81 BCC. The perinatal mortality rate was 29% and fetal demise of the co-twins occurred in 19%. The lowest mortality rate was seen after BCC (17%, p = 0.012). PPROM occurred in 18% patients without significant differences between techniques. The mean gestational age at delivery in liveborn children was 35 weeks and did not differ between techniques. Severe cerebral injury and neonatal morbidity were reported in 4% and 14%, respectively, without significant differences between techniques. CONCLUSIONS: Selective fetal reductions in MC twins are precarious procedures with an increased risk of perinatal mortality of the co-twins. Our results show the lowest mortality rates after BCC. However, high PPROM rates were seen irrespective of the technique.

Dutch professionals' discussion preferences with the parents of extremely premature infants varied, but the trend was towards shared decision-making.

AIM: We explored professionals' views on sharing decision-making with parents before and after an extremely preterm birth and what healthcare professionals considered severe outcomes. METHODS: A nationwide, multi-centre online survey was carried out among a wide range of perinatal healthcare professionals in the Netherlands from 4 November 2020 to 10 January 2021. The medical chairs of all nine Dutch Level III and IV perinatal centres helped to disseminate the survey link. RESULTS: We received 769 survey responses. Most respondents (53%) preferred to place equal emphasis on two treatment options during shared prenatal decision-making: early intensive care or palliative comfort care. The majority (61%) wanted to include a conditional intensive care trial as a third treatment option, but 25% disagreed. Most (78%) felt that healthcare professionals were responsible for initiating postnatal conversations to justify continuing or withdrawing neonatal intensive care if complications were associated with poor outcomes. Finally, 43% were satisfied with the current definitions of severe long-term outcomes, 41% were unsure and there were numerous for a broader definition. CONCLUSION: Although Dutch professionals expressed diverse preferences on how to reach decisions about extremely premature infants, we observed a trend towards shared decision-making with parents. These results could inform future guidelines.

Identification and management of fetal anemia due to hemolytic disease.

INTRODUCTION: Hemolytic disease of the fetus and newborn (HDFN) is a condition caused by maternal alloantibodies against fetal red blood cells (RBCs) that can cause severe morbidity and mortality in the fetus and newborn. Adequate screening programs allow for timely prevention and intervention resulting in significant reduction of the disease over the last decades. Nevertheless, HDFN still occurs and with current treatment having reached an optimum, focus shifts toward noninvasive therapy options. AREAS COVERED: This review focusses on the timely identification of high risk cases and antenatal management. Furthermore, we elaborate on future perspectives including improvement of screening, identification of high risk cases and promising treatment options. EXPERT OPINION: In high-income countries mortality and morbidity rates due to HDFN have drastically been reduced over the last decades, yet worldwide anti-D mediated HDFN still accounts for 160,000 perinatal deaths and 100,000 patients with disabilities every year. Much of these deaths and disabilities could have been avoided with proper identification and prophylaxis. By implementing sustainable prevention, screening, and disease treatment measures in all countries this will systemically reduce unnecessary perinatal deaths. There is a common responsibility to engage in this cause.

The Impact of Maternal Prenatal Stress Related to the COVID-19 Pandemic during the First 1000 Days: A Historical Perspective.

The COVID-19 pandemic has a major impact on society, particularly affecting its vulnerable members, including pregnant women and their unborn children. Pregnant mothers reported fear of infection, fear of vertical transmission, fear of poor birth and child outcomes, social isolation, uncertainty about their partner's presence during medical appointments and delivery, increased domestic abuse, and other collateral damage, including vaccine hesitancy. Accordingly, pregnant women's known vulnerability for mental health problems has become a concern during the COVID-19 pandemic, also because of the known effects of prenatal stress for the unborn child. The current narrative review provides a historical overview of transgenerational effects of exposure to disasters during pregnancy, and the role of maternal prenatal stress. We place these effects into the perspective of the COVID-19 pandemic. Hereby, we aim to draw attention to the psychological impact of the COVID-19 pandemic on women of reproductive age (15-49 year) and its potential associated short-term and long-term consequences for the health of children who are conceived, carried, and born during this pandemic. Timely detection and intervention during the first 1000 days is essential to reduce the burden of transgenerational effects of the COVID-19 pandemic.

Twin pregnancy reduction is not an 'all or nothing' problem: a response to Räsänen.

In his paper, 'Twin pregnancy, fetal reduction and the 'all or nothing problem', Räsänen sets out to apply Horton's 'all or nothing' problem to the ethics of multifetal pregnancy reduction from a twin to a singleton pregnancy (2-to-1 MFPR). Horton's problem involves the following scenario: imagine that two children are about to be crushed by a collapsing building. An observer would have three options: do nothing, save one child by allowing their arms to be crushed, or save both by allowing their arms to be crushed. Horton offers two intuitively plausible claims: (1) it is morally permissible not to save either child and (2) it is morally impermissible to save only one of the children, which taken together lead to the problematic conclusion that (3) if an observer does not save both children, then it is better to save neither than save only one. Räsänen applies this problem to the case of 2-to-1 MFPR, arguing ultimately that, in cases where there is no medical reason to reduce, the woman ought to bring both fetuses to term. We will argue that Räsänen does not provide adequate support for the claim, crucial to his argument, that aborting only one of the fetuses in a twin pregnancy is wrong, so the 'all or nothing' problem does not arise in this context. Furthermore, we argue that the scenario Räsänen presents is highly unrealistic because of the clinical realities of 2-to-1 MFPR, making his argument of limited use for real-life decision making in this area.

Dutch guidelines on care for extremely premature infants: Navigating between personalisation and standardization.

OBJECTIVE: There is no international consensus on what type of guideline is preferred for care at the limit of viability. We aimed to conceptualize what type of guideline is preferred by Dutch healthcare professionals: 1) none; 2) gestational-age-based; 3) gestational-age-based-plus; or 4) prognosis-based via a survey instrument. Additional questions were asked to explore the grey zone and attitudes towards treatment variation. FINDING: 769 surveys were received. Most of the respondents (72.8%) preferred a gestational-age-based-plus guideline. Around 50% preferred 24+0/7 weeks gestational age as the lower limit of the grey zone, whereas 26+0/7 weeks was the most preferred upper limit. Professionals considered treatment variation acceptable when it is based upon parental values, but unacceptable when it is based upon the hospital's policy or the physician's opinion. CONCLUSION: In contrast to the current Dutch guideline, our results suggest that there is a preference to take into account individual factors besides gestational age.

Prenatal counseling for extreme prematurity at the limit of viability: A scoping review.

OBJECTIVES: To explore, based on the existing body of literature, main characteristics of prenatal counseling for parents at risk for extreme preterm birth. METHODS: A scoping review was conducted searching Embase, Medline, Web of Science, Cochrane, CINAHL, and Google Scholar. RESULTS: 46 articles were included. 27 of them were published between 2017 and 2021. More than half of them were conducted in the United States of America. Many different study designs were represented. The following characteristics were identified: personalization, parent-physician relationships, shared decision-making, physician bias, emotions, anxiety, psychosocial factors, parental values, religion, spirituality, hope, quality of life, and uncertainty. CONCLUSIONS: Parental values are mentioned in 37 of the included articles. Besides this, uncertainty, shared decision-making, and emotions are most frequently mentioned in the literature. However, reflecting on the interrelation between all characteristics leads us to conclude that personalization is the most notable trend in prenatal counseling practices. More and more, it is valued to adjust the counseling to the parent(s). PRACTICE IMPLICATIONS: This scoping review emphasizes again the complexity of prenatal counseling at the limit of viability. It offers an exploration of how it is currently approached, and reflects on how future research can contribute to optimizing it.

Ethical Development of Artificial Amniotic Sac and Placenta Technology: A Roadmap.

In this paper we present an initial roadmap for the ethical development and eventual implementation of artificial amniotic sac and placenta technology in clinical practice. We consider four elements of attention: (1) framing and societal dialogue; (2) value sensitive design, (3) research ethics and (4) ethical and legal research resulting in the development of an adequate moral and legal framework. Attention to all elements is a necessary requirement for ethically responsible development of this technology. The first element concerns the importance of framing and societal dialogue. This should involve all relevant stakeholders as well as the general public. We also identify the need to consider carefully the use of terminology and how this influences the understanding of the technology. Second, we elaborate on value sensitive design: the technology should be designed based upon the principles and values that emerge in the first step: societal dialogue. Third, research ethics deserves attention: for proceeding with first-in-human research with the technology, the process of recruiting and counseling eventual study participants and assuring their informed consent deserves careful attention. Fourth, ethical and legal research should concern the status of the subject in the AAPT. An eventual robust moral and legal framework for developing and implementing the technology in a research setting should combine all previous elements. With this roadmap, we emphasize the importance of stakeholder engagement throughout the process of developing and implementing the technology; this will contribute to ethically and responsibly innovating health care.