Development of a Web-Based Oxygenation Dashboard for Preterm Neonates: A Quality Improvement Initiative.

BACKGROUND: Preterm neonates are extensively monitored to require strict oxygen target attainment for optimal outcomes. In daily practice, detailed oxygenation data are hardly used and crucial patterns may be missed due to the snapshot presentations and subjective observations. This study aimed to develop a web-based dashboard with both detailed and summarized oxygenation data in real-time and to test its feasibility to support clinical decision making. METHODS: Data from pulse oximeters and ventilators were synchronized and stored to enable real-time and retrospective trend visualizations in a web-based viewer. The dashboard was designed based on interviews with clinicians. A preliminary version was evaluated during daily clinical rounds. The routine evaluation of the respiratory condition of neonates (gestational age < 32 weeks) with respiratory support at the NICU was compared to an assessment with the assistance of the dashboard. RESULTS: The web-based dashboard included data on the oxygen saturation (SpO2), fraction of inspired oxygen (FiO2), SpO2/FiO2 ratio, and area < 80% and > 95% SpO2 curve during time intervals that could be varied. The distribution of SpO2 values was visualized as histograms. In 65% of the patient evaluations (n = 86) the level of hypoxia was assessed differently with the use of the dashboard. In 75% of the patients the dashboard was judged to provide added value for the clinicians in supporting clinical decisions. CONCLUSIONS: A web-based customized oxygenation dashboard for preterm neonates at the NICU was developed and found feasible during evaluation. More clear and objective information was found supportive for clinicians during the daily rounds in tailoring treatment strategies.

Core outcome set for perinatal interventions for congenital diaphragmatic hernia.

OBJECTIVE: To develop a core set of prenatal and neonatal outcomes for clinical studies evaluating perinatal interventions for congenital diaphragmatic hernia, using a validated consensus-building method. METHODS: An international steering group comprising 13 leading maternal-fetal medicine specialists, neonatologists, pediatric surgeons, patient representatives, researchers and methodologists guided the development of this core outcome set. Potential outcomes were collected through a systematic review of the literature and entered into a two-round online Delphi survey. A call was made for stakeholders with experience of congenital diaphragmatic hernia to review the list and score outcomes based on their perceived relevance. Outcomes that fulfilled the consensus criteria defined a priori were discussed subsequently in online breakout meetings. Results were reviewed in a consensus meeting, during which the core outcome set was defined. Finally, the definitions, measurement methods and aspirational outcomes were defined in online and in-person definition meetings by a selection of 45 stakeholders. RESULTS: Overall, 221 stakeholders participated in the Delphi survey and 198 completed both rounds. Fifty outcomes met the consensus criteria and were discussed and rescored by 78 stakeholders in the breakout meetings. During the consensus meeting, 93 stakeholders agreed eventually on eight outcomes, which constituted the core outcome set. Maternal and obstetric outcomes included maternal morbidity related to the intervention and gestational age at delivery. Fetal outcomes included intrauterine demise, interval between intervention and delivery and change in lung size in utero around the time of the intervention. Neonatal outcomes included neonatal mortality, pulmonary hypertension and use of extracorporeal membrane oxygenation. Definitions and measurement methods were formulated by 45 stakeholders, who also added three aspirational outcomes: duration of invasive ventilation, duration of oxygen supplementation and use of pulmonary vasodilators at discharge. CONCLUSIONS: We developed with relevant stakeholders a core outcome set for studies evaluating perinatal interventions in congenital diaphragmatic hernia. Its implementation should facilitate the comparison and combination of trial results, enabling future research to better guide clinical practice. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

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.

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.

Maternal folic acid use during pregnancy, methylenetetrahydrofolate reductase gene polymorphism, and child's lung function and asthma.

BACKGROUND: Folic acid supplement use during pregnancy might affect childhood respiratory health, potentially mediated by methylenetetrahydrofolate reductase polymorphism C677T (MTHFR-C677T) carriership. OBJECTIVES: We examined the associations of maternal folic acid supplement use and folate, vitamin B12 and homocysteine concentrations during pregnancy with childhood lung function and asthma. METHODS: This study was embedded in a population-based prospective cohort study among 5653 children. Folic acid supplement use was assessed by questionnaires. Folate, vitamin B12 and homocysteine plasma concentrations were measured in early pregnancy and at birth. At age 10 years, forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), FEV1 /FVC, forced expiratory flow between 25% and 75% (FEF25-75 ), at 75% of FVC (FEF75 ), and asthma were examined. RESULTS: Maternal folic acid supplement use during pregnancy was associated with higher childhood FEV1 and FVC and with a lower FEV1 /FVC, compared with no folic acid supplement use. Among mothers carrying MTHFR-C677T variants, preconceptional start of folic acid supplement use was associated with lower FEV1 /FVC (-0.17 [-0.32, -0.02]) and FEF25-75 (-0.24 [-0.40, -0.07]). Among children carrying MTHFR-C677T wild-type, a higher vitamin B12 level at birth was associated with a lower FEV1 (-0.07 [-0.12, -0.01]) and FVC (-0.09 [-0.15, -0.04]). Folate and homocysteine concentrations were not consistently associated with lower childhood lung function or asthma. CONCLUSIONS: Preconceptional start of maternal folic acid supplement use and higher vitamin B12 concentrations at birth might adversely affect childhood lung function depending on MTHFR-C677T carriership. The clinical implications need to be evaluated.

Prenatal cerebellar growth trajectories and the impact of periconceptional maternal and fetal factors.

STUDY QUESTION: CAN WE assess human prenatal cerebellar growth from the first until the third trimester of pregnancy and create growth trajectories to investigate associations with periconceptional maternal and fetal characteristics? SUMMARY ANSWER: Prenatal growth trajectories of the human cerebellum between 9 and 32 weeks gestational age (GA) were created using three-dimensional ultrasound (3D-US) and show negative associations with pre-pregnancy and early first trimester BMI calculated from self-reported and standardized measured weight and height, respectively. WHAT IS KNOWN ALREADY: The cerebellum is essential for normal neurodevelopment and abnormal cerebellar development has been associated with neurodevelopmental impairments and psychiatric diseases. Cerebellar development is particularly susceptible to exposures during the prenatal period, including maternal folate status, smoking habit and alcohol consumption. STUDY DESIGN, SIZE, DURATION: From 2013 until 2015, we included 182 singleton pregnancies during the first trimester as a subgroup in a prospective periconception cohort with follow-up until birth. For the statistical analyses, we selected 166 pregnancies ending in live born infants without congenital malformations. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured transcerebellar diameter (TCD) at 9, 11, 22, 26 and 32 weeks GA on ultrasound scans. Growth rates were calculated and growth trajectories of the cerebellum were created. Linear mixed models were used to estimate associations between cerebellar growth and maternal age, parity, mode of conception, geographic origin, pre-pregnancy and first trimester BMI, periconceptional smoking, alcohol consumption, timing of folic acid supplement initiation and fetal gender. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 166 pregnancies provided 652 (87%) ultrasound images eligible for TCD measurements. Cerebellar growth rates increased with advancing GA being 0.1691 mm/day in the first trimester, 0.2336 mm/day in the second trimester and 0.2702 mm/day in the third trimester. Pre-pregnancy BMI, calculated from self-reported body weight and height, was significantly associated with decreased cerebellar growth trajectories (ß = -0.0331 mm, 95% CI = -0.0638; -0.0024, P = 0.035). A similar association was found between cerebellar growth trajectories and first trimester BMI, calculated from standardized measurements of body weight and height (ß = -0.0325, 95% CI = -0.0642; -0.0008, P = 0.045, respectively). LIMITATIONS, REASONS FOR CAUTION: As the study population largely consisted of tertiary hospital patients, external validity should be studied in the general population. Whether small differences in prenatal cerebellar growth due to a higher pre-pregnancy and first trimester BMI have consequences for neurodevelopmental outcome needs further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings further substantiate previous evidence for the detrimental impact of a higher maternal BMI on neurodevelopmental health of offspring in later life. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Department of Obstetrics and Gynecology, Erasmus MC University Medical Centre and Sophia Children's Hospital Fund, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.

Maternal obesity, gestational weight gain and childhood cardiac outcomes: role of childhood body mass index.

BACKGROUND: Maternal obesity may affect cardiovascular outcomes in the offspring. We examined the associations of maternal prepregnancy body mass index and gestational weight gain with childhood cardiac outcomes and explored whether these associations were explained by parental characteristics, infant characteristics or childhood body mass index. METHODS: In a population-based prospective cohort study among 4852 parents and their children, we obtained maternal weight before pregnancy and in early, mid- and late pregnancy. At age 6 years, we measured aortic root diameter (cm) and left ventricular dimensions. We calculated left ventricular mass (g), left ventricular mass index (g m(-2.7)), relative wall thickness ((2 × left ventricular posterior wall thickness)/left ventricular diameter), fractional shorting (%), eccentric left ventricular hypertrophy and concentric remodeling. RESULTS: A one standard deviation score (SDS) higher maternal prepregnancy body mass index was associated with higher left ventricular mass (0.10 SDS (95% confidence interval (CI) 0.08, 0.13)), left ventricular mass index (0.06 SDS (95% CI 0.03, 0.09)) and aortic root diameter (0.09 SDS (95% CI 0.06, 0.12)), but not with relative wall thickness or fractional shortening. A one SDS higher maternal prepregnancy body mass index was associated with an increased risk of eccentric left ventricular hypertrophy (odds ratio 1.21 (95% CI 1.03, 1.41)), but not of concentric remodeling. When analyzing the effects of maternal weight in different periods simultaneously, only maternal prepregnancy weight and early pregnancy weight were associated with left ventricular mass, left ventricular mass index and aortic root diameter (P-values<0.05), independent of weight in other pregnancy periods. All observed associations were independent of parental and infant characteristics, but attenuated to non-significance after adjustment for childhood body mass index. CONCLUSION: Maternal prepregnancy body mass index and weight gain in early pregnancy are both associated with offspring cardiac structure in childhood, but these associations seem to be fully explained by childhood body mass index.

Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood lung function and asthma: the Generation R Study.

BACKGROUND: Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma. OBJECTIVE: We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with higher airway resistance and inflammation, and increased risks of wheezing and asthma in school-age children. METHODS: We performed a population-based prospective cohort study among 3130 mothers and their children. Maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels. At age of 6, airway resistance (Rint) was measured by interrupter technique and airway inflammation by fractional exhaled nitric oxide (FENO) using NIOX chemiluminescence analyser. Wheezing and asthma were prospectively assessed by annual questionnaires until age 6. RESULTS: Maternal levels of 25-hydroxyvitamin D in mid-gestation were not associated with Rint, FeNO, wheezing patterns, or asthma. Children in the lowest tertile of 25-hydroxyvitamin D levels at birth had a higher Rint (Z-score (95% confidence interval [95% CI]): -0.42 (-0.84, -0.01), P-value for trend< 0.05), compared to those in the highest tertile group. The effect estimate attenuated when child's current 25-hydroxyvitamin D level was taken into account [Z-score (95% CI): -0.55 (-1.08, 0.01)]. CONCLUSION AND CLINICAL RELEVANCE: Low levels of 25-hydroxyvitamin D at birth were associated with a higher airway resistance in childhood. Additional adjustment for child's current 25-hydroxyvitamin D level reduced the effect size of the association. Further studies are needed to replicate these findings and to examine mechanisms underlying the observed association and the long-term consequences.

Growth trajectories of the human embryonic head and periconceptional maternal conditions.

STUDY QUESTION: Can growth trajectories of the human embryonic head be created using 3D ultrasound (3D-US) and virtual reality (VR) technology, and be associated with second trimester fetal head size and periconceptional maternal conditions? SUMMARY ANSWER: Serial first trimester head circumference (HC) and head volume (HV) measurements were used to create reliable growth trajectories of the embryonic head, which were significantly associated with fetal head size and periconceptional maternal smoking, age and ITALIC! in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) treatment. WHAT IS KNOWN ALREADY: Fetal growth is influenced by periconceptional maternal conditions. STUDY DESIGN, SIZE, DURATION: We selected 149 singleton pregnancies with a live born non-malformed fetus from the Rotterdam periconception cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Bi-parietal diameter and occipital frontal diameter to calculate HC, HV and crown-rump length (CRL) were measured weekly between 9 + 0 and 12 + 6 weeks gestational age (GA) using 3D-US and VR. Fetal HC was obtained from second trimester structural anomaly scans. Growth trajectories of the embryonic head were created with general additive models and linear mixed models were used to estimate associations with maternal periconceptional conditions as a function of GA and CRL, respectively. MAIN RESULTS: A total of 303 3D-US images of 149 pregnancies were eligible for embryonic head measurements (intra-class correlation coefficients >0.99). Associations were found between embryonic HC and fetal HC ( ITALIC! ρ = 0.617, ITALIC! P < 0.001) and between embryonic HV and fetal HC ( ITALIC! ρ = 0.660, ITALIC! P < 0.001) in ITALIC! Z-scores. Maternal periconceptional smoking was associated with decreased, and maternal age and IVF/ICSI treatment with increased growth trajectories of the embryonic head measured by HC and HV (All ITALIC! P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The consequences of the small effect sizes for neurodevelopmental outcome need further investigation. As the study population consists largely of tertiary hospital patients, external validity should be studied in the general population. WIDER IMPLICATIONS OF THE FINDINGS: Assessment of growth trajectories of the embryonic head may be of benefit in future early antenatal care. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Department of Obstetrics and Gynaecology, Erasmus MC University Medical Centre and Sophia Foundation for Medical Research, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.

Maternal and Neonatal Outcomes of Preterm Premature Rupture of Membranes before Viability.

BACKGROUND: To investigate maternal and neonatal outcomes of previable preterm premature rupture of membranes (PPROM) and compare outcome between previable PPROM before and after 20 weeks of pregnancy, with data from one single center. PATIENTS: All women with singleton or twin pregnancies, from 2002 through 2011, who presented with PPROM before 24 weeks of gestation. METHOD: A retrospective cohort study in a university teaching hospital in the Netherlands. Data were analyzed and compared between pregnancies with previable PPROM before and after 20 weeks of pregnancy. Main outcome measures were maternal and neonatal morbidity and mortality. RESULTS: A total of 160 women (164 fetuses) were included. 90 women (56.2%) developed complications (intra-uterine infection, retained placenta, placental abruption or sepsis). There was no maternal mortality. 68 neonates were admitted after birth. PPHN (64.7%, p=0.001) and contractures (58.8%, p<0.001) occurred significantly more in neonates born after PPROM<20 weeks of pregnancy. Eventually 38.4% of the neonates survived. Neonates born after previable PPROM > 20 weeks had a greater likelihood of being alive at discharge (22.7 vs. 46.9%, p=0.008). DISCUSSION: This study of previable PPROM shows that more than 50% of the mothers develop one or more complications. Neonates have a high mortality rate, especially neonates born after PPROM<20 weeks of pregnancy. In particular neonates born after PPROM<20 weeks of pregnancy should be watched closely for PPHN and contractures. CONCLUSION: This large single center study can provide good foundation for counseling parents on previable PPROM, especially the prognosis of PPROM<20 weeks of pregnancy is of additional value.

Cutaneous microcirculation in preterm neonates: comparison between sidestream dark field (SDF) and incident dark field (IDF) imaging.

Incident dark field imaging (IDF) is a new generation handheld microscope for bedside visualization and quantification of microcirculatory alterations. IDF is the technical successor of sidestream dark field imaging (SDF), currently the most used device for microcirculatory measurements. In (pre)term neonates the reduced thickness of the skin allows non-invasive transcutaneous measurements. The goal of this study was to compare the existing device (SDF) and its technical successor (IDF) in preterm neonates. We hypothesized that IDF imaging produces higher quality images resulting in a higher vessel density. After written informed consent was given by the parents, skin microcirculation was consecutively measured on the inner upper arm with de SDF and IDF device. Images were exported and analyzed offline using existing software (AVA 3.0). Vessel density and perfusion were calculated using the total vessel density (TVD) proportion of perfused vessels (PPV) and perfused vessel density. The microcirculation images quality score was used to evaluate the quality of the video images. In a heterogeneous group of twenty preterm neonates (median GA 27.6 weeks, range 24-33.4) IDF imaging visualized 19.9% more vessels resulting in a significantly higher vessel density (TVD 16.9 vs. 14.1/mm, p value < 0.001). The perfusion of vessels could be determined more accurately in the IDF images, resulting in a significant lower PPV (88.7 vs. 93.9%, p value 0.002). The IDF video images scored optimal in a higher percentage compared to the SDF video images. IDF imaging of the cutaneous microcirculation in preterm neonates resulted in a higher vessel density and lower perfusion compared to the existing SDF device.

Quantification of stress exposure in very preterm infants: Development of the NeO-stress score.

BACKGROUND: Stress during treatment at the Neonatal Intensive Care Unit (NICU) has long-term negative consequences on preterm infants' development. AIMS: We developed an instrument suited to validly determine the cumulative stress exposure for preterm infants in a NICU. STUDY DESIGN: This survey study made use of two consecutive questionnaires. SUBJECTS: NICU nurses and physicians from the nine NICUs in the Netherlands. OUTCOME MEASURES: First, respondents rated the relevance of 77 items encompassing potentially stressful procedures, commented on their comprehensibility and the comprehensiveness of the list. We calculated the content validity per item (CVI-I) and included only the relevant items in a second questionnaire in which the participants rated the stressfulness from 0 (not stressful) to 10 (extremely stressful). A stressfulness index - representing the median score - was calculated for each included item. RESULTS: Based on the CVI-I of the 77 items, step 1 resulted in 38 items considered relevant to quantify stress in preterm infants during the first 28 days of life. This list of 38 items exists of 34 items with a CVI-I if 0.78 or higher, one of these items was split into two items, and three items were added to improve comprehensiveness. The stressfulness index ranged from five to nine. CONCLUSIONS: The NeO-stress score consists of stressful items including their severity index and was developed to determine cumulative stress exposure of preterm infants. Evaluating the cross-cultural validity, correlating it to behavioural and biological stress responses, and evaluating its ability to predict preterm infants at risk for the negative effects following stress might expand the possibilities for this instrument.

Effects of the neonatal intensive care environment on circadian health and development of preterm infants.

The circadian system in mammals ensures adaptation to the light-dark cycle on Earth and imposes 24-h rhythmicity on metabolic, physiological and behavioral processes. The central circadian pacemaker is located in the brain and is entrained by environmental signals called Zeitgebers. From here, neural, humoral and systemic signals drive rhythms in peripheral clocks in nearly every mammalian tissue. During pregnancy, disruption of the complex interplay between the mother's rhythmic signals and the fetal developing circadian system can lead to long-term health consequences in the offspring. When an infant is born very preterm, it loses the temporal signals received from the mother prematurely and becomes totally dependent on 24/7 care in the Neonatal Intensive Care Unit (NICU), where day/night rhythmicity is usually blurred. In this literature review, we provide an overview of the fetal and neonatal development of the circadian system, and short-term consequences of disruption of this process as occurs in the NICU environment. Moreover, we provide a theoretical and molecular framework of how this disruption could lead to later-life disease. Finally, we discuss studies that aim to improve health outcomes after preterm birth by studying the effects of enhancing rhythmicity in light and noise exposure.

Regenerative therapies in neonatology: clinical perspectives.

Regenerative therapy based on stem cells is applied as standard therapy in pediatric oncology. Furthermore, they are frequently used to treat immunodeficiency disorders of infants. For severe neonatal diseases, e. g. hypoxic-ischemic encephalopathy in term neonates or bronchopulmonary dysplasia in preterm infants, animal models have been established. According to some first preclinical results stem cell administration appears as a promising tool to improve the clinical outcome in high-risk infants. Provided the benefit of regenerative therapies can further be evaluated in appropriate preclinical neonate models, carefully controlled clinical trials to assess the significance of regenerative therapies, such as autologous stem cell administration, are indicated.

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.

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.

Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis.

BACKGROUND: Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother-newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. RESULTS: Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. CONCLUSION: Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.

Early Ultrasonic Monitoring of Brain Growth and Later Neurodevelopmental Outcome in Very Preterm Infants.

BACKGROUND AND PURPOSE: In infants born very preterm, monitoring of early brain growth could contribute to prediction of later neurodevelopment. Therefore, our aim was to investigate associations between 2 early cranial ultrasound markers (corpus callosum-fastigium and corpus callosum length) and neurodevelopmental outcome and the added value of both markers in the prediction of neurodevelopmental outcome based on neonatal risk factors and head circumference in very preterm infants. MATERIALS AND METHODS: This prospective observational study included 225 infants born at <30 weeks' gestational age, of whom 153 were without any brain injury on cranial ultrasound. Corpus callosum-fastigium and corpus callosum length and head circumference were measured at birth, 29 weeks' gestational age, transfer from the neonatal intensive care unit to a level II hospital, and 2 months' corrected age. We analyzed associations of brain markers and their growth with cognitive, motor, language, and behavioral outcome at 2 years' corrected age. RESULTS: In infants without brain injury, greater corpus callosum-fastigium length at 2 months was associated with better cognitive outcome. Corpus callosum length at 2 months was positively associated with cognitive, motor, and language outcome. Faster growth of the corpus callosum length between birth and 2 months was associated with better cognitive and motor function. Prediction of neurodevelopmental outcome based on neonatal risk factors with or without head circumference was significantly improved by adding corpus callosum length. CONCLUSIONS: Both corpus callosum-fastigium and corpus callosum length on cranial ultrasound are associated with neurodevelopmental outcome of very preterm infants without brain injury at 2 years, but only corpus callosum length shows the added clinical utility in predicting neurodevelopmental outcome.

Actual outcome in infants with congenital diaphragmatic hernia: the role of a standardized postnatal treatment protocol.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly with a high rate of mortality and morbidity. OBJECTIVE: Our aim was to determine a possible effect of standardized treatment on outcome in infants with CDH. METHODS: All prenatally diagnosed patients with unilateral CDH born alive between January 2006 and December 2009 at the Erasmus MC or the University Hospital Mannheim were eligible for inclusion. Patients who underwent a fetal tracheal occlusion were excluded. From November 1, 2007, all CDH patients were treated according to a standardized treatment protocol. Patients were divided into two chronological groups according to their date of birth: without standardized treatment (group 1, Jan 2006-Oct 2007) and with standardized treatment (group 2, Nov 2007-Dec 2009). Outcome measures were mortality by day 28, bronchopulmonary dysplasia (BPD), defined as oxygen dependency at day 28, and need for extracorporeal membrane oxygenation (ECMO) therapy. Uni- and multivariate analyses were performed. RESULTS: 167 patients were included. By day 28, 18% of the infants had died. Of the patients who were alive at day 28, 49% had BPD. An ECMO procedure was performed in 31% of the patients. Overall mortality for all included patients was 22%. In group 1, overall mortality was 33% and in group 2 overall mortality was 12% (p = 0.004). A standardized treatment protocol was independently associated with a reduced risk for mortality by day 28 (OR 0.28, 95% CI 0.11-0.68). Higher observed-to-expected lung-to-head ratios were independently associated with a lower risk for mortality by day 28 (OR 0.97, 95% CI 0.95-0.99), BPD (OR 0.97, 95% CI 0.94-0.98) and need for ECMO (OR 0.98, 95% CI 0.96-0.99). An intrathoracic position of the liver was independently associated with an increased risk for BPD (OR 3.12, 95% CI 1.41-6.90) and need for ECMO therapy (OR 3.25, 95% CI 1.54-6.88). CONCLUSION: Survival rates in patients with CDH increased significantly after the implementation of a standardized treatment protocol.

The Edge of Perinatal Viability: Understanding the Dutch Position.

The current Dutch guideline on care at the edge of perinatal viability advises to consider initiation of active care to infants born from 24 weeks of gestational age on. This, only after extensive counseling of and shared decision-making with the parents of the yet unborn infant. Compared to most other European guidelines on this matter, the Dutch guideline may be thought to stand out for its relatively high age threshold of initiating active care, its gray zone spanning weeks 24 and 25 in which active management is determined by parental discretion, and a slight reluctance to provide active care in case of extreme prematurity. In this article, we explore the Dutch position more thoroughly. First, we briefly look at the previous and current Dutch guidelines. Second, we position them within the Dutch socio-cultural context. We focus on the Dutch prioritization of individual freedom, the abortion law and the perinatal threshold of viability, and a culturally embedded aversion of suffering. Lastly, we explore two possible adaptations of the Dutch guideline; i.e., to only lower the age threshold to consider the initiation of active care, or to change the type of guideline.