Publications by authors named "Irwin K M Reiss"

130 Publications

Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial).

BMC Pediatr 2021 11 18;21(1):517. Epub 2021 Nov 18.

Department of Pediatrics, Division Neonatology, Research Neonatology (Sk-4246), Erasmus Medical Center, PO Box 2060, Rotterdam, 300 CB, The Netherlands.

Background: Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies.

Methods: The PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics.

Discussion: The study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals.

Trial Registration: Clinicaltrials.gov, NCT04152980 , Registered November 6th, 2019.
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http://dx.doi.org/10.1186/s12887-021-02975-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603542PMC
November 2021

Early Screening of Visual Processing Dysfunctions in Children Born Very or Extremely Preterm.

Front Hum Neurosci 2021 1;15:729080. Epub 2021 Nov 1.

Department Neuroscience, Erasmus MC, Rotterdam, Netherlands.

Children with early brain damage or dysfunction are at risk of developing cerebral visual impairment (CVI), including visual processing dysfunctions (VPD), which currently remain largely undetected until school age. Our aim was to systematically screen for possible VPD in children born very or extremely preterm from 1 to 2 years corrected age (CA) and to evaluate the effectiveness of early referral. We included = 48 children born < 30 weeks from 1 year CA. They underwent a two-step VPD screening based on (1) neurological signs indicative of visual brain damage evaluated by neonatologists and/or pediatric neurologist and (2) a functional assessment of visual orienting functions (VOF) with an eye tracking-based test. If at least one of these assessments was abnormal for their age, the children were classified as a risk of VPD and referred to undergo conventional visual diagnostics: ophthalmic exam and visual function assessment (VFA). At 2 years CA, VOF screening was repeated and neurodevelopment was assessed. 18 children (38%) were classified as at risk of VPD at 1 year CA. 7 children had abnormal neurological signs, 5 children had abnormal VOF, and 6 children had both. Subsequent ophthalmic exams ( = 14) showed severe hypermetropia in 21% and strabismus in 14%. VFA ( = 10) showed abnormal visual function and behavior in only 1 child. At 2 years CA, the total group showed an increase in abnormal VOF. Whereas the children at risk showed some normalization, the group without VPD risk at 1 year CA showed deterioration of VOF. Neurodevelopmental outcome did not clearly differ between risk groups. Our findings show a substantial risk of VPD during visual screening (in 38%) at 1 year CA, but relatively few deficits on subsequent conventional ophthalmic exams and VFA. The data suggest that most conventional visual diagnostic methods at this young age are not related to the established VPD risks. VOF assessment should be used complimentary to these methods. The fact that at 2 years CA the number of children with a VPD risk based on abnormal VOF increased argues for more extensive and continuous screening in risk groups, at least until school age.
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http://dx.doi.org/10.3389/fnhum.2021.729080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591256PMC
November 2021

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

Int J Environ Res Public Health 2021 11 3;18(21). Epub 2021 Nov 3.

Division of Experimental Cardiology, Department of Cardiology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.

(-)tryptophan is metabolized via the kynurenine pathway into several kynurenine metabolites with distinct functions. Dysfunction of the kynurenine pathway can lead to impairments in vascular regulation, immune regulation, and tolerance. The first and rate limiting enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is highly expressed in the placenta and reduced in placentas from complicated pregnancies. IDO is essential during pregnancy, as IDO inhibition in pregnant mice resulted in fetal loss. However, the exact function of placental IDO, as well as its exact placental localization, remain controversial. This review identified that two isoforms of IDO; IDO1 and IDO2, are differently expressed between placental cells, suggesting spatial segregation. Furthermore, this review summarizes how the placental kynurenine pathway is altered in pregnancy complications, including recurrent miscarriage, preterm birth, preeclampsia, and fetal growth restriction. Importantly, we describe that these alterations do not affect maternally circulating metabolite concentrations, suggesting that the kynurenine pathway functions as a local signaling pathway. In the placenta, it is an important source of de novo placental NAD synthesis and regulates fetal tryptophan and kynurenine metabolite supply. Therefore, kynurenine pathway interventions might provide opportunities to treat pregnancy complications, and this review discusses how such treatment could affect placental function and pregnancy development.
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http://dx.doi.org/10.3390/ijerph182111545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582682PMC
November 2021

Neonatal sepsis definitions from randomised clinical trials.

Pediatr Res 2021 Nov 6. Epub 2021 Nov 6.

Department of Pediatrics, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, Providence, USA.

Introduction: Neonatal sepsis is a leading cause of infant mortality worldwide with non-specific and varied presentation. We aimed to catalogue the current definitions of neonatal sepsis in published randomised controlled trials (RCTs).

Method: A systematic search of the Embase and Cochrane databases was performed for RCTs which explicitly stated a definition for neonatal sepsis. Definitions were sub-divided into five primary criteria for infection (culture, laboratory findings, clinical signs, radiological evidence and risk factors) and stratified by qualifiers (early/late-onset and likelihood of sepsis).

Results: Of 668 papers screened, 80 RCTs were included and 128 individual definitions identified. The single most common definition was neonatal sepsis defined by blood culture alone (n = 35), followed by culture and clinical signs (n = 29), and then laboratory tests/clinical signs (n = 25). Blood culture featured in 83 definitions, laboratory testing featured in 48 definitions while clinical signs and radiology featured in 80 and 8 definitions, respectively.

Discussion: A diverse range of definitions of neonatal sepsis are used and based on microbiological culture, laboratory tests and clinical signs in contrast to adult and paediatric sepsis which use organ dysfunction. An international consensus-based definition of neonatal sepsis could allow meta-analysis and translate results to improve outcomes.
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http://dx.doi.org/10.1038/s41390-021-01749-3DOI Listing
November 2021

Are multidisciplinary neurodevelopmental profiles of children born very preterm at age 2 relevant to their long-term development? A preliminary study.

Child Neuropsychol 2021 Nov 2:1-21. Epub 2021 Nov 2.

Department of Otorhinolaryngology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.

To identify distinctive multidisciplinary neurodevelopmental profiles of relatively healthy children born very preterm (VPT) and describe the longitudinal course of these profiles up to age 10. At 2 years of corrected age, 84 children born VPT underwent standardized testing for cognitive, language, speech, motor, behavioral, and auditory nerve function. These data were submitted to factor and cluster analysis. Sixty-one of these children underwent cognitive, language, and behavioral assessment again at age 10. Descriptive statistics were used to analyze longitudinal trajectories for each profile. Four neurodevelopmental profiles were identified at age 2. Profile 1 children ( = 22/26%) had excellent cognitive-language-motor function, normal behavioral and auditory nerve function, but showed an unexpected severe decline up to age 10. Profile 2 children ( = 16/19%) had very low behavioral function, low cognitive-language-motor function, and accelerated auditory nerve function. Their scores remained low up until age 10. Profile 3 children ( = 17/20%) had delayed auditory nerve function, low behavioral function, and slightly lower cognitive-language-motor function. They showed the most increasing trajectory. Profile 4 children ( = 29/35%) had very low cognitive-language-motor function, normal behavioral and auditory nerve function, but showed wide variation in their trajectory. Our preliminary study showed that a multidisciplinary profile-oriented approach may be important in children born VPT to improve counseling and provide targeted treatment for at risk children. High performers at age 2 may not be expected to maintain their favorable development. Behavioral problems might negatively impact language development. Delayed auditory nerve function might represent a slow start and catch-up development.
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http://dx.doi.org/10.1080/09297049.2021.1991296DOI Listing
November 2021

Foetal tobacco and cannabis exposure, body fat and cardio-metabolic health in childhood.

Pediatr Obes 2021 Oct 21:e12863. Epub 2021 Oct 21.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Foetal tobacco and cannabis exposure may have persistent cardio-metabolic consequences in the offspring.

Objective: We examined the associations of maternal and paternal tobacco and cannabis use during pregnancy with offspring body fat and cardio-metabolic outcomes.

Methods: In a population-based prospective cohort study among 4792 mothers, fathers, and children, we assessed parental substance use by questionnaires. Childhood outcomes included body mass index (BMI), body fat, blood pressure, and lipid, glucose and insulin concentrations at 10 years.

Results: Children exposed to maternal tobacco use during pregnancy had a higher android/gynoid fat mass ratio (difference 0.22 SDS, 95% confidence interval [CI]: 0.13, 0.30), fat mass index (difference 0.20 SDS, 95% CI: 0.12, 0.28), triglyceride concentrations (difference 0.15 SDS, 95% CI: 0.04, 0.26), and a higher risk of overweight (odds ratio [OR] 1.35, 95% CI: 1.07, 1.71), compared to non-exposed. Children exposed to maternal cannabis during pregnancy had a higher BMI (difference 0.26 SDS, 95% CI: 0.08, 0.44), android/gynoid fat mass ratio (difference 0.21 SDS, 95% CI: 0.04, 0.39), and fat-free mass index (difference 0.24 SDS, 95% CI: 0.06, 0.41), compared to non-exposed. The associations for paternal substance use with child cardio-metabolic health outcomes were similar as those for maternal use.

Conclusions: Similar associations for maternal and paternal substance use during pregnancy suggest that these findings may be explained by shared family-based social and lifestyle factors, rather than by direct foetal programming.
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http://dx.doi.org/10.1111/ijpo.12863DOI Listing
October 2021

COVID-19 lockdown impacts the wellbeing of parents with infants on a Dutch neonatal intensive care unit.

J Pediatr Nurs 2021 Sep 28. Epub 2021 Sep 28.

Department of Pediatrics, Division of Neonatology, Erasmus MC -Sophia Children's Hospital, Rotterdam, the Netherlands.

Purpose: Parents of infants admitted to a neonatal intensive care unit (NICU) experience additional stress due to restrictions on their presence and visits by other family members during the COVID-19 pandemic. Our study aims to describe how this impacted parents and how NICU staff could support them.

Design And Methods: This was a cross-sectional study in which 25 parents (16 mothers, 9 fathers) of infants admitted to our NICU during the first COVID-19 lockdown completed online questionnaires with socio-demographic questions, the Parental Stressor Scale:NICU (PSS:NICU) and questions related to COVID-19.

Results: Being separated from, and not being able to hold their infant at all times were among the most important PSS:NICU stressors. Parents experienced additional stress because other family members were not allowed to visit. They indicated that NICU staff could support them by clearly explaining the reasons for visitor restrictions and by ensuring that they felt heard. Most parents supported the restrictions, but also mentioned that less strict measures would really help them.

Conclusions: Parents who participated in this study found it very stressful that they could not be with their infant together with their partner and other family members. Furthermore, parents recommended the hospital management to continuously reconsider whether particular restrictions could be lifted in case of a new lockdown. Together with clear communication, this would result in less parenteral stress.

Practice Implications: Hospital management should be cautious on restricting the presence of parents and other family members and scale restrictions back whenever possible.
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http://dx.doi.org/10.1016/j.pedn.2021.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482115PMC
September 2021

The Potential of Metabolomic Analyses as Predictive Biomarkers of Preterm Delivery: A Systematic Review.

Front Endocrinol (Lausanne) 2021 6;12:668417. Epub 2021 Sep 6.

Division of Obstetrics and Prenatal Diagnosis, Erasmus University Medical Centre, Rotterdam, Netherlands.

Scope: as the leading cause of perinatal mortality and morbidity worldwide, the impact of premature delivery is undisputable. Thus far, non-invasive, cost-efficient and accurate biochemical markers to predict preterm delivery are scarce. The aim of this systematic review is to investigate the potential of non-invasive metabolomic biomarkers for the prediction of preterm delivery.

Methods And Results: Databases were systematically searched from March 2019 up to May 2020 resulting in 4062 articles, of which 45 were retrieved for full-text assessment. The resulting metabolites used for further analyses, such as ferritin, prostaglandin and different vitamins were obtained from different human anatomical compartments or sources (vaginal fluid, serum, urine and umbilical cord) and compared between groups of women with preterm and term delivery. None of the reported metabolites showed uniform results, however, a combination of metabolomics biomarkers may have potential to predict preterm delivery and need to be evaluated in future studies.
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http://dx.doi.org/10.3389/fendo.2021.668417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451156PMC
September 2021

Knowledge gaps in late-onset neonatal sepsis in preterm neonates: a roadmap for future research.

Pediatr Res 2021 Sep 8. Epub 2021 Sep 8.

Department of Pediatrics, Division Neonatology, Erasmus MC, University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.

Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. IMPACT: This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts. Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use. Methods to personalize medicine and technologies feasible for bedside clinical use are described.
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http://dx.doi.org/10.1038/s41390-021-01721-1DOI Listing
September 2021

Unique Severe COVID-19 Placental Signature Independent of Severity of Clinical Maternal Symptoms.

Viruses 2021 08 23;13(8). Epub 2021 Aug 23.

Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center, 3015 GD Rotterdam, The Netherlands.

Background: Although the risk for transplacental transmission of SARS-CoV-2 is rare, placental infections with adverse functional consequences have been reported. This study aims to analyse histological placental findings in pregnancies complicated by SARS-CoV-2 infection and investigate its correlation with clinical symptoms and perinatal outcomes. We want to determine which pregnancies are at-risk to prevent adverse pregnancy outcomes related to COVID-19 in the future.

Methods: A prospective, longitudinal, multicentre, cohort study. All pregnant women presenting between April 2020 and March 2021 with a nasopharyngeal RT-PCR-confirmed SARS-CoV-2 infection were included. Around delivery, maternal, foetal and placental PCR samples were collected. Placental pathology was correlated with clinical maternal characteristics of COVID-19.

Results: Thirty-six patients were included, 33 singleton pregnancies ( = 33, 92%) and three twin pregnancies ( = 3, 8%). Twenty-four (62%) placentas showed at least one abnormality. Four placentas (4/39, 10%) showed placental staining positive for the presence of SARS-CoV-2 accompanied by a unique combination of diffuse, severe inflammatory placental changes with massive perivillous fibrin depositions, necrosis of syncytiotrophoblast, diffuse chronic intervillositis, and a specific, unprecedented CD20+ B-cell infiltration. This SARS-CoV-2 placental signature seems to correlate with foetal distress (75% vs. 15.6%, = 0.007) but not with the severity of maternal COVID-19 disease.

Conclusion: We describe a unique placental signature in pregnant patients with COVID-19, which has not been reported in a historical cohort. We show that the foetal environment can be seriously compromised by disruption of placental function due to local, devastating SARS-CoV-2 infection. Maternal clinical symptoms did not predict the severity of the SARS-CoV-2-related placental signature, resulting in a lack of adequate identification of maternal criteria for pregnancies at risk. Close foetal monitoring and pregnancy termination in case of foetal distress can prevent adverse pregnancy outcomes due to COVID-19 related placental disease.
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http://dx.doi.org/10.3390/v13081670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402730PMC
August 2021

Zebrafish larvae as experimental model to expedite the search for new biomarkers and treatments for neonatal sepsis.

J Clin Transl Sci 2021 18;5(1):e140. Epub 2021 Jun 18.

Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.

Neonatal sepsis is a major cause of death and disability in newborns. Commonly used biomarkers for diagnosis and evaluation of treatment response lack sufficient sensitivity or specificity. Additionally, new targets to treat the dysregulated immune response are needed, as are methods to effectively screen drugs for these targets. Available research methods have hitherto not yielded the breakthroughs required to significantly improve disease outcomes, we therefore describe the potential of zebrafish (Danio rerio) larvae as preclinical model for neonatal sepsis. In biomedical research, zebrafish larvae combine the complexity of a whole organism with the convenience and high-throughput potential of methods. This paper illustrates that zebrafish exhibit an immune system that is remarkably similar to humans, both in terms of types of immune cells and signaling pathways. Moreover, the developmental state of the larval immune system is highly similar to human neonates. We provide examples of zebrafish larvae being used to study infections with pathogens commonly causing neonatal sepsis and discuss known limitations. We believe this species could expedite research into immune regulation during neonatal sepsis and may hold keys for the discovery of new biomarkers and novel treatment targets as well as for screening of targeted drug therapies.
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http://dx.doi.org/10.1017/cts.2021.803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358844PMC
June 2021

Disease modeling following organoid-based expansion of airway epithelial cells.

Am J Physiol Lung Cell Mol Physiol 2021 10 11;321(4):L775-L786. Epub 2021 Aug 11.

Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.

Air-liquid interface (ALI) cultures are frequently used in lung research but require substantial cell numbers that cannot readily be obtained from patients. We explored whether organoid expansion [three-dimensional (3D)] can be used to establish ALI cultures from clinical samples with low epithelial cell numbers. Airway epithelial cells were obtained from tracheal aspirates (TA) from preterm newborns and from bronchoalveolar lavage (BAL) or bronchial tissue (BT) from adults. TA and BAL cells were 3D-expanded, whereas cells from BT were expanded in 3D and 2D. Following expansion, cells were cultured at ALI to induce differentiation. The impact of cell origin and 2D or 3D expansion was assessed with respect to ) cellular composition, ) response to cigarette smoke exposure, and ) effect of Notch inhibition or IL-13 stimulation on cellular differentiation. We established well-differentiated ALI cultures from all samples. Cellular compositions (basal, ciliated, and goblet cells) were comparable. All 3D-expanded cultures showed a similar stress response following cigarette smoke exposure but differed from the 2D-expanded cultures. Higher peak levels of antioxidant genes and and a more rapid return to baseline, and a lower unfolded protein response was observed after cigarette smoke exposure in 3D-derived cultures compared to 2D-derived cultures. In addition, TA- and BAL-derived cultures were less sensitive to modulation by DAPT or IL-13 than BT-derived cultures. Organoid-based expansion of clinical samples with low cell numbers, such as TA from preterm newborns is a valid method and tool to establish ALI cultures.
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http://dx.doi.org/10.1152/ajplung.00234.2020DOI Listing
October 2021

Cardiorespiratory monitoring of red blood cell transfusions in preterm infants.

Eur J Pediatr 2021 Aug 9. Epub 2021 Aug 9.

Pediatric Intensive Care Unit, Department of Pediatrics and Pediatric Surgery, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands.

Clinical improvement after red blood cell (RBC) transfusions in preterm infants remains debated. This study aims to investigate the effect of RBC transfusion on the occurrence of desaturations and hypoxia, and other cardiorespiratory outcomes in preterm infants. In this longitudinal observational study, prospectively stored cardiorespiratory parameters of preterm infants who received at least one RBC transfusion between July 2016 and June 2017 were retrospectively analyzed. Sixty infants with 112 RBC transfusions, median GA of 26.7 weeks, were included. The number of desaturations and area < 80% SpO limit, as a measure of the hypoxic burden, were calculated in 24 h before and after RBC transfusion. A mixed effects model was used to account for repeated measurements. Overall, the mean (SE) number of desaturations per hour decreased from 3.28 (0.55) to 2.25 (0.38; p < 0.001), and area < 80% SpO limit decreased from 0.14 (0.04) to 0.08 (0.02) %/s (p = 0.02). These outcomes were stratified for the number of desaturations in 24 h prior to RBC transfusion. The largest effect was observed in the group with the highest mean number of desaturations (≥ 6) prior to RBC transfusion, with a decrease from 7.50 (0.66) to 4.26 (0.38) (p < 0.001) in the number of desaturations and 0.46 (0.13) to 0.20 (0.06) in the area < 80% SpO. Perfusion index increased significantly after RBC transfusion (p < 0.001). No other significant effects of RBC transfusion on cardiorespiratory data were observed.Conclusions: RBC transfusions in preterm newborns could help decrease the incidence of desaturations and the area < 80% SpO as a measure of the hypoxic burden. The higher the number of desaturations prior to the RBC transfusion, the larger the effect observed. What is Known: •Red blood cell transfusions potentially prevent hypoxia in anemic preterm infants by increasing the circulatory hemoglobin concentration and improving tissue oxygenation. •There is not a predefined hemoglobin concentration cut-off for the occurrence of symptomatic anemia in preterm infants. What is New: •Oxygen desaturations and hypoxia in anemic preterm infants can be improved by RBC transfusions, especially if more desaturations have occurred before transfusion. •Cardiorespiratory monitor data may help identify infants who will benefit most from red blood cell transfusions.
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http://dx.doi.org/10.1007/s00431-021-04218-5DOI Listing
August 2021

Implementation of Delayed Cord Clamping for 3 Min During Term Cesarean Sections Does Not Influence Maternal Blood Loss.

Front Pediatr 2021 22;9:662538. Epub 2021 Jun 22.

Department of Obstetrics and Gynecology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands.

To assess maternal safety outcomes after a local protocol adjustment to change the interval of cord clamping to 3 min after term cesarean section. A retrospective cohort study in a tertiary referral hospital (Erasmus MC, Rotterdam). We included pregnant women who gave birth at term after cesarean section. A cohort (Nov 2016-Oct 2017) prior to the protocol implementation was compared to a cohort after its implementation (Nov 2017-Nov 2018). The study population covered 789 women ( = 376 pre-cohort; = 413 post-cohort). Implementation of a local protocol changing the interval of cord clamping to 3 min in all term births. Primary outcomes were the estimated maternal blood loss and the occurrence of postpartum hemorrhage (blood loss >1,000 ml). Secondary outcomes included both maternal as well as neonatal outcomes. Estimated maternal blood loss was not significantly different between the pre-cohort and post-cohort (400 mL [300-600] vs. 400 mL [300-600], = 0.52). The incidence of postpartum hemorrhage (26 [6.9%] vs. 35 (8.5%), OR 1.24, 95% CI 0.73-2.11) and maternal blood transfusion (9 [2%] vs. 13 (3%), OR 1.33, 95% CI 0.56-3.14) were not different. Hemoglobin change was significantly higher in the post-cohort (-0.8 mmol/L [-1.3 to -0.5] vs. -0.9 mmol/L [-1.4 to -0.6], = 0.01). In the post-cohort, neonatal hematocrit levels were higher (51 vs. 55%, = 0.004) and need for phototherapy was increased (OR 1.95, 95% CI 0.99-3.84). Implementation of delayed cord clamping for 3 min in term cesarean sections was not associated with increased maternal bleeding complications.
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http://dx.doi.org/10.3389/fped.2021.662538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257925PMC
June 2021

Maternal Iron Status in Pregnancy and Child Health Outcomes after Birth: A Systematic Review and Meta-Analysis.

Nutrients 2021 Jun 28;13(7). Epub 2021 Jun 28.

Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia, University Medical Center, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.

In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother-child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.
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http://dx.doi.org/10.3390/nu13072221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308244PMC
June 2021

Women of reproductive age in a tertiary intensive care unit: indications, outcome and the impact of pregnancy-a retrospective cohort study.

BMC Womens Health 2021 06 19;21(1):248. Epub 2021 Jun 19.

Department of Obstetrics and Gynecology, Erasmus MC - Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: To evaluate the indications for admission and mortality rates of women of reproductive age admitted to a tertiary Intensive Care Unit (ICU) and to compare the outcomes of obstetric and non-obstetric admissions.

Methods: A retrospective cohort study was performed, including all women aged 17-41 years admitted to a level 3 ICU in the Netherlands, between January 1, 2000 and January 1, 2016. Primary outcome was indication for admission and mortality. Mortality, length of stay (LOS), need for mechanical ventilation and APACHE II score were compared between obstetric and non-obstetric admissions. The obstetric group was further analyzed for maternal and perinatal outcomes.

Results: 3461 women (median age 32 years) were included, with an overall mortality rate of 13.3%. The obstetric group consisted of 265 women (7.7%). The non-obstetric group (n = 3196) was admitted most often for cardiovascular disease (19.6%), followed by oncologic disease (15%). Mortality was the highest in women with oncologic disease (23.9%). The obstetric group had lower mortality compared to the non-obstetric group (4.9% vs. 14%, p < 0.001), despite higher APACHE II score (14 vs. 11, p < 0.001) and a higher ventilation rate (47.9% vs. 39%, p = 0.004). Major surgical or endovascular interventions, besides caesarean section, were performed in 46% of the obstetric group. Perinatal death occurred in 17.2% and of the surviving infants, 63.2% were born preterm and 45.1% required Neonatal Intensive Care Unit admission.

Conclusions: Cardiovascular disease is the most important indication for admission and oncologic disease is associated with highest mortality in women of reproductive age. Obstetric patients constitute a small percentage of all ICU admissions in a tertiary ICU center. They have lower mortality rates than non-obstetric young female patients, despite a more severe initial presentation. Nevertheless lasting maternal morbidity and perinatal mortality and morbidity is frequent.
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http://dx.doi.org/10.1186/s12905-021-01396-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214372PMC
June 2021

Parental cannabis and tobacco use during pregnancy and childhood hair cortisol concentrations.

Drug Alcohol Depend 2021 08 21;225:108751. Epub 2021 May 21.

Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands; Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam, 3000CB, Rotterdam, the Netherlands; Department of Psychology, Education and Child Studies, Erasmus School of Social and Behavioral Sciences, Erasmus University Rotterdam, 3062PA, Rotterdam, the Netherlands.

Background: Fetal exposure to cannabis and tobacco during pregnancy leads to adverse fetal and childhood outcomes. We hypothesized that fetal exposure to cannabis and tobacco have persistent programming effects on hypothalamic pituitary adrenal (HPA) axis functioning in childhood. Therefore, we examined the associations of parental cannabis and tobacco use during pregnancy with childhood hair cortisol and cortisone concentrations at 6 years, as biomarkers of long-term HPA-axis functioning.

Method: In a population-based prospective birth cohort among 2577 mothers and their children, information of parental cannabis and tobacco use was collected by questionnaires, and maternal urine samples were additionally analyzed to detect cannabis metabolite concentrations. Cortisol and cortisone were measured in hair samples at 6 years. Linear regression analysis with adjustment for several confounders was used to test our hypothesis.

Results: As compared to non-exposed children, offspring exposed to cannabis during pregnancy (in combination with tobacco) had higher childhood cortisol concentrations (log-10 transformed difference 0.16, 95 % Confidence Interval 0.04 to 0.28). This association was not mediated by birth weight. No differences in cortisone concentrations among cannabis-exposed children were observed. Maternal tobacco use during pregnancy was not associated with childhood cortisol or cortisone concentrations. Further, paternal cannabis or tobacco use was not associated with childhood cortisol or cortisone concentrations.

Conclusions: Our findings suggest that maternal cannabis use, combined with tobacco, during pregnancy is associated with alterations in offspring HPA-axis functioning. Further studies need to replicate these findings, and assess the causality and long-term consequences of these associations.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108751DOI Listing
August 2021

Stratified Management for Bacterial Infections in Late Preterm and Term Neonates: Current Strategies and Future Opportunities Toward Precision Medicine.

Front Pediatr 2021 1;9:590969. Epub 2021 Apr 1.

Division of Neonatology, Department of Pediatrics, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, Netherlands.

Bacterial infections remain a major cause of morbidity and mortality in the neonatal period. Therefore, many neonates, including late preterm and term neonates, are exposed to antibiotics in the first weeks of life. Data on the importance of inter-individual differences and disease signatures are accumulating. Differences that may potentially influence treatment requirement and success rate. However, currently, many neonates are treated following a "one size fits all" approach, based on general protocols and standard antibiotic treatment regimens. Precision medicine has emerged in the last years and is perceived as a new, holistic, way of stratifying patients based on large-scale data including patient characteristics and disease specific features. Specific to sepsis, differences in disease susceptibility, disease severity, immune response and pharmacokinetics and -dynamics can be used for the development of treatment algorithms helping clinicians decide when and how to treat a specific patient or a specific subpopulation. In this review, we highlight the current and future developments that could allow transition to a more precise manner of antibiotic treatment in late preterm and term neonates, and propose a research agenda toward precision medicine for neonatal bacterial infections.
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http://dx.doi.org/10.3389/fped.2021.590969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049115PMC
April 2021

The Pharmacokinetics of Caffeine in Preterm Newborns: No Influence of Doxapram but Important Maturation with Age.

Neonatology 2021 24;118(1):106-113. Epub 2021 Feb 24.

Division of Neonatology, Department of Paediatrics, Erasmus UMC - Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Apnea of prematurity can persist despite caffeine therapy in preterm infants. Doxapram may additionally support breathing. Although multiple small studies have reported the efficacy of doxapram, the structural co-treatment with caffeine impedes to ascribe the efficacy to doxapram itself or to a pharmacokinetic (PK) interaction where doxapram increases the exposure to caffeine. We examined whether there is a PK drug-drug interaction between doxapram and caffeine by developing a PK model for caffeine including infants with and without doxapram treatment.

Methods: In preterm neonates receiving caffeine, we determined caffeine plasma concentrations before, during, and directly after doxapram co-treatment and used these to develop a population PK model in NONMEM 7.3. Patient characteristics and concomitant doxapram administration were tested as covariates.

Results: 166 plasma samples were collected from 39 preterm neonates receiving caffeine (median gestational age 25.6 [range 24.0-28.0] weeks) of which 65 samples were taken during co-treatment with doxapram (39%, from 32/39 infants). Clearance of caffeine was 9.99 mL/h for a typical preterm neonate with a birth weight of 0.8 kg and 23 days postnatal age and increased with birth weight and postnatal age, resulting in a 4-fold increase in clearance during the first month of life. No PK interaction between caffeine and doxapram was identified.

Discussion: Caffeine clearance is not affected by concomitant doxapram therapy but shows a rapid maturation with postnatal age. As current guidelines do not adjust the caffeine dose with postnatal age, decreased exposure to caffeine might partly explain the need for doxapram therapy after the first week of life.
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http://dx.doi.org/10.1159/000513413DOI Listing
August 2021

Assessing knowledge and skills of maternity care professionals regarding neonatal hyperbilirubinaemia: a nationwide survey.

BMC Pregnancy Childbirth 2021 Jan 19;21(1):63. Epub 2021 Jan 19.

Department of Paediatrics, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, University Medical Centre Rotterdam, PO Box 2060, 3000 CB, Rotterdam, Netherlands.

Background: Neonatal hyperbilirubinaemia is a physiologic phenomenon, but, when severe, may cause lifelong disability. Maternity care assistants (MCAs) play an important role in timely recognition of severe neonatal jaundice. We assessed knowledge and skills of MCAs regarding neonatal hyperbilirubinaemia.

Methods: All Dutch MCAs (n = 9065) were invited to fill out a questionnaire assessing knowledge, expertise, and handling of neonatal jaundice. Additionally, we developed an e-learning and provided training sessions to a subgroup of MCAs (n = 99), and assessed their knowledge on neonatal hyperbilirubinaemia before and after the training.

Results: One thousand four hundred sixty-five unique online questionnaires were completed (response 16.2%). The median number of correctly answered knowledge questions was 5 (out of six; IQR 1). Knowledge was significantly better when respondents had had in-service training on neonatal hyperbilirubinaemia in the previous year (p = 0.024). Although 82% of respondents felt highly skilled or skilled to assess jaundice, accuracy of estimation of total serum bilirubin levels by assessing skin colour was generally poor and prone to underestimation. Among participants attending a training session, those who completed the e-learning beforehand had higher pre-training scores (5 (IQR 1) vs. 4 (IQR 2); p < 0.001). The median post-training score was higher than pre-training (6 (IQR 1) vs. 5 (IQR 2); p < 0.001).

Conclusions: Background knowledge of MCAs regarding neonatal hyperbilirubinaemia was adequate, but can be improved by further training. Estimation of total serum bilirubin levels based on skin colour was often inadequate. Approaches to improve timely recognition of jaundiced neonates are needed.
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http://dx.doi.org/10.1186/s12884-020-03463-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814718PMC
January 2021

Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates.

Crit Care 2021 01 6;25(1):12. Epub 2021 Jan 6.

Department of Pediatrics, Division Neonatology, Erasmus Medical Center, Erasmus MC, University Medical Center-Sophia Children's Hospital, Research Neonatology (Sk-4246), PO Box 2060, 300 CB, Rotterdam, The Netherlands.

Background: Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis.

Methods: The study was conducted at the Erasmus University Medical Center-Sophia Children's Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia).

Results: A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64-3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70-5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68-2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support.

Conclusions: Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.
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http://dx.doi.org/10.1186/s13054-020-03423-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788923PMC
January 2021

Severe Acute Respiratory Syndrome Coronavirus 2 Placental Infection and Inflammation Leading to Fetal Distress and Neonatal Multi-Organ Failure in an Asymptomatic Woman.

J Pediatric Infect Dis Soc 2021 May;10(5):556-561

Department of Neonatology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood.

Methods: Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy.

Results: RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts.

Conclusions: Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic.
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http://dx.doi.org/10.1093/jpids/piaa153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798999PMC
May 2021

Early weight gain trajectories and body composition in infancy in infants born very preterm.

Pediatr Obes 2021 06 17;16(6):e12752. Epub 2020 Nov 17.

Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia's Children's Hospital, Rotterdam, The Netherlands.

Background: Concerns are raised about the influence of rapid growth on excessive fat mass (FM) gain in early life and later cardiometabolic health of infants born preterm.

Objectives: To study the association between postnatal weight gain trajectories and body composition in infancy in infants born very preterm.

Methods: In infants born <30 weeks gestation, we evaluated associations between weight Z-score trajectories for three consecutive timeframes (NICU stay, level-II hospital stay and at home) and body composition, measured at 2 and 6 months corrected age by air-displacement plethysmography.

Results: Of 120 infants included, median gestational age at birth was 27 (interquartile range 26 ;28 ) and birth weight 1015 g (801;1250). The majority of infants did not make up for their initial loss of weight Z-score, but growth and later body composition were within term reference values. Weight gain during NICU stay was not associated with fat mass (absolute, %FM or FM index) in infancy. Weight gain during NICU and level II hospital stay was weakly associated with higher absolute lean mass (LM), but not after adjustment for length (LM index). Weight gain in the level-II hospital was positively associated with fat mass parameters at 2 months but not at 6 months. Strongest associations were found between weight gain at home and body composition (at both time points), especially fat mass.

Conclusions: Weight gain in different timeframes after preterm birth is associated with distinct parameters of body composition in infancy, with weight gain at home being most strongly related to fat mass.
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http://dx.doi.org/10.1111/ijpo.12752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244114PMC
June 2021

Early visuospatial attention and processing and related neurodevelopmental outcome at 2 years in children born very preterm.

Pediatr Res 2021 Sep 18;90(3):608-616. Epub 2020 Oct 18.

Vestibular and Oculomotor Research Group, Department of Neuroscience, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: The ability to perceive and process visuospatial information is a condition for broader neurodevelopment. We examined the association of early visuospatial attention and processing with later neurodevelopmental outcome in very preterm infants.

Methods: Visuospatial attention and processing was assessed in 209 children (<30 weeks gestation) using an easy applicable eye tracking-based paradigm at 1 and 2 years. Average reaction times to fixation (RTF) on specific visual stimuli were calculated, representing time needed for overall attention (Cartoon stimuli) and processing (Motion and Form stimuli). Associations between RTFs and various measures of development at 2 years including cognitive and motor development (Bayley Scales of Infant and Toddler Development-Third edition; Bayley-III), language (Lexi test) and behavior (Child Behavior Checklist) were examined.

Results: At 1 year, 100 ms slower Cartoon and Motion RTFs were associated with lower cognitive Bayley-III scores (-4.4 points, 95%CI: -7.4; -1.5 and -1.0 points, -1.8; -0.2, respectively). A 100 ms slower Cartoon RTF was associated with a 3.5 (-6.6; -0.5) point decrease in motor Bayley-III score.

Conclusions: Visuospatial attention and motion processing at 1 year is predictive of overall cognitive and motor development 1 year later. The nonverbal eye tracking-based test can assist in early detection of preterm children at risk of adverse neurodevelopment.

Impact: Visuospatial attention and processing at 1 year corrected age is predictive for overall cognitive and motor development 1 year later in preterm infants. First study to relate early visuospatial attention and processing with later neurodevelopmental outcome in preterm children. Early detection of preterm children at risk of adverse neurodevelopment, which allows for more timely interventions.
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http://dx.doi.org/10.1038/s41390-020-01206-7DOI Listing
September 2021

Impact of COVID-19 mitigation measures on the incidence of preterm birth: a national quasi-experimental study.

Lancet Public Health 2020 11 14;5(11):e604-e611. Epub 2020 Oct 14.

Division of Neonatology, Department of Paediatrics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands.

Background: Preterm birth is the leading cause of child mortality globally, with many survivors experiencing long-term adverse consequences. Preliminary evidence suggests that numbers of preterm births greatly reduced following implementation of policy measures aimed at mitigating the effects of the COVID-19 pandemic. We aimed to study the impact of the COVID-19 mitigation measures implemented in the Netherlands in a stepwise fashion on March 9, March 15, and March 23, 2020, on the incidence of preterm birth.

Methods: We used a national quasi-experimental difference-in-regression-discontinuity approach. We used data from the neonatal dried blood spot screening programme (2010-20) cross-validated against national perinatal registry data. Stratified analyses were done according to gestational age subgroups, and sensitivity analyses were done to assess robustness of the findings. We explored potential effect modification by neighbourhood socioeconomic status, sex, and small-for-gestational-age status.

Findings: Data on 1 599 547 singleton neonates were available, including 56 720 births that occurred after implementation of COVID-19 mitigation measures on March 9, 2020. Consistent reductions in the incidence of preterm birth were seen across various time windows surrounding March 9 (± 2 months [n=531 823] odds ratio [OR] 0·77, 95% CI 0·66-0·91, p=0·0026; ± 3 months [n=796 531] OR 0·85, 0·73-0·98, p=0·028; ± 4 months [n=1 066 872] OR 0·84, 0·73-0·97, p=0·023). Decreases in incidence observed following the March 15 measures were of smaller magnitude, but not statistically significant. No changes were observed after March 23. Reductions in the incidence of preterm births after March 9 were consistent across gestational age strata and robust in sensitivity analyses. They appeared confined to neighbourhoods of high socioeconomic status, but effect modification was not statistically significant.

Interpretation: In this national quasi-experimental study, initial implementation of COVID-19 mitigation measures was associated with a substantial reduction in the incidence of preterm births in the following months, in agreement with preliminary observations elsewhere. Integration of comparable data from across the globe is needed to further substantiate these findings and start exploring underlying mechanisms.

Funding: None.
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http://dx.doi.org/10.1016/S2468-2667(20)30223-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553867PMC
November 2020

Associations of Plasma Fatty Acid Patterns during Pregnancy with Respiratory and Allergy Outcomes at School Age.

Nutrients 2020 Oct 7;12(10). Epub 2020 Oct 7.

Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands.

Fatty acids might play a role in asthma and allergy development as they can modulate immune responses. We examined among 4260 mother-child pairs participating in a population-based cohort the associations of maternal plasma fatty acid patterns during pregnancy with a child's respiratory and allergy outcomes at school-age. In mid-pregnancy, 22 individual fatty acids were measured from maternal blood. Three patterns were previously identified by principal component analysis: A 'high n-6 polyunsaturated fatty acid (PUFA)', a 'monounsaturated and saturated fatty acid', and a 'high n-3 PUFA' pattern. At the age of 10 years, a child's lung function was assessed by spirometry, current asthma and physician-diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. A higher 'high n-6 PUFA' pattern was associated with a higher forced expiratory volume in 1 s/forced vital capacity and forced expiratory flow after exhaling 75% of forced vital capacity (Z-score difference (95% CI) 0.04 (0, 0.07) and 0.04 (0.01, 0.07), respectively, per SD increase in the fatty acid pattern). We observed no associations of maternal fatty acid patterns with a child's asthma or allergy outcomes. Our results showed limited associations of maternal patterns of high n-6 PUFA concentrations in pregnancy with a better lung function in school-aged children.
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http://dx.doi.org/10.3390/nu12103057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601105PMC
October 2020

Spontaneous Closure of the Ductus Arteriosus in Preterm Infants: A Systematic Review.

Front Pediatr 2020 11;8:541. Epub 2020 Sep 11.

Division of Neonatology, Department of Pediatrics, Erasmus UMC-Sophia Children's Hospital, Rotterdam, Netherlands.

The optimal management strategy for patent ductus arteriosus in preterm infants remains a topic of debate. Available evidence for a treatment strategy might be biased by the delayed spontaneous closure of the ductus arteriosus in preterm infants, which appears to depend on patient characteristics. We performed a systematic review of all literature on PDA studies to collect patient characteristics and reported numbers of patients with a ductus arteriosus and spontaneous closure. Spontaneous closure rates showed a high variability but were lowest in studies that only included preterm infants with gestational ages below 28 weeks or birth weights below 1,000 g (34% on day 4; 41% on day 7) compared to studies that also included infants with higher gestational ages or higher birth weights (up to 55% on day 3 and 78% on day 7). The probability of spontaneous closure of the ductus arteriosus keeps increasing until at least 1 week after birth which favors delayed treatment of only those infants that do not show spontaneous closure. Better prediction of the spontaneous closure of the ductus arteriosus in the individual newborn is a key factor to find the optimal management strategy for PDA in preterm infants.
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http://dx.doi.org/10.3389/fped.2020.00541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516116PMC
September 2020

Validation of a New Transcutaneous tcPO2/tcPCO2 Sensor with an Optical Oxygen Measurement in Preterm Neonates.

Neonatology 2020 30;117(5):628-636. Epub 2020 Sep 30.

Department of Pediatrics, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Introduction: Traditional transcutaneous oxygen (tcPO2) measurements are affected by measurement drift, limiting accuracy and usability. The new potentially drift-free oxygen fluorescence quenching technique has been combined in a single sensor with conventional transcutaneous carbon dioxide (tcPCO2) monitoring. This study aimed to validate optical tcPO2 and conventional tcPCO2 against arterial blood gas samples in preterm neonates and determine measurement drift.

Methods: In this prospective observational study, during regular care, transcutaneous measurements were paired to arterial blood gases from preterm neonates aged 24-31 weeks of gestational age (GA) with an arterial catheter. Samples were included based on stability criteria and stratified for sepsis status. Agreement was assessed using the Bland-Altman analysis. Measurement drift per hour was calculated.

Results: Sixty-eight premature neonates were included {median (interquartile range [IQR]) GA of 26 4/7 [25 3/7-27 5/7] weeks}, resulting in 216 stable paired samples. Agreement of stable samples in neonates without sepsis (n = 38) and with suspected sepsis (n = 112) was acceptable for tcPO2 and good for tcPCO2. However, in stable samples of neonates with sepsis (n = 66), tcPO2 agreement (bias and 95% limits of agreement) was -32.6 (-97.0 to 31.8) mm Hg and tcPCO2 agreement was 4.2 (-10.5 to 18.9) mm Hg. The median (IQR) absolute drift values were 0.058 (0.0231-0.1013) mm Hg/h for tcPO2 and 0.30 (0.11-0.64) mm Hg/h for tcPCO2.

Conclusion: The accuracy of optical tcPO2 in premature neonates was acceptable without sepsis, while electrochemically measured tcPCO2 remained accurate under all circumstances. Measurement drift was negligible for tcPO2 and highly acceptable for tcPCO2.
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http://dx.doi.org/10.1159/000510659DOI Listing
August 2021
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