Objective To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA).Design... Show moreObjective To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA).Design Secondary analysis of a randomised placebo-controlled trial.Setting Dutch and Belgian neonatal intensive care units.Patients Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life.Intervention Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190).Main outcome measures The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots.Results The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); >= 27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); =27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups.Conclusion This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by itscomponent death. There was insufficient evidence for other selected candidate effect modifiers. Show less
Vos, T.W. de; Zagten, M. van; Haas, M. de; Oepkes, D.; Tan, R.N.G.B.; Schoot, C.E. van der; ... ; Klink, J.M.M. van 2023
ObjectiveTo evaluate the neurodevelopmental outcome at school age in children newly diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT).Study designThis observational cohort study... Show moreObjectiveTo evaluate the neurodevelopmental outcome at school age in children newly diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT).Study designThis observational cohort study included children diagnosed with FNAIT between 2002 and 2014. Children were invited for cognitive and neurological testing. Behavioral questionnaires and school performance results were obtained. A composite outcome of neurodevelopmental impairment (NDI) was used, defined, and subdivided into mild-to-moderate and severe NDI. Primary outcome was severe NDI, defined as IQ <70, cerebral palsy with Gross Motor Functioning Classification System level ≥ III, or severe visual/hearing impairment. Mild-to-moderate NDI was defined as IQ 70-85, minor neurological dysfunction or cerebral palsy with Gross Motor Functioning Classification System level ≤ II, or mild visual/hearing impairment.ResultsIn total, 44 children were included at a median age of 12 years (range: 6-17 years). Neuroimaging at diagnosis was available in 82% (36/44) of children. High-grade intracranial hemorrhage (ICH) was detected in 14% (5/36). Severe NDI was detected in 7% (3/44); two children had high-grade ICH, and one had low-grade ICH and perinatal asphyxia. Mild-to-moderate NDI was detected in 25% (11/44); one child had high-grade ICH, and eight children were without ICH, yet for two children, neuroimaging was not performed. Adverse outcome (perinatal death or NDI) was 39% (19/49). Four children (9%) attended special needs education, three of whom had severe NDI and one had mild-to-moderate NDI. Total behavioral problems within the clinical range were reported in 12%, which is comparable with 10% in the general Dutch population.ConclusionChildren who are newly diagnosed with FNAIT are at increased risk for long-term neurodevelopmental problems, even those without ICH. Show less
Halbmeijer, N.M.; Onland, W.; Cools, F.; Swarte, R.M.; Heide-Jalving, M. van der; Dijk, P.; ... ; STOP-BPD Study Grp 2023
ObjectiveTo report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years' corrected... Show moreObjectiveTo report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years' corrected age (CA). DesignRandomised placebo-controlled trial. SettingDutch and Belgian neonatal intensive care units. PatientsInfants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. InterventionInfants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). Main outcome measuresParent-reported behavioural outcomes at 2 years' CA assessed with the Child Behavior Checklist (CBCL 11/2-5). ResultsParents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference -1.52 (95% CI -4.00 to 0.96), -2.40 (95% CI -4.99 to 0.20) and -0.81 (95% CI -3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference -1.26, 95% CI -2.41 to -0.12). ConclusionThis study found high rates of behaviour problems at 2 years' CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants. Show less
Background: Psychosocial development in monochorionic (MC) twins born after selective fetal growth restriction (sFGR) has been unreported to date, despite its importance for daily functioning and... Show moreBackground: Psychosocial development in monochorionic (MC) twins born after selective fetal growth restriction (sFGR) has been unreported to date, despite its importance for daily functioning and future relationships. Aims: To investigate psychosocial development, attachment and school functioning in MC twins with sFGR and compare outcomes with the general population and between smaller and larger twins. Study design: Observational cohort study. Subjects: MC twins with sFGR (defined as a birth weight discordance >= 20 %) born between 2002 and 2017 and aged 3-17 years. Outcome measures: Multiple parent report questionnaires: the Child Behavior Checklist (social-emotional devel-opment and behavior), the (Early) Childhood Behavior Questionnaire Very Short Form (temperament), the Attachment Insecurity Screening Inventory (attachment) and a school functioning questionnaire. Results: Median age for the 48 twin pairs was 11 (interquartile range (IQR) 8-13) years. Attachment insecurity for both twins was higher than in the general population for ambivalence/resistance (34 % (21/62) vs. 16 %, p = 0.024) and total attachment insecurity (35 % (22/62) vs. 16 %, p = 0.016). Smaller twins had more internalizing behavioral problems, i.e. negative emotions and behaviors turned inwards (22 % (10/46) vs. 11 % (5/46), p = 0.021) and a higher negative affect, i.e. more likely to experience negative emotions (3.2 (2.9-3.7) vs. 2.9 (2.2-3.2), p = 0.009) than larger twins, as well as a lower secondary school level (p = 0.031). Conclusion: MC twins with sFGR have more ambivalent/resistant attachment insecurity following the compli-cated pregnancy course. Smaller twins have a tendency towards negative emotions and internalizing behaviors compared to larger twins, indicating an increased sensitivity for depression and anxiety. Show less
Vos, T.W. de; Haas, M. de; Oepkes, D.; Tan, R.N.G.B.; Schoot, C.E. van der; Steggerda, S.J.; ... ; Klink, J.M.M. van 2022
BACKGROUND: Children with fetal and neonatal alloimmune throm-bocytopenia face increased risk of intracranial hemorrhage potentially leading to developmental impairment. To prevent intracranial... Show moreBACKGROUND: Children with fetal and neonatal alloimmune throm-bocytopenia face increased risk of intracranial hemorrhage potentially leading to developmental impairment. To prevent intracranial hemorrhage, pregnant women with alloantibodies against fetal platelets are often treated with intravenous immunoglobulin. Intravenous immunoglobulin seems effective in vastly reducing the risk of fetal or neonatal bleeding complications. However, information on long-term neurodevelopment of these children is lacking. OBJECTIVE: This study aimed to evaluate long-term neurodevelopmental outcome in children with fetal and neonatal alloimmune thrombocytopenia who were treated with intravenous immunoglobulin antenatally. STUDY DESIGN: An observational cohort study was performed, including children of mothers treated with intravenous immunoglobulin during pregnancy because a previous child was diagnosed with fetal and neonatal alloimmune thrombocytopenia. Children were invited for a follow-up assessment including standardized cognitive and neurologic tests. The parents were asked to complete a behavioral questionnaire and school performance reports. The primary outcome was severe neurodevelopmental impairment, defined as severe cognitive impairment (intelligence quotient <70), cerebral palsy with Gross Motor Function Classification System Level >= 3, bilateral blindness, and/or bilateral deafness (requiring amplification). The secondary outcome was mild to moderate neurodevelopmental impairment, defined as either mild to moderate cognitive impairment (intelligence quotient <85), cerebral palsy with Gross Motor Function Classification System Level <= 2, minor neurologic dysfunction, vision loss, and/or hearing loss.RESULTS: Between 2003 and 2017, 51 children were live-born after antenatal intravenous immunoglobulin treatment. One family moved abroad and was therefore not eligible for inclusion. In total, 82% (41/50) of the eligible cases were included for neurodevelopmental assessment at a median age of 9 years and 8 months. Severe neurodevelopmental impairment was not detected. The incidence of mild to moderate neurodevelopmental impairment was 14% (6/41; 95% confidence interval, 6% -29%). The children's mean cognitive score, behavioral scores, and academic achievement were not different from those observed in the Dutch norm groups. Neuroimaging was performed in 90% (37/41) of cases. Severe intracranial hemorrhage was diagnosed in 2 cases (5%), one antenatally before the start of intravenous immunoglobulin and the other case 1 day after birth. Both cases had a normal neurodevelopmental outcome. CONCLUSION: The risk of neurodevelopmental impairment in children whose mothers were treated for fetal and neonatal alloimmune thrombocytopenia with antenatal intravenous immunoglobulin is comparable to that reported in the general population. Show less
Background: Singletons born after fetal growth restriction (FGR) are at increased risk of poor neurodevelopmental outcomes. Studies of singletons with FGR usually compare outcomes with those... Show moreBackground: Singletons born after fetal growth restriction (FGR) are at increased risk of poor neurodevelopmental outcomes. Studies of singletons with FGR usually compare outcomes with those without FGR, a comparison that is inherently biased by obstetrical, parental, and genetic factors. We aim to compare neurodevelopmental outcomes between the smaller and larger twin in a population of discordant identical twins who shared a single placenta (monochorionic diamniotic), naturally eliminating these confounders. Methods: This study is part of the cohort study LEMON of monochorionic diamniotic twins with selective FGR. All monochorionic diamniotic twins with selective FGR who were born in Leiden University Medical Center (Leiden, Netherlands) between March 1, 2002, and Dec 31, 2017, were eligible for inclusion. Twin pregnancies that were complicated by twin-twin transfusion syndrome, twin anaemia polycythaemia sequence, or monoamnionicity were excluded. Cognitive performance was evaluated with two standardised psychometric age-appropriate tests, producing a full-scale intelligence quotient (FSIQ). Motor functioning was assessed with a standardised neurological examination. A composite outcome of neurodevelopmental impairment (NDI) was used, subdivided into mild NDI (defined as FSIQ <85, minor neurological dysfunction or cerebral palsy grade 1, or mild visual or hearing impairment) and severe NDI (defined as FSIQ <70, severe neurological dysfunction, or severe visual or hearing impairment). Findings: Between Jan 25, 2021, and March 15, 2022, 47 twin pairs were enrolled in the study and underwent neurodevelopmental assessment. The median gestational age at birth was 33middot9 weeks (IQR 31middot3-36middot0) for the 47 included twin pairs, with median birthweights of 1400 g (1111-1875) in the smaller twin and 2003 g (1600-2680) in the larger twin. The median age at neurodevelopmental assessment was 11 years (8-13). Median FSIQ was 94 (86-101) for the smaller twin and 100 (92-108) for the larger twin (p<0middot0001). More smaller twins had mild NDI (17 [36%] of 47) than did the larger twins (five [11%] of 47; odds ratio 4middot8 [95% CI 1middot6-14middot1]; p=0middot0049). There was no difference in the proportion of children with severe NDI (two [4%] of 47 in both groups, p=1middot0). Interpretation: As mild NDI can impede children in their daily functioning, we recommend standardised long-term follow-up, including neurodevelopmental testing, for monochorionic diamniotic twins with selective FGR to facilitate early identification of children at risk. Show less
Knijnenburg, P.J.C.; Spruijt, M.S.; Jansen, L.; Rijken, M.; Tan, R.N.G.B.; Slaghekke, F.; ... ; Klink, J.M.M. van 2022
Objective: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or... Show moreObjective: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or small for gestational age. Study design: At 2 and 5 years of age, standardized neurologic, motor, and cognitive assessments were performed by a neonatologist, a pediatric physical therapist, and a psychologist. Behavior was assessed using a validated questionnaire completed by parents. Results: Neurodevelopmental assessment at both time points was available for 73 survivors of TITS. Mild to moderate neurodevelopmental impairment (NDI) was detected in 34% of survivors (25 of 73) at 5 years, compared with 25% (18 of 73) at 2 years (P = .178). Severe NDI was observed in 12% (9 of 73) at 5 years and in 3% (2 of 73) at 2 years (P = .035). Mean cognitive score was lower at the 5-year follow-up (90.7 +/- 12.3 vs 95.6 +/- 13.1 at 2 years; P = .001), and more children were diagnosed with mild cognitive impairment at 5 years (29% vs 11 % at 2 years; P = .007). When comparing individual outcomes at both time points, 35% (25 of 71) moved from a normal outcome or mild to moderate impairment at 2 years toward more severe impairment at 5 years. Conclusions: A high rate of mild to moderate cognitive impairment and severe NDI at age 5 years was not identified at age 2 years. Our data highlight the importance of longitudinal follow-up of survivors of TTTS beyond age 2 years and emphasize the precautions that should be taken when diagnosing an absence of impairment before school age. Show less
Steggerda, S.J.; Tan, R.N.G.B.; Laat, P.C.J. de 2020
Objective To assess leakage caused by the Pedi-Cap.Methods Bench test I: Pedi-Caps were connected between the Neopuff and a test lung and placed underwater to detect the leak. Bench test II: the... Show moreObjective To assess leakage caused by the Pedi-Cap.Methods Bench test I: Pedi-Caps were connected between the Neopuff and a test lung and placed underwater to detect the leak. Bench test II: the disposable Avea VarFlex Flow Transducer measured the leak. Retrospective analysis: recordings of intubations in the delivery room were analysed.Results The (rippled) male end of the Pedi-Cap is the origin of the leak. In bench test I, 32% of the Pedi-Caps caused inevitable extensive leaks and 34% caused leaks that diminished after sealing the end. In bench test II (n=44) and the retrospective analysis (n=17), the flow transducer measured 22% (18-60) and 39% (8-82) leakage, respectively. Leakage decreased after removal of the Pedi-Cap (before vs after; 17% (7-75) vs 4% (2-10), p=0.004).Conclusion The Pedi-Cap causes the leak which can compromise respiratory support. We recommend to remove the Pedi-Cap directly after change of colour and to be cautious when using the device as evaluation tool. Show less
Objectives To evaluate the long-term neurodevelopmental and behavioral outcomes in surviving infants of pregnancies with spontaneous twin anemia-polycythemia sequence (TAPS), to compare outcome... Show moreObjectives To evaluate the long-term neurodevelopmental and behavioral outcomes in surviving infants of pregnancies with spontaneous twin anemia-polycythemia sequence (TAPS), to compare outcome between donors and recipients, and to investigate potential risk factors for neurodevelopmental impairment (NDI).Methods This was a retrospective study of a consecutive cohort of spontaneous-TAPS survivors delivered between 2005 and 2017 at the Leiden University Medical Center, The Netherlands. Neurological, motor, cognitive and behavioral development were assessed at a median age of 4 years. The primary outcome was NDI, which was a composite outcome of cerebral palsy, deafness, blindness and motor and/or cognitive delay. NDI was subdivided into two grades of severity: mild-to-moderate and severe NDI. Outcome was compared between surviving donor and recipient twins. Logistic regression analysis was used to assess risk factors for NDI.Results Forty-nine twin pregnancies complicated by spontaneous TAPS were eligible for inclusion. The perinatal survival rate was 83% (81/98) of twins. Neurodevelopmental assessment was performed in 91% (74/81) of surviving twins. NDI occurred in 30% (22/74) of TAPS survivors, and was found more often in donors (44%; 15/34) than in recipients (18%; 7/40) (odds ratio (OR), 4.1; 95% CI, 1.8-9.1; P = 0.001). Severe NDI was detected in 9% (7/74) of survivors and was higher in donors compared with recipients (18% (6/34) vs 3% (1/40)), although the difference did not reach statistical significance; P = 0.056). Donors demonstrated lower cognitive scores compared with recipients (P = 0.011). Bilateral deafness was identified in 15% (5/34) of donors compared with 0% (0/40) of recipients (P = 0.056). Parental concern regarding development was reported more often for donor than for recipient twins (P = 0.001). On multivariate analysis, independent risk factors for NDI were gestational age at delivery (OR, 0.7; 95% CI, 0.5-0.9; P = 0.003) and severe anemia (OR, 6.4; 95% CI, 2.4-17.0; P < 0.001).Conclusion Surviving donor twins of pregnancies complicated by spontaneous TAPS have four-fold higher odds of NDI compared with recipient cotwins, are at increased risk of cognitive delay and have a high rate of deafness. Copyright (C) 2019 ISUOG. Published by John Wiley & Sons Ltd. Show less
Objective To assess leakage caused by the Pedi-Cap. Methods Bench test I: Pedi-Caps were connected between the Neopuff and a test lung and placed underwater to detect the leak. Bench test II: the... Show moreObjective To assess leakage caused by the Pedi-Cap. Methods Bench test I: Pedi-Caps were connected between the Neopuff and a test lung and placed underwater to detect the leak. Bench test II: the disposable Avea VarFlex Flow Transducer measured the leak. Retrospective analysis: recordings of intubations in the delivery room were analysed. Results The (rippled) male end of the Pedi-Cap is the origin of the leak. In bench test I, 32% of the Pedi-Caps caused inevitable extensive leaks and 34% caused leaks that diminished after sealing the end. In bench test II (n=44) and the retrospective analysis (n=17), the flow transducer measured 22% (18–60) and 39% (8–82) leakage, respectively. Leakage decreased after removal of the Pedi-Cap (before vs after; 17% (7–75) vs 4% (2–10), p=0.004). Conclusion The Pedi-Cap causes the leak which can compromise respiratory support. We recommend to remove the Pedi-Cap directly after change of colour and to be cautious when using the device as evaluation tool. Show less
Objective To assess benefits of recording and reviewing neonatal resuscitation as experienced by neonatal care providers. Design A qualitative study using semistructured interviews questioning... Show moreObjective To assess benefits of recording and reviewing neonatal resuscitation as experienced by neonatal care providers. Design A qualitative study using semistructured interviews questioning neonatal care providers about their experiences with recording and reviewing neonatal resuscitation. Data were analysed using the qualitative data analysis software Atlas.ti V.7.0. Setting Neonatal care providers working at neonatal intensive care units (NICUs) of the Leiden University Medical Center, the Netherlands, and the University of Pennsylvania School of Medicine, USA, participated in this study. Results In total, 48 NICU staff members were interviewed. Reported experiences and attitudes are broadly similar for both NICUs. All interviewed providers reported positive experiences and benefits, with special emphasis on educational benefits. Recording and reviewing neonatal resuscitation is used for various learning activities, such as plenary review meetings and as tool for objective feedback. Providers reported to learn from reviewing their own performance during resuscitation, as well as from reviewing performances of others. Improved time perception, reflection on guideline compliance and acting less invasively during resuscitations were often mentioned as learning outcomes. All providers would recommend other NICUs to implement recording and reviewing neonatal resuscitation, as it is a powerful tool for learning and improving. However, they emphasised preconditions for successful implementation, such as providing information, not being punitive and focusing on the benefits for learning and improving. Conclusion Recording and reviewing neonatal resuscitation is considered highly beneficial for learning and improving resuscitation skills and is recommended by providers participating in it. Show less
Spruijt, M.S.; Lopriore, E.; Tan, R.N.G.B.; Slaghekke, F.; Klumper, F.J.C.M.; Middeldorp, J.M.; ... ; Klink, J. van 2019
Objective: Evaluate the incidence of and risk factors for behavioural problems in twin-twin transfusion syndrome (TTTS) survivors treated with fetoscopic laser coagulation.Design: Observational... Show moreObjective: Evaluate the incidence of and risk factors for behavioural problems in twin-twin transfusion syndrome (TTTS) survivors treated with fetoscopic laser coagulation.Design: Observational cohort study.Setting: National referral center for fetal therapy, Leiden University Medical Center, The Netherlands.Patients: Behavioural outcome was assessed in 417 TTTS survivors, at the age of 2 years.Interventions: Parents completed the Child Behavior Checklist for their twins. Antenatal, neonatal and follow-up data including Bayley III and a neurological exam were recorded from the medical database.Main outcome measures: The incidence of and risk factors for behavioural problems.Results: 332 twin pregnancies (664 fetuses) were treated with fetoscopic laser for TTTS between 2008 and 2015. For 517 children eligible for follow-up, 417 (81%) Child Behavior Checklist questionnaires were completed. The study group was born at a mean gestational age of 32.8 weeks±3.2. Total behavioural problems within the borderline to clinical range were reported in 8% (95% CI 5.9 to 11.2) of survivors, compared with 10% in the general Dutch population (p=0.12). No difference between donors and recipients was detected (p=0.84). Internalising and externalising problems were reported in 9.4% (95% CI 6.9 to 12.6) and 11.5% (95% CI 8.8 to 15.0), respectively. Severe neurodevelopmental impairment was more frequent in the children with behavioural problems. High maternal educational level was associated with lower behavioural problem scores.Conclusion: Parents of twins treated with fetoscopic laser therapy for TTTS do not report more behavioural problems compared with general population norms. More behavioural problems are reported in children with severe neurodevelopmental impairment. Show less
