How to measure patient and family important outcomes in extremely preterm infants: A scoping review.

AIM: Parents of children born preterm have identified outcomes to be measured for audit and research at 18-24 months of age: child well-being, quality of life/function, socio-emotional/behavioural outcomes, respiratory, feeding, sleeping, and caregiver mental health. The aim was to identify the best tools to measure these seven domains. METHODS: Seven working groups completed literature reviews and evaluated potential tools to measure these outcomes in children aged 18-24 months. A group of experts and parents voted on the preferred tools in a workshop and by questionnaire. Consensus was 80% agreement. RESULTS: Consensus was obtained for seven brief, inexpensive, parent friendly valid measures available in English or French for use in a minimum dataset and potential alternative measures for use in funded research. CONCLUSION: Valid questionnaires and tools to measure parent-identified outcomes in young preterm children exist. This study will facilitate research and collection of data important to families.

Neonatal and Early Childhood Outcomes of Twin and Singleton Infants Born Preterm.

OBJECTIVE: To compare neonatal and early-childhood outcomes of twins and singletons born preterm and explore the association of chorionicity with outcomes. STUDY DESIGN: This was a national retrospective cohort study of singleton and twin infants admitted at 230/7-286/7 weeks to level III neonatal intensive care units in Canada (2010-2020). The primary neonatal outcome was a composite of neonatal death or severe neonatal morbidities. The primary early-childhood outcome was a composite of death or significant neurodevelopmental impairment. RESULTS: The study cohort included 3554 twin and 12 815 singleton infants. Twin infants born at 230/7-256/7 weeks had a greater risk of the composite neonatal outcome (adjusted risk ratio 1.04, 95% CI 1.01-1.07). However, these differences were limited to the subgroups of same-sex and monochorionic twin pregnancies. Twin infants of 230/7-256/7 weeks were also at an increased risk of the composite early-childhood outcome (adjusted risk ratio 1.22, 95% CI 1.09-1.37). Twin infants of 260/7-286/7 weeks were not at an increased risk of adverse neonatal outcomes or the composite early-childhood outcome compared with singleton infants. CONCLUSIONS: Among infants born at 230/7-256/7 weeks, twins have a greater risk of adverse neonatal outcomes and the composite early-childhood outcome than singleton infants. However, the increased risk of adverse neonatal outcomes is mostly limited to monochorionic twins and may thus be driven by complications related to monochorionic placentation.

A systematic review of paediatric neurogenic lower urinary tract dysfunction guidelines using the Appraisal of Guidelines and Research Evaluation (AGREE) II instrument.

OBJECTIVE: To examine and critique current international clinical practice guidelines (CPGs) on management of paediatric neurogenic lower urinary tract dysfunction (NLUTD) and assess the applicability of these guidelines to clinical practice. MATERIALS AND METHODS: We conducted a systematic review of all CPGs on NLUTD published in English from the year 2010 to 2022. Six reviewers independently used the Appraisal of Guidelines and Research Evaluation (AGREE) II instrument to appraise all eligible CPGs. This instrument is comprised of 23 items organised into six quality domains. The scores for each item and domain were tabulated for each reviewer and interrater reliability was assessed for each domain using the intraclass correlation coefficient (ICC). RESULTS: Six CPGs were appraised and these included: National Institute for Health and Care Excellence (NICE), European Society for Paediatric Urology, International Children's Continence Society, Irish, Spina Bifida Association (SBA), and International Brazilian Journal of Urology guidelines. They had high mean standardised scores in the domain on 'scope and purpose' and 'clarity of presentation' but had low scores in the domain of 'applicability'. The top three CPGs based on overall score were the NICE, Irish and SBA guidelines and the reviewers had high degree of interrater reliability (ICC 0.912, P < 0.001). The mean scores in various domains for the top three guidelines were 95.8 (scope and purpose), 87.5 (stakeholder involvement), 69.1 (rigour of development), 94.0 (clarity of presentation), 68.4 (applicability), and 59.7 (editorial independence). The diagnostic and treatment recommendations of the top three guidelines were presented. CONCLUSION: The existing CPGs on paediatric NLUTD provide high-quality evidence based recommendations. The NICE, Irish and SBA guidelines were the top three CPGs identified. They scored high on most domains except applicability and editorial independence. These domains need to be considered for future updates to improve the utility.

Parental perspectives of outcomes following very preterm birth: Seeing the good, not just the bad.

AIM: To describe parental perspective on health and developmental outcomes of their preterm child in relation to level of neurodevelopmental impairment (NDI). METHODS: A parental survey about their children aged 15-36 months corrected age born ˂29 weeks' gestation investigated parental concerns and positive attributes. Parental responses in relation to their child's level of NDI were examined using Kruskal-Wallis and chi-square for trend tests. RESULTS: One hundred ninety-nine parental responses were obtained for 163 children, including 44% with NDI. Vast majority of parents reported their children were developing well with good physical health. All parents, irrespective of NDI, reported their children were happy and had a positive personality. Appreciation of social interactions was higher for parents of children without versus with NDI (96% vs. 87%, p = 0.039). Parents of children with NDI were more likely to express concerns than those without NDI. Overall, development was the most common area of concern (45%), followed by the child's future (40%) and physical health (35%). CONCLUSION: Parents of preterm children report many positive points and concerns, some of which are not examined in neonatal follow-up data. These parental perspectives could be used to inform parents of preterm infants, both antenatally and in the neonatal unit.

Lower Maternal Chronic Physiological Stress and Better Child Behavior at 18 Months: Follow-Up of a Cluster Randomized Trial of Neonatal Intensive Care Unit Family Integrated Care.

OBJECTIVE: To assess whether Family Integrated Care (FICare) in the neonatal intensive care unit improves maternal chronic physiological stress and child behavior at 18 months of corrected age for infants born preterm. STUDY DESIGN: Follow-up of a multicenter, prospective cluster-randomized controlled trial comparing FICare and standard care of children born at <33 weeks of gestation and parents, stratified by tertiary neonatal intensive care units, across Canada. Primary outcomes at 18 months of corrected age were maternal stress hormones (cortisol, ie, hair cumulative cortisol [HCC], dehydroepiandrosterone [DHEA]) assayed from hair samples. Secondary outcomes included maternal reports of parenting stress, child behaviors (Internalizing, Externalizing, Dysregulation), and observer-rated caregiving behaviors. Outcomes were analyzed using multilevel modeling. RESULTS: We included 126 mother-child dyads from 12 sites (6 FICare sites, n = 83; 6 standard care sites, n = 43). FICare intervention significantly lowered maternal physiological stress as indicated by HCC (B = -0.22 [-0.41, -0.04]) and cortisol/DHEA ratio (B = -0.25 [-0.48, -0.02]), but not DHEA (B = 0.01 [-0.11, 0.14]). Enrollment in FICare led to lower child Internalizing (B = -0.93 [-2.33, 0.02]) and Externalizing behavior T scores (B = -0.91 [-2.25, -0.01]) via improvements to maternal HCC (mediation). FICare buffered the negative effects of high maternal HCC on child Dysregulation T scores (B = -11.40 [-23.01, 0.21]; moderation). For mothers reporting high parenting stress at 18 months, FICare was related to lower Dysregulation T scores via maternal HCC; moderated mediation = -0.17 (-0.41, -0.01). CONCLUSIONS: FICare has long-term beneficial effects for mother and child, attenuating maternal chronic physiological stress, and improving child behavior in toddlerhood. CLINICAL TRIAL REGISTRATION: NCT01852695.

Le suivi de l'extrême prématuré après le congé des soins intensifs néonatals.

La survie des extrêmes prématurés (moins de 28 semaines d'âge gestationnel) s'est améliorée au fil du temps. Bon nombre s'en sortent bien et ont une bonne qualité de vie. Ils demeurent toutefois vulnérables à des problèmes de santé, y compris des difficultés neurosensorielles et neurodéveloppementales, que les médecins de première ligne, les pédiatres et les cliniques spécialisées doivent surveiller. Le présent document de principes passe en revue les conséquences médicales et neurodéveloppementales potentielles pour les extrêmes prématurés dans les deux ans suivant leur congé et fournit des stratégies de counseling, de dépistage précoce et d'intervention. Parce qu'ils sont tous liés à l'extrême prématurité, la dysplasie bronchopulmonaire ou les troubles respiratoires, les problèmes d'alimentation et de croissance, le développement neurosensoriel (vision et audition), la paralysie cérébrale et le trouble du spectre de l'autisme doivent faire rapidement l'objet d'une évaluation. Pour évaluer la croissance et le développement, il faut corriger l'âge chronologique en fonction de l'âge gestationnel jusqu'à 36 mois de vie. Par ailleurs, l'attention au bien-être émotionnel des parents et des proches fait partie intégrante des soins de qualité de l'extrême prématuré.

Follow-up care of the extremely preterm infant after discharge from the neonatal intensive care unit.

The survival of babies born extremely preterm (EP, <28 weeks gestation) has improved over time, and many have good outcomes and quality of life. They remain at risk for health issues, including neurosensory and neurodevelopmental difficulties requiring monitoring by primary physicians, paediatricians, and specialty clinics. This statement reviews potential medical and neurodevelopmental consequences for EP infants in the first 2 years after discharge and provides strategies for counselling, early detection, and intervention. EP-related conditions to assess for early include bronchopulmonary dysplasia or respiratory morbidity, feeding and growth concerns, neurosensory development (vision and hearing), cerebral palsy, and autism spectrum disorder. Correction for gestational age should be used for growth and development until 36 months of age. Integral to quality care of the child born EP is attention to the emotional well-being of parents and caregivers.

Automated movement recognition to predict motor impairment in high-risk infants: a systematic review of diagnostic test accuracy and meta-analysis.

AIM: To assess the sensitivity and specificity of automated movement recognition in predicting motor impairment in high-risk infants. METHOD: We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Scopus databases and identified additional studies from the references of relevant studies. We included studies that evaluated automated movement recognition in high-risk infants to predict motor impairment, including cerebral palsy (CP) and non-CP motor impairments. Two authors independently assessed studies for inclusion, extracted data, and assessed methodological quality using the Quality Assessment of Diagnostic Accuracy Studies-2. Meta-analyses were performed using hierarchical summary receiver operating characteristic models. RESULTS: Of 6536 articles, 13 articles assessing 59 movement variables in 1248 infants under 5 months corrected age were included. Of these, 143 infants had CP. The overall sensitivity and specificity for motor impairment were 0.73 (95% confidence interval [CI] 0.68-0.77) and 0.70 (95% CI 0.65-0.75) respectively. Comparatively, clinical General Movements Assessment (GMA) was found to have sensitivity and specificity of 98% (95% CI 74-100) and 91% (95% CI 83-93) respectively. Sensor-based technologies had higher specificity (0.88, 95% CI 0.80-0.93). INTERPRETATION: Automated movement recognition technology remains inferior to clinical GMA. The strength of this study is its meta-analysis to summarize performance, although generalizability of these results is limited by study heterogeneity.

Directive clinique no 410 : Anomalies du tube neural : Prévention, dépistage, diagnostic et prise en charge de la grossesse.

OBJECTIF: La présente directive clinique révisée vise à fournir une mise à jour sur les aspects génétiques, la prévention, le dépistage, le diagnostic et la prise en charge des anomalies du tube neural. POPULATION CIBLE: Les femmes enceintes ou qui pourraient le devenir. Il convient d'offrir le dépistage des anomalies du tube neural à toutes les femmes enceintes. OPTIONS: Pour la prévention : un régime alimentaire riche en acide folique et des suppléments d'acide folique et de vitamine B12 selon une posologie d'après le niveau de risque. Pour le dépistage : l'échographie obstétricale du deuxième trimestre, le dépistage échographique du premier trimestre, le dosage de l'alphafœtoprotéine sérique maternelle et l'imagerie par résonance magnétique prénatale. Pour les tests génétiques : l'amniocentèse diagnostique avec analyse chromosomique sur micropuce et le dosage de l'alphafœtoprotéine et de l'acétylcholinestérase dans le liquide amniotique et le séquençage de l'exome fœtal. Pour la prise en charge de la grossesse : la réparation chirurgicale prénatale, la réparation chirurgicale postnatale et l'interruption de grossesse avec autopsie. Pour les grossesses subséquentes : les options de prévention et de dépistage et les conseils. RéSULTATS: La recherche et la mise en œuvre du traitement chirurgical fœtal en cas de diagnostic prénatal de myéloméningocèle ont ajouté une option thérapeutique fœtale importante aux options précédentes (réparation postnatale ou interruption de grossesse), mais cette nouvelle option comporte un risque accru de morbidité maternelle. La prévention, le dépistage, le diagnostic et le traitement des anomalies du tube neural se révèlent entraîner des améliorations importantes à la mère et au nourrisson en matière de santé et de qualité de vie. BéNéFICES, RISQUES ET COûTS: Le type et l'ampleur des bénéfices, risques et coûts attendus pour les patientes grâce à la mise en œuvre de la présente directive clinique par un établissement de soins de santé intègrent un canal maternel préconception et prénatal adéquat comprenant l'accès des patientes aux soins, les conseils, les analyses et examens, l'imagerie, le diagnostic et l'interprétation. Les bénéfices relatifs à l'autonomie de la patiente et au processus décisionnel sont énoncés dans la présente directive clinique. Les risques comprennent un diagnostic fœtal inattendu et les décisions de prise en charge subséquentes. Le fait que la patiente refuse les échographies habituelles et le retard du conseil ou d'accès aux soins en cas d'anomalie du tube neural comportent également des risques. L'analyse des coûts (personnels, familiaux, santé publique) ne fait pas partie de la portée de la présente directive clinique. DONNéES PROBANTES: Afin de mettre à jour et réviser la présente directive, une revue de la littérature ciblée et dirigée a été effectuée à l'aide des termes de recherche suivants : spina bifida, neural tube defect, myelomeningocele, prenatal diagnosis, fetal surgery, neural tube defect prevention, neural tube defect screening, neural tube defect diagnosis et neural tube defect management. Un processus d'examen par les pairs a été utilisé pour la validation et la clarté du contenu, avec des considérations appropriées d'ordre éthique. MéTHODES DE VALIDATION: Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant l'approche d'évaluation, de développement et d'évaluation (GRADE). Consulter l'annexe A en ligne (le tableau A1 pour les définitions et le tableau A2 pour les interprétations des recommandations fortes et faibles). PROFESSIONNELS CONCERNéS: Professionnels des soins de maternité qui offrent des soins préconception, prénataux, obstétricaux ou néonataux. La présente directive clinique convient également aux fins d'éducation des patientes. RECOMMANDATIONS (CLASSEMENT GRADE ENTRE PARENTHèSES).

Guideline No. 410: Prevention, Screening, Diagnosis, and Pregnancy Management for Fetal Neural Tube Defects.

OBJECTIVE: This revised guideline is intended to provide an update on the genetic aspects, prevention, screening, diagnosis, and management of fetal neural tube defects. TARGET POPULATION: Women who are pregnant or may become pregnant. Neural tube defect screening should be offered to all pregnant women. OPTIONS: For prevention: a folate-rich diet, and folic acid and vitamin B12 supplementation, with dosage depending on risk level. For screening: second-trimester anatomical sonography; first-trimester sonographic screening; maternal serum alpha fetoprotein; prenatal magnetic resonance imaging. For genetic testing: diagnostic amniocentesis with chromosomal microarray and amniotic fluid alpha fetoprotein and acetylcholinesterase; fetal exome sequencing. For pregnancy management: prenatal surgical repair; postnatal surgical repair; pregnancy termination with autopsy. For subsequent pregnancies: prevention and screening options and counselling. OUTCOMES: The research on and implementation of fetal surgery for prenatally diagnosed myelomeningocele has added a significant treatment option to the previous options (postnatal repair or pregnancy termination), but this new option carries an increased risk of maternal morbidity. Significant improvements in health and quality of life, both for the mother and the infant, have been shown to result from the prevention, screening, diagnosis, and treatment of fetal neural tube defects. BENEFITS, HARMS, AND COSTS: The benefits for patient autonomy and decision-making are provided in the guideline. Harms include an unexpected fetal diagnosis and the subsequent management decisions. Harm can also result if the patient declines routine sonographic scans or if counselling and access to care for neural tube defects are delayed. Cost analysis (personal, family, health care) is not within the scope of this clinical practice guideline. EVIDENCE: A directed and focused literature review was conducted using the search terms spina bifida, neural tube defect, myelomeningocele, prenatal diagnosis, fetal surgery, neural tube defect prevention, neural tube defect screening, neural tube defect diagnosis, and neural tube defect management in order to update and revise this guideline. A peer review process was used for content validation and clarity, with appropriate ethical considerations. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). INTENDED AUDIENCE: Maternity care professionals who provide any part of pre-conception, antenatal, delivery, and neonatal care. This guideline is also appropriate for patient education. RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES).

Fetal Surgery for Open Spina Bifida in Canada: Initial Results.

OBJECTIVE: Fetal myelomeningocele closure results in better infant outcomes than postnatal closure at the cost of potential prematurity and maternal morbidity. Our aim is to describe the setup of a fetal myelomeningocele closure program in Canada and document its outcomes. METHODS: We conducted a retrospective review of all open fetal myelomeningocele closure surgeries performed at the Ontario Fetal Centre in its first 3 years of operation (2017-2020). Maternal and fetal baseline characteristics, surgical details, pregnancy outcomes, and infant follow-up until 1 year of age were recorded. RESULTS: Twenty-seven women underwent fetal myelomeningocele closure surgery, 10 of whom (37%) resided outside of Ontario. Mean gestational age at surgery was 25.0 ± 0.7 weeks. All surgeries were technically uncomplicated and no fetal deaths occurred. There was a significant negative correlation between increasing experience and skin-to-skin surgical time (R²â€¯= 0.36; P = 0.001). Of the 26 patients who have delivered, 4 (15.4%) experienced preterm prelabour rupture of membranes. Mean gestational age at delivery was 34.9±3.0 weeks. All but 1 patient delivered by cesarean. Maternal complications occurred in 9 women (34.6%). There were no maternal deaths, but 3 (11.5%) infant deaths. Of the 14 surviving infants who have reached at least 1 year of age, 5 (35.7%) underwent ventriculo-peritoneal shunting. Of the 9 infants who have not yet reached 1 year of age, 3 (33.3%) underwent endoscopic third ventriculostomy and none underwent shunting. CONCLUSION: Fetal open spina bifida closure can be performed in Canada, with results similar to those reported by other international expert centres. Long-term follow-up is ongoing.

Neonatal follow-up programs in Canada: A national survey.

BACKGROUND: A 2006 Canadian survey showed a large variability in neonatal follow-up practices. In 2010, all 26 tertiary level Neonatal Follow-Up clinics joined the Canadian Neonatal Follow-Up Network (CNFUN) and agreed to implement a standardized assessment (including the Bayley Scales of Infant and Toddler Development-III (Bayley-III) at 18 months corrected age for children born < 29 weeks' gestation. It is unknown whether the variability in follow-up practices lessened as a result. OBJECTIVES: To describe the current status of neonatal follow-up services in Canada and changes over time. METHODS: A comprehensive online survey was sent to all tertiary level CNFUN Follow-up programs. Questions were based on previous survey results, current literature, and investigator expertise and consensus. RESULTS: Respondents included 23 of 26 (88%) CNFUN programs. All sites provide neurodevelopmental screening and referrals in a multidisciplinary setting with variations in staffing. CNFUN programs vary with most offering five to seven visits. Since 2006, assessments at 18 months CA increased from 84% to 91% of sites, Bayley-III use increased from 21% to 74% (P=0.001) and eligibility for follow-up was expanded for children with stroke, congenital diaphragmatic hernia and select anomalies detected in utero. Audit data is collected by > 80% of tertiary programs. CONCLUSION: Care became more consistent after CNFUN; 18-month assessments and Bayley-III use increased significantly. However, marked variability in follow-up practices persists.

Exploring Acceptance and Commitment Therapy for parents of preterm infants.

The start of a parenting journey in the neonatal intensive care unit (NICU) presents many stressors to parents. Previous research has shown parents of infants admitted to the NICU experience heightened stress, anxiety, and depression. Mental health support varies across Canadian NICUs with mixed results. One promising intervention that has not been explored in the NICU is Acceptance and Commitment Therapy (ACT), a behavioural therapy that has had positive mental health-related outcomes in similar parental populations. ACT differs from previous mental health interventions such as traditional Cognitive Behavioural Therapy (CBT) as it involves mindfulness and acceptance to increase psychological flexibility. Increased psychological flexibility is linked to greater emotional well-being, a higher quality of life, and decreased stress, anxiety, and depression. There is a need for research investigating the utility of ACT in improving mental health outcomes for parents of preterm infants.

Fetal spina bifida: What we tell the parents.

Worldwide, about 150 000 infants are born with spina bifida yearly, making this condition one of the most common fetal central nervous system anomalies compatible with life. Over the last decade, major changes have been introduced in the prenatal diagnosis and management of spina bifida. In this review, we provide a brief summary of the current management of fetal spina bifida and present essential information that should be provided to expecting parents when their fetus has been diagnosed with spina bifida. This information is focused around common parental questions, as encountered in our typical clinical practice, to facilitate knowledge translation.

Split-week gestational age model provides valuable information on outcomes in extremely preterm infants.

AIM: To compare composite outcomes of neonatal mortality or morbidity using a split-week gestational age (GA) model to completed weeks GA maturity at 23-26 weeks gestation. METHODS: This was a retrospective cohort study of infants born at 23-26 weeks GA. Outcomes using a split-week GA model defined as early (X, 0-3) and late (X, 4-6) with X being 23-26 weeks GA were compared to outcomes using completed weeks GA, with a similar comparison between the late split of the preceding week (X, 4-6) and early split of the subsequent week (X + 1, 0-3). RESULTS: A total of 1345 infants were included in the study. Statistically significant differences were noted in outcomes between the early and late split of the gestational week at 24 (early vs late, 85.6% vs 73.0%), 25 (69.6% vs 56.6%) and 26 weeks (55.9% vs 37.4%), but not at 23 weeks GA (95.2% vs 94.5%). No statistically significant differences were noted between the late vs early part of the subsequent week (23, 4-6) vs (24, 0-3), and (24, 4-6) vs (25, 0-3) GA. CONCLUSION: Neonatal outcome estimates using a split week model differs from that based on the use of completed weeks of gestational maturity.

Fetal myelomeningocele surgery: Only treating the tip of the iceberg.

OBJECTIVE: Fetal myelomeningocele (fMMC) surgery improves infant outcomes when compared with postnatal surgery. Surgical selection criteria and the option of pregnancy termination, however, limit the number of cases that are eligible for prenatal surgery. We aimed to quantify what proportion of cases could ultimately benefit from fetal therapy. METHODS: We retrospectively reviewed all cases of fMMC referred to a large tertiary care center over a 10-year period and assessed their eligibility for fetal surgery, pregnancy termination rates, and actual uptake of the surgery. RESULTS: Of 158 cases, 67 (42%) were ineligible for fetal surgery based on surgical exclusion criteria. Eleven fetuses (7%) had chromosomal anomalies, 10 of which (91%) had other anomalies on ultrasound. Thirty-four patients had a combination of maternal and fetal contraindications. Of the remaining 91 eligible cases (58%), 45 (49%) pregnancies were terminated, leaving only 46 (29% of initial 158 cases) as potential candidates for fetal repair. Actual uptake of fetal surgery was 15% (n = 14 of 91), but this increased after a national program was started. CONCLUSION: Only a minority of fMMC cases will ultimately undergo fetal surgery. These numbers support the centralization of care in expert centers.

Severe Neurodevelopmental Impairment in Neonates Born Preterm: Impact of Varying Definitions in a Canadian Cohort.

OBJECTIVE: To assess the impact of variations in the definition of severe neurodevelopmental impairment (NDI) on the incidence of severe NDI and the association with risk factors using the Canadian Neonatal Follow-Up Network cohort. STUDY DESIGN: Literature review of severe NDI definitions and application of these definitions were performed in this database cohort study. Infants born at 23-28 completed weeks of gestation between 2009 and 2011 (n = 2187) admitted to a Canadian Neonatal Network neonatal intensive care unit and assessed at 21 months' corrected age were included. The incidence of severe NDI, aORs, and 95% CIs were calculated to express the relationship between risk factors and severe NDI using the definitions with the highest and the lowest incidence rates of severe NDI. RESULTS: The incidence of severe NDI ranged from 3.5% to 14.9% (highest vs lowest rate ratio 4.29; 95% CI 3.37-5.47). The associations between risk factors and severe NDI varied depending on the definition used. Maternal ethnicity, employment status, antenatal corticosteroid treatment, and gestational age were not associated consistently with severe NDI. Although maternal substance use, sex, score of neonatal acute physiology >20, late-onset sepsis, bronchopulmonary dysplasia, and brain injury were consistently associated with severe NDI irrespective of definition, the strength of the associations varied. CONCLUSIONS: The definition of severe NDI significantly influences the incidence and the associations between risk factors and severe NDI. A standardized definition would facilitate site comparisons and scientific communication.