Change in Volumes and Location of Preterm White Matter Injury over a Period of 15 Years.

OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: 528 infants born <32 weeks' gestational age from two sequential prospective cohorts (cohort 1 2006 through 2012 and cohort 2 2014 through 2019) underwent early-life (median 32.7 weeks) and/or term-equivalent-age MRI (median 40.7 weeks). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI (n=152) with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts (over time). RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß =-0.6, 95%CI -0.8, -0.3, p<0.001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

Maternal "mirror" syndrome: Evaluating the benefits of fetal therapy.

OBJECTIVE: To evaluate maternal and perinatal outcomes following fetal intervention in the context of maternal "mirror" syndrome. STUDY DESIGN: A multicenter retrospective study of all cases of fetal hydrops complicated by maternal "mirror" syndrome and treated by any form of fetal therapy between 1995 and 2022. Medical records and ultrasound images of all cases were reviewed. "Mirror" syndrome was defined as fetal hydrops and/or placentomegaly associated with the maternal development of pronounced edema, with or without pre-eclampsia. Fetal hydrops was defined as the presence of abnormal fluid collections in ≥2 body cavities. RESULTS: Twenty-one pregnancies met the inclusion criteria. Causes of fetal hydrops and/or placentomegaly included fetal lung lesions (n = 9), twin-twin transfusion syndrome (n = 6), severe fetal anemia (n = 4), and others (n = 2). Mean gestational age at "mirror" presentation was 27.0 ± 3.8 weeks. Maternal "mirror" syndrome was identified following fetal therapeutic intervention in 14 cases (66.6%). "Mirror" symptoms resolved or significantly improved before delivery in 8 (38.1%) cases with a mean interval from fetal intervention to maternal recovery of 13.1 days (range 4-35). Three women needed to be delivered because of worsening "mirror" syndrome. Of the 21 pregnancies treated (27 fetuses), there were 15 (55.5%) livebirths, 7 (25.9%) neonatal deaths and 5 (18.5%) intra-uterine deaths. CONCLUSION: Following successful treatment and resolution of fetal hydrops, maternal "mirror" syndrome can improve or sometimes completely resolve before delivery. Furthermore, the recognition that "mirror" syndrome may arise only after fetal intervention necessitates hightened patient maternal surveillance in cases of fetal hydrops.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

Pain Exposure and Brain Connectivity in Preterm Infants.

Importance: Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown. Objective: To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants. Design, Setting, and Participants: This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023. Exposure: Pain was quantified in the initial weeks after birth as the total number of invasive procedures. Main Outcome and Measure: Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education. Results: A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes. Conclusions and Relevance: In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

Major Surgery, Brain Injury, and Neurodevelopmental Outcomes in Very Preterm Infants.

OBJECTIVES: We determined whether (1) major surgery is associated with an increased risk for brain injury and adverse neurodevelopment and (2) brain injury modifies associations between major surgery and neurodevelopment in very preterm infants. METHODS: Prospectively enrolled infants across 3 tertiary neonatal intensive care units underwent early-life and/or term-equivalent age MRI to detect moderate-severe brain injury. Eighteen-month neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development, third edition. Multivariable logistic and linear regressions were used to determine associations of major surgery with brain injury and neurodevelopment, adjusting for clinical confounders. RESULTS: There were 294 infants in this study. Major surgery was associated with brain injury (odds ratio 2.54, 95% CI 1.12-5.75, p = 0.03) and poorer motor outcomes (ß = -7.92, 95% CI -12.21 to -3.64, p < 0.001), adjusting for clinical confounders. Brain injury x major surgery interaction significantly predicted motor scores (p = 0.04): Lowest motor scores were in infants who required major surgery and had brain injury. DISCUSSION: There is an increased risk for brain injury and adverse motor outcomes in very preterm infants who require major surgery, which may be a marker of clinical illness severity. Routine brain MRI to detect brain injury and close neurodevelopmental surveillance should be considered in this subgroup of infants.

Fungal infection and neurodevelopmental outcomes at 18-30 months in preterm infants.

Background: Invasive fungal infection (IFI) is associated with significant mortality and morbidity among preterm infants but there has been no population-based study of long-term neurodevelopmental outcomes. The objective of this study was to examine population-based incidence trends as well as mortality, short term in-hospital morbidity and long-term neurodevelopmental outcomes among preterm infants with IFI, non-fungal infections (NFI) and no infections in Canada. Methods: We conducted a retrospective cohort study of 8,408 infants born at <29 weeks gestational age (GA), admitted to Canadian Neonatal Network neonatal intensive care units (NICU) from April 2009 to December 2017, and followed up at 18-30 months corrected age (CA) in Canadian Neonatal Follow-Up Network clinics. We compared mortality, long term neurodevelopmental outcomes and short term in-hospital morbidity among 3 groups of infants (IFI, NFI, and no infections). Results: The incidence of IFI was 1.3%, non-IFI 26.9% and no infections 71.7%. IFI incidence varied between 0.93% and 1.94% across the study period with no significant trend over time. Infants of higher gestational age were significantly (p < 0.01) less likely to have IFI. Among infants with IFI, NFI and no infections, the incidence of the significant neurodevelopmental impairment (sNDI) was 44.26%, 21.63% and 14.84% respectively, while mortality was 50%, 25.35% and 22.25% respectively. Even after risk adjustment for confounders (GA, Score for Neonatal Acute Physiology Version II, ruptured membranes >24 h, maternal antibiotic treatment, antenatal steroid use, cesarean section), infants with IFI had significantly higher odds of sNDI than NFI (aOR: 2.19; 95% CI: 1.23, 3.91) or no infections (aOR: 2.97; 95% CI: 1.55, 5.71), and higher odds of mortality than NFI (aOR: 1.55; 95% CI: 1.07, 2.26) or no infections (aOR: 1.45; 95% CI: 0.97, 2.17). Conclusions: Preterm infants with invasive fungal infections have significantly higher incidence of mortality and adverse neurodevelopmental outcomes than those with non-invasive fungal infections and no infections.

Child Neurology: Cortical Malformations in Preterm Infants: Case From a Prospective Cohort.

Malformations of cortical development (MCD) are a rare group of disorders with heterogeneous clinical, neuroimaging, and genetic features. MCD consist of disruptions in the development of the cerebral cortex secondary to genetic, metabolic, infectious, or vascular etiologies. MCD are typically classified by stage of disrupted cortical development as secondary to abnormal: (1) neuronal proliferation or apoptosis, (2) neuronal migration, or (3) postmigrational cortical development. MCD are typically detected with brain MRI when an infant or child becomes symptomatic, presenting with seizures, developmental delay, or cerebral palsy. With recent advances in neuroimaging, cortical malformations can be detected using ultrasound or MRI during the fetal period or in the neonatal period. Of interest, preterm infants are born at a time when many cortical developmental processes are still occurring. However, there is a paucity of literature describing the neonatal imaging findings, clinical presentation, and evolution over time of cortical malformations in preterm infants. In this study, we present the neuroimaging findings from early life to term-equivalent age and childhood neurodevelopmental outcomes of an infant born very preterm (<32 weeks' postmenstrual age) with MCD detected incidentally on neonatal research brain MRI. These brain MRIs were performed as part of a prospective longitudinal cohort study of 160 very preterm infants; MCD were detected incidentally in 2 infants.

Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants.

BACKGROUND: We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment. METHODS: Multicenter prospective study of 276 very preterm infants (born <24-32 weeks' gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development-Third edition. RESULTS: Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days). CONCLUSIONS: Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants. IMPACT: In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population. We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada. Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure. Further trials of optimal treatment approaches with morphine in preterm infants are warranted.

Very-low-birth-weight infant short-term post-discharge outcomes: A retrospective study of specialized compared to standard care.

OBJECTIVE: Ongoing health care challenges, low breast milk intake, and the need for rehospitalization are common during the first year of life after hospital discharge for very low birth weight (VLBW) infants. This retrospective cohort study examined breast milk intake, growth, emergency department (ED) visits, and non-surgical rehospitalizations for VLBW infants who received specialized post-discharge follow-up in western Canada, compared to VLBW infants who received standard follow-up in central Canada. DESIGN: Data were collected from two neonatal follow-up programs for VLBW babies (n = 150 specialized-care; n = 205 standard-care). Logistic regression was used to examine odds of breast milk intake and generalized estimating equations were used for odds of growth, ED visits and non-surgical rehospitalization by site. RESULTS: Specialized-care was associated with enhanced breast milk intake duration; the odds of receiving breastmilk at 4 months in the specialized-care cohort was 6 times that in the standard-care cohort. The specialized-care cohort had significantly more ED visits and rehospitalizations. However, for infants with oxygen use beyond 36 weeks compared to those with no oxygen use, the standard-care cohort had over 7 times the odds of rehospitalization where as the specialized-care cohort with no increased odds of rehospitalization. CONCLUSION: Specialized neonatal nursing follow-up was associated with continued breastmilk intake beyond discharge. Infants in the specialized-care cohort used the ED and were hospitalized more often than the standard-care cohort with the exception of infants with long term oxygen needs.

Intravenous immunoglobulin in the management of severe early onset red blood cell alloimmunisation.

Our objective was to assess the effect of maternal intravenous immunoglobulin (IVIG) administration for severe red blood cell (RBC) alloimmunisation on fetal outcomes. This is a case-control study. Women with a history of severe early onset alloimmunisation resulting in fetal loss in a previous pregnancy and high anti-D or anti-K antibody titres received IVIG in a subsequent pregnancy. We assessed gestational age at first transfusion and fetal outcomes in the subsequent pregnancy and compared these with the outcomes in the previous pregnancy. The most responsible antibody was anti-D in 17 women and anti-K in two others, whilst seven had more than one antibody. In all, 19 women received IVIG in 22 pregnancies, two of which did not even need an intrauterine transfusion (IUT). For previous early losses despite transfusion, IVIG was associated with a relative increase in fetal haemoglobin between treated and untreated pregnancies of 36.5 g/L (95% confidence interval 19.8-53.2, p = 0.0013) and improved perinatal survival (eight of eight vs. none of six, p = 0.001). For previous losses at <20 weeks, it enabled first transfusion deferral in subsequent pregnancies to at least 19.9 weeks (mean 23.2 weeks). Overall, IVIG decreases the severity of haemolytic disease of the fetus and newborn and allows deferral of the first IUT to a safer gestation in severe early-onset RBC alloimmunisation and rarely may even avoid the need for IUT entirely.

Grading of Intraventricular Hemorrhage and Neurodevelopment in Preterm <29 Weeks' GA in Canada

Objective: The aim of this study was to evaluate the neurodevelopmental outcome at 18−24 months in surviving preterm infants with grades I−IV intraventricular hemorrhages (IVHs) compared to those with no IVH. Study Design: We included preterm survivors <29 weeks' GA admitted to the Canadian Neonatal Network's NICUs from April 2009 to September 2011 with follow-up data at 18−24 months in a retrospective cohort study. The neonates were grouped based on the severity of the IVH detected on a cranial ultrasound scan and recorded in the database: no IVH; subependymal hemorrhage or IVH without ventricular dilation (grades I−II); IVH with ventricular dilation (grade III); and persistent parenchymal echogenicity/lucency (grade IV). The primary outcomes of neurodevelopmental impairment (NDI), significant neurodevelopmental impairment (sNDI), and the effect modification by other short-term neonatal morbidities were assessed. Using multivariable regression analysis, the adjusted ORs (AOR) and 95% of the CIs were calculated. Results: 2327 infants were included. The odds of NDI were higher in infants with grades III and IV IVHs (AOR 2.58, 95% CI 1.56, 4.28 and AOR 2.61, 95% CI 1.80, 3.80, respectively) compared to those without IVH. Infants with an IVH grade ≤II had similar outcomes for NDI (AOR 1.08, 95% CI 0.86, 1.35) compared to those without an IVH, but the odds of sNDI were higher (AOR 1.58, 95% CI 1.16, 2.17). Conclusions: There were increased odds of sNDI in infants with grades I−II IVHs, and an increased risk of adverse NDI in infants with grades ≥III IVHs is corroborated with the current literature.

Association of Pediatric Buccal Epigenetic Age Acceleration With Adverse Neonatal Brain Growth and Neurodevelopmental Outcomes Among Children Born Very Preterm With a Neonatal Infection.

Importance: Very preterm neonates (24-32 weeks' gestation) remain at a higher risk of morbidity and neurodevelopmental adversity throughout their lifespan. Because the extent of prematurity alone does not fully explain the risk of adverse neonatal brain growth or neurodevelopmental outcomes, there is a need for neonatal biomarkers to help estimate these risks in this population. Objectives: To characterize the pediatric buccal epigenetic (PedBE) clock-a recently developed tool to measure biological aging-among very preterm neonates and to assess its association with the extent of prematurity, neonatal comorbidities, neonatal brain growth, and neurodevelopmental outcomes at 18 months of age. Design, Setting, and Participants: This prospective cohort study was conducted in 2 neonatal intensive care units of 2 hospitals in Toronto, Ontario, Canada. A total of 35 very preterm neonates (24-32 weeks' gestation) were recruited in 2017 and 2018, and neuroimaging was performed and buccal swab samples were acquired at 2 time points: the first in early life (median postmenstrual age, 32.9 weeks [IQR, 32.0-35.0 weeks]) and the second at term-equivalent age (TEA) at a median postmenstrual age of 43.0 weeks (IQR, 41.0-46.0 weeks). Follow-ups for neurodevelopmental assessments were completed in 2019 and 2020. All neonates in this cohort had at least 1 infection because they were originally enrolled to assess the association of neonatal infection with neurodevelopment. Neonates with congenital malformations, genetic syndromes, or congenital TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes and other agents) infection were excluded. Exposures: The extent of prematurity was measured by gestational age at birth and PedBE age difference. PedBE age was computed using DNA methylation obtained from 94 age-informative CpG (cytosine-phosphate-guanosine) sites. PedBE age difference (weeks) was calculated by subtracting PedBE age at each time point from the corresponding postmenstrual age. Main Outcomes and Measures: Total cerebral volumes and cerebral growth during the neonatal intensive care unit period were obtained from magnetic resonance imaging scans at 2 time points: approximately the first 2 weeks of life and at TEA. Bayley Scales of Infant and Toddler Development, Third Edition, were used to assess neurodevelopmental outcomes at 18 months. Results: Among 35 very preterm neonates (21 boys [60.0%]; median gestational age, 27.0 weeks [IQR, 25.9-29.9 weeks]; 23 [65.7%] born extremely preterm [<28 weeks' gestation]), extremely preterm neonates had an accelerated PedBE age compared with neonates born at a later gestational age (ß = 9.0; 95% CI, 2.7-15.3; P = .01). An accelerated PedBE age was also associated with smaller cerebral volumes (ß = -5356.8; 95% CI, -6899.3 to -2961.7; P = .01) and slower cerebral growth (ß = -2651.5; 95% CI, -5301.2 to -1164.1; P = .04); these associations remained significant after adjusting for clinical neonatal factors. These findings were significant at TEA but not earlier in life. Similarly, an accelerated PedBE age at TEA was associated with lower cognitive (ß = -0.4; 95% CI, -0.8 to -0.03; P = .04) and language (ß = -0.6; 95% CI, -1.1 to -0.06; P = .02) scores at 18 months. Conclusions and Relevance: This cohort study of very preterm neonates suggests that biological aging may be associated with impaired brain growth and neurodevelopmental outcomes. The associations between epigenetic aging and adverse neonatal brain health warrant further attention.

Epidemiology of post-hemorrhagic ventricular dilatation in very preterm infants.

OBJECTIVE: To describe the incidence, trends, management's variability and short-term outcomes of preterm infants with severe post-hemorrhagic ventricular dilatation (sPHVD). METHODS: We reviewed infants <33 weeks' gestation who had PHVD and were admitted to the Canadian Neonatal Network between 2010 and 2018. We compared perinatal characteristics and short-term outcomes between those with sPHVD and those with mild/moderate PHVD and those with and without ventriculo-peritoneal (VP) shunt. RESULTS: Of 29,417 infants, 2439 (8%) had PHVD; rate increased from 7.3% in 2010 to 9.6% in 2018 (P = 0.005). Among infants with PHVD, sPHVD (19%) and VP shunt (29%) rates varied significantly across Canadian centers and between geographic regions (P < 0.01 and P = 0.0002). On multivariable analysis, sPHVD was associated with greater mortality, seizures and meningitis compared to mild/moderate PHVD. CONCLUSIONS: Significant variability in sPHVD and VP shunt rates exists between centers and regions in Canada. sPHVD was associated with increased mortality and morbidities.

Clinical burden associated with therapies for cardio-pulmonary critical decompensation in preterm neonates across Canadian neonatal intensive care units.

The aim of this retrospective cohort study was to study the clinical burden associated with cardio-pulmonary critical decompensations (CPCDs) in preterm neonates and factors associated with mortality. Through the Canadian Neonatal Network (30 tertiary NICUs, 2010-2017), we identified infants < 32-week gestational age with CPCDs, defined by "significant exposure" to cardiotropes and/or inhaled nitric oxide (iNO): (1) either therapy for ≥ 3 consecutive days, (2) both for ≥ 2 consecutive days, or (3) any exposure within 2 days of death. Early CPCDs (≤ 3 days of age) and late CPCDs (> 3 days) were examined separately. Outcomes included CPCD-incidence, mortality, and inter-site variability using standardized ratios (observed/adjusted expected rate) and network funnel plots. Mixed-effects analysis was used to quantify unit-level variability in mortality. Overall, 10% of admissions experienced CPCDs (n = 2915). Late CPCDs decreased by ~ 5%/year, while early CPCDs were unchanged during the study period. Incidence and CPCD-associated mortality varied between sites, for both early (0.6-7.5% and 0-100%, respectively) and late CPCDs (2.5-15% and 14-83%, respectively), all p < 0.01. Units' late-CPCD incidence and mortality demonstrated an inverse relationship (slope = -2.5, p < 0.01). Mixed-effects analysis demonstrated clustering effect, with 6.4% and 8.6% of variability in mortality after early and late CPCDs respectively being site-related, unexplained by available patient-level characteristics or unit volume. Mortality was higher with combined exposure than with only-cardiotropes or only-iNO (41.3%, 24.8%, 21.5%, respectively; p < 0.01). CONCLUSIONS: Clustering effects exist in CPCD-associated mortality among Canadian NICUs, with higher incidence units showing lower mortality. These data may aid network-level benchmarking, patient-level risk stratification, parental counseling, and further research and quality improvement work. WHAT IS KNOWN: • Preterm neonates remain at high risk of acute and chronic complications; the most critically unwell require therapies such as cardiotropic drugs and inhaled nitric oxide. • Infants requiring these therapies are known to be at high risk for adverse neonatal outcomes and for mortality. WHAT IS NEW: • This study helps illuminate the national burden of acute cardio-pulmonary critical decompensation (CPCD), defined as the need for cardiotropic drugs or inhaled nitric oxide, and highlights the high risk of morbidity and mortality associated with this disease state. • Significant nationwide variability exists in both CPCD incidence and associated mortality; a clustering effect was observed with higher incidence sites showing lower CPCD-associated mortality.

Association of inotrope use with neurodevelopmental outcomes in infants <29 weeks gestation: a retrospective cohort study.

OBJECTIVE: The primary objective was to compare neurodevelopmental (ND) outcomes at 18-24 months in preterm infants <29 weeks gestational age (GA) who received versus those who did not receive inotropes in the first week of life. The secondary objective was to assess ND outcomes according to the duration of inotropic support in the first week of life (≤3 or >3 days). STUDY DESIGN: Retrospective population-based cohort study of preterm infants <29 weeks GA admitted to participating neonatal intensive care units (NICUs) of the Canadian Neonatal Network (CNN) from January 2010 to September 2011 with follow-up data available at 18-24 months. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Long-term outcomes were categorized as neurodevelopmental impairment (NDI) and significant neurodevelopmental impairment (sNDI), and effect modification due to other neonatal morbidities including receipt of antenatal steroids, GA, small for gestational age (SGA) status, sex, score for neonatal acute physiology (SNAP-II) >20, postnatal steroids, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) grade ≥3/periventricular leukomalacia (PVL), early- and late-onset sepsis, retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC) was assessed. Maternal and infant demographic characteristics and short- and long-term outcomes were compared using Pearson's Chi-square test for categorical variables and Student's t-test or the Wilcoxon rank test for continuous variables. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated using multivariable regression analysis. RESULTS: Of the 491 (18.7%) eligible preterm infants who received inotropes during the first week of life, 314 (64%) survived to NICU discharge and 245 (78%) had ND outcome data available. A total of 1775 eligible preterm infants did not receive inotropes in the first week of life; 1647 (92.7%) survived to NICU discharge and 1149 (70%) had ND outcome data. Maternal and infant characteristics associated with infants receiving inotropes included: younger maternal age, clinical chorioamnionitis, no antenatal steroids, outborn, lower GA, BW and Apgar scores at both one and five minutes; and higher SNAP-II scores (p < .05). Infants who received inotropes in the first week of life were more likely to be require postnatal steroids, had higher rates of BPD, IVH grade ≥3/PVL, early- and late-onset sepsis, ROP, NEC and mortality (p < .05). Infants who received inotropes in the first week of life also had higher rates of sensorineural or mixed hearing loss with an AOR (95% CI) of 1.99 (1.13, 3.49). After adjusting for confounding variables, there was no difference in the risk of NDI or sNDI between infants who did and did not receive inotropes in the first week of life. Of the infants with neurodevelopmental outcome data available, 186 received inotropes for ≤3 days and 59 for >3 days. After adjusting for confounding variables there was no difference in the risk of NDI or sNDI. Infants who received inotropes for >3 days were more likely to have lower BSID-III cognitive [AOR 2.43 95% CI (1.03, 5.76)] and motor scores <85 [AOR 2.38 95% CI (1.07, 5.30)] respectively. CONCLUSIONS: In this large, population-based cohort, infants who received inotropes in the first week of life were at increased risk for sensorineural or mixed hearing loss. There was no difference in NDI or sNDI after adjusting for confounding variables. A longer duration of inotrope use in the first week of life was associated with lower BSID-III cognitive and motor scores, but no difference in overall NDI or sNDI.

Family integrated care: very preterm neurodevelopmental outcomes at 18 months.

OBJECTIVE: To examine whether the family integrated care (FICare) programme, a multifaceted approach which enables parents to be engaged as primary caregivers in the neonatal intensive care unit, impacts infant neurodevelopment and growth at 18 months' corrected age. DESIGN/METHODS: Prospective cohort study of infants born <29 weeks' gestational age (GA) who participated in the FICare cluster randomised control trial (cRCT) and were assessed in the Canadian Neonatal Follow-Up Network (CNFUN). The primary outcome measure, Cognitive or Language composite score <85 on the Bayley-III, was compared between FICare exposed and routine care children using logistic regression, adjusted for potential confounders and employing generalised estimation equations to account for clustering of infants within sites. RESULTS: Of 756 infants <29 weeks' GA in the FICare cRCT, 505 were enrolled in CNFUN and 455 were assessed (238 FICare, 217 control). Compared with controls, FICare infants had significantly higher incidence of intraventricular haemorrhage (IVH) (19.5% vs 11.7%, p=0.024) and higher proportion of employed mothers (76.6% vs 73.6%, p=0.043). There was no significant difference in the odds of the primary outcome (adjusted OR: 0.92 (0.59 to 1.42) FiCare vs Control) on multivariable analyses adjusted for GA, IVH and maternal employment. However, Bayley-III Motor scores (adjusted difference in mean (95% CI) 3.87 (1.22 to 6.53) and body mass index 0.67 (0.36 to 0.99) were higher in the FICare group. CONCLUSIONS: Very preterm infants exposed to FICare had no significant difference in incidence of cognitive or language delay but had better motor development. TRIAL REGISTRATION NUMBER: Participants in this cohort study were previously enrolled in a registered trial: NCT01852695.

Outcome predictors for maternal red blood cell alloimmunisation with anti-K and anti-D managed with intrauterine blood transfusion.

Red blood cell (RBC) alloimmunisation with anti-D and anti-K comprise the majority of cases of fetal haemolytic disease requiring intrauterine red cell transfusion (IUT). Few studies have investigated which haematological parameters can predict adverse fetal or neonatal outcomes. The aim of the present study was to identify predictors of adverse outcome, including preterm birth, intrauterine fetal demise (IUFD), neonatal death (NND) and/or neonatal transfusion. We reviewed the records of all pregnancies alloimmunised with anti-K and anti-D, requiring IUT over 27 years at a quaternary fetal centre. We reviewed data for 128 pregnancies in 116 women undergoing 425 IUTs. The median gestational age (GA) at first IUT was significantly earlier for anti-K than for anti-D (24·3 vs. 28·7 weeks, P = 0·004). Women with anti-K required more IUTs than women with anti-D (3·84 vs. 3·12 mean IUTs, P = 0·036) and the fetal haemoglobin (Hb) at first IUT was significantly lower (51.0 vs. 70.5 g/l, P = 0·001). The mean estimated daily decrease in Hb did not differ between the two groups. A greater number of IUTs and a slower daily decrease in Hb (g/l/day) between first and second IUTs were predictive of a longer period in utero. Earlier GA at first IUT and a shorter interval from the first IUT until delivery predicted IUFD/NND. Earlier GA and lower Hb at first IUT significantly predicted need for phototherapy and/or blood product use in the neonate. In the anti-K group, a greater number of IUTs was required in women with a higher titre. Furthermore, the higher the titre, the earlier the GA at which an IUT was required in both groups. The rate of fall in fetal Hb between IUTs decreased, as the number of transfusions increased. Our present study identified pregnancies at considerable risk of an unfavourable outcome with anti-D and anti-K RBC alloimmunisation. Identifying such patients can guide pregnancy management, facilitates patient counselling, and can optimise resource use. Prospective studies can also incorporate these characteristics, in addition to laboratory markers, to further identify and improve the outcomes of these pregnancies.

Impact of a "Brain Protection Bundle" in Reducing Severe Intraventricular Hemorrhage in Preterm Infants <30 Weeks GA: A Retrospective Single Centre Study.

BACKGROUND: despite advances in perinatal care, periventricular/intraventricular hemorrhage (IVH) continues to remain high in neonatal intensive care units (NICUs) worldwide. Studies have demonstrated the benefits of implementing interventions during the antenatal period, stabilization after birth (golden hour management) and postnatally in the first 72 h to reduce the incidence of IVH. OBJECTIVE: to compare the incidence of severe intraventricular hemorrhage (IVH ≥ Grade III) before and after implementation of a "brain protection bundle" in preterm infants <30 weeks GA. STUDY DESIGN: a pre- and post-implementation retrospective cohort study to compare the incidence of severe IVH following execution of a "brain protection bundle for the first 72 h from 2015 to 2018. Demographics, management practices at birth and in the NICU, cranial ultrasound results and short-term morbidities were compared. RESULTS: a total of 189 and 215 infants were included in the pre- and post-implementation phase, respectively. No difference in the incidence of severe IVH (6.9% vs. 9.8%, p = 0.37) was observed on the first cranial scan performed after 72 h of age. CONCLUSION: the implementation of a "brain protection bundle" was not effective in reducing the incidence of severe IVH within the first 72 h of life in our centre.

Perinatal Outcome in Fetuses with Dislodged Thoraco-Amniotic Shunts.

OBJECTIVE: Fetal thoraco-amniotic shunts (TASs) can dislodge in utero, migrating internally into the fetal thorax or externally into the amniotic cavity. Our objective was to evaluate the perinatal and long-term outcome of fetuses with TAS dislodgement and conduct a review of the literature. METHODS: This is a retrospective review of all TAS inserted for primary pleural effusions and macrocystic congenital pulmonary airway malformations (CPAMs) in a tertiary fetal medicine center (1991-2020). Antenatal history, procedural factors, and perinatal and long-term outcomes were reviewed in all fetuses with dislodged shunts and compared to fetuses with shunts that did not dislodge. RESULTS: Of 211 TAS inserted at a mean gestational age of 27.8 weeks ± 5.47 (17.4-38.1 weeks), 187 (89%) were inserted for pleural effusions and 24 (11%) for macrocystic CPAMs. Shunts dislodged in 18 fetuses (8.5%), 17 (94%) of which were for pleural effusions. Shunts migrated into the chest wall/amniotic cavity or into the thorax among 7/18 (39%) and 11/18 (61%) fetuses, respectively. Eleven (61%) fetuses were initially hydropic, which resolved in 8 (72%) cases. Effusions were bilateral in 9 (50%), amnioreduction was required in 6 (33%), and fetal rotation in 8 cases (44%). Four (22%) fetuses underwent repeat shunting, 12 (67%) neonates required ventilatory support, and 2 (11%) neonates required chest tubes. There was no significant difference in technical factors or outcomes between infants with shunts that dislodged and those that did not. Among 11 intrathoracic shunts, 2 (18%) were removed postnatally and the remainder are in situ without any shunt-related or respiratory complications over a follow-up period of 9 months to 22 years. CONCLUSION: TAS dislodged antenatally in 8.5% of fetuses, with 2/3 of shunts migrating into the thorax, and nearly 25% requiring re-shunting. Retained intrathoracic shunts were well tolerated and may not necessarily require surgical removal after birth.