Postnatal serum IGF-1 levels associate with brain volumes at term in extremely preterm infants.

BACKGROUND: Growth factors important for normal brain development are low in preterm infants. This study investigated the link between growth factors and preterm brain volumes at term. MATERIAL/METHODS: Infants born <28 weeks gestational age (GA) were included. Endogenous levels of insulin-like growth factor (IGF)-1, brain-derived growth factor, vascular endothelial growth factor, and platelet-derived growth factor (expressed as area under the curve [AUC] for serum samples from postnatal days 1, 7, 14, and 28) were utilized in a multivariable linear regression model. Brain volumes were determined by magnetic resonance imaging (MRI) at term equivalent age. RESULTS: In total, 49 infants (median [range] GA 25.4 [22.9-27.9] weeks) were included following MRI segmentation quality assessment and AUC calculation. IGF-1 levels were independently positively associated with the total brain (p < 0.001, ß = 0.90), white matter (p = 0.007, ß = 0.33), cortical gray matter (p = 0.002, ß = 0.43), deep gray matter (p = 0.008, ß = 0.05), and cerebellar (p = 0.006, ß = 0.08) volume adjusted for GA at birth and postmenstrual age at MRI. No associations were seen for other growth factors. CONCLUSIONS: Endogenous exposure to IGF-1 during the first 4 weeks of life was associated with total and regional brain volumes at term. Optimizing levels of IGF-1 might improve brain growth in extremely preterm infants. IMPACT: High serum levels of insulin-like growth factor (IGF)-1 during the first month of life were independently associated with increased total brain volume, white matter, gray matter, and cerebellar volume at term equivalent age in extremely preterm infants. IGF-1 is a critical regulator of neurodevelopment and postnatal levels are low in preterm infants. The effects of IGF-1 levels on brain development in extremely preterm infants are not fully understood. Optimizing levels of IGF-1 may benefit early brain growth in extremely preterm infants. The effects of systemically administered IGF-1/IGFBP3 in extremely preterm infants are now being investigated in a randomized controlled trial (Clinicaltrials.gov: NCT03253263).

Low fraction of fetal haemoglobin is associated with retinopathy of prematurity in the very preterm infant.

BACKGROUND: Blood loss and adult blood transfusions are common during the neonatal period in preterm infants. The objective of the study was to clarify if degree of loss of fetal haemoglobin (HbF) was associated with later retinopathy of prematurity (ROP). METHODS: Retrospective observational cohort study. In total, 452 infants born <30 gestational weeks at a tertiary level neonatal intensive care unit in Sweden in 2009-2015 were included, 385 of whom had final ROP outcome. Mean fractions of HbF (%) during the first postnatal week were calculated from 11 861 arterial blood gas analyses. The relationship between fractions of HbF (%) and ROP was evaluated. RESULTS: The mean (SD) gestational age (GA) at birth was 26.4 (1.8) weeks. In total, 104 (27 %) infants developed ROP. Higher fraction of HbF (%) was associated with a lower prevalence of ROP, OR by a 10% increase 0.83 (95% CI: 0.71 to 0.97; p=0.019), following adjustment for GA at birth, small for GA and sex. Infants with HbF (%) in the lowest quartile had OR of 22.0 (95% CI: 8.1 to 59.2; p<0.001) for ROP development compared with those in the highest quartile. The predictive ability (area under the curve) of HbF (%) in the full model during the first week was 0.849 for ROP. CONCLUSIONS: Early low fraction of HbF is independently associated with abnormal retinal neurovascular development in the very preterm infant. The potential benefit of minimising blood loss on development of ROP will be investigated in a multicenter randomised trial (NCT04239690).

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial.

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.

Fetal haemoglobin and bronchopulmonary dysplasia in neonates: an observational study.

OBJECTIVE: Early decrease in fetal haemoglobin (HbF) is an indicator of loss of endogenous blood components that might have predictive value for development of bronchopulmonary dysplasia (BPD). The link between HbF and BPD has not been evaluated. DESIGN: Retrospective observational study. SETTING: Tertiary level neonatal intensive care unit, referral centre for Southern Sweden. PATIENTS: 452 very preterm infants (<30 gestational weeks) born 2009-2015. INTERVENTIONS: Regular clinical practice. MAIN OUTCOME MEASURES: Mean HbF, haemoglobin (Hb) and partial oxygen pressure (PaO2) levels calculated from 11 861 arterial blood gas analyses postnatal week 1. Relationship between HbF (%) and BPD (requirement of supplemental oxygen at 36 weeks' postmenstrual age) and the modifying influence of PaO2 (kPa) and total Hb (g/L) was evaluated. RESULTS: The mean gestational age (GA) at birth was 26.4 weeks, and 213 (56%) infants developed BPD. A 10% increase in HbF was associated with a decreased prevalence of BPD, OR 0.64 (95% CI 0.49 to 0.83; p<0.001). This association remained when adjusting for mean PaO2 and Hb. Infants with an HbF in the lowest quartile had an OR of 27.1 (95% CI 11.6 to 63.4; p<0.001) for development of BPD as compared with those in the highest quartile. The area under the curve for HbF levels and development of BPD in the full statistical model was 0.871. CONCLUSIONS: Early rapid postnatal decline in HbF levels was associated with development of BPD in very preterm infants. The association between HbF and BPD was not mediated by increased oxygen exposure. The potential benefit of minimising loss of endogenous blood components on BPD outcome will be investigated in a multicentre randomised trial.

Docosahexaenoic Acid and Arachidonic Acid Levels Are Associated with Early Systemic Inflammation in Extremely Preterm Infants.

Fetal and early postnatal inflammation have been associated with increased morbidity in extremely preterm infants. This study aimed to demonstrate if postpartum levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) were associated with early inflammation. In a cohort of 90 extremely preterm infants, DHA and AA in cord blood, on the first postnatal day and on postnatal day 7 were examined in relation to early systemic inflammation, defined as elevated C-reactive protein (CRP) and/or interleukin-6 (IL-6) within 72 h from birth, with or without positive blood culture. Median serum level of DHA was 0.5 mol% (95% CI (confidence interval) 0.2-0.9, P = 0.006) lower than the first postnatal day in infants with early systemic inflammation, compared to infants without signs of inflammation, whereas levels of AA were not statistically different between infants with and without signs of inflammation. In cord blood, lower serum levels of both DHA (correlation coefficient -0.40; P = 0.010) and AA (correlation coefficient -0.54; p < 0.001) correlated with higher levels of IL-6. Levels of DHA or AA did not differ between infants with and without histological signs of chorioamnionitis or fetal inflammation. In conclusion, serum levels of DHA at birth were associated with the inflammatory response during the early postnatal period in extremely preterm infants.

Neonatal clinical blood sampling led to major blood loss and was associated with bronchopulmonary dysplasia.

AIM: Studies indicate that reduced foetal haemoglobin levels are related to increased neonatal morbidity rates. This study investigated the relationships between sampling-related blood loss and adult blood transfusions administered during postnatal days 1-14 and the development of severe neonatal morbidities in extremely preterm infants born before 28 weeks of gestation. METHODS: The medical files of 149 extremely preterm infants born at two university hospitals in Sweden from 2013 to 2018 were investigated. RESULTS: Blood sampling resulted in a 58% depletion of the endogenous blood volume postnatal days 1-14 (median 40.4 mL/kg, interquartile range 23.9-53.3 mL/kg) and correlated with the adult erythrocyte transfusion volume (rS  = 0.870, P < .001). Sampling-related blood loss on postnatal days 1-7, adjusted for gestational age at birth and birth weight standard deviation score, was associated with the development of bronchopulmonary dysplasia (BPD) (odds ratio by a 10-unit increase 2.4, 95% confidence interval 1.1-5.4) (P = .03). No associations were found between blood sampling and intraventricular haemorrhage or necrotising enterocolitis in the full statistical model. The largest proportion of sampling-related blood was used for blood gas analyses (48.7%). CONCLUSION: Diagnostic blood sampling led to major endogenous blood loss replaced with adult blood components and was associated with the development of BPD.