Arachidonic acid and docosahexaenoic acid levels correlate with the inflammation proteome in extremely preterm infants.

BACKGROUND & AIM: Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants. METHODS: A retrospective exploratory study of infants (n = 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center. RESULTS: On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-modulating cytokines IL-6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period. CONCLUSIONS: This study supports postnatal non-antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population. CLINICAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03201588).

Human milk derived fortifiers are associated with glucose, phosphorus, and calcium derangements.

OBJECTIVE: In 2017, our Level IV NICU switched from providing bovine-derived (BOV-fort) to human milk-derived fortifiers (HM-fort) and donor human milk (DHM) to premature infants born ≤ 30 weeks or ≤1250 g. Following this change, providers anecdotally observed increased hypoglycemia, hypercalcemia, and hyperphosphatemia. This study investigated potential laboratory differences between infants fed Bovine vs. Human milk derived fortifier. METHODS: Lab measurements from 402 infants (232 BOV-fort, 170 HM-fort) born between 2015 and 2019 were compared between groups. RESULTS: The proportion of infants ever having a blood glucose ≤ 45 mg/dL (p < 0.0001) was higher in the HM-fort group. The proportion of infants ever experiencing a phosphorus > 8.0 mg/dL were higher in the HM-fort group (p < 0.0001). The proportion of infants ever experiencing calcium > 11.4 mg/dL was higher in the HM-Fort group (p = 0.019). CONCLUSIONS: Provision of HM-Fort and DHM to extremely premature infants is associated with metabolic derangements.

Prevalence and Implications of Low Reticulocyte-Hemoglobin Levels among Extreme Preterm Neonates: A Single-Center Retrospective Study.

This retrospective cohort study aims to determine the epidemiology of iron deficiency among extreme preterm neonates and the association of iron-deficient status during the NICU stay with neurodevelopmental outcomes at 18−24 months. Neonates ≤29 weeks gestational age (GA) born between June 2016 and December 2019, who received routine iron supplementation were enrolled. Iron deficiency was defined as reticulocyte−hemoglobin (Ret-Hb) levels ≤ 29 pg at 36 weeks corrected age. A subcohort of neonates completed standardized developmental assessment at 18−24 months corrected age. Significant neurodevelopmental impairment (sNDI) was defined as either Bayley Scales of Infant Development score < 70 or cerebral palsy or blindness or hearing aided. Among a cohort of 215 neonates [GA 25.8 (1.7) weeks, birthweight 885 (232) g], prevalence of iron deficiency was 55%, 21%, 26%, and 13%, in neonates <24 weeks, 24−25 + 6 weeks, 26−27 + 6 weeks, and ≥ 28 weeks GA, respectively. Male sex and receipt of corticosteroid therapy were associated with iron-deficiency. In the subcohort analysis (n = 69), there was no statistically significant association between Ret-Hb levels at 36 weeks corrected age and the risk of sNDI [OR 0.99 (95% CI 0.85−1.2)]. Male infants and those who received postnatal corticosteroids are likely to have iron-limited erythropoiesis at corrected term despite routine iron-supplementation; however, low Ret-Hb levels during the neonatal period were not associated with significant neurological disability in early childhood.

Sphingolipidomics of serum in extremely preterm infants: Association between low sphingosine-1-phosphate levels and severe retinopathy of prematurity.

BACKGROUND: Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP) that can cause impaired vision or blindness. Changes in blood lipids have been associated with ROP. This study aimed to monitor longitudinal changes in the serum sphingolipidome of extremely preterm infants and investigate the relationship to development of severe ROP. METHODS: This is a prospective study that included 47 infants born <28 gestational weeks. Serum samples were collected from cord blood and at postnatal days 1, 7, 14, and 28, and at postmenstrual weeks (PMW) 32, 36, and 40. Serum sphingolipids and phosphatidylcholines were extracted and analyzed by LC-MS/MS. Associations between sphingolipid species and ROP were assessed using mixed models for repeated measures. RESULTS: The serum concentration of all investigated lipid classes, including ceramide, mono- di- and trihexosylceramide, sphingomyelin, and phosphatidylcholine displayed distinct temporal patterns between birth and PMW40. There were also substantial changes in the lipid species composition within each class. Among the analyzed sphingolipid species, sphingosine-1-phosphate showed the strongest association with severe ROP, and this association was independent of gestational age at birth and weight standard deviation score change. CONCLUSIONS: The serum phospho- and sphingolipidome undergoes significant remodeling during the first weeks of the preterm infant's life. Low postnatal levels of the signaling lipid sphingosine-1-phosphate are associated with the development of severe ROP.

Dramatic changes in blood protein levels during the first week of life in extremely preterm infants.

BACKGROUND: Preterm birth and its complications are the primary cause of death among children under the age of 5. Among the survivors, morbidity both perinatally and later in life is common. The dawn of novel technical platforms for comprehensive and sensitive analysis of protein profiles in blood has opened up new possibilities to study both health and disease with significant clinical accuracy, here used to study the preterm infant and the physiological changes of the transition from intrauterine to extrauterine life. METHODS: We have performed in-depth analysis of the protein profiles of 14 extremely preterm infants using longitudinal sampling. Medical variables were integrated with extensive profiling of 448 unique protein targets. RESULTS: The preterm infants have a distinct unified protein profile in blood directly at birth regardless of clinical background; however, the pattern changed profoundly postnatally, expressing more diverse profiles only 1 week later and further on up to term-equivalent age. Clusters of proteins depending on temporal trend were identified. CONCLUSION: The protein profiles and the temporal trends here described will contribute to the understanding of the physiological changes in the intrauterine-extrauterine transition, which is essential to adjust early-in-life interventions to prone a normal development in the vulnerable preterm infants. IMPACT: We have performed longitudinal and in-depth analysis of the protein profiles of 14 extremely preterm infants using a novel multiplex protein analysis platform. The preterm infants had a distinct unified protein profile in blood directly at birth regardless of clinical background. The pattern changed dramatically postnatally, expressing more diverse profiles only 1 week later and further on up to term-equivalent age. Certain clusters of proteins were identified depending on their temporal trend, including several liver and immune proteins. The study contributes to the understanding of the physiological changes in the intrauterine-extrauterine transition.

Hypothyroxinemia Detected at 4 Weeks of Life in Preterm Infants Born at Less than 30 Weeks of Gestation.

OBJECTIVE: Data on free thyroxine (FT4) concentrations beyond first 2 weeks of preterm infants are limited. This study was aimed to describe the association between perinatal characteristics and FT4 concentrations and the incidence of hypothyroxinemia at 4 weeks. STUDY DESIGN: Retrospective analysis of serum thyroid function tests at 4 weeks in preterm infants <30 weeks of gestation. Association between FT4 at 4 weeks of life and perinatal characteristics were determined by bivariate analysis and multivariable regression. Incidence of hypothyroxinemia was determined using a gestational age adjusted definition based on in utero levels at the equivalent postmenstrual age. RESULTS: The study cohort consisted of 280 infants. FT4 concentrations at 4 weeks of life were significantly associated with gestational age, birth weight, gender, and maternal history of thyroid disease. Hypothyroxinemia was found in 32.8% of the study cohort. CONCLUSION: Perinatal characteristics are associated with FT4 concentrations at 4 weeks of life. Nearly one-third of infants born <30 weeks had hypothyroxinemia at 4 weeks of life when compared with in utero levels at the equivalent postmenstrual age.

Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants.

BACKGROUND: Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia. METHODS: We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity. RESULTS: A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively. CONCLUSIONS: In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

Exacerbated mini-puberty of infancy in an ex-extreme preterm girl.

Vaginal bleeding can occur shortly after delivery in 3%-5% of newborns as a consequence of placental hormone withdrawal . Although usually benign, its differential diagnosis includes central precocious puberty, tumours and other pathological conditions. A girl born at 26 weeks of gestation presented with five episodes of vaginal bleeding, each lasting less than a week, initiated at 4 months of age. Luteinising hormone and oestradiol levels were in the pubertal range. Later, she exhibited breast development, with no other pubertal signs. An ultrasonography test revealed an impregnated endometrium and a right ovarian cyst with 43 mm of diameter. A cranioencephalic MRI was unremarkable. Clinicians adopted expectant management and there was clinical, hormonal and radiological resolution in 3 months. The spontaneous resolution suggested mini-puberty of infancy. This is usually an asymptomatic condition, but to date, four cases of an exacerbated form in extremepremature infants have been reported. Long-term follow-up data are missing.A girl born at 26 weeks of gestation presented with five episodes of vaginal bleeding, each lasting less than a week, initiated at 4 months of age. Luteinising hormone and oestradiol levels were in the pubertal range. Later, she exhibited breast development, with no other pubertal signs. An ultrasonography test revealed an impregnated endometrium and a right ovarian cyst with 43 mm of diameter. A cranioencephalic MRI was unremarkable. Clinicians adopted expectant management and there was clinical, hormonal and radiological resolution in 3 months. The spontaneous resolution suggested mini-puberty of infancy. This is usually an asymptomatic condition, but to date, four cases of an exacerbated form in extremepremature infants have been reported. Long-term follow-up data are missing.

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.

Effect of repeat transfusion exposure on plasma cytokine and markers of endothelial activation in the extremely preterm neonate.

BACKGROUND: Very preterm newborns receive up to three to five red blood cell (RBC) transfusions, often early, after birth. Despite awareness of the association of transfusion with increases in cytokines and markers of endothelial activation, research has focused on single transfusions weeks after birth. With pathophysiologic processes contributing to the development of morbidities starting soon after delivery, we investigated the response to early, repeated transfusion exposure. STUDY DESIGN AND METHODS: Three consecutive transfusion exposures were studied in transfusion-naive infants less than 30 weeks' gestation (n = 46). Plasma cytokines and markers of endothelial activation were measured before and 2 to 4 hours after transfusion by multiplex enzyme-linked immunosorbent assay. RESULTS: The median (IQR) age was 3 (1-9) days at first transfusion, 7 (3-20) days at the second, and 18 (7-28) days at the third. Baseline concentrations did not differ between the three transfusions. Interleukin (IL)-17A and tumor necrosis factor (TNF)-α did not change after the first transfusion but increased after the second (P < .05) and third transfusions (P < .01). While IL-1ß, IL-6, and IL-8 concentrations did not differ after the first and second transfusions, all increased after the third (IL-1ß, P < .01; IL-6, P < .01; IL-8, P < .05). The magnitude of posttransfusion increase in IL-1ß, IL-17A, and TNF-α increased between the first and third transfusion exposure. CONCLUSION: Early, repeated transfusion results in alterations in proinflammatory cytokines and markers of endothelial activation in the very preterm newborn and suggests that the potential for transfusion-related immunomodulation is present in the initial days after birth rather than confined to later in the postnatal period.

Inflammatory predictors of neurobehavior in very preterm infants.

BACKGROUND: Preterm infants are at risk for impaired neurodevelopment. Inflammation may be an important modifiable mediator of preterm birth and neurodevelopmental impairment, but few studies have examined longitudinal measures of inflammation. OBJECTIVE: To determine the relationship between longitudinal measures of inflammation and neurobehavior in very preterm infants. STUDY DESIGN: Non-experimental, repeated measures cohort study. METHODS: Very preterm infants were enrolled between October 2017 and December 2018. Blood was collected weekly until 35 weeks post-menstrual age for the quantification of plasma cytokines. Neurobehavior was assessed at 35 weeks post-menstrual age using the cluster scores for motor development and vigor and alertness/orientation from the Neurobehavioral Assessment of the Preterm Infant. Multiple linear regression models with robust standard errors were used to analyze the data. Average levels of individual cytokines, cytokine trends, and composite scores were used as measures of inflammation. RESULTS: Seventy-three infants were enrolled in the study. Interleukin-1 receptor antagonist was associated with motor development and vigor scores. Interleukin-6 was associated with alertness/orientation scores. Tumor necrosis factor-alpha and composite scores of inflammation were associated with motor development and vigor and alertness/orientation scores. There were interactions with post-menstrual age at birth and infant sex. CONCLUSION: Inflammation may be an important predictor of short-term neurobehavior in preterm infants. Interleukin-1 receptor antagonist, interleukin-6, and tumor necrosis factor-alpha are key cytokines for studies of preterm infants, but composite scores may be a better measure of inflammation than individual cytokines. Inflammation can be damaging to the immature brain and may be a specific target for future interventions to improve outcomes.

Circulating Forms of B-Type Natriuretic Peptide in Very Preterm Infants.

BACKGROUND: B-type natriuretic peptide (BNP) is a cardiac hormone released with an N-terminal fragment (NTproBNP) under conditions of ventricular pressure or volume overload. BNP has been proposed for use as a biomarker of cardiac dysfunction in premature infants in the setting of hemodynamically significant patent ductus arteriosus (HsPDA) and bronchopulmonary dysplasia (BPD). In adult settings the presence of proBNP and glycosylated isoforms may affect assay interpretation. However, there are limited data on how immature preterm physiology may affect BNP or NTproBNP levels and no published data on post-translational BNP processing in premature infants. METHODS: Pooled serial plasma samples from preterm infants born at less than 30 weeks gestation were analyzed for BNP congeners using Luminex® assay and high performance liquid chromatography. Samples were grouped according to clinical status: Group 1, no HsPDA and no BPD, Group 2 HsPDA and no/mild BPD, Group 3 HsPDA and moderate/severe BPD. RESULTS: Plasma from 15 infants was analyzed, and across all three groups NTproBNP predominated with minimal amounts of other isoforms; no glycosylation was detected. CONCLUSIONS: NTproBNP appears to be the predominant isoform across each of our clinical groups in our pooled sample analysis with no evidence of significant glycosylation. This suggests NTproBNP is likely to be a robust marker in this clinical setting.

Neonatal hyperglycemia in a preterm infant managed with a subcutaneous insulin pump.

PURPOSE: Successful use of a subcutaneous insulin pump to administer regular insulin to a preterm infant with neonatal hyperglycemia is described. SUMMARY: A 520-g female infant born at 23 weeks' gestational age via caesarian section was noted to have elevated blood glucose concentrations ranging up to 180 mg/dL (in SI units, 10 mmol/L) on day of life (DOL) 3 and peaking on DOL 9 at 250 mg/dL (13.9 mmol/L) despite conservative glucose infusion rates. Continuous infusion of regular insulin was begun on DOL 8 and continued through DOL 44, with an average insulin infusion rate of 0.08 units/kg/h. The patient experienced blood glucose concentration lability due to multiple factors, resulting in the need for frequent and routine blood glucose concentration monitoring to minimize hypoglycemia events. On DOL 44, a subcutaneous insulin pump was placed and used to provide diluted regular insulin (25 units/mL). After 1 week, the patient's blood glucose concentration normalized, which led to a reduction in the frequency of glucose monitoring. After 3 weeks, insulin pump use was discontinued. The patient remained euglycemic thereafter. CONCLUSION: The use of an insulin pump resulted in decreased blood glucose checks, discontinuation of central line access, and overall better patient care.

Effect of fluctuation of oxygenation on the development of severe retinopathy of prematurity in extremely preterm infants.

OBJECTIVE: To investigate factors associated with development of severe retinopathy of prematurity (ROP) in extremely preterm (EP) infants. STUDY DESIGN: This retrospective cohort study included 213 EP infants (22 + 0 to 27 + 6 weeks gestation) who were admitted to the neonatal intensive care unit of Osaka Women's and Children's Hospital between 2009 and 2017. Multivariable logistic regression analysis was used to identify neonatal factors associated with severe ROP requiring treatment. RESULT: After adjustments for gestational age (GA), birth weight, sex, red blood cell transfusion, average SpO2, and fluctuations of SpO2 from birth to 32 weeks postmenstrual age, fluctuations of SpO2 (odds ratio [OR]: 2.10, 95% confidence interval [CI]: 1.03-4.27), and low GA (OR: 0.95, 95% CI: 0.91-0.98) were significantly associated with severe ROP. CONCLUSIONS: Fluctuations of SpO2 from birth to 32 weeks postmenstrual age and low GA were significantly associated with development of severe ROP requiring treatment in EP infants.

Renal functional markers in extremely premature infants with and without twin-twin transfusion syndrome.

OBJECTIVE: Describe renal function of preterm infants <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) who received laser therapy. DESIGN: Retrospective analysis of premature TTTS compared with dichorionic-diamniotic (di-di) twins from 2006 to 2015. Primary outcome was biomarkers of renal injury. RESULTS: Thirty-three TTTS-laser and 101 di-di newborns with similar GA at birth (26.4 ± 1.4 vs 26.9 ± 1.6 weeks, p = 0.07) were included. Creatinine and urea levels were higher in TTTS-laser group at day of life (DOL) 2-7 (123.5 ± 12.4 vs 75.8 ± 2 µmol/L, p = 0.0001 and 11.9 ± 1.1 mmol/L vs 8.7 ± 0.3 mmol/L, p = 0.0001) and DOL 8-14, (98.1 ± 14.2 vs 64.8 ± 2.3 µmol/L, p = 0.0001 and 9.1 ± 1.2 vs 5.4 ± 0.3 mmol/L, p = 0.0001). There was a significant effect of TTTS status on creatinine level at DOL 8-14. CONCLUSION: In extremely preterm with TTTS treated by laser, biomarkers of renal function were higher compared with di-di twins in the first 2 weeks of life.

The accuracy of transcutaneous bilirubinometry in preterm infants.

OBJECTIVE: To evaluate the correlation between total serum and transcutaneous bilirubin and to determine the reliability of transcutaneous bilirubinometry for screening and monitoring of neonatal jaundice among preterms. STUDY DESIGN: Ninety nine infants with gestational ages ≤34 weeks were prospectively enrolled. Babies were classified into three groups as; 24-28, 29-31, and 32-34 weeks. Total serum bilirubin and simultaneous transcutaneous bilirubin were measured before the onset of phototheraphy, during and at 24 h after discontinuing phototherapy. RESULTS: Total serum bilirubin significantly correlated with transcutaneous bilirubin in the whole cohort (r = 0.867, p < 0.001) and in each group before, during and after phototheraphy. Hypotension was the only variable which effects the difference between two methods at postnatal first day of life (p = 0.039). CONCLUSION: Transcutaneous bilirubin levels were highly correlated with total serum bilirubin levels even in 24-28 GW babies. Transcutaneous bilirubin may be useful for screening and monitoring of jaundice in very preterm newborns.

Rate of rise of total serum bilirubin in very low birth weight preterm infants.

BACKGROUND: To assess the postnatal rate of rise (ROR) of total serum bilirubin (TSB) in very low birth weight (VLBW) preterm infants, to determine risk factors associated with a rapid rise (>90th percentile), and to compare ROR and hour-specific TSB at postnatal 12-48 h with data of term infants retrieved from the literature. METHODS: Retrospective analysis of 2430 routine TSB concentrations obtained between birth and initiation of phototherapy in 483 VLBW infants. RESULTS: TSB increased by a median (interquartile range) ROR of 0.15 (0.11-0.19) mg/dL/h. The 50th percentile of TSB was below the 40th percentile of (near-)term counterparts at 12-48 h. TSB ROR correlated with the age at initiation (RS = -0.687; p < 0.001) and the duration (RS = 0.444; p < 0.001) of phototherapy. ROR >90th percentile (>0.25 mg/dL/h) was associated with lower gestational ages [27.2 (25.4-29.3) vs. 28.4 (26.4-30.4) weeks], lower birth weights [978 (665-1120) vs. 1045 (814-1300) g], and lower 5-min Apgar scores [7 (7-8) vs. 8 (7-9)]. CONCLUSION: ROR of TSB is an indicator for early and prolonged phototherapy. While hour-specific TSB and ROR at 12-48 h are lower than those reported for (near-)term infants, TSB appears to rise more rapidly in infants with low gestational age, low birth weight, and low 5-min Apgar score.

Plasma unbound free fatty acid profiles in premature infants before and after intralipid infusion.

Background: Unbound free fatty acids (FFAu) are the bioactive fraction of plasma free fatty acids (FFA). Most plasma FFA are bound to albumin. Only when FFA dissociate from albumin, do they become biologically active.Objective: To measure the first FFAu profiles in human infants and to measure these profiles before and during intravenous administration of the soybean lipid, intralipid (IL).Study design: The study population was 16 premature infants, from a parent study of 130 infants with birth weights 500-2000 g and gestational age 23-34 weeks. The infants chosen had plasma samples of ≥120 µL (volume needed for each FFAu profile measurement) in the first day of life. Infants received IL infusions starting in the second day of life at 1 g/kg/day, increasing by 1-g/kg/day daily up to 3 g/kg/day. FFAu profiles were determined during IL infusion when plasma was available. Profiles are the concentrations of the nine most abundant long-chain FFAu and were determined using novel fluorescent probes.Results: Before intralipid infusion unbound myristic acid was the dominant FFAu, as high as 78% of the total FFAu (sum of the 9 FFAu). In contrast, unbound linoleic acid was 0% in all infants. With increasing infusion of IL to 3 g/kg/day, unbound linoleic increased to 26% of the total FFAu, with unbound oleic, myristic, and linolenic acid the second, third and fourth most abundant. The average total FFAu concentration also increased from 4 nM before intralipid to 53 nM at 3 g/kg/day. During IL infusion the FFAu profiles approached the fatty acid composition of intralipid at 3 g/kg/day.Conclusions: This first study of FFAu profiles in neonates revealed that before IL infusion unbound linoleic acid was zero in all 16 infants and levels of myristic acid were exceptionally large, as much as 78% of the total FFAu profile. These results suggest important and previously unrecognized roles of lipid metabolism in early development. Zero unbound linoleic acid before IL infusion may help promote closure of the ductus arteriosus but after IL infusion, synthesis of arachidonic from linoleic acid may tend to promote patency. The high levels of unbound myristate may be needed for immediate neonatal energy needs.

Hypoxia with acidosis in extremely preterm born infants was not associated with an increased risk of death or impaired neurodevelopmental outcome at 6.5 years.

AIM: It is not clear whether perinatal acidosis can predict poor outcomes in extremely preterm infants and we investigated associations between intrapartum hypoxia and mortality and neurodevelopmental outcomes. METHODS: We used nationwide data on 705 infants from the Extremely Preterm Infants in Sweden Study, delivered at 22-26 weeks of gestation during 2004-2007. Comprehensive neurodevelopmental assessments were performed on survivors at 2.5 (n = 456) and 6.5 (n = 441) years of corrected age. Gestational age-related changes in umbilical cord arterial pH were compared with reference values for term newborn infants, and base excess was also calculated. Associations between low blood gas values (<10th percentile) and mortality and neurodevelopmental outcome were estimated. RESULTS: Cord blood determination was more common in surviving infants (P < .001), with pH determined in 322/705 (46%) and base excess in 311/705 (44%). Extremely preterm infants had higher pH values than term infants (P < .0001), with no change from 22 to 26 weeks of gestation (P = .61, r2  = .001). Multiple logistic regression showed no association between low blood gas values and risk of death or neurodevelopmental impairment at 6.5 years (P ≥ .17). CONCLUSION: Hypoxia with acidosis at birth was not associated with an increased risk of death or impaired neurodevelopmental in extremely preterm born children at 6.5 years.