Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS).

Importance: Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective: To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants: This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions: Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures: Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results: A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and Relevance: In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Use of term reference infants in assessing the developmental outcome of extremely preterm infants: lessons learned in a multicenter study.

OBJECTIVE: Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital. STUDY DESIGN: Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age. RESULTS: We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds (O.R. = 1.86; [95% CI 1.56-2.23], especially for severe impairment (36% vs. 24%; p ≤ 0.001). Difficulty recruiting TR patients at 2 years extended the study by 14 months and affected their demographics. CONCLUSION: Impairment rates among EP infants appear to be substantially underestimated from Bayley III norms. These rates may be best assessed by comparison with healthy term infants followed with minimal attrition from birth in the same centers. GOV ID: Term Reference (under the Generic Database Study): NCT00063063.

Postnatal Leptin Levels Correlate with Breast Milk Leptin Content in Infants Born before 32 Weeks Gestation.

Perinatal leptin deficiency and reduced intake of mother's milk may contribute to the development of childhood obesity. Preterm infants have reduced leptin production, and they are at heightened risk of neonatal leptin deficiency. Because fresh human milk contains significantly more leptin than donor milk, we used a cross-over design to determine if blood leptin levels in maternal milk-fed preterm infants fall during conversion to donor human milk. Infants born between 22 0/7 and 31 6/7 weeks gestation on exclusive maternal milk feedings were enrolled into a 21-day cross-over trial. On days 1−7 and 15−21, infants were fed maternal milk, and on days 8−14, infants were fed donor milk. On day 1, study infants had a mean postmenstrual age of 33 weeks. Plasma leptin correlated with milk leptin, and leptin levels in maternal milk far exceed the leptin levels of donor milk. Plasma leptin did not increase during donor milk administration, but it did following resumption of maternal milk (p < 0.05). In this crossover trial, preterm infant blood leptin levels correlated with milk leptin content. This suggests that preterm infants can enterally absorb leptin from human milk, and leptin-rich breast milk may be a targeted therapy for the prevention of obesity.

The relationship of neurodevelopmental impairment to concurrent early childhood outcomes of extremely preterm infants.

OBJECTIVE: Determine how neurodevelopmental impairment (NDI) relates to concurrent outcomes for children born extremely preterm. STUDY DESIGN: Retrospective cohort study children born 22 0/7-26 6/7 weeks' gestation at NICHD Neonatal Research Network hospitals. Outcomes were ascertained at 18-22 months' corrected age. RESULT: Of 6562 children, 2618 (40%) died and 441 (7%) had no follow-up. Among the remaining 3483 children, 825 (24%), 1576 (45%), 657 (19%), and 425 (12%) had no, potential/mild, moderate, and severe NDI, respectively. Rehospitalization, respiratory medications, surgery, and medical support services were associated with greater NDI severity but affected >10% of children without NDI. Rehospitalization occurred in 40% of children with no NDI (mean (SD): 1.7 (1.3) episodes). CONCLUSION: Medical, functional, and social outcomes at 18-22 months' corrected age were associated with NDI; however, many children without NDI were affected. These data should contribute to counseling families and the design of studies for childhood outcomes beyond NDI.

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.).

Pituitary Glycoprotein Hormones in Human Milk before and after Pasteurization or Refrigeration.

Our aims were to investigate the presence of pituitary glycoprotein hormones in preterm and donor milk, and to examine the effects of Holder pasteurization and refrigeration on the levels of these hormones. We measured follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) in milk samples from mothers who delivered prematurely (n = 27) and in samples of mothers who delivered at term and donated milk to the Mother's Milk Bank of Iowa (n = 30). The gonadotropins and TSH were present in similar amounts within human milk produced for preterm and term infants. FSH increased 21% after refrigeration (p < 0.05), while LH declined by 39% (p < 0.05). Holder pasteurization decreased LH by 24% (p < 0.05) and increased TSH by 17% (p < 0.05). Holder pasteurization followed by refrigeration resulted in a 21% increase in FSH and a 41% decrease in LH (both p < 0.05), resulting in more than a 3-fold increase in donor milk FSH:LH ratios (p < 0.05 versus fresh donor milk). Despite structural similarities, the gonadotropins are differentially impacted by Holder pasteurization and refrigeration, and this results in marked alterations in the relative amount of FSH and LH that may be administered to preterm infants, potentially swinging hormonal balance towards ovarian hyperstimulation in females and hypogonadism in males.

Hormone levels in preterm and donor human milk before and after Holder pasteurization.

BACKGROUND: After birth, breastfeeding is the exclusive source of hormonal signaling between mother and infant. Hospitalized infants often receive donor milk when their own mother's milk is unavailable. METHODS: The presence of insulin, leptin, cortisol, progesterone, and testosterone was examined in samples from milk bank donors and mothers of preterm infants. We further investigated the effect of Holder pasteurization (HoP) on hormone levels. RESULTS: Comparing nonpasteurized samples, leptin levels were nearly threefold higher in milk from mothers of preterm infants versus donated milk, and regardless of milk source, leptin levels were significantly decreased by HoP. Insulin concentrations were also decreased by HoP, and among mothers of preterm infants, obesity was associated with significantly higher content of leptin and insulin. While combined use of donor milk and HoP was associated with cortisol levels nearly threefold higher than those in nonpasteurized own mother's milk, progesterone and testosterone content did not differ by source or pasteurization. CONCLUSIONS: The hormonal composition of breast milk is impacted by HoP and maternal obesity. Compared to nonpasteurized maternal milk, use of pasteurized donor milk dramatically decreases the intake of leptin while increasing the intake of cortisol. Further research is necessary to define optimal breast milk processing practices.

Origins of neonatal leptin deficiency in preterm infants.

BACKGROUND: Cord blood leptin increases with advancing gestation. Preterm delivery leads to premature separation from the maternal and placental leptin source predisposing infants to postnatal leptin deficiency, but this has not been fully described. METHOD: Blood leptin levels were measured for infants born before 33 weeks gestation daily for the first 2 days, then weekly until 36 weeks postmenstrual age (PMA). Cord blood was obtained to provide gestational age (GA)-specific standards. RESULTS: Cord blood leptin levels were positively associated with GA at birth, maternal body mass index (BMI) and pregnancy weight gain (all P < 0.05). Following birth, infant leptin levels decreased rapidly (74% decrease within 48 h). The extent of this decline correlated with GA (P < 0.05). Postnatal leptin began to increase by 33-36 weeks PMA, but remained below cord blood leptin levels (P < 0.01). At 36 weeks PMA, leptin levels were influenced by infant's weight and sex (P < 0.01), with females having higher leptin levels (1213 pg/ml vs. 984, P < 0.05). CONCLUSION: Cord blood leptin is influenced by maternal weight gain and BMI, suggesting an important role for trans-placental leptin delivery. Preterm delivery leads to sustained leptin deficiency through 36 weeks PMA, with the most premature male infants facing the longest and harshest deficiency.

Body temperatures of very low birth weight infants on admission to a neonatal intensive care unit.

OBJECTIVE: Hypothermia occurs frequently in the first minutes after birth in preterm infants. Hyperthermia also occurs, often as a consequence of efforts to provide thermal support. Both hypothermia and hyperthermia are potentially harmful. Our objective was to examine the distribution of admission temperatures of very low birth weight (VLBW) infants, the effect of gestational age on admission temperatures, and the time required for correction of low temperatures. METHODS: Admission axillary temperatures were retrieved from the medical records for all VLBW infants born in our hospital during a 5-year period. The temperatures were classified as severe (<35.0 °C), moderate (35.0-35.9 °C), or mild (36.0-36.4 °C) hypothermia, normothermia (36.5-37.4 °C), or hyperthermia (≥37.5 °C). The relationship between gestational age and admission temperature was examined. In addition, we analyzed the time required for normalization of low temperatures. RESULTS: Overall, 12% of infants were severely hypothermic, 40% moderately hypothermic, 27% mildly hypothermic, 19% normothermic, and 2% hyperthermic. Gestational age was inversely related to hypothermia risk and to the time required for recovery to normothermia. CONCLUSION: Admission hypothermia is common among VLBW infants and is affected by gestational age.

Temporal Artery Temperature Measurement in the Neonate.

Objective We compared an infrared temporal artery thermometer with our clinical standard axillary thermometer for temperature measurements in neonatal patients. Study Design We measured temporal artery (Tta), axillary (Tax, clinical standard), and rectal (Tr, gold standard) temperatures of 49 infants. The difference between Tr and Tta was compared with that between Tr and Tax, and the data were analyzed based on bed type and postmenstrual age. Results The mean Tta, Tax, and Tr were 37.16 (SD 0.36) °C, 36.61 (SD 0.30) °C, and 36.82 (SD 0.30) °C, respectively. The measurements by these methods were all significantly different. The mean Tr-Tax was 0.21 (SD 0.26) °C, and the mean Tr-Tta was -0.34 (SD 0.37) °C, indicating that Tax was closer to Tr than was Tta (p < 0.0001). Tta agreed more closely with Tr for infants in cribs than for those in incubators. Adjusting for bed type and body weight, with each week of postmenstrual age, the discrepancy between Tr-Tta and Tr-Tax decreased by 0.005°C (p = 0.034). Conclusion Compared with the gold standard, Tr, Tta is not more accurate than Tax. The temporal artery thermometer was less accurate for infants in incubators than for infants in cribs. The accuracy of temporal artery temperature increased with postmenstrual age.

Genome-wide association study of sepsis in extremely premature infants.

OBJECTIVE: To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants. STUDY DESIGN: Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10-5. Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. RESULTS: Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10-8); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values<0.001 and FDR<20%). CONCLUSIONS: No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.

Effect of Body Position on Energy Expenditure of Preterm Infants as Determined by Simultaneous Direct and Indirect Calorimetry.

Background Indirect calorimetry is the standard method for estimating energy expenditure in clinical research. Few studies have evaluated indirect calorimetry in infants by comparing it with simultaneous direct calorimetry. Our purpose was (1) to compare the energy expenditure of preterm infants determined by these two methods, direct calorimetry and indirect calorimetry; and (2) to examine the effect of body position, supine or prone, on energy expenditure. Study Design We measured energy expenditure by simultaneous direct (heat loss by gradient-layer calorimeter corrected for heat storage) and indirect calorimetry (whole-body oxygen consumption and carbon dioxide production) in 15 growing preterm infants during two consecutive interfeeding intervals, once in the supine position and once in the prone position. Results The mean energy expenditure for all measurements in both positions did not differ significantly by the method used: 2.82 (standard deviation [SD] 0.42) kcal/kg/h by direct calorimetry and 2.78 (SD 0.48) kcal/kg/h by indirect calorimetry. The energy expenditure was significantly lower, by 10%, in the prone than in the supine position, whether examined by direct calorimetry (2.67 vs. 2.97 kcal/kg/h, p < 0.001) or indirect calorimetry (2.64 vs. 2.92 kcal/kg/h, p = 0.017). Conclusion Direct calorimetry and indirect calorimetry gave similar estimates of energy expenditure. Energy expenditure was 10% lower in the prone position than in the supine position.

Parental Support for Language Development During Joint Book Reading for Young Children With Hearing Loss.

Parent and child joint book reading (JBR) characteristics and parent facilitative language techniques (FLTs) were investigated in two groups of parents and their young children; children with normal hearing (NH; n = 60) and children with hearing loss (HL; n = 45). Parent-child dyads were videotaped during JBR interactions, and parent and child behaviors were coded for specific JBR behaviors using a scale developed for this study. Children's oral language skills were assessed using the Preschool Language Scale-4 (PLS-4). Parents of children with HL scored higher on two of the four subscales of JBR: Literacy Strategies and Teacher Techniques. Parents of children with NH utilized higher level FLTs with their children who had higher language skills. Higher level FLTs were positively related to children's oral language abilities. Implications are discussed for professionals who work with families of very young children with HL.

Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth.

OBJECTIVE: Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage. METHODS: Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing. RESULTS: Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL. CONCLUSIONS: A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

Acute physiological effects of packed red blood cell transfusion in preterm infants with different degrees of anaemia.

OBJECTIVE: The safe lower limit of haematocrit or haemoglobin that should trigger a red blood cell (RBC) transfusion has not been defined. The objective of this study was to examine the physiological effects of anaemia and compare the acute responses to transfusion in preterm infants who were transfused at higher or lower haematocrit thresholds. METHODS: The authors studied 41 preterm infants with birth weights 500-1300 g, who were enrolled in a clinical trial comparing high ('liberal') and low ('restrictive') haematocrit thresholds for transfusion. Measurements were performed before and after a packed RBC transfusion of 15 ml/kg, which was administered because the infant's haematocrit had fallen below the threshold defined by study protocol. Haemoglobin, haematocrit, RBC count, reticulocyte count, lactic acid and erythropoietin were measured before and after transfusion using standard methods. Cardiac output was measured by echocardiography. Oxygen consumption was determined using indirect calorimetry. Systemic oxygen transport and fractional oxygen extraction were calculated. RESULTS: Systemic oxygen transport rose in both groups following transfusion. Lactic acid was lower after transfusion in both groups. Oxygen consumption did not change significantly in either group. Cardiac output and fractional oxygen extraction fell after transfusion in the low haematocrit group only. CONCLUSIONS: These study's results demonstrate no acute physiological benefit of transfusion in the high haematocrit group. The fall in cardiac output with transfusion in the low haematocrit group shows that these infants had increased their cardiac output to maintain adequate tissue oxygen delivery in response to anaemia and, therefore, may have benefitted from transfusion.

Determination of genetic predisposition to patent ductus arteriosus in preterm infants.

OBJECTIVE: Patent ductus arteriosus is a common morbidity associated with preterm birth. The incidence of patent ductus arteriosus increases with decreasing gestational age to approximately 70% in infants born at 25 weeks' gestation. Our major goal was to determine if genetic risk factors play a role in patent ductus arteriosus seen in preterm infants. METHODOLOGY: We investigated whether single-nucleotide polymorphisms in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation, and other processes are markers for persistent patency of ductus arteriosus. Initially, 377 single-nucleotide polymorphisms from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of <32 weeks. A family-based association test was performed on genotyping data to evaluate overtransmission of alleles. RESULTS: P values of <.01 were detected for genetic variations found in 7 genes. This prompted additional analysis with an additional set of 162 infants, focusing on the 7 markers with initial P values of <.01, and 1 genetic variant in the angiotensin II type I receptor previously shown to be related to patent ductus arteriosus. Of the initial positive signals, single-nucleotide polymorphisms in the transcription factor AP-2 beta and tumor necrosis factor receptor-associated factor 1 genes remained significant. Additional haplotype analysis revealed genetic variations in prostacyclin synthase to be associated with patent ductus arteriosus. An angiotensin II type I receptor polymorphism previously reported to be associated with patent ductus arteriosus after prophylactic indomethacin administration was not associated with the presence of a patent ductus arteriosus in our population. CONCLUSIONS: Overall, our data support a role for genetic variations in transcription factor AP-2 beta, tumor necrosis factor receptor-associated factor 1, and prostacyclin synthase in the persistent patency of the ductus arteriosus seen in preterm infants.

A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints.

BACKGROUND: Most neonates less than 1.0 kg birth weight need red blood cell (RBC) transfusions. Delayed clamping of the umbilical cord 1 minute after delivery transfuses the neonate with autologous placental blood to expand blood volume and provide 60 percent more RBCs than after immediate clamping. This study compared hematologic and clinical effects of delayed versus immediate cord clamping. STUDY DESIGN AND METHODS: After parental consent, neonates not more than 36 weeks' gestation were randomly assigned to cord clamping immediately or at 1 minute after delivery. The primary endpoint was an increase in RBC volume/mass, per biotin labeling, after delayed clamping. Secondary endpoints were multiple clinical and laboratory comparisons over the first 28 days including Score for Neonatal Acute Physiology (SNAP). RESULTS: Problems with delayed clamping techniques prevented study of neonates of less than 30 weeks' gestation, and 105 neonates 30 to 36 weeks are reported. Circulating RBC volume/mass increased (p = 0.04) and weekly hematocrit (Hct) values were higher (p < 0.005) after delayed clamping. Higher Hct values did not lead to fewer RBC transfusions (p > or = 0.70). Apgar scores after birth and daily SNAP scores were not significantly different (p > or = 0.22). Requirements for mechanical ventilation with oxygen were similar. More (p = 0.03) neonates needed phototherapy after delayed clamping, but initial bilirubin levels and extent of phototherapy did not differ. CONCLUSIONS: Although a 1-minute delay in cord clamping significantly increased RBC volume/mass and Hct, clinical benefits were modest. Clinically significant adverse effects were not detected. Consider a 1-minute delay in cord clamping to increase RBC volume/mass and RBC iron, for neonates 30 to 36 weeks' gestation, who do not need immediate resuscitation.

Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants.

OBJECTIVE: Although many centers have introduced more restrictive transfusion policies for preterm infants in recent years, the benefits and adverse consequences of allowing lower hematocrit levels have not been systematically evaluated. The objective of this study was to determine if restrictive guidelines for red blood cell (RBC) transfusions for preterm infants can reduce the number of transfusions without adverse consequences. DESIGN, SETTING, AND PATIENTS: We enrolled 100 hospitalized preterm infants with birth weights of 500 to 1300 g into a randomized clinical trial comparing 2 levels of hematocrit threshold for RBC transfusion. INTERVENTION: The infants were assigned randomly to either the liberal- or the restrictive-transfusion group. For each group, transfusions were given only when the hematocrit level fell below the assigned value. In each group, the transfusion threshold levels decreased with improving clinical status. MAIN OUTCOME MEASURES: We recorded the number of transfusions, the number of donor exposures, and various clinical and physiologic outcomes. RESULTS: Infants in the liberal-transfusion group received more RBC transfusions (5.2 +/- 4.5 [mean +/- SD] vs 3.3 +/- 2.9 in the restrictive-transfusion group). However, the number of donors to whom the infants were exposed was not significantly different (2.8 +/- 2.5 vs 2.2 +/- 2.0). There was no difference between the groups in the percentage of infants who avoided transfusions altogether (12% in the liberal-transfusion group versus 10% in the restrictive-transfusion group). Infants in the restrictive-transfusion group were more likely to have intraparenchymal brain hemorrhage or periventricular leukomalacia, and they had more frequent episodes of apnea, including both mild and severe episodes. CONCLUSIONS: Although both transfusion programs were well tolerated, our finding of more frequent major adverse neurologic events in the restrictive RBC-transfusion group suggests that the practice of restrictive transfusions may be harmful to preterm infants.