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.

Care from Birth to Discharge of Infants Born at 22 to 23 Weeks' Gestation.

The clinical care of infants born at 22 weeks' gestation must be well-designed and standardized if optimal results are to be expected. Although several approaches to care in this vulnerable population are possible, protocols should be neither random nor inconsistent. We describe the approach taken at the University of Iowa Stead Family Children's Hospital neonatal intensive care unit with respect to preterm infants born at 22 weeks' gestation. We have chosen to present our standardize care plan with respect to prenatal, neurologic, nutritional, gastrointestinal, and skin management. Respiratory and cardiopulmonary care will be briefly reviewed, as these strategies have been published previously.

Secular Trends in Patent Ductus Arteriosus Management in Infants Born Preterm in the National Institute of Child Health and Human Development Neonatal Research Network.

We evaluated changes in patent ductus arteriosus (PDA) diagnosis and treatment from 2012 through 2021 in a network of US academic hospitals. PDA treatment decreased among infants born at 26-28 weeks but not among infants born at 22-25 weeks. Rates of indomethacin use and PDA ligation decreased while acetaminophen use and transcatheter PDA closure increased.

Inflammatory Biomarker Profiles in Very Preterm Infants within the Context of Preeclampsia, Chorioamnionitis, and Clinically Diagnosed Postnatal Infection.

Preterm delivery can be precipitated by preeclampsia or infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (clinical chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22-32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. Independent of gestational age, MCP-1 was significantly increased (p < 0.001) in association with maternal preeclampsia, but MCP-1 was decreased (p < 0.01), and CRP was increased (p < 0.01) in the presence of chorioamnionitis with funisitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection, with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age, including over a 2-fold increase in MCP-1 among newborns of mothers with preeclampsia. Further, in those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants delivered for maternal indications.

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.

Neonatal Leptin Levels Predict the Early Childhood Developmental Assessment Scores of Preterm Infants.

Preterm infants have low circulating levels of leptin, a key trophic hormone that influences growth and development. While the clinical importance of prematurity-associated leptin deficiency is undefined, recent preclinical and clinical investigations have shown that targeted enteral leptin supplementation can normalize neonatal leptin levels. We tested the hypothesis that, independent of growth velocity, prematurity-related neonatal leptin deficiency predicts adverse cardiovascular and neurodevelopmental outcomes. In a planned 2-year longitudinal follow-up of 83 preterm infants born at 22 to 32 weeks' gestation, we obtained blood pressures from 58 children and the Ages & Stages Questionnaire (ASQ-3) for 66 children. Based on univariate analysis, blood pressures correlated with gestational age at birth (R = 0.30, p < 0.05) and weight gain since discharge (R = 0.34, p < 0.01). ASQ-3 scores were significantly higher in female than male children. Utilizing best subset regression with Mallows' Cp as the criterion for model selection, higher systolic blood pressure was predicted by rapid postnatal weight gain, later gestation at delivery and male sex (Cp = 3.0, R = 0.48). Lower ASQ-3 was predicted by lower leptin levels at 35 weeks postmenstrual age, earlier gestation at delivery and male sex (Cp = 2.9, R = 0.45). Children that had leptin levels above 1500 pg/mL at 35 weeks postmenstrual age had the highest ASQ-3 scores at 2 years. In conclusion, independent of growth velocity, higher leptin levels at 35 weeks' gestation are associated with better developmental assessment scores in early childhood. While longer-term follow-up of a larger cohort is needed, these findings support investigations that have suggested that targeted neonatal leptin supplementation could improve the neurodevelopmental outcomes of preterm infants.

Relationships between retinopathy of prematurity without ophthalmologic intervention and neurodevelopment and vision at 2 years.

BACKGROUND: Severe retinopathy of prematurity (ROP) is associated with adverse outcomes. Relationships between milder ROP and outcomes have not been defined. We hypothesized that children with ROP stage ≤3 who did not receive ophthalmologic intervention would have worse motor, cognitive, and language skills and more vision abnormalities than children without ROP. METHODS: This was a secondary analysis of a randomized trial evaluating the effects of myo-inositol on ROP in the NICHD Neonatal Research Network. Primary outcomes were Bayley Scales of Infant Development composite scores; secondary outcomes included behavioral difficulties and ophthalmologic measures. Outcomes were compared using adjusted linear or modified Poisson models. RESULTS: Of 506 children, 173 (34%) had no ROP, 262 (52%) had ROP stage ≤3 without intervention, and 71 (14%) had ROP with intervention. There was no difference in motor, cognitive, or language scores between children with ROP stage ≤3 without intervention and children without ROP. Children with ROP stage ≤3 without intervention had a higher rate of strabismus compared to children without ROP (p = 0.040). CONCLUSION: Children with ROP stage ≤3 without intervention did not have adverse neurodevelopmental outcomes at 2 years' corrected age compared to children without ROP but did have an increased incidence of strabismus. IMPACT: This study addresses a gap in the literature regarding the relationship between milder forms of retinopathy of prematurity (ROP) that regress without intervention and neurodevelopment and vision outcomes. Children with a history of ROP stage ≤3 without intervention have similar neurodevelopmental outcomes at 2 years' corrected age as children born extremely preterm without a history of ROP and better outcomes than children with a history of ROP with ophthalmologic intervention. Counseling about likely neurodevelopment and vision outcomes for children born extremely preterm with a history of ROP may be tailored based on the severity of ROP. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: Inositol to Reduce Retinopathy of Prematurity Trial: NCT01954082.

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.

Ventilator Management in Extremely Preterm Infants.

Advances in ventilation strategies for infants in the NICU have led to increased survival of extremely preterm infants. More than 75% of infants born at less than or equal to 27 weeks' gestation require initial mechanical ventilation for survival due to developmental immaturity of their lungs and respiratory drive. Various ventilators using different technologies and involving multiple management strategies are available for use in this population. Centers across the world have successfully used conventional, high-frequency oscillatory and high-frequency jet ventilation to manage respiratory failure in extremely preterm infants. This review explores the existing evidence for each mode of ventilation and the importance of individualizing ventilator management strategies when caring for extremely preterm infants.

Respiratory management for extremely premature infants born at 22 to 23 weeks of gestation in proactive centers in Sweden, Japan, and USA.

Survival of preterm newborn infants have increased steadily since the introduction of surfactant treatment and antenatal steroids. In the absence of randomized controlled trials on ventilatory strategies in extremely preterm infants, we present ventilatory strategies applied during the initial phase and the continued ventilatory care as applied in three centers with proactive prenatal and postnatal management and well documented good outcomes in terms of mortality and morbidity in this cohort of infants.

Survival and short-term respiratory outcomes of <750 g infants initially intubated with 2.0 mm vs. 2.5 mm endotracheal tubes.

OBJECTIVES: To compare survival and short-term respiratory outcomes of infants weighing <750 g initially intubated with 2.0 mm versus 2.5 mm endotracheal tube (ETT). STUDY DESIGN: Retrospective, observational cohort study. RESULTS: Of 149 inborn infants weighing <750 g admitted to the NICU, 69 (46%) were intubated with 2.0 mm ETT, 78 with 2.5 mm ETT (53%), and 2 infants never required intubation. Infants intubated with 2.0 mm ETT were more premature (median gestational age (GA) 23 weeks (22, 24) vs. 24 weeks (24, 25) p < 0.0001), smaller (median birth weight 545 g (450, 616) vs. 648 g (579, 700), p < 0.0001), and more frequently intubated at delivery (96% vs. 68%, p < 0.00001). Survival to discharge was similar 77%, 53/69 and 87%, 68/78 (p = 0.09). Adjusted for GA, there were no significant differences in ventilator days (p = 0.7338) or Grade 3 BPD. CONCLUSIONS: Premature infants born at a median GA of 23 weeks and median birth weight of 545 g can be successfully managed with 2.0 mm ETT.

Cardiorespiratory management of infants born at 22 weeks' gestation: The Iowa approach.

The approach to clinical care of infants born at 22 weeks' gestation must be consistent and well-designed if optimal results are to be expected. Publications from several international centers have demonstrated that, although there may be variance in aspects of care in this vulnerable population, treatment should be neither random nor inconsistent. In designing a standardized approach, careful attention should be paid to the unique anatomy, physiology, and biochemistry of this vulnerable patient population. Emerging evidence, suggesting a link between cardiopulmonary health and longer-term sequela, highlights the importance of understanding the relationship between cardiorespiratory illnesses of the 22-week infant, treatments provided, and subsequent cardiopulmonary development. In this review we will provide an overview to our approach to cardiopulmonary assessment and treatment, with a particular emphasis on the importance of early recognition of atypical phenotypes, timely interventions with evidence-based treatments, and longitudinal monitoring.

Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial.

OBJECTIVE: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial. STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed. RESULTS: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8 ± 1.3 weeks and mean birthweight was 805 ± 192 g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40). CONCLUSIONS: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data.

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.

Effects of milk banking procedures on nutritional and bioactive components of donor human milk.

Pasteurized donor human milk is in wide use for preterm infants in neonatal intensive care units when maternal milk is unavailable. Pasteurization of donor milk is required to prevent bacterial contamination, and multiple methods are used in the non-profit and commercial milk banking industries. Pasteurization results in changes in the nutrient and bioactive components in donor milk compared to unpasteurized human milk, and these changes vary by the type of pasteurization process. Other milk bank practices including freezing of milk, pooling of milk from multiple donors and use of pre-processing macronutrient analysis also affect the nutritional composition of donor milk. This review compiles evidence regarding three common pasteurization techniques for donor milk: Holder pasteurization, vat pasteurization, and retort pasteurization and their effects on the nutritional content and bioactive factors in human milk. It also includes review of literature investigating the impact of freezing and storage, and best practices for multi-donor milk pooling.

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.

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.

Behavior Profiles at 2 Years for Children Born Extremely Preterm with Bronchopulmonary Dysplasia.

OBJECTIVE: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior. RESULTS: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P < .001) and pervasive developmental problems (P < .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values < .05). CONCLUSIONS: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

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.