Supplementation with antioxidant micronutrients in pregnant women with obesity: a randomized controlled trial.

BACKGROUND/OBJECTIVE: Obesity increases maternal morbidity and adversely affects child health. Maternal inflammation may play a role in adverse outcomes. The objective of this study was to determine whether providing a higher dose of antioxidant micronutrients to pregnant women with obesity would raise concentrations of key antioxidant vitamins and impact inflammation and oxidative stress during pregnancy. SUBJECTS/METHODS: This was a double-blind, randomized controlled trial. We recruited pregnant women with a body mass index (BMI) ≥ 30 kg/m2 at their initial prenatal visit ( < 13 weeks gestation) and collected blood and urine samples at baseline, 24-28 weeks, and 32-36 weeks to measure micronutrient concentrations (vitamin C, E, B6 and folate), markers of inflammation (C-reactive protein, interleukin-6, 8, and 1ß) and oxidative stress (8-epi-PGF2α and malondialdehyde). We collected maternal and infant health data from enrollment to delivery as secondary outcomes. We enrolled 128 participants (64 in each arm), and 98 (49 in each arm) completed follow-up through delivery. INTERVENTION: Both groups received a standard prenatal vitamin containing the recommended daily allowance of micronutrients in pregnancy. In addition, the intervention group received a supplement with 90 mg vitamin C, 30 αTU vitamin E, 18 mg vitamin B6, and 800 µg folic acid, and the control group received a placebo. RESULTS: The intervention group had higher vit B6 (log transformed (ln), ß 24-28 weeks: 0.76 nmol/L (95% CI: 0.40, 1.12); ß 32-36 weeks: 0.52 nmol/L (95% CI: 0.17, 0.88)) than the control group. Vitamins C, E, erythrocyte RBC folate concentrations did not differ by randomization group. The intervention did not impact biomarkers of inflammation or oxidative stress. There were no differences in maternal or neonatal clinical outcomes by randomization group. CONCLUSIONS: Higher concentrations of antioxidant vitamins during pregnancy increased specific micronutrients and did not impact maternal inflammation and oxidative stress, which may be related to dosing or type of supplementation provided. CLINICAL TRIAL REGISTRATION: Clinical Trial Identification Number: NCT02802566; URL of the Registration Site: www. CLINICALTRIALS: gov .

Establishing a regional registry for neonatal encephalopathy: impact on identification of gaps in practice.

BACKGROUND: Neonatal encephalopathy (NE) continues to be a significant risk for death and disability. To address this risk, regional guidelines were developed with the support of a malpractice insurance patient safety organization. A NE registry was also established to include 14 centers representing around 50% of deliveries in the state of Massachusetts. The aim of this study was to identify areas of variation in practice that could benefit from quality improvement projects. METHODS: This manuscript reports on the establishment of the registry and the primary findings to date. RESULTS: From 2018 to 2020, 502 newborns with NE were evaluated for Therapeutic Hypothermia (TH), of which 246 (49%) received TH, representing a mean of 2.91 per 1000 live births. The study reports on prenatal characteristics, delivery room resuscitation, TH eligibility screening, and post-natal management of newborns with NE who did and did not receive TH. CONCLUSIONS: The registry has allowed for the identification of areas of variation in clinical practices, which have guided ongoing quality improvement projects. The authors advocate for the establishment of local and regional registries to standardize and improve NE patient care. They have made the registry data collection tools freely available for other centers to replicate this work. IMPACT: Malpractice insurance companies can take an active role in supporting clinicians in establishing clinical practice guidelines and regional registries. Establishing a collaborative regional neonatal encephalopathy (NE) registry is feasible. Data Collection tools for a NE registry have been made publicly available to be adopted and replicated by other groups. Establishing a regional NE registry allowed for the identification of gaps in knowledge, variations in practice, and the opportunity to advance care through quality improvement projects.

Lactoferrin intake from maternal milk during the neonatal hospitalization and early brain development among preterm infants.

BACKGROUND: Lactoferrin is an immuno-modulatory nutrient in human milk that may be neuroprotective. METHODS: In 36 infants born <32 weeks' gestation, we sampled human milk at 14 and 28 days of chronologic age and measured lactoferrin by electrochemiluminescence multiplex immunoassay. Using 3T quantitative brain magnetic resonance imaging scans obtained at term equivalent, we estimated total and regional brain volumes. We compared outcomes between infants exposed to low (bottom tertile, range 0.06-0.13 mg/mL) vs. high (top tertile, range 0.22-0.35 mg/mL) lactoferrin using median regression in models adjusted for gestational age, birth weight z-score, sex, and postmenstrual age. RESULTS: Compared to infants exposed to low lactoferrin, infants exposed to high lactoferrin had 43.9 cc (95% CI: 7.6, 80.4) larger total brain volume, 48.3 cc (95% CI: 12.1, 84.6) larger cortical gray matter, and 3.8 cc (95% CI: 0.7, 7.0) larger deep gray matter volume at term equivalent age. Other regional brain volumes were not statistically different between groups. CONCLUSION: Higher lactoferrin exposure during the neonatal hospitalization was associated with larger total brain and gray matter volumes, suggesting that lactoferrin may have potential as a dietary supplement to enhance brain growth in the neonatal intensive care unit setting. IMPACT: This study suggests that lactoferrin, a whey protein found in human milk, may be beneficial for preterm infant brain development, and therefore has potential as a dietary supplement in the neonatal intensive care unit setting.

Perinatal inflammation, fetal growth restriction, and long-term neurodevelopmental impairment in Bangladesh.

BACKGROUND: There are limited data on the impact of perinatal inflammation on child neurodevelopment in low-middle income countries and among growth-restricted infants. METHODS: Population-based, prospective birth cohort study of 288 infants from July 2016-March 2017 in Sylhet, Bangladesh. Umbilical cord blood was analyzed for interleukin(IL)-1α, IL-1ß, IL-6, IL-8, and C-reactive protein(CRP). Child neurodevelopment was assessed at 24 months with Bayley-III Scales of Infant Development. We determined associations between cord blood inflammation and neurodevelopmental outcomes, controlling for potential confounders. RESULTS: 248/288 (86%) live born infants were followed until 24 months, among whom 8.9% were preterm and 45.0% small-for-gestational-age(SGA) at birth. Among all infants, elevated concentrations (>75%) of CRP and IL-6 at birth were associated with increased odds of fine motor delay at 24 months; elevated CRP was also associated with lower receptive communication z-scores. Among SGA infants, elevated IL-1α was associated with cognitive delay, IL-8 with language delay, CRP with lower receptive communication z-scores, and IL-1ß with lower expressive communication and motor z-scores. CONCLUSIONS: In rural Bangladesh, perinatal inflammation was associated with impaired neurodevelopment at 24 months. The associations were strongest among SGA infants and noted across several biomarkers and domains, supporting the neurobiological role of inflammation in adverse fetal development, particularly in the setting of fetal growth restriction. IMPACT: Cord blood inflammation was associated with fine motor and language delays at 24 months of age in a community-based cohort in rural Bangladesh. 23.4 million infants are born small-for-gestational-age (SGA) globally each year. Among SGA infants, the associations between cord blood inflammation and adverse outcomes were strong and consistent across several biomarkers and neurodevelopmental domains (cognitive, motor, language), supporting the neurobiological impact of inflammation prominent in growth-restricted infants. Prenatal interventions to prevent intrauterine growth restriction are needed in low- and middle-income countries and may also result in long-term benefits on child development.

"My Brigham Baby" Application: A Pilot Study Using Technology to Enhance Parent's Experience in the Neonatal Intensive Care Unit.

OBJECTIVE: This study aimed to describe the family psychosocial experience in a level-III neonatal intensive care unit (NICU), and to assess how it evolved after rollout of an educational smartphone application (App) called "My Brigham Baby." STUDY DESIGN: We surveyed 25 NICU parents pre-App rollout (before coronavirus disease 2019 [COVID-19] pandemic) and 25 parents post-App rollout (during pandemic). Collected data included parental self-reported discharge readiness, symptoms of stress and anxiety, and parenting skill confidence. Survey scores were assessed as total or mean scores, and by category of severity. RESULTS: Pre-and post-App parents had comparable demographics, and their infants had similar clinical characteristics during their NICU stay. Discharge readiness differed by group status (p = 0.02) and was characterized by a greater frequency in being "very ready" for discharge among the post-App rollout parent group compared with the pre-App group (56 vs. 20%, p = 0.027), and parenting confidence shifted toward more optimal scores post-App rollout. Parental stress and anxiety symptoms did not significantly differ between groups despite possible stress contagion from the COVID-19 pandemic. CONCLUSION: This pilot study suggests that technology Apps are feasible interventions within NICU settings and may enhance parental experiences related to NICU hospitalization. KEY POINTS: · Parents' experience increased psychological distress during the time their infant is cared for in the NICU, which has downstream consequences for the family unit.. · In our study, surveyed parents reported higher discharge readiness and parenting confidence shifted toward improvement after rollout of a family education and support smartphone application in a level-III NICU.. · This pilot study suggests that technology applications are feasible interventions that might enhance parental experiences during NICU hospitalization..

Effective Use of Extended Dwell Peripheral Intravenous Catheters in Neonatal Intensive Care Patients.

BACKGROUND: Implementing innovative approaches to vascular access can be challenging in the newborn intensive care unit (NICU). PURPOSE: The purpose of this project was to describe the implementation of extended dwell peripheral intravenous (EPIV) catheters, a vascular access device not widely used in the NICU. The implementation involved (1) designing clinical criteria for EPIV catheter use, (2) education of vascular access NICU nurses, and (3) comparing clinical outcomes between vascular access devices (ie, PIV and EPIV catheters). METHODS: We developed evidence-based clinical criteria guiding the use of vascular access devices. We then developed an educational plan for NICU nurses focused on vascular access. Finally, we collected and compared demographic characteristics and clinical data on catheter type and placement attempts, dwell time, and clinical complications associated with each catheter. RESULTS: EPIV catheters were implemented according to evidence-based criteria by a vascular access NICU nursing team. Fifteen percent of PIV catheter placements required 3 or more attempts compared with just 1% of EPIV catheter placement attempts. EPIV catheters had a longer median dwell time (3.5 vs 1 day) and fewer complications than PIV catheters (P < .001). IMPLICATIONS FOR PRACTICE AND RESEARCH: Implementation of an evidence-based approach to vascular access by a team of NICU nurses may improve clinical outcomes. EPIV catheters may be an appropriate alternative device to PIV catheters due to fewer placement attempts, longer dwell times, and overall fewer complications during use. Future vascular access research in the NICU may include a greater focus on innovative placement strategies, optimal maintenance and infection control, and prevention of complications.

Intestinal Inflammation is Significantly Associated With Length Faltering in Preterm Infants at Neonatal Intensive Care Unit Discharge.

OBJECTIVE: The aim of the study was to assess intestinal inflammatory measures, urinary intestinal fatty acid-binding protein (IFABP), and fecal calprotectin (FC) by gestational age (GA) and postmenstrual age (PMA) and determine the association between intestinal inflammation and growth in preterm infants from birth to hospital discharge. We hypothesized that intestinal inflammation is associated with adverse growth in preterm infants. METHODS: We assayed repeated measures of IFABP and FC in 72 hospitalized preterm infants (<34 weeks' gestation). We calculated weight and length z scores at birth and discharge using the Fenton growth reference. Associations between mean IFABP or FC, growth z scores at discharge, and growth faltering (weight or length z score difference <-0.8 from birth to discharge) were assessed using mixed linear and logistic regression models, adjusted for intrafamilial correlation and potential confounders: GA, sex, birth z score, race/ethnicity, and maternal age. RESULTS: Mean IFABP was greater among infants born at earlier GA and decreased with increasing PMA. Mean FC did not vary by GA or PMA. Higher mean IFABP and FC were associated with lower discharge growth z scores and greater likelihood of growth faltering significant only for mean IFABP and discharge length z score (ß = -0.353, 95% confidence interval [CI]: -0.704 to -0.002) and mean IFABP and length faltering (odds ratio [OR] 1.99, P = 0.018). CONCLUSIONS: Intestinal inflammation, measured by IFABP, was associated with lower length z scores and length faltering at discharge. Interventions to prevent intestinal inflammation may improve linear growth among preterm infants.

A Graded Approach to Intravenous Dextrose for Neonatal Hypoglycemia Decreases Blood Glucose Variability, Time in the Neonatal Intensive Care Unit, and Cost of Stay.

OBJECTIVE: To determine associations between a graded approach to intravenous (IV) dextrose treatment for neonatal hypoglycemia and changes in blood glucose (BG), length of stay (LOS), and cost of care. STUDY DESIGN: Retrospective cohort study of 277 infants born at ≥35 weeks of gestation in an urban academic delivery hospital, comparing the change in BG after IV dextrose initiation, neonatal intensive care unit (NICU) LOS, and cost of care in epochs before and after a hospital protocol change. During epoch 1, all infants who needed IV dextrose for hypoglycemia were given a bolus and started on IV dextrose at 60 mL/kg/day. During epoch 2, infants received IV dextrose at 30 or 60 mL/kg/day based on the degree of hypoglycemia. Differences in BG outcomes, LOS, and cost of hospital care between epochs were compared using adjusted median regression. RESULTS: In epoch 2, the median (IQR) rise in BG after initiating IV dextrose (19 [10, 31] mg/dL) was significantly lower than in epoch 1 (24 [14,37] mg/dL; adjusted ß = -6.0 mg/dL, 95% CI -11.2, -0.8). Time to normoglycemia did not differ significantly between epochs. NICU days decreased from a median (IQR) of 4.5 (2.1, 11.0) to 3.0 (1.5, 6.5) (adjusted ß = -1.9, 95% CI -3.0, -0.7). Costs associated with NICU hospitalization decreased from a median (IQR) $14 030 ($5847, $30 753) to $8470 ($5650, $19 019) (adjusted ß = -$4417, 95% CI -$571, -$8263) after guideline implementation. CONCLUSIONS: A graded approach to IV dextrose was associated with decreased BG lability and length and cost of NICU stay for infants with neonatal hypoglycemia.

Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial.

BACKGROUND: Human milk is recommended for very preterm infants, but its variable macronutrient content may contribute to undernutrition during a critical period in development. We hypothesize that individually targeted human milk fortification is more effective in meeting macronutrient requirements than the current standard of care. METHODS: We designed a single-center randomized, controlled trial enrolling 130 infants born < 31 completed weeks' gestation. Participants will receive fortified maternal and/or pasteurized donor milk but no formula. For participants in the intervention group, milk will be individually fortified with protein and fat modulars to achieve target levels based on daily point-of-care milk analysis with mid-infrared spectroscopy, in addition to standard fortification. The study diet will continue through 36 weeks' postmenstrual age (PMA). Clinical staff and parents will be masked to study group. Primary outcomes include: 1) body length and lean body mass by air displacement plethysmography at 36 weeks' PMA; 2) quantitative magnetic resonance imaging-based measures of brain size and microstructure at term equivalent age; and 3) Bayley-IV scales at 2 years' corrected age. DISCUSSION: We expect this trial to provide important data regarding the effectiveness of individually targeted human milk fortification in the neonatal intensive care unit (NICU). TRIAL REGISTRATION: NCT03977259 , registered 6 June, 2019.

Association of Poor Postnatal Growth with Neurodevelopmental Impairment in Infancy and Childhood: Comparing the Fetus and the Healthy Preterm Infant References.

OBJECTIVES: To compare the classification of preterm postnatal poor growth using healthy preterm vs fetal growth references and to examine associations with neurodevelopmental impairment in infancy and childhood. STUDY DESIGN: We included 613 infants born at <33 weeks of gestation. Using the INTERGROWTH-21st (healthy-preterm growth) reference and the Fenton and Olsen (fetal growth) references, we classified poor growth as a decline in z-score from birth to term-equivalent >0.8 SD (weight), >1 SD (head), and >2 SD (length). We used generalized estimating equations to estimate aOR for neurodevelopmental impairment at 18 months and 7 years of corrected age, comparing infants with and without poor growth by each reference, accounting for multiple births and covariates. RESULTS: The prevalence of poor growth was higher with INTERGROWTH-21st than with fetal references for all measurements. Agreement was higher between the Fenton and Olsen (fetal) growth references (0.72-0.81) than between INTERGROWTH-21st and fetal references (0.41-0.59). Poor growth by fetal references (but not by INTERGROWTH-21st) was associated with low neurodevelopmental scores in infancy and childhood. Poor weight gain using the Fenton reference was associated with 18-month Mental Developmental Index <85 (aOR 1.6, 95%CI: 1.1, 2.4) whereas poor weight gain by the INTERGROWTH-21st reference was not (aOR 1.0, 95%CI: 0.6, 1.7). Poor linear growth by the Olsen reference, but not INTERGROWTH-21st, was associated with 7-year verbal intelligence quotient <70 (aOR 3.5, 95%CI: 1.1, 12.7). CONCLUSIONS: Poor neonatal growth categorized using fetal references showed stronger associations with long term neurodevelopment than poor growth categorized using the INTERGROWTH-21st standards.

Problematic internet use/computer gaming among US college students: Prevalence and correlates with mental health symptoms.

BACKGROUND: Despite widespread internet use and computer gaming, as well as concerns about online addiction, little is known regarding the relationship between problematic internet use/computer gaming and mental health (MH) symptomatology among US college students. To address this gap, the present study examines a large, nation-wide sample of US college students to assess the rate of problematic internet use/computer gaming and its association with MH symptoms. METHODS: Using data from 43,003 undergraduates participating in the 2017 American College Health Association-National College Health Assessment, we examined rates of problematic internet use/computer gaming, defined as self-reported internet use/computer gaming that negatively affected academic performance. Logistic regression using a generalized estimating equations approach to adjust for clustering by school examined whether rates of MH symptomatology differed among students who reported problematic versus nonproblematic internet use and computer gaming. RESULTS: Ten percent of students reported problematic internet use/computer gaming that had negatively impacted academic performance. Adjusting for a range of covariates, students reporting problematic internet use/computer gaming had higher rates of all 11 MH indicators examined, with odds ratios ranging from 1.42 ("ever attempted suicide") to 3.90 ("ever felt overwhelmed by all you had to do"). CONCLUSIONS: Problematic internet use/computer gaming is reported by 10% of undergraduate students and represents a significant correlate of MH symptomatology. These findings suggest that problematic internet use/computer gaming will be an important public health focus for college campuses.

Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood.

Children raised in economically disadvantaged households face increased risks of poor health in adulthood, suggesting that inequalities in health have early origins. From the child's perspective, exposure to economic hardship may begin as early as conception, potentially via maternal neuroendocrine-immune responses to prenatal stressors, which adversely impact neurodevelopment. Here we investigate whether socioeconomic disadvantage is associated with gestational immune activity and whether such activity is associated with abnormalities among offspring during infancy. We analyzed concentrations of five immune markers (IL-1ß, IL-6, IL-8, IL-10, and TNF-α) in maternal serum from 1,494 participants in the New England Family Study in relation to the level of maternal socioeconomic disadvantage and their involvement in offspring neurologic abnormalities at 4 mo and 1 y of age. Median concentrations of IL-8 were lower in the most disadvantaged pregnancies [-1.53 log(pg/mL); 95% CI: -1.81, -1.25]. Offspring of these pregnancies had significantly higher risk of neurologic abnormalities at 4 mo [odds ratio (OR) = 4.61; CI = 2.84, 7.48] and 1 y (OR = 2.05; CI = 1.08, 3.90). This higher risk was accounted for in part by fetal exposure to lower maternal IL-8, which also predicted higher risks of neurologic abnormalities at 4 mo (OR = 7.67; CI = 4.05, 14.49) and 1 y (OR = 2.92; CI = 1.46, 5.87). Findings support the role of maternal immune activity in fetal neurodevelopment, exacerbated in part by socioeconomic disadvantage. This finding reveals a potential pathophysiologic pathway involved in the intergenerational transmission of socioeconomic inequalities in health.

Impact of sex and reproductive status on memory circuitry structure and function in early midlife using structural covariance analysis.

Research on age-related memory alterations traditionally targets individuals aged ≥65 years. However, recent studies emphasize the importance of early aging processes. We therefore aimed to characterize variation in brain gray matter structure in early midlife as a function of sex and menopausal status. Subjects included 94 women (33 premenopausal, 29 perimenopausal, and 32 postmenopausal) and 99 demographically comparable men from the New England Family Study. Subjects were scanned with a high-resolution T1 sequence on a 3 T whole body scanner. Sex and reproductive-dependent structural differences were evaluated using Box's M test and analysis of covariances (ANCOVAs) for gray matter volumes. Brain regions of interest included dorsolateral prefrontal cortex (DLPFC), inferior parietal lobule (iPAR), anterior cingulate cortex (ACC), hippocampus (HIPP), and parahippocampus. While we observed expected significant sex differences in volume of hippocampus with women of all groups having higher volumes than men relative to cerebrum size, we also found significant differences in the covariance matrices of perimenopausal women compared with postmenopausal women. Associations between ACC and HIPP/iPAR/DLPFC were higher in postmenopausal women and correlated with better memory performance. Findings in this study underscore the importance of sex and reproductive status in early midlife for understanding memory function with aging.

Associations of Growth and Body Composition with Brain Size in Preterm Infants.

OBJECTIVE: To assess the association of very preterm infants' brain size at term-equivalent age with physical growth from birth to term and body composition at term. STUDY DESIGN: We studied 62 infants born at <33 weeks of gestation. At birth and term, we measured weight and length and calculated body mass index. At term, infants underwent air displacement plethysmography to determine body composition (fat and fat-free mass) and magnetic resonance imaging to quantify brain size (bifrontal diameter, biparietal diameter, transverse cerebellar distance). We estimated associations of physical growth (Z-score change from birth to term) and body composition with brain size, adjusting for potential confounders using generalized estimating equations. RESULTS: The median gestational age was 29 weeks (range, 24.0-32.9 weeks). Positive gains in weight and body mass index Z-score were associated with increased brain size. Each additional 100 g of fat-free mass at term was associated with larger bifrontal diameter (0.6 mm; 95% CI, 0.2-1.0 mm), biparietal diameter (0.7 mm; 95% CI, 0.3-1.1 mm), and transverse cerebellar distance (0.3 mm; 95% CI, 0.003-0.5 mm). Associations between fat mass and brain metrics were not statistically significant. CONCLUSIONS: Weight and body mass index gain from birth to term, and lean mass-but not fat-at term, were associated with larger brain size. Factors that promote lean mass accrual among preterm infants may also promote brain growth.

Human Milk Oligosaccharides, Growth, and Body Composition in Very Preterm Infants.

Human milk oligosaccharides (HMOs) are bioactive factors that benefit neonatal health, but little is known about effects on growth in very preterm infants (<32 weeks' gestation). We aimed to quantify HMO concentrations in human milk fed to very preterm infants during the neonatal hospitalization and investigate associations of HMOs with infant size and body composition at term-equivalent age. In 82 human-milk-fed very preterm infants, we measured HMO concentrations at two time points. We measured anthropometrics and body composition with air displacement plethysmography at term-equivalent age. We calculated means of individual and total HMOs, constructed tertiles of mean HMO concentrations, and assessed differences in outcomes comparing infants in the highest and intermediate tertiles with the lowest tertile using linear mixed effects models, adjusted for potential confounders. The mean (SD) infant gestational age was 28.2 (2.2) weeks, and birthweight was 1063 (386) grams. Exposure to the highest (vs. lowest) tertile of HMO concentrations was not associated with anthropometric or body composition z-scores at term-corrected age. Exposure to the intermediate (vs. lowest) tertile of 3FL was associated with a greater head circumference z-score (0.61, 95% CI 0.15, 1.07). Overall, the results do not support that higher HMO intakes influence growth outcomes in this very preterm cohort.

Sex differences in the genetic risk for schizophrenia: history of the evidence for sex-specific and sex-dependent effects.

Although there is a long history to examinations of sex differences in the familial (and specifically, genetic) transmission of schizophrenia, there have been few investigators who have systematically and rigorously studied this issue. This is true even in light of population and clinical studies identifying significant sex differences in incidence, expression, neuroanatomic and functional brain abnormalities, and course of schizophrenia. This review highlights the history of work in this arena from studies of family transmission patterns, linkage and twin studies to the current molecular genetic strategies of large genome-wide association studies. Taken as a whole, the evidence supports the presence of genetic risks of which some are sex-specific (i.e., presence in one sex and not the other) or sex-dependent (i.e., quantitative differences in risk between the sexes). Thus, a concerted effort to systematically investigate these questions is warranted and, as we argue here, necessary in order to fully understand the etiology of schizophrenia.

Serial neuroimaging of brain growth and development in very preterm infants receiving tailored neuropromotive support in the NICU. Protocol for a prospective cohort study.

Introduction: Children born very preterm (VP) remain at risk for long-term neurodevelopmental impairment. Patterns of brain growth and injury, and how early neuropromotive therapies might mitigate developmental risk in VP infants remain insufficiently understood. Methods: This is a prospective cohort study of VP infants born at/before 32 weeks gestation. The study will enroll n = 75 consecutively-born VP infants in a level-III NICU. Exposed infants will be categorized into two groups (group 1: low-risk, n = 25 or group 2: high-risk, n = 25) based on the degree of neurological injury on early brain magnetic resonance imaging (MRI) at enrollment. Infants in the low-risk group (i.e., without significant injury defined as intraventricular hemorrhage with dilation, moderate or severe white matter injury, or cerebellar hemorrhage) will receive neurodevelopmental support utilizing the Supporting and Enhancing NICU Sensory Experiences (SENSE) program, while infants in the high-risk group (with neurological injury) will receive more intensive neurorehabilitative support (SENSE-plus). Age-specific, tailored sensory experiences will be facilitated contingently, preferentially by the infant's family with coaching from NICU staff. VP infants in exposure groups will undergo a brain MRI approximately every 2 weeks from enrollment until term-equivalent to monitor brain growth and evolution of injury. Exposed infants will be compared with a reference group (group 3: n = 25), i.e. VP infants whose families decline initial enrollment in SENSE, and subsequently undergo a term-equivalent brain MRI for other purposes. The primary aim of this study is characterization of term-equivalent brain growth and development among VP infants receiving NICU-based neuropromotive interventions compared to VP infants receiving the standard of care. Secondary aims include defining the timing and factors associated with total and regional brain growth on serial brain MRI among VP infants, (Aim 2), and using early imaging to tailor developmental intervention in the NICU while exploring associations with outcomes in VP infants at discharge and at two years corrected age (Aim 3). Discussion: This study will address gaps in understanding patterns of brain growth and injury drawing on serial MRI of hospitalized VP infants. These data will also explore the impact of intensive, tailored neuropromotive support delivered prior to term-equivalent on child and family outcomes.

Maternal Milk Provision in the Neonatal Intensive Care Unit and Mother-Infant Emotional Connection for Preterm Infants.

Maternal milk (MM) intake during neonatal intensive care unit (NICU) hospitalization is associated with improved neurodevelopment in preterm infants. Underlying mechanisms may include stronger mother-infant emotional connection. This paper examines associations between MM provision in the NICU with maternal connection to her infant using three factors validated in our sample: maternal sensitivity, emotional concern, and positive interaction/engagement. We studied 70 mothers of infants born <1500 g and/or <32 weeks' gestation. Associations between MM provision and mother-infant connection were modeled using median regression adjusted for clustering. Mothers who provided exclusive MM (i.e., 100% MM, no other milk) reported higher levels of maternal sensitivity by a median score of 2 units (ß = 2.00, 95% CI: 0.76, 3.24, p = 0.002) than the mixed group (i.e., MM < 100% days, other milk ≥1 days), as well as greater emotional concern (ß = 3.00, 95% CI: -0.002, 6.00, p = 0.05). Among mothers of very preterm infants, greater milk provision was associated with greater maternal sensitivity, but also with greater emotional concern about meeting the infant's needs. These findings highlight the importance of supporting MM provision and early infant care as an integrated part of lactation support. The findings may also provide insight into links between MM provision in the NICU and infant neurodevelopment.

Associations of Macronutrient Intake Determined by Point-of-Care Human Milk Analysis with Brain Development among very Preterm Infants.

Point-of-care human milk analysis is now feasible in the neonatal intensive care unit (NICU) and allows accurate measurement of macronutrient delivery. Higher macronutrient intakes over this period may promote brain growth and development. In a prospective, observational study of 55 infants born at <32 weeks' gestation, we used a mid-infrared spectroscopy-based human milk analyzer to measure the macronutrient content in repeated samples of human milk over the NICU hospitalization. We calculated daily nutrient intakes from unfortified milk and assigned infants to quintiles based on median intakes over the hospitalization. Infants underwent brain magnetic resonance imaging at term equivalent age to quantify total and regional brain volumes and fractional anisotropy of white matter tracts. Infants in the highest quintile of energy intake from milk, as compared with the lower four quintiles, had larger total brain volume (31 cc, 95% confidence interval [CI]: 5, 56), cortical gray matter (15 cc, 95%CI: 1, 30), and white matter volume (23 cc, 95%CI: 12, 33). Higher protein intake was associated with larger total brain (36 cc, 95%CI: 7, 65), cortical gray matter (22 cc, 95%CI: 6, 38) and deep gray matter (1 cc, 95%CI: 0.1, 3) volumes. These findings suggest innovative strategies to close nutrient delivery gaps in the NICU may promote brain growth for preterm infants.

Associations of body composition with regional brain volumes and white matter microstructure in very preterm infants.

OBJECTIVE: To determine associations between body composition and concurrent measures of brain development including (1) Tissue-specific brain volumes and (2) White matter microstructure, among very preterm infants at term equivalent age. DESIGN: Prospective observational study. SETTING: Single-centre academic level III neonatal intensive care unit. PATIENTS: We studied 85 infants born <33 weeks' gestation. METHODS: At term equivalent age, infants underwent air displacement plethysmography to determine body composition, and brain MRI from which we quantified tissue-specific brain volumes and fractional anisotropy (FA) of white matter tracts. We estimated associations of fat and lean mass Z-scores with each brain outcome, using linear mixed models adjusted for intrafamilial correlation among twins and potential confounding variables. RESULTS: Median gestational age was 29 weeks (range 23.4-32.9). One unit greater lean mass Z-score was associated with larger total brain volume (10.5 cc, 95% CI 3.8 to 17.2); larger volumes of the cerebellum (1.2 cc, 95% CI 0.5 to 1.9) and white matter (4.5 cc, 95% CI 0.7 to 8.3); and greater FA in the left cingulum (0.3%, 95% CI 0.1% to 0.6%), right uncinate fasciculus (0.2%, 95% CI 0.0% to 0.5%), and right posterior limb of the internal capsule (0.3%, 95% CI 0.03% to 0.6%). Fat Z-scores were not associated with any outcome. CONCLUSIONS: Lean mass-but not fat-at term was associated with larger brain volume and white matter microstructure differences that suggest improved maturation. Lean mass accrual may index brain growth and development.