Growth-Restricted Fetuses and Offspring Reveal Adverse Sex-Specific Metabolic Responses in Preeclamptic Mice Expressing Human sFLT1.

Fetal adaptations to harmful intrauterine environments due to pregnancy disorders such as preeclampsia (PE) can negatively program the offspring's metabolism, resulting in long-term metabolic changes. PE is characterized by increased circulating levels of sFLT1, placental dysfunction and fetal growth restriction (FGR). Here we examine the consequences of systemic human sFLT1 overexpression in transgenic PE/FGR mice on the offspring's metabolic phenotype. Histological and molecular analyses of fetal and offspring livers as well as examinations of offspring serum hormones were performed. At 18.5 dpc, sFLT1 overexpression resulted in growth-restricted fetuses with a reduced liver weight, combined with reduced hepatic glycogen storage and histological signs of hemorrhages and hepatocyte apoptosis. This was further associated with altered gene expression of the molecules involved in fatty acid and glucose/glycogen metabolism. In most analyzed features males were more affected than females. The postnatal follow-up revealed an increased weight gain of male PE offspring, and increased serum levels of Insulin and Leptin. This was associated with changes in hepatic gene expression regulating fatty acid and glucose metabolism in male PE offspring. To conclude, our results indicate that sFLT1-related PE/FGR in mice leads to altered fetal liver development, which might result in an adverse metabolic pre-programming of the offspring, specifically targeting males. This could be linked to the known sex differences seen in PE pregnancies in human.

The effect of live music therapy on white matter microstructure in very preterm infants - A randomized controlled trial.

OBJECTIVE: Music therapy (MT) is proposed to enrich the acoustic environment of very preterm infants (VPT) on the neonatal intensive care unit during a vulnerable period of brain development. The objective of this study was to investigate the effect of MT on the white matter (WM) microstructure. It is hypothesized that MT affects WM integrity in VPT. METHODS: Randomized controlled trial enrolling infants born <32 weeks' gestation. Infants were randomized to MT or standard care. Live MT was provided twice weekly from the second postnatal week onwards by a trained music therapist. At term equivalent age, participants underwent a cranial magnetic resonance imaging scan including sequences for diffusion tensor imaging analysis. Differences in WM microstructure were assessed using tract based spatial statistics with fractional anisotropy. RESULTS: Of 80 infants enrolled, 42 were eligible for diffusion tensor imaging analysis (MT: n = 22, standard care: n = 20). While primary tract based spatial statistics analysis revealed no significant differences between groups, post hoc analysis with uncorrected p-values and a significance threshold of p < 0.01 revealed significant fractional anisotropy differences in several WM tracts including the bilateral superior longitudinal fasciculus, the left forceps minor and left fasciculus uncinatus, the corpus callosum, the left external capsule, and the right corticospinal tract. CONCLUSION: Post hoc analysis results suggest an effect of MT on WM integrity in VPT. Larger studies including long-term outcome are necessary to confirm these effects of MT on WM microstructure and to assess its impact on clinical neurodevelopment. CLINICAL TRIAL REGISTRATION: Clinical trial number DRKS00025753.

COMFORTneo scale in preterm infants during live performed music therapy-Difference between close physical contact and hand touch contact.

There is evidence that music therapy combined with physical contact to parents stabilizes the vital signs of hospitalized preterm infants. Yet, there is no evidence for the difference between simple contact by touching the infant in the incubator or cod, or close physical contact during music therapy sessions (MT). Behavioral effects of the various forms of attention toward the infant during therapy need to be elucidated. Our study aimed to quantify the effects of hand touch contact (HTC) and close physical contact (CPC) during live performed MT in preterm infants regardless of gestational age on behavioral state (assessed via COMFORTneo scale) and vital signs. A maximum of ten live music therapy sessions were delivered three to four times a week until hospital discharge to 50 stable infants. Pre-, during- and post-therapy heart rates, respiratory rates, oxygen saturations and COMFORTneo scores were recorded for each session. A total of 486 sessions was performed with 243 sessions using HTC and CPC each. The mean gestational age was 33 + 3 weeks, with 27 (54%) infants being male. We observed lower COMFORTneo scores, heart and respiratory rates and higher oxygen saturation during and after live performed music therapy independent of the kind of physical contact than before therapy. While pre-therapy values were better in the CPC group for all four variables, a higher mean response on COMFORTneo scale and vital signs was observed for HTC (COMFORTneo score -5.5, heart rate -12.4 beats per min., respiratory rate -8.9 breaths per min, oxygen saturation + 1.5%) compared to CPC (COMFORTneo score -4.6, heart rate -9.6 beats per min., respiratory rate -7.0 breaths per min, oxygen saturation + 1.1%). Nonetheless, post-therapy values were better for all four measures in the CPC group. Regression modeling with correction for individual responses within each patient also yielded attenuated effects of MT in the CPC group compared to HTC, likely caused by the improved pre-therapy values. Live performed music therapy benefits preterm infants' vital signs and behavioral state. During CPC with a parent, the absolute therapeutic effect is attenuated but resulting post-therapy values are nonetheless better for both the COMFORTneo scale and vital signs.

Music therapy modulates mothers' perception of their preterm infants.

Premature birth imposes considerable challenges on the preterm infant, but also challenges the mother, who may not yet be prepared for motherhood and encounter psychological stress during the post-partum period. This secondary analysis of a prospective randomized controlled trial (RCT) aimed to investigate how mothers perceive their preterm infants. We surveyed 33 mothers of preterm infants born before 32 weeks of gestation, who were participating in an RCT on music therapy. We employed the neonatal perception inventory (NPI), an instrument designed to assess the mother's perception and expectations regarding her infant immediately after birth. Infants were randomly assigned to either standard care (control group) or standard care plus music therapy (intervention group). Eighteen mothers from the intervention group participated in the survey (mean age 34.1 ± 4.6 years) and 15 mothers from the control group (mean age 29.6 ± 4.2 years). At the time of the infant's hospital discharge, mothers rated their expectations of how they felt a baby should behave (NPI I) and how they perceived their own infant (NPI II). The NPI score difference was calculated by subtracting the NPI II from the NPI I. Mean NPI I scores were comparable between both groups, but NPI II scores in the intervention group were better [18.0, 95% confidence interval (CI) 16.6-19.4] than in the control group (19.1, 95% CI 18.0-20.3). The relative probability of mothers rating their own baby as better than average was 1.94 (95% CI 1.00-3.79) for mothers whose infants received music therapy. These findings suggest that music therapy in the neonatal intensive care unit can positively influence mothers' perception of their hospitalized preterm infant.

Impact of Physical Contact on Preterm Infants' Vital Sign Response to Live Music Therapy.

Evidence that music therapy stabilises vital parameters in preterm infants is growing, but the optimal setting for therapy is still under investigation. Our study aimed to quantify the effect of physical contact during live music therapy in preterm infants born < 32 weeks' gestational age (GA) on post-therapy vital sign values. Live music therapy was delivered twice-weekly until discharge from hospital to 40 stable infants < 32 weeks' GA. Baseline and post-therapy heart rate, respiratory rate, oxygen saturation and physical contact during each session were recorded. 159 sessions were performed with, and 444 sessions without, physical contact. Descriptive and multivariable regression analyses based on directed acyclic graphs were performed. The mean GA was 28.6 ± 2.6 weeks, and 26 (65%) infants were male. Mean absolute values for heart and respiratory rates lowered during music therapy regardless of physical contact. The mean post-therapy SaO2 was higher compared to baseline values regardless of physical contact (mean differences −8.6 beats/min; −13.3 breaths/min and +2.0%). There were no clinically relevant changes in vital sign responses between therapy sessions, with or without physical contact, or adjusted post-therapy values for any of the studied vital signs. Physical contact caused better baseline and post-therapy vital sign values but did not enhance the vital sign response to music therapy. Thus, the effect of music therapy on preterm infants' vital signs is independent of physical contact and parents' presence during music therapy in the neonatal intensive care unit.

Music Therapy in Preterm Infants Reduces Maternal Distress.

Preterm delivery is a stressful event for mothers, posing them at risk for post-traumatic stress reactions. This study examined the degree of depressive symptoms and post-traumatic stress in mothers of preterm infants born before 32 gestational weeks depending on whether the infant received music therapy in the neonatal intensive care unit (NICU) or not. We included 33 mothers of preterm infants enrolled in a previously described prospective randomized controlled trial, of whom 18 received music therapy (mean mothers' age 34.1 ± 4.6 years) and 15 did not (mean mothers' age 29.6 ± 4.2). The degree of depressive symptoms, anxiety and acute stress reactions of these mothers were measured by using the German version of the Center for Epidemiologic Studies Depression Scale (CES-D) and Impact of Events Scale-Revised (IES-R) one week after birth (T1) and at infants' hospital discharge (T2). 605 music therapy sessions with a mean duration of 24.2 ± 8.6 min (range 10 to 50 min) were conducted two times a week from the second week of life (T1) until discharge (T2) to the infants from the intervention group. The infants from the control group received standard medical care without music therapy. The mean total CES-D score decreased from T1 (mean 34.7, 95% Confidence Interval (CI) 31.1-38.1) until T2 in all mothers (mean 16.3, 95% CI 12.6-20.1). Mothers whose infants received music therapy showed stronger declines of depressive and stress symptoms (with music therapy: CES-D mean difference of total score 25.7, 95% CI 20.0-31.3, IES-R mean difference of total score 1.7, 95% CI 0.9-2.5, IES-R mean difference of subcategory hyperarousal 10.2, 95% CI 6.2-14.3; without music therapy: CES-D mean difference of total score 9.5, 95% CI 3.8-15.3, IES-R mean difference of total score 0.1, 95% CI -1.0-1.2, IES-R mean difference of subcategory hyperarousal 1.6, 95% CI -4.7-7.9). Effect sizes were strong for CES-D, IES-R, and the hyperarousal subcategory, moderate for intrusion, and low for avoidance. These findings show that mothers of preterm infants are highly susceptible to supportive non-medical interventions such as music therapy to reduce psychological symptoms and distress during their infants' NICU stay.

Parents' Perception of Family-Centered Music Therapy with Stable Preterm Infants.

Premature birth places considerable demands on preterm infants and their families. Most of these infants are treated on a neonatal intensive care unit immediately after birth, leading to psychosocial stress for parents and making it more difficult to build a stable parent-child bond. We hypothesized that accompaniment with live music therapy by a music therapist supports the parents to get in contact with their child and to promote the parents' wellbeing. Preterm infants born at less than 32 gestational weeks received creative music therapy twice a week until discharge. At the time of discharge, the parents were asked to complete a Likert-style questionnaire to evaluate the music therapy. Six items related to socio-demographic characteristics, 4 items to observations on the infant and 10 items to personal perception. Of 40 preterm infants receiving music therapy, 32 (80%) parents completed the questionnaires. Thirty (94%) of these parents were able to relax during the music therapy session. Relaxation in their infants was observed by 29 (91%) during and by 28 (88%) after music therapy. Parents perceived music therapy as a positive change and enrichment during their infant's hospital stay. All parents were thankful for the music therapy they received. Music therapy supports the parents of preterm infants in the first time after birth until discharge from the hospital.

Music Therapy Is Effective during Sleep in Preterm Infants.

Recent research found evidence supporting music therapy for preterm infants to stabilize vital signs and possibly promote neurodevelopment. Even though preterm infants spend a considerable amount of time sleeping, the effectiveness of music therapy during sleep has not been studied. The aim of this study was to investigate the effect of music therapy on preterm infants' vital signs with respect to the state of wakefulness. The first 20 consecutive infants born with <32 weeks' gestational age (GA) from the intervention group of an ongoing randomized controlled trial received live music therapy twice a week until hospital discharge. The heart rate, respiratory rate, oxygen saturation, and state of wakefulness were recorded before and after therapy. We observed significantly lower heart and respiratory rates and higher oxygen saturation after live music therapy sessions in general (mean differences -4.9 beats per min; -7.0 breaths per min and +1.5%, respectively). When music therapy was applied during sleep, respiratory rates significantly lowered by 8.8 breaths per min and oxygen saturation increased by 1.6%, whereas in the awake state the vital parameters did not significantly change (heart rate -5.2 beats per min; respiratory rate +0.6 breaths per min and oxygen saturation +1.0%). Music therapy stabilized the respiratory rates and oxygen saturations in sleeping preterm infants.

Hyperoxia Leads to Transient Endocrine Alterations in the Neonatal Rat During Postnatal Development.

Introduction: High oxygen concentrations have been identified as one factor contributing to the pathogenesis of the retinopathia of prematurity, chronic lung disease of the preterm infant and preterm brain injury. Preterm infants also show short- and long-term alterations of the endocrine system. If hyperoxia is one pathogenetic factor has not been investigated yet. With regard to the high prevalence of neurodevelopmental impairments in preterm infants, the hypothalamus-pituitary-thyroid (HPT) axis, the hypothalamus-pituitary-adrenal (HPA) axis and the hypothalamus-pituitary-somatotropic (HPS) axis are of special interest due to their important role in neurodevelopment. Objective: The aim of this study was to investigate the effect of hyperoxia on the endocrine system in the neonatal rat by analyzing the activities of the HPT, HPA and HPS axes, respectively. Methods: Three-days old Wistar rats were exposed to hyperoxia (oxygen 80%, 48 h). On postnatal day 5 (P5) and P11, transcript levels of thyroid-stimulating hormone (TSH), proopiomelanocortin and growth hormone (GH) were analyzed in pituitary sections by in situ hybridization. Serologic quantification of TSH and thyroxine (T4), adrenocorticotropic hormone and GH were performed by Multiplex analysis and Enzyme-linked Immunosorbent Assay. Results: At P5, significantly lower GH levels were observed in pituitaries (mRNA) and in sera of rats exposed to hyperoxia. Serum TSH was significantly elevated without changes in T4. Conclusion: This is the first study demonstrating transient endocrine alterations following hyperoxia in the neonatal rat making oxygen a possible contributor to the pathogenesis of endocrine alterations seen in preterm infants. Considering the detrimental multi-organ effects of hyperoxia on the immature organism, a rational use of therapeutic oxygen in the treatrnent of preterm infants is of utmost importance.

Repetitive Erythropoietin Treatment Improves Long-Term Neurocognitive Outcome by Attenuating Hyperoxia-Induced Hypomyelination in the Developing Brain.

Introduction: Preterm infants born before 28 weeks of gestation are at high risk of neurodevelopmental impairment in later life. Cerebral white and gray matter injury is associated with adverse outcomes. High oxygen levels, often unavoidable in neonatal intensive care, have been identified as one of the main contributing factors to preterm brain injury. Thus, preventive and therapeutic strategies against hyperoxia-induced brain injury are needed. Erythropoietin (Epo) is a promising and also neuroprotective candidate due to its clinical use in infants as erythropoiesis-stimulating agent. Objective: The objective of this study was to investigate the effects of repetitive Epo treatment on the cerebral white matter and long-term motor-cognitive outcome in a neonatal rodent model of hyperoxia-induced brain injury. Methods: Three-day old Wistar rats were exposed to hyperoxia (48 h, 80% oxygen). Four doses of Epo (5,000 IU/kg body weight per day) were applied intraperitoneally from P3-P6 with the first dose at the onset of hyperoxia. Oligodendrocyte maturation and myelination were evaluated via immunohistochemistry and Western blot on P11. Motor-cognitive deficits were assessed in a battery of complex behavior tests (Open Field, Novel Object Recognition, Barnes maze) in adolescent and fully adult animals. Following behavior tests animals underwent post-mortem diffusion tensor imaging to investigate long-lasting microstructural alterations of the white matter. Results: Repetitive treatment with Epo significantly improved myelination deficits following neonatal hyperoxia at P11. Behavioral testing revealed attenuated hyperoxia-induced cognitive deficits in Epo-treated adolescent and adult rats. Conclusion: A multiple Epo dosage regimen protects the developing brain against hyperoxia-induced brain injury by improving myelination and long-term cognitive outcome. Though current clinical studies on short-term outcome of Epo-treated prematurely born children contradict our findings, long-term effects up to adulthood are still lacking. Our data support the essential need for long-term follow-up of preterm infants in current clinical trials.

Are Simple Magnetic Resonance Imaging Biomarkers Predictive of Neurodevelopmental Outcome at Two Years in Very Preterm Infants?

BACKGROUND: Preterm infants are at increased risk of neurodevelopmental impairment due to the vulnerability of the immature brain. Early risk stratification is necessary for predicting outcome in the period of highest neuroplasticity. Several biomarkers in magnetic resonance imaging (MRI) at term equivalent age (TEA) have therefore been suggested. OBJECTIVE: To assess the predictive value of simple brain metrics and the total abnormality score (TAS) - a modified score for brain injury and growth - in relation to neurodevelopmental outcome of very preterm infants in MRI at TEA. METHODS: Single-centre cohort study including preterm infants with gestational age (GA) ≤32 weeks and birth weight ≤1,500 g. Biparietal width (BPW), interhemispheric distance, transcerebellar diameter (TCD) and TAS were assessed. To detect subtle haemorrhages, additional susceptibility-weighted imaging (SWI) was used in addition to conventional MRI to evaluate its clinical relevance. Neurodevelopment was tested by the Mental and Psychomotor Developmental Index (MDI/PDI) of the Bayley Scales of Infant Development II at a corrected age of 24 months. RESULTS: One hundred twenty-nine children with median GA of 28.1 weeks and median birth weight of 980 g were included. BPW significantly correlated with PDI (p= 0.01, R2 = 0.06) and TCD with MDI (p < 0.01, R2 = 0.05) and PDI (p < 0.01, R2 = 0.06) but explained variances were low. TAS was not predictive of neurodevelopmental outcome. By using SWI, additional 4 cases of low grade haemorrhages were identified compared to conventional sequences. In one case this additional information was clinically relevant (MDI/PDI below average). CONCLUSION: Simple brain metrics and TAS did not reliably predict neurodevelopmental outcome in a cohort with low prevalence of high grade brain injury. The additional value of SWI is yet to be determined in larger cohorts. The combination of imaging and functional biomarkers may be advisable for the prediction of neurodevelopmental outcome.