Stability of neurodevelopmental trajectories in moderately late and early preterm children born 15 years apart.

BACKGROUND: Neurodevelopmental trajectories of preterm children may have changed due to changes in care and in society. We aimed to compare neurodevelopmental trajectories in early and moderately late preterm children, measured using the Developmental (D)-score, in two cohorts born 15 years apart. METHODS: We included early preterm and moderately late preterm children from two Dutch cohorts (LOLLIPOP, 2002-2003 and ePREM, 2016-2017). ePREM counterparts were matched to LOLLIPOP participants by gestational age and sex. D-score trajectories were summarized by a multilevel model with random intercepts and random slopes, and multigroup analyses were used to test if the intercepts and slopes differed across cohorts. RESULTS: We included 1686 preterm children (1071 moderately late preterm, 615 early preterm) from LOLLIPOP, and matched these with 1686 ePREM counterparts. The neurodevelopmental trajectories of the two cohorts were mostly similar. For early preterm children, we found no statistically significant differences. For moderately late preterm children, both the intercept (43.0 vs. 42.3, p < 0.001) and slope (23.5 vs. 23.9, p = 0.002) showed some, but only clinically minor, differences. CONCLUSION: Developmental trajectories, measured using the D-score, in the first four years of life are comparable and stable across a period of 15 years for both early and moderately late preterm children. IMPACT: Neurodevelopmental trajectories are similar for early and moderately late preterm children born 15 years apart and thus seem quite stable in time. The validated Developmental score visualizes these trajectories based on developmental milestone attainment Because of its stability over time, the Developmental score trajectory may aid clinicians in neurodevelopmental assessment of preterm children as this simplifies monitoring and interpretation, similar to a growth chart.

Assessing HeartSong as a Neonatal Music Therapy Intervention: A Qualitative Study on Personal and Professional Caregivers' Perspectives.

BACKGROUND: The music therapy HeartSong intervention pairs newborn infant heartbeats with parents' Song of Kin. Formal evidence on professional and personal caregiver perspectives of this intervention is lacking. PURPOSE: This survey study evaluates the HeartSong music therapy intervention from parent and staff perspectives. METHODS: A qualitative study assessing inclusion of HeartSong for family neonatal intensive care unit (NICU) care surveyed 10 professional caregivers comprising medical and psychosocial NICU teams anonymously reflecting their impressions of the intervention. Digital survey of parents/guardians contacted through semistructured phone interviews relayed impressions of recordings: subsequent setup, Song of Kin selection, and use of HeartSong, including thoughts/feelings about it as an intervention. RESULTS: Professional and personal caregivers valued the HeartSong intervention for bereavement support, family support, including parental, extended family/infant support, and to enhance bonding. Emergent themes: memory-making, connectedness/closeness, support of parent role, processing mental health needs of stressful NICU days, and subsequent plans for lifelong HeartSong use. Therapeutic experience was named as a crucial intervention aspect and participants recommended the HeartSong as a viable, accessible NICU intervention. IMPLICATIONS FOR PRACTICE AND RESEARCH: HeartSong's use showed efficacy as a clinical NICU music therapy intervention for families of critically ill and extremely preterm infants, when provided by trained, specialized, board-certified music therapists. Future research focusing on HeartSong in other NICU populations might benefit infants with cardiac disease, parental stress, and anxiety attending to parent-infant bonding. Costs and time benefits related to investment are needed before implementation is considered.

Attainment of smiling and walking in infancy associates with developmental delays at school entry in moderately-late preterm children: a community-based cohort study.

BACKGROUND: Moderately-late preterm (MLP) children (gestational age [GA] 32-36 weeks) are followed-up within community services, which often use developmental milestones as indicators of delay. We aimed to examine associations of parental report of smiling-age and walking-age with developmental delay upon school entry for MLP and full-term children. METHODS: This study regards a community-based cohort study, including 1241 children. Parent-reported smiling-age (n = 514) and walking-age (n = 1210) were recorded in preventive child healthcare. To determine developmental delay at school entry (at age 4) we used the Ages and Stages Questionnaire (ASQ) total and domain scores. We assessed the association of smiling-age and walking-age with dichotomized ASQ-scores, using logistic regression analyses. RESULTS: For MLP children, each week later corrected smiling-age was associated with a relative increased likelihood of delays of 31, 43, 36 and 35% in the personal-social, problem-solving, gross motor and general developmental functioning, respectively. Each month later corrected walking-age was associated with a relative increased likelihood of delays of 10, 15 and 13% in the personal-social, gross motor and general developmental functioning, respectively. All corrected smiling-ages and walking-ages were within normal full-term ranges. For full-term children, we only found that later walking-age was associated with delays in the personal-social and gross motor domains. CONCLUSIONS: Smiling-age and walking-age are associated with developmental delay in several domains for MLP and full-term children. Professionals could use these milestones to identify children that may benefit from closer monitoring of their development. TRIAL REGISTRATION: Clinical Trial Registry name and registration number: controlled-trials.com , ISRCTN80622320 .

Early stress during NICU stay and parent-reported health-related quality of life after extremely preterm birth: an exploratory study with possible targets for early intervention.

Introduction: The association between neonatal intensive care unit (NICU) related stress in preterm infants and their health-related quality of life (HRQoL) in the first year following preterm birth remains unexplored. Understanding this association is crucial for enhancing preventive and supportive measures for infants and parents within and beyond the NICU. Methods: From a single center observational cohort study, we included infants with gestational ages below 30 weeks and/or birth weights under 1,000 grams. HRQoL was quantified using the Infant Quality of Life Instrument (IQI) at 3-, 6-, 9- and 12-months corrected age, covering seven domains. NICU stress was quantified using the Neonatal Infant Stressor Scale (NISS) for the first week of life. We performed Spearman's correlation analyses to test this association. Results: Of the 45 included infants, the IQI was completed for 27 (60%) at 3, 15 (33%) at 6, 14 (31%) at 9 and 15 (33%) at 12 months. The HRQoL sum scores were related to neonatal stress at 9 and 12 months (ρ = 0.643 and 0.591, p = 0.013 and p = 0.019, respectively) but not at 3 and 6 months (ρ = -0.001 and -0.077 respectively, p > 0.05). Higher NICU stress tended to be associated with more respiratory and mood problems throughout the first year. Discussion: From a parental perspective on infant HRQoL, extremely preterm infants with higher stress exposure show more problems in the second half-year of life, mainly breathing and possibly mood-related problems. This knowledge may help improve our neonatal care, both during NICU stay and in follow-up clinics, by implementing targeted interventions.

Neonatal stress exposure and DNA methylation of stress-related and neurodevelopmentally relevant genes: An exploratory study.

BACKGROUND: Stress exposure during Neonatal Intensive Care Unit (NICU) stay may have long-lasting effects on neurodevelopmental outcomes in extremely preterm infants. Altered DNA methylation of stress-related and neurodevelopmentally relevant genes may be an underlying mechanism. AIMS: This exploratory study aimed to investigate the association between neonatal stress exposure and DNA methylation in these genes at two different time points: early during the NICU stay (7-14 days after birth) and later, at discharge from the NICU. SUBJECTS: We included 45 extremely preterm infants in this prospective cohort study, gestational age 24-30 weeks. OUTCOME MEASURES: We collected fecal samples at days 7-14 (n = 44) and discharge (n = 28) and determined DNA methylation status in predefined regions of NR3C1, SLC6A4, HSD11B2, OPRM1, SLC7A5, SLC1A2, IGF2, NNAT, BDNF and GABRA6 using pyrosequencing. Because of low DNA concentrations in some fecal samples, we could do so in 25-50 % of collected samples. We prospectively quantified daily neonatal stress exposure using the Neonatal Infant Stressor Scale (NISS) and explored associations between cumulative NISS scores and average DNA methylation status. RESULTS: Rates of methylation of most genes were not statistically different between day 7-14 and discharge, except for OPRM1. We found moderately high and mostly negative correlation coefficients upon discharge with the cumulative NISS for the NR3C1, SLC6A4, SLC1A2, IGF2, BDNF and OPRM1 genes, albeit not statistically significant. CONCLUSIONS: Findings suggest that expression of stress-related and neurodevelopmentally relevant genes may be differently regulated following higher neonatal stress exposure. Larger studies should challenge the findings of this study and ideally test the effects on gene expression.

Effects of Live Music on the Perception of Noise in the SICU/PICU: A Patient, Caregiver, and Medical Staff Environmental Study.

Intensive Care Units (ICUs) require a multidisciplinary team that consists of, but is not limited to, intensivists (clinicians who specialize in critical illness care), pharmacists and nurses, respiratory care therapists, and other medical consultants from a broad range of specialties. The complex and demanding critical care environment provides few opportunities for patients and personal and professional caregivers to evaluate how sound effects them. A growing body of literature attests to noise's adverse influence on patients' sleep, and high sound levels are a source of staff stress, as noise is an ubiquitous and noxious stimuli. Vulnerable patients have a low threshold tolerance to audio-induced stress. Despite these indications, peak sound levels often register as high, as can ventilators, and the documented noise levels in hospitals continue to rise. This baseline study, carried out in two hospitals' Surgical and Pediatric Intensive Care Units, measured the effects of live music on the perception of noise through surveying patients, personal caregivers and staff in randomized conditions of no music, and music as provided by music therapists through our hospital system's environmental music therapy program.

Course of Stress during the Neonatal Intensive Care Unit Stay in Preterm Infants.

INTRODUCTION: Understanding the course of stress during the neonatal intensive care unit stay may provide targets for interventions. Our aim was to describe the course of stress in preterm infants during the first 28 days of life, the influence of gestational age, and associations with clinical characteristics. METHODS: In a single centre prospective cohort study, we included infants with a gestational age <30 weeks and/or birth weight <1,000 g. We measured stress over the first 28 days using the Neonatal Infant Stressor Scale (NISS). We plotted daily NISS total and subcategory scores by gestational age. The subcategories were (1) nursing, (2) skin-breaking, (3) monitoring and imaging, and (4) medical morbidity-related scores. We assessed associations of cumulative NISS scores over the first 7, 14, and 28 days with clinical characteristics using regression analyses. RESULTS: We included 45 infants, with a median gestational age of 27 weeks. The mean daily NISS score was 66.5 (SD 8.7), with highest scores in the first 7 days of life. Scores decreased the slowest for the lowest gestational ages, in particular for nursing scores, rather than skin-breaking, monitoring and imaging, and medical morbidity-related scores. Adjusted for gestational age, infants with lower Apgar scores, sepsis, intraventricular haemorrhages, and on mechanical ventilation had significantly higher cumulative NISS scores at 7, 14, and 28 days. CONCLUSION: NISS scores varied greatly within infants and over time, with the highest mean scores in the first week after birth. The course of declining NISS scores in the first 28 days depended on gestational age at birth.

Differential Placental DNA Methylation of NR3C1 in Extremely Preterm Infants With Poorer Neurological Functioning.

Background: Understanding underlying mechanisms of neurodevelopmental impairment following preterm birth may enhance opportunities for targeted interventions. We aimed to assess whether placental DNA methylation of selected genes affected early neurological functioning in preterm infants. Methods: We included 43 infants, with gestational age <30 weeks and/or birth weight <1,000 g and placental samples at birth. We selected genes based on their associations with several prenatal conditions that may be related to poor neurodevelopmental outcomes. We determined DNA methylation using pyrosequencing, and neurological functioning at 3 months post-term using Prechtl's General Movement Assessment, including the Motor Optimality Score-Revised (MOS-R). Results: Twenty-four infants had atypical MOS-R, 19 infants had near-optimal MOS-R. We identified differences in average methylation of NR3C1 (encoding for the glucocorticoid receptor) [3.3% (95%-CI: 2.4%-3.9%) for near-optimal vs. 2.3% (95%-CI: 1.7%-3.0%), p = 0.008 for atypical], and at three of the five individual CpG-sites. For EPO, SLC6A3, TLR4, VEGFA, LEP and HSD11B2 we found no differences between the groups. Conclusion: Hypomethylation of NR3C1 in placental tissue is associated with poorer neurological functioning at 3 months post-term in extremely preterm infants. Alleviating stress during pregnancy and its impact on preterm infants and their neurodevelopmental outcomes should be further investigated.

Criterion Validity and Applicability of Motor Screening Instruments in Children Aged 5-6 Years: A Systematic Review.

The detection of motor developmental problems, especially developmental coordination disorder, at age 5-6 contributes to early interventions. Here, we summarize evidence on (1) criterion validity of screening instruments for motor developmental problems at age 5-6, and (2) their applicability. We systematically searched seven databases for studies assessing criterion validity of these screening instruments using the M-ABC as reference standard. We applied COSMIN criteria for systematic reviews of screening instruments to describe the correlation between the tests and the M-ABC. We extracted information on correlation coefficients or area under the receiver operating curve, sensitivity and specificity, and applicability in practice. We included eleven studies, assessing eight instruments: three performance-based tests (MAND, MOT 4-6, BFMT) and five questionnaires (DCD-Q, PQ, ASQ-3, MOQ-T-FI, M-ABC-2-C). The quality of seven studies was fair, one was good, and three were excellent. Seven studies reported low correlation coefficients or AUC (<0.70), four did not report these. Sensitivities ranged from 21-87% and specificities from 50-96%, with the MOT4-6 having the highest sensitivity and specificity. The DCD-Q, PQ, ASQ-3, MOQ-T-FI, and M-ABC-2-C scored highest on applicability. In conclusion, none of the instruments were sufficiently valid for motor screening at age 5-6. More research is needed on screening instruments of motor delay at age 5-6.

Self-reported sensitivity to pain in early and moderately-late preterm-born adolescents: A community-based cohort study.

We aimed to compare ratings of self-reported and parent-reported pain sensitivity between early preterm (EP), moderately-late preterm (MLP), and full-term (FT) adolescents. For EP adolescents, we aimed to determine whether pain sensitivity was associated with early-life events. EP (n = 68, response rate 47.4%), MLP (n = 128, response rate 33.0%), and FT (n = 78, response rate 31.1%) adolescents and their parents (n = 277) answered an author-generated question on pain sensitivity at 14-15 years of age within a community-based cohort study. Differences between groups were determined using the chi-square test for trends. For EP adolescents, we assessed associations of treatment modalities (inotrope treatment, mechanical ventilation, and C-section) and neonatal morbidities (sepsis/necrotizing enterocolitis, small-for-gestational age status, asphyxia, and cerebral pathologies) with adolescent pain sensitivity using logistic regression analyses. Increased pain sensitivity was reported by 18% of EP adolescents, compared with 12% of MLP adolescents, and 7% of FT adolescents (P = 0.033). Parent-reported pain sensitivity did not differ by gestational age group. For EP adolescents, inotrope treatment was associated with increased pain sensitivity (odds ratio, 5.00, 95% confidence interval, 1.23-20.4, P = 0.025). No other neonatal treatment modalities or morbidities were associated with pain sensitivity in adolescence. In conclusion, we observed higher proportions of increased pain sensitivity for EP and MLP adolescents. Physicians treating preterm adolescents should be aware of altered pain sensitivity.

Neonatal Stress, Health, and Development in Preterms: A Systematic Review.

CONTEXT: An overview of the full range of neonatal stressors and the associated clinical, laboratory, and imaging outcomes regarding infants' health and development may contribute to the improvement of neonatal care. OBJECTIVE: To systematically review existing literature on the associations between all kinds of neonatal stressors and the health and development of preterm infants. DATA SOURCES: Data sources included Embase, Medline, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and reference lists. STUDY SELECTION: Studies were eligible if they included a measure of neonatal stress during the NICU stay, reported clinical, laboratory, and/or imaging outcomes regarding health and/or development on discharge from the NICU or thereafter, included preterm infants, and were written in English or Dutch. DATA EXTRACTION: Two reviewers independently screened the sources and extracted data on health and development. Study quality was assessed by using the Newcastle-Ottawa Quality Assessment Scale. RESULTS: We identified 20 articles that reported on neonatal stress associated negatively with clinical outcomes, including cognitive, motor, and emotional development, and laboratory and imaging outcomes, including epigenetic alterations, hypothalamic-pituitary-adrenal axis functioning, and structural brain development. We found no evidence regarding associations with growth, cardiovascular health, parent-infant interaction, the neonatal immune system, and the neonatal microbiome. LIMITATIONS: The studies were all observational and used different definitions of neonatal stress. CONCLUSIONS: Neonatal stress has a profound impact on the health and development of preterm infants, and physicians involved in their treatment and follow-up should be aware of this fact.

Combining Kangaroo Care and Live-Performed Music Therapy: Effects on Physiological Stability and Neurological Functioning in Extremely and Very Preterm Infants.

Interventions such as kangaroo care (KC) and live-performed music therapy (LPMT), are increasingly used to facilitate stress reduction in neonates. This study aims to investigate the effect of combining the two on physiological responses and neurological functioning in very preterm infants. Infants received six sessions of LPMT. KC was added to one LPMT session. Physiological responses included heart rate, respiratory rate and oxygen saturation. We videotaped infants for 30 min before and after two sessions to assess general movements (GMs). We included 17 infants, gestational age median 26.0 weeks (IQR 25.6-30.6 weeks), of whom six were males. Combined interventions showed a decrease in heart rate from mean 164 bpm before to 157 bpm during therapy, p = 0.001. Oxygen saturation levels increased during combination therapy from median 91.4% to 94.5%, p = 0.044. We found no effects of LPMT or combined interventions on GMs. Infants with a postnatal age (PNA) <7 days generally seem to display less optimal GMs after therapy compared with infants with a PNA >7 days. In conclusion, combining interventions is equally beneficial for physiological stability and neurological functioning as LPMT alone. Future studies should focus on the effects of this combination on parent-infant bonding.

Maternal Anxiety, Infant Stress, and the Role of Live-Performed Music Therapy during NICU Stay in The Netherlands.

Having an infant in the neonatal intensive care unit (NICU) elicits maternal anxiety, which may hamper parent-child bonding. We performed a prospective cohort study to describe anxiety in mothers of infants born before 30 weeks of gestation during NICU stay in The Netherlands, and investigated the influence of infant stress and gestational age. Second, we performed a randomized-controlled live-performed music therapy trial (LPMT trial) to investigate whether music therapy applied to the infant alleviated maternal anxiety. The relation between infant stress, gestational age, and maternal anxiety was measured in 45 mother-infant dyads, using the Neonatal Infant Stressor Scale and the State-Trait Anxiety Inventory (STAI). The effect of LPMT on anxiety was assessed in 21 mothers whose infants were assigned to either LPMT (n = 12) or waitlist (n = 9). Mothers completed the STAI before and after this period. Maternal anxiety decreased over time in all mothers, and was strongly related with infant stress (r = 0.706, p < 0.001), but not with gestational age. Anxiety scores decreased by 12% after LMPT, and increased by 1% after a waitlist period (p = 0.30). Our results indicate that LPMT in the weeks after birth may accelerate the reduction of maternal anxiety. Further research should focus on the effects on mother-child bonding.

Development of a Prediction Model to Identify Children at Risk of Future Developmental Delay at Age 4 in a Population-Based Setting.

Our aim was to develop a prediction model for infants from the general population, with easily obtainable predictors, that accurately predicts risk of future developmental delay at age 4 and then assess its performance. Longitudinal cohort data were used (N = 1983), including full-term and preterm children. Development at age 4 was assessed using the Ages and Stages Questionnaire. Candidate predictors included perinatal and parental factors as well as growth and developmental milestones during the first two years. We applied multiple logistic regression with backwards selection and internal validation, and we assessed calibration and discriminative performance (i.e., area under the curve (AUC)). The model was evaluated in terms of sensitivity and specificity at several cut-off values. The final model included sex, maternal educational level, pre-existing maternal obesity, several milestones (smiling, speaking 2-3 word sentences, standing) and weight for height z score at age 1. The fit was good, and the discriminative performance was high (AUC: 0.837). Sensitivity and specificity were 73% and 80% at a cut-off probability of 10%. Our model is promising for use as a prediction tool in community-based settings. It could aid to identify infants in early life (age 2) with increased risk of future developmental problems at age 4 that may benefit from early interventions.

Feasibility of Live-Performed Music Therapy for Extremely and Very Preterm Infants in a Tertiary NICU.

Objective: We aimed to investigate the feasibility of live-performed music therapy for extremely and very preterm infants admitted to the neonatal intensive care unit (NICU), and their parents, starting the 1st-2nd week after birth. They may benefit from live-performed music therapy as comforting non-pharmacological intervention. Study Design: We included infants born before 30 weeks' gestation in a single center NICU study. Live-performed music therapy was provided three times per week, tailored to the infant's medical condition. Parents were actively involved. Feasibility was determined as a combination of participation, drop-out, overstimulation (based on COMFORT-Neo scores), and evaluations of the intervention by parents and nurses (using a questionnaire on perceived effects on the parent, their infant and the NICU sound environment). Results: We included 18 infants (90% participation rate), with a gestational age of median 27 weeks (IQR 26-28 weeks), 61% males. One infant (5.6%) dropped-out. Differences of COMFORT-Neo scores during and after sessions compared with before sessions were non-significant; overstimulation by music therapy did not occur. Parents reported high satisfaction (highest score possible of 7) with the interventions and reported improvements in both infant and their own respiratory rates. Nurses also reported high satisfaction with the intervention and perceived a quieter NICU sound environment during and after sessions. Conclusion: Live-performed music therapy for extremely and very preterm infants is feasible and well-tolerated, and is experienced as an added value to developmental care. Future studies should assess both short-term and long-term effects, to determine whether this intervention should be part of routine care at the NICU and whether it is most beneficial to start shortly after birth.

Risk factors for emotional and behavioral problems in moderately-late preterms.

OBJECTIVE: To assess which factors, including maternal, lifestyle, pregnancy- and delivery-related, fetal and neonatal factors adjusted for socio-economic status, are related to emotional and behavioral problems in moderately-late preterm born children (MLPs; gestational age 32.0-35.9 weeks) at 4 years of age. MLPs are at greater risk of emotional and behavioral problems than full-term born children. Especially for MLPs, knowledge about factors that increase or decrease the risk of emotional and behavioral problems is scarce. DESIGN AND SETTING: We assessed emotional and behavioral problems in 809 MLPs between ages 41 and 49 months from the prospective community-based Longitudinal Preterm Outcome Project (LOLLIPOP), using the parent-reported Child Behavior Checklist (CBCL). We collected potential risk factors from hospital records and parental questionnaires. Univariable and multiple logistic regression analyses were applied. MAIN OUTCOME MEASURES: (Sub)clinical CBCL scores. RESULTS: Perinatal infection increased the risk of CBCL total problem scores with an OR 2.22 (p<0.01). Perinatal infection, maternal smoking, and male gender increased the risk of CBCL externalizing problem scores with ORs between 1.64 and 2.46 (all p<0.05). Multiple birth decreased the risk of CBCL internalizing problem scores with an OR 0.63 (p<0.05). CONCLUSIONS: Risk factors for behavioral problems in MLPs are male gender, perinatal infection and maternal smoking, the latter two being potentially modifiable. Multiple birth is a protective factor for emotional problems in MLPs. These results suggest potential factors for targeting preventive intervention in MLPs, comprising the large majority of all preterm born children.

Attainment of gross motor milestones by preterm children with normal development upon school entry.

BACKGROUND: Little is known on the motor development of moderately preterm born (MPT) children, in comparison with early preterm born (EPT) children and fullterm born (FT), for children with normal motor outcomes at school entry. AIMS: To compare attainment rates of gross motor milestones reached between ages 1-24 months for MPT, EPT, and FT children, all with normal development upon school entry. STUDY DESIGN: Prospective cohort study. SUBJECTS: We included 1247 preterm (PT) children (gestational age [GA] 24.0-35.6 weeks) and 488 FT children (GA 38.0-41.6 weeks), with normal gross motor development at 4 years according to the Ages and Stages Questionnaire. OUTCOME MEASURES: We assessed 11 gross motor milestones assessed in preventive child healthcare during six standardized visits at calendar age. RESULTS: During the first six months, all PT categories had lower milestone attainment-rates than FTs children (differences 9-60% for PTs compared with FTs children). For all PT categories attainment rates gradually increased during toddlerhood. For PT children with higher GA, differences in attainment rates compared with FTs children were smaller and attainment rates became comparable to FT children at an earlier age. At age 24 months only attainment rates for PT children born <30 weeks GA remained lower than for FTs children (85% versus 95%, P < 0.01). CONCLUSION: Milestone attainment rates are highly dependent on GA during the first two years. Differences between PT and FT children are larger and persist longer with lower GA. For PT children <30 weeks GA, differences still occur at 24 months. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: controlled-trials.com, ISRCTN 80622320.