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.

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.

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.

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. 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.

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.

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. 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. We included 45 extremely preterm infants in this prospective cohort study, gestational age 24-30 weeks. 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. 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. 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.