Evaluation of the Relationship between Pain Exposure and Somatosensory Evoked Potentials in Preterm Infants: A Prospective Cohort Study.

BACKGROUND AND AIM: First, to compare somatosensory evoked potentials (SEPs) in preterm newborns without major brain injury studied at term equivalent age (TEA) with a term historical control group. Second, to investigate the impact of pain exposure during the first 28 days after birth on SEPs. Third, to evaluate the association between SEPs and Bayley-III at 2 years corrected age (CA). METHODS: Infants born at <32 weeks' gestational age (GA) were studied with continuous-SEPs. First, SEP differences between preterm and term infants were analyzed. Second, regression analyses were conducted to explore the association between SEPs and painful procedures, and then between SEPs and neurodevelopment. RESULTS: 86 preterm infants were prospectively enrolled. Preterm infants exhibited prolonged N1 latencies, central conduction times (CCTs), lower N1-P1 amplitudes, and more recurrently abnormal SEPs compared to term infants. Higher pain exposure predicted longer N1 latency and slower CCT (all p < 0.005), adjusting for clinical risk factors. Younger GA and postmenstrual age (PMA) at SEP recording were associated with longer N1 latency and lower N1-P1 amplitude (all p < 0.005). A normal SEP at TEA positively predicted cognitive outcome at 2 years CA (p < 0.005). CONCLUSION: Pain exposure and prematurity were risk factors for altered SEP parameters at TEA. SEPs predicted cognitive outcome.

A structured programme to promote breastfeeding improved the rates in very preterm infants at discharge.

AIM: We developed the Promotion of Breastfeeding (PROBREAST) programme and evaluated what effect it had on the breastfeeding rate in infants born at less than 32 weeks of gestation or weighing ≤1500 grams. METHODS: We compared the breastfeeding rate in two cohorts of patients who were born before (n = 72; January 2017 to June 2018) and after (n = 80; July 2018 to December 2019) the application of the programme. Moreover, we compared the correlation between type of feeding at discharge and post-discharge breastfeeding rate, between exclusive breastfeeding, postnatal growth and neurodevelopment. RESULTS: Infants in the PROBREAST group had an exclusive breastfeeding rate at discharge higher (42 vs. 16%, p < 0.001) than that in the historical control group. Exclusive breastfeeding was negatively correlated with weight z-score at discharge, but not at 12 and 24 months corrected age, and was positively correlated with cognitive score at 24 months corrected age. CONCLUSION: The application of a structured programme for the promotion of breastfeeding improved the breastfeeding rate in very preterm infants. We demonstrated that exclusive breastfeeding at discharge improved their neurodevelopment without impairing growth.

Morphine exposure and prematurity affect flash visual evoked potentials in preterm infants.

Objective: The present study aimed to explore first the impact of perinatal risk factors on flash-VEP waves and morphology in a group of preterm infants studied at term equivalent age (TEA). Second, to correlate VEP morphology with neurological outcome at 2 years corrected age (CA). Methods: Infants with a gestational age (GA) at birth <32 weeks, without major brain injury, were enrolled. Multivariate regression analyses were performed, and the models were run separately for each dependent variable N2, P2, N3 latencies and P2 amplitude. Logistic regression was applied to study N4 component (present/absent) and VEP morphology (regular/irregular). The predictors were GA, bronchopulmonary dysplasia (BPD), postmenstrual age at VEP registration, cumulative morphine and fentanyl dose, and painful procedures. Lastly, linear regression models were performed to assess the relation between the Bayley-III cognitive and motor scores at 2 years CA and VEP morphology, in relation to GA, BPD, painful procedures and cumulative morphine dose. Results: Eighty infants were enrolled. Morphine was the predictor of N2 (R2 = 0.09, p = 0.006), P2 (R2 = 0.11, p = 0.002), and N3 (R2 = 0.13, p = 0.003) latencies. Younger GA was associated with lower amplitude (R2 = 0.05, p = 0.029). None of the independent variables predicted the presence of N4 component, nor VEP morphology in the logistic analysis. VEP morphology was not associated with cognitive and motor scores at 2 years. Conclusions: Morphine treatment and prematurity were risk factors for altered VEPs parameters at TEA. In our cohort VEP morphology did not predict neurological outcome. Significance: Morphine administration should be evaluated according to potential risks and benefits, and dosage individually accustomed, according to pain and comfort scores, considering the possible risk for neurodevelopmental impairment.

Cardiac Hypertrophy Associated with Insulin Therapy in Extremely Preterm Infants.

BACKGROUND: In the neonatal period, cardiac hypertrophy (CH) has been commonly associated with hyperinsulinemic pathologies, and the first case of CH in an extremely preterm infant treated with insulin infusion has recently been reported. To confirm this association, we report a case series of patients who developed CH after insulin therapy. METHODS: Infants with gestational age < 30 weeks and birth weight < 1500 g, born from November 2017 to June 2022, were studied if they developed hyperglycemia requiring treatment with insulin and had echocardiographic diagnosis of CH. RESULTS: We studied 10 extremely preterm infants (24.3 ± 1.4 weeks) who developed CH at a mean age of 124 ± 37 h of life, 98 ± 24 h after the initiation of insulin therapy. All surviving patients had resolution of CH at discharge, while three of four (75%) of the deceased patients had persistent CH. CONCLUSIONS: Our case series supports the association between the development of CH and insulin therapy in extremely preterm infants and suggests further caution and the need for echocardiographic monitoring when treating these fragile patients with insulin.

Morphine exposure and neurodevelopmental outcome in infants born extremely preterm.

AIM: To investigate the association between morphine exposure in the neonatal period and neurodevelopment at 2 and 5 years of age while controlling for potential confounders. METHOD: We performed a retrospective, single-centre cohort study on 106 infants (60 males, 46 females; mean gestational age 26 weeks [SD 1]) born extremely preterm (gestational age < 28 weeks). Morphine administration was expressed as cumulative dose (mg/kg) until term-equivalent age. Neurodevelopmental outcome was assessed at 2 years with the Bayley Scales of Infant and Toddler Development, Third Edition, Dutch version and at 5 years with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, Dutch version. Multiple linear regression analysis was used to assess the association between morphine exposure and outcome. RESULTS: Sixty-four out of 106 (60.4%) infants included in the study received morphine. Morphine exposure was not associated with poorer motor, cognitive, and language subscores of the Bayley Scales of Infant and Toddler Development, Third Edition, Dutch version at 2 years. Morphine exposure was associated with lower Full-Scale IQ scores (p = 0.008, B = -9.3, 95% confidence interval [CI] = -15.6 to -3.1) and Performance IQ scores (p = 0.005, B = -17.5, 95% CI = -27.9 to -7) at 5 years of age. INTERPRETATION: Morphine exposure in infants born preterm is associated with poorer Full-Scale IQ and Performance IQ at 5 years. Individualized morphine administration is advised in infants born extremely preterm.

Oxidative Stress Biomarkers and Early Brain Activity in Extremely Preterm Infants: A Prospective Cohort Study.

Early brain activity, measured using amplitude-integrated EEG (aEEG), is correlated with neurodevelopmental outcome in preterm newborns. F2-isoprostanes (IPs) are early biomarkers predictive for brain damage. We aimed to investigate the relationship between perinatal IPs concentrations and quantitative aEEG measures in preterm newborns. Thirty-nine infants (gestational age (GA) 24-27 ± 6 weeks) who underwent neuromonitoring using aEEG during the first two days after birth were enrolled. The rate of spontaneous activity transients per minute (SAT rate) and inter-SAT interval (ISI) in seconds were computed. Two postnatal time-points were examined: within 12 h (day 1) and between 24 and 48 h (day 2). IPs were measured in plasma from cord blood (cb-IPs) and between 24 and 48 h (pl-IPs). Multivariable regression analyses were performed to assess the correlation between IPs and brain activity. Cb-IPs were not associated with SAT rate and ISI at day 1. Higher pl-IPs were followed by longer ISI (R = 0.68; p = 0.034) and decreased SAT rate (R = 0.58; p = 0.007) at day 2 after adjusting for GA, FiO2 and IVH. Higher pl-IPs levels are associated with decreased functional brain activity. Thus, pl-IPs may represent a useful biomarker of brain vulnerability in high-risk infants.

Platelet Count and Volume and Pharmacological Closure with Paracetamol of Ductus Arteriosus in Preterm Infants.

Background: Low platelet count might promote resistance to pharmacological closure with indomethacin and ibuprofen of a hemodynamically significant patent ductus arteriosus (hsPDA). However, no studies have investigated if this occurs with paracetamol. Methods: We retrospectively assessed the correlation between platelet count, mean platelet volume (MPV), and plateletcrit (PCT), as well as the effectiveness of paracetamol in closing hsPDA in infants born at 23+0-31+6 weeks of gestation who were treated with 15 mg/kg/6 h of i.v. paracetamol for 3 days. Results: We studied 79 infants: 37 (47%) Had closure after a course of paracetamol and 42 (53%) did not. Platelet count and PCT did not correlate with paracetamol success or failure in closing hsPDA, while MPV was lower at birth (10.7 ± 1.4 vs. 9.5 ± 1.1; p < 0.001) and prior to starting therapy (11.7 ± 1.9 vs. 11.0 ± 1.6; p = 0.079) in refractory infants. Regression analysis confirmed that the low MVP measured prior to starting the treatment increased the risk of hsPDA paracetamol closure failure (OR 1.664, 95% CI 1.153-2.401). Conclusions: The greater MPV correlated positively with the effectiveness of paracetamol in closing hsPDA, while platelet count and PCT did not influence closure rates. Additional studies are needed to confirm our results.

The management of late preterm infants: effects of rooming-in assistance versus direct admission to neonatal care units.

Late preterm infants (LPIs) represent a significant percentage of all neonates (6-8%), but there are limited published data on their postnatal management. Our aim was to compare the frequency of neonatal intensive care unit (NICU) admission and the breastfeeding rate of LPIs born at 35+0-36+6 weeks of gestation who were cared for by initial rooming in strategy rather than directly admitted to the special care unit (SCU) and, eventually, to the NICU. We carried out a retrospective study in the perinatal centers of Careggi University Hospital (CUH) and San Giovanni di Dio Hospital in Florence, Italy, where the first and second strategies were applied, respectively. Main outcomes were LPIs admission rate at SCU/NICU and breastfeeding rate at discharge. We studied 190 LPIs born at SGDH and 240 born at CUH. The admission rate in SCU (81 vs. 43%; P < 0.001) and NICU (20 vs. 10%; P = 0.008) was higher in SGDH than in CUH, as was the exclusive breastfeeding rate (36 vs. 22%; P < 0.001). However, infants who were assisted in rooming-in at CUH and infants with similar clinical characteristics at SGDH had similar mixed (60 vs. 69%) and exclusive (35 vs. 31%) breastfeeding rates.  Conclusion: Postnatal assistance of LPIs in rooming-in, eventually followed by admission in SCU/NICU based on their clinical conditions, allowed to safely halve their hospitalization. The assistance of infants in rooming-in did not negatively affect their breastfeeding rate. These results support the possibility of assisting LPIs in rooming-in. What is Known: • Late preterm infants represent a significant percentage of all neonates. • Early rooming-in and breastfeeding is recommended for late preterm infants. What is New: • Postnatal assistance of late preterm infants in rooming-in, followed when necessary by admission in neonatal units based on clinical conditions, allowed to safely avoid about half the number of hospitalizations in comparison with direct admission in neonatal units. • This strategy did not affect breastfeeding rate. Infants who were admitted to SCU/NICU after initial rooming-in had worst breastfeeding rate.

In vivo magnetic resonance imaging evidence of olfactory bulbs changes in a newborn with congenital Citomegalovirus: a case report.

BACKGROUND: Citomegalovirus (CMV) infects approximately 1% of live newborns. About 10% of the infants affected by congenital CMV infection are symptomatic at birth and up to 60% of these infants will develop permanent neurological disabilities. Depending on gestational age (GA) at the time of infection, the involvement of central nervous system (CNS) can lead to malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia. CASE PRESENTATION: We report the MRI findings in a Caucasian female born at 32 weeks of post-menstrual age with post-birth diagnosis of congenital CMV infection showing an unusual and peculiar marked T2 hyperintensity of the inner part of olfactory bulbs in addition to the CMV related diffuse brain involvement. Despite the known extensively described fetal and neonatal Magnetic Resonance Imaging (MRI) findings in CMV infected fetuses and newborns, any in vivo MRI depiction of olfactory system damage have never been reported so far. Nevertheless, in murine studies CMV is known to infect the placenta during pregnancy showing particular tropism for neural stem cells of the olfactory system and previous neuropathologic study on CMV infected human fetal brains from 23 to 28 weeks of GA reported damage in the olfactory bulbs (OB) consisting in disseminated cytomegalic cells, inflammation, necrosis and neuronal and radial glial cell loss. Therefore, we assume an OB involvement and damage in congenital CMV infection. CONCLUSION: To our knowledge this is the first in vivo MRI evidence of OB damage in a newborn with congenital CMV infection that may give new insights on CMV infection.

Cerebral and splanchnic oxygenation during automated control of inspired oxygen (FiO2 ) in preterm infants.

OBJECTIVES: Our aim in this study was to assess the effect of the Predictive Intelligent Control of Oxygenation (PRICO® ) system on cerebral (rSO2 C) and splanchnic (rSO2 S) oxygenation in a cohort of preterm infants with frequent desaturations. METHODS: Twenty infants with gestational age <32 weeks (n = 20) were assigned in random sequence to 12 h of automated or manual adjustment of FiO2 . Over this period, they were studied continuously by near-infrared spectroscopy (NIRS). RESULTS: We found that rSO2 C [68.0% (60.5%-74.7%) vs. 68.5% (62%-72%); p = .824] and rSO2 S [27.0% (17.3%-45.7%) vs. 27.0% (15%-53%); p = .878] were similar during automatic and manual control of FiO2 . Time spent with SpO2 90%-95% was higher during the automatic than manual control of FiO2 , while time spent with SpO2 <80% or >95% was lower. CONCLUSIONS: Automated control of FiO2 with PRICO® system did not improve brain and splanchnic oxygenation in comparison with manual control in a cohort of preterm infants, but it significantly decreased SpO2 fluctuations and limited the duration of both hypoxemia and hyperoxemia.

Incidence and risk factors of retinopathy of prematurity in an Italian cohort of preterm infants.

OBJECTIVE: Non-negligible differences in retinopathy of prematurity (ROP) and its risk factors between different neonatal intensive care units (NICUs) are reported. Our aim was to assess the incidence and risk factors for ROP development in a large cohort of very preterm infants who were assisted in two Italian NICUs. METHODS: Preterm infants with gestational age between 23+ 0 and 29+ 6 weeks were stratified into subgroups of infants who developed ROP and those who did not; their clinical characteristics were compared with univariate and multivariable logistic regression analyses. RESULTS: We studied a total of 178 infants of whom 67 (38%) developed ROP (stage 1: n = 12; stage 2: n = 41; stage 3: n = 14). Regression analysis demonstrated that maternal milk (OR 0.979, 95% Cl 0.961-0.998) decreased the risk of developing ROP, while intraventricular hemorrhage (IVH) (OR 2.055, 95% Cl 1.120-3.772) increased it. Moreover, maternal milk was found to decrease (OR 0.981, 95% Cl 0.964-0.997) the risk of ROP at discharge, while RBC transfusion increased it (OR 1.522, 95% Cl 1.208-1.916). CONCLUSIONS: In our cohort the occurrence of ROP was similar to that previously reported. Strategies for promoting the use of mother's own milk, preventing IVH, and standardizing the approach to RBC transfusions could contribute to decreasing the risk of ROP in very preterm infants.

Effect on splanchnic oxygenation of breast milk, fortified breast milk, and formula milk in preterm infants.

BACKGROUND: Enteral feeding induces mesenteric hemodynamic changes in preterm infants, which may vary according to the milk used. Our aim in this study was to evaluate changes of splanchnic regional oxygenation (rSO2S) measured by near-infrared spectroscopy (NIRS) in infants fed with mother's own milk (MOM), fortified human milk (FHM), or preterm formula (PTF). METHODS: Infants born at 25-31 weeks of gestational age (n = 54) received a bolus of MOM, FHM, or PTF. rSO2S and splanchnic fractional oxygen extraction ratio (FOES) were recorded 60 min before (T0), and 30 min (T1) and 120 min (T2) after the beginning of bolus feeding. RESULTS: In the MOM group, rSO2S and FOES did not change during the study period. In the FBM group, rSO2S decreased from T0 to T1 and increased from T1 to T2, while FOES changed in reverse. In the PTF group, rSO2S decreased from T0 to T1 and from T1 to T2, while FOES changed in reverse. CONCLUSIONS: Splanchnic oxygenation was not affected by MOM feeding, was transiently decreased by FBM feeding, and was persistently decreased by PTF. These results suggest that preterm infants who received PTF has higher splanchnic tissue oxygen extraction compared to those who received MOM or FBM. IMPACT: Human milk feeding is associated to a lower splanchnic energy expenditure than preterm formula feeding. Fortified human milk transiently increases splanchnic energy expenditure. Preterm formula should be used only in the absence of human milk.

Isoprostanes as Biomarker for Patent Ductus Arteriosus in Preterm Infants.

Context: It has been reported that isoprostanes (IPs) have a role in the pathophysiology of ductus arteriosus during the fetal and neonatal period. Our aim in this study was to assess if urinary IPs (uIPs) levels correlate with the risk of developing a hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. Materials and methods: Infants with 23 + 0 - 33 + 6 weeks of gestational age and respiratory distress syndrome (RDS) were consecutively enrolled. Urine samples were collected on the 2nd and 10th day of life (DOL) for uIPs measurement. Echocardiography for hsPDA diagnosis was performed between 24 and 48 h of life. Regression analysis was performed to assess the correlation between uIPs and hsPDA. Receiver operating characteristic (ROC) curve analysis was used to evaluate the accuracy of the uIPs in predicting the occurrence of hsPDA. Results: Sixty patients were studied: 33 (55%) developed a hsPDA, 27 (45%) had ibuprofen hsPDA closure, and six (10%) required surgical closure. uIPs levels decreased from the 2nd to the 10th DOL. Adjusted regression analysis demonstrated that uIPs on the 2nd DOL were associated (p = 0.02) with the risk of developing a hsPDA. A cut-off level of 1627 ng/mg of creatinine of uIPs predicted the development of a hsPDA with a sensitivity of 82% and a specificity of 73%. Conclusion: Early measurement of uIPs on the 2nd DOL is a reliable biomarker of hsPDA development and, alone or combined with other markers, might represent a non-invasive tool useful for planning the management of PDA in preterm infants.

Neonatal Cerebellar Hemorrhage and Facial Nerve Palsy: An Unusual Association.

Cerebellar hemorrhage is rare in term newborns and is most often seen after traumatic birth. Lifelong sequelae include motor and cognitive impairment. We report the uncommon case of a late preterm infant born by spontaneous delivery who showed right peripheral facial palsy at 24 hours of life. Cranial ultrasound showed lateral ventricles dilatation and a diffuse hyperechoic round lesion in the right cerebellar hemisphere. The computed tomography scan confirmed a hemorrhagic lesion in the right cerebellar hemisphere and in the vermis with midline shift and intraventricular bleeding. Ommaya reservoir was inserted and used for a few days. The facial palsy gradually recovered to a complete remission after 6 weeks. Follow-up examinations at 12 and 18 months evidenced infant's delayed motor function, hyperreflexia, tremors, and speech delay.

Erratum: Neonatal Cerebellar Hemorrhage and Facial Nerve Palsy: An Unusual Association.

[This corrects the article DOI: 10.1055/s-0040-1715162.][This corrects the article DOI: 10.1055/s-0040-1715162.].

Isoprostanes as Biomarker for White Matter Injury in Extremely Preterm Infants.

Background and Aim: Preterm white matter is vulnerable to lipid peroxidation-mediated injury. F2-isoprostanes (IPs), are a useful biomarker for lipid peroxidation. Aim was to assess the association between early peri-postnatal IPs, white matter injury (WMI) at term equivalent age (TEA), and neurodevelopmental outcome in preterm infants. Methods: Infants with a gestational age (GA) below 28 weeks who had an MRI at TEA were included. IPs were measured in cord blood (cb) at birth and on plasma (pl) between 24 and 48 h after birth. WMI was assessed using Woodward MRI scoring system. Multiple regression analyses were performed to assess the association between IPs with WMI and then with BSITD-III scores at 24 months corrected age (CA). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of pl-IPs for the development of WMI. Results: Forty-four patients were included. cb-IPs were not correlated with WMI score at TEA, whereas higher pl-IPs and lower GA predicted higher WMI score (p = 0.037 and 0.006, respectively) after controlling for GA, FiO2 at sampling and severity of IVH. The area under the curve was 0.72 (CI 95% = 0.51-0.92). The pl-IPs levels plotted curve indicated that 31.8 pg/ml had the best predictive threshold with a sensitivity of 86% and a specificity of 60%, to discriminate newborns with any WMI from newborns without WMI. IPs were not associated with outcome at 24 months. Conclusion: Early measurement of pl-IPs may help discriminate patients showing abnormal WMI score at TEA, thus representing an early biomarker to identify newborns at risk for brain injury.

Lung ultrasound findings in congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 2500 to 5000 infants. The use of lung ultrasound (LUS) for its diagnosis has been reported in only two case reports. The aim of this study was to report the LUS pattern of CDH in a case series of infants with respiratory distress. This case series was part of a cohort enrolled in a larger prospective observational study. LUS was performed at the point-of-care during the first 24 h of life of the neonates and its operation time was measured. Seven cases (six left and one right CDH) were diagnosed. We found that the pattern of LUS for CDH diagnosis includes (1) partial absence of the hyperechoic line representing the normal diaphragmatic profile, (2) partial absence of the pleural line in the affected hemithorax, (3) absence of A lines in the affected area, (4) presence of multi-layered area with hyperechoic contents in motion (normal gut), and (5) possible presence of parenchymatous organs inside the thorax (i.e., liver or spleen).Conclusion: A description of LUS pattern in infants with CDH is provided. LUS at the point-of-care may allow the prompt diagnosis of CDH and this is particularly useful in cases of missed prenatal diagnosis. What is Known: • Congenital diaphragmatic hernia occurs in approximately 1 in 2500 to 5000 infants but the use of lung ultrasound for its diagnosis has been reported in only two case reports. What is New: • Research provided a description of lung ultrasound pattern in infants with congenital diaphragmatic hernia. • Lung ultrasound at the point-of-care may allow a prompt diagnosis of congenital diaphragmatic hernia, particularly useful in cases of missed prenatal diagnosis.