Current pain management practices for preterm infants with necrotizing enterocolitis: a European survey.

BACKGROUND: Necrotizing enterocolitis (NEC) is a highly painful intestinal complication in preterm infants that requires adequate pain management to prevent short- and long-term effects of neonatal pain. There is a lack of international guidelines for pain management in NEC patients. Therefore, this study aims to describe current pain management for NEC patients in European neonatal intensive care units (NICUs). METHODS: An online survey was designed and conducted to assess current practices in pain management for NEC patients in European NICUs. The survey was distributed via neonatal societies, digital platforms, and professional contacts. RESULTS: Out of the 259 responding unique European NICUs from 36 countries, 61% had a standard protocol for analgesic therapy, 73% assessed pain during NEC, and 92% treated NEC patients with intravenous analgosedatives. There was strong heterogeneity in the used pain scales and initial analgesic therapy, which mainly included acetaminophen (70%), fentanyl (56%), and/or morphine (49%). A third of NICU representatives considered their pain assessment adequate, and half considered their analgesic therapy adequate for NEC patients. CONCLUSIONS: Various pain scales and analgesics are used to treat NEC patients in European NICUs. Our results provide the first step towards an international guideline to improve pain management for NEC patients. IMPACT: This study provides an overview of current pain management practices for infants with necrotizing enterocolitis (NEC) in European neonatal intensive care units. Choice of pain assessment tools, analgosedatives, and dosages vary considerably among NICUs and countries. A third of NICU representatives were satisfied with their current pain assessment practices and half of NICU representatives with their analgesic therapy practices in NEC patients in their NICU. The results of this survey may provide a first step towards developing a European pain management consensus guideline for patients with NEC.

Pain management for necrotizing enterocolitis: getting the balance right.

BACKGROUND: Adequate pain management for preterm born neonates suffering from the extremely painful disease necrotizing enterocolitis (NEC) is essential, since neonatal exposure to pain is related to negative short-term and long-term consequences. The aim of this study was to describe the current pain management and its effectiveness in NEC patients. METHODS: In this single-center, retrospective study, neonates (gestational age < 32 weeks and/or birth weight < 1500 g) with NEC Bell's stage II or III were included. Information on pain (based on COMFORTneo and NRS scores) and analgesic therapy was collected and analyzed for the acute disease period. RESULTS: Of 79 patients included, 74 (94%) received intravenous analgesic therapy: most commonly morphine, fentanyl, and acetaminophen. The median COMFORTneo score was 11 (IQR 10-11), however, 49 patients had at least one COMFORTneo score ≥ 14 indicating pain. Nineteen patients had persistent high pain scores ≥ 14 with a median duration of 7.2 h (IQR 2.8-14.0). CONCLUSIONS: This study showed that despite analgesic therapy, most NEC patients showed signs of pain, and in some, pain persisted for several hours. It suggests that current analgesic therapy frequently failed to prevent pain and existing pain was often insufficiently treated. This supports the urgent need for individualized pain management guidelines for NEC patients. IMPACT: This study is unique in reporting on pain management in neonates suffering from necrotizing enterocolitis (NEC) during the full acute disease period. Despite analgesic therapy, the majority of NEC patients experience pain, and in some patients, pain persists for several hours. These findings highlight the need for improvement of neonatal pain management in NEC patients, including better pain monitoring and guidelines for individualized analgesic therapy. Improved pain management guidelines may help to prevent short-term and long-term consequences of neonatal exposure to pain, as well as excessive exposure to opioids.

COVID-19 lockdown impacts the wellbeing of parents with infants on a Dutch neonatal intensive care unit.

PURPOSE: Parents of infants admitted to a neonatal intensive care unit (NICU) experience additional stress due to restrictions on their presence and visits by other family members during the COVID-19 pandemic. Our study aims to describe how this impacted parents and how NICU staff could support them. DESIGN AND METHODS: This was a cross-sectional study in which 25 parents (16 mothers, 9 fathers) of infants admitted to our NICU during the first COVID-19 lockdown completed online questionnaires with socio-demographic questions, the Parental Stressor Scale:NICU (PSS:NICU) and questions related to COVID-19. RESULTS: Being separated from, and not being able to hold their infant at all times were among the most important PSS:NICU stressors. Parents experienced additional stress because other family members were not allowed to visit. They indicated that NICU staff could support them by clearly explaining the reasons for visitor restrictions and by ensuring that they felt heard. Most parents supported the restrictions, but also mentioned that less strict measures would really help them. CONCLUSIONS: Parents who participated in this study found it very stressful that they could not be with their infant together with their partner and other family members. Furthermore, parents recommended the hospital management to continuously reconsider whether particular restrictions could be lifted in case of a new lockdown. Together with clear communication, this would result in less parenteral stress. PRACTICE IMPLICATIONS: Hospital management should be cautious on restricting the presence of parents and other family members and scale restrictions back whenever possible.

Neonatal critical illness and development: white matter and hippocampus alterations in school-age neonatal extracorporeal membrane oxygenation survivors.

AIM: To examine the neurobiology of long-term neuropsychological deficits after neonatal extracorporeal membrane oxygenation (ECMO). METHOD: This cross-sectional study assessed white matter integrity and hippocampal volume of ECMO survivors (8-15y) and healthy children (8-17y) using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI) respectively. Neuropsychological outcome was evaluated in ECMO survivors. Included clinical predictors of white matter integrity: age start ECMO, ECMO duration, highest oxygenation index before ECMO, highest mean airway pressure, and mechanical ventilation duration. RESULTS: ECMO survivors (n=23) had lower global fractional anisotropy than healthy children (n=54) (patients=0.368; comparison group=0.381; p=0.018), but similar global mean diffusivity (p=0.410). ECMO survivors had lower fractional anisotropy in the left cingulum bundle (ECMO survivors=0.345; comparison group=0.399; p<0.001) and higher mean diffusivity in a region of the left parahippocampal cingulum (patients=0.916; comparison group=0.871; p<0.001). Higher global mean diffusivity predicted worse verbal memory in ECMO survivors (n=17) (ß=-0.74, p=0.008). ECMO survivors (n=23) had smaller bilateral hippocampal volume than healthy children (n=43) (left, p<0.001; right, p<0.001) and this was related to worse verbal memory (left, ß=0.65, p=0.018; right, ß=0.71, p=0.006). INTERPRETATION: Neonatal ECMO survivors are at risk for long-term brain alterations, which may partly explain long-term neuropsychological impairments. Neuroimaging may contribute to better risk stratification of long-term impairments.

Thermal quantitative sensory testing in healthy Dutch children and adolescents standardized test paradigm and Dutch reference values.

BACKGROUND: Quantitative sensory testing (QST) is often used to measure children's and adults' detection- and pain thresholds in a quantitative manner. In children especially the Thermal Sensory Analyzer (TSA-II) is often applied to determine thermal detection and pain thresholds. As comparisons between studies are hampered by the different testing protocols used, we aimed to present a standard protocol and reference values for thermal detection- and pain thresholds in children. METHODS: Our standard testing protocol includes reaction time dependent and independent tests and takes about 14-18 min to complete. Reference values were obtained from a sample of 69 healthy term born children and adolescents with a median age of 11.2 years (range 8.2 to 17.9 years old). Seventy-one children were recruited and data of 28 males and 41 females was obtained correctly. We studied possible age and sex differences. RESULTS: This study provides Dutch reference values and presents a standard quantitative sensory testing protocol for children with an age from 8 years onwards. This protocol appeared to be feasible, since only two out of 71 participants were not able to correctly complete the protocol due to attention deficits and were therefore excluded. We found some significant age and sex differences: females were statistically significantly more sensitive for both cold and heat pain compared to males, and the youngest children (8-9 years old) were less sensitive to detect a warm stimulus. The youngest children tend to be more sensitive to heat pain in comparison to older participants, although the difference was not statistically significant. CONCLUSIONS: We present a feasible thermal quantitative sensory testing protocol for children and reference values that are easy to interpret and may serve as normative values for future studies.

Neuroimaging, Pain Sensitivity, and Neuropsychological Functioning in School-Age Neonatal Extracorporeal Membrane Oxygenation Survivors Exposed to Opioids and Sedatives.

OBJECTIVES: Animal studies found negative long-term effects of exposure to sedatives and opioids in early life, especially when administered in the absence of pain. Around the world, children who require extracorporeal membrane oxygenation receive opioids and sedatives for extended periods, generally in the absence of major pain as extracorporeal membrane oxygenation cannulation is considered minor surgery. Therefore, our objective was to determine the long-term effects of extracorporeal membrane oxygenation treatment with respect to pain sensitivity, brain functioning during pain, brain morphology, and neuropsychological functioning in humans. DESIGN: Prospective follow-up study. SETTING: Level III university hospital. SUBJECTS: Thirty-six extracorporeal membrane oxygenation survivors (8.1-15.5 yr) and 64 healthy controls (8.2-15.3 yr). MEASUREMENTS AND MAIN RESULTS: We measured detection and pain thresholds, brain activity during pain (functional MRI), brain morphology (high-resolution structural MRI), and neuropsychological functioning and collected information regarding the subject's experience of chronic pain. We found a significant difference in the detection threshold for cold measured in a reaction time-dependent fashion (extracorporeal membrane oxygenation group, 29.9°C [SD, 1.4]; control group, 30.6°C [SD, 0.8]; p < 0.01), but no differences in other modalities or in pain sensitivity between groups. Furthermore, no differences in brain activation during pain, brain morphology, or in the occurrence of chronic pain were observed. However, extracorporeal membrane oxygenation survivors performed significantly worse on a verbal memory test compared with controls (p = 0.001). CONCLUSIONS: While the most critically ill newborns receive extracorporeal membrane oxygenation and, relatedly, large doses of opioids and sedatives for extended periods, global measures of pain sensitivity and neurobiological and neuropsychological development appear to have minor long-term consequences. Possible memory deficits in extracorporeal membrane oxygenation survivors require additional study, but neonatal extracorporeal membrane oxygenation treatment and associated exposure to opioids and sedatives seem less harmful to humans than expected from animal studies.

Brain connectivity during verbal working memory in children and adolescents.

Working memory (WkM) is a fundamental cognitive process that serves as a building block for higher order cognitive functions. While studies have shown that children and adolescents utilize similar brain regions during verbal WkM, there have been few studies that evaluate the developmental differences in brain connectivity. Our goal was to study the development of brain connectivity related to verbal WkM in typically developing children and adolescents. Thirty-five healthy children and adolescents, divided into three groups: 9-12 (children), 13-16 (young adolescents), and 17-19 (older adolescents) years, were included in this functional magnetic resonance imaging (fMRI) study. The verbal WkM task involved a modified Sternberg item recognition paradigm using three different loads. Brain connectivity analysis was performed using independent component analyses and regressing the components with the design matrix to determine task-related networks. Connectivity analyses resulted in four components associated solely with encoding, four solely with recognition and two with both. Two networks demonstrated age-related differences with respect to load, (1) the left motor area and right cerebellum, and 2) the left prefrontal cortex, left parietal lobe, and right cerebellum. Post hoc analyses revealed that the first network showed significant effects of age between children and the two older groups. There was increasing connectivity with increasing load for adolescents. The second network demonstrated age-related differences between children and older adolescents. Children have higher task-related connectivity at lower loads, but they tend to equalize with the adolescents with higher loads. Finally, a non-load related network involving the orbital frontal and anterior cingulate cortices showed less connectivity in children. Hum Brain Mapp 35:698-711, 2014. © 2012 Wiley Periodicals, Inc.

A comparison of ultrafast and conventional spectral Doppler ultrasound to measure cerebral blood flow velocity during inguinal hernia repair in infants.

BACKGROUND: Ultrafast cerebral Doppler ultrasound enables simultaneous quantification and visualization of cerebral blood flow velocity. The aim of this study is to compare the use of conventional and ultrafast spectral Doppler during anesthesia and their potential to show the effect of anesthesiologic procedures on cerebral blood flow velocities, in relation to blood pressure and cerebral oxygenation in infants undergoing inguinal hernia repair. METHODS: A single-center prospective observational cohort study in infants up to six months of age. We evaluated conventional and ultrafast spectral Doppler cerebral ultrasound measurements in terms of number of successful measurements during the induction of anesthesia, after sevoflurane induction, administration of caudal analgesia, a fluid bolus and emergence of anesthesia. Cerebral blood flow velocity was quantified in pial arteries using conventional spectral Doppler and in the cerebral cortex using ultrafast Doppler by peak systolic velocity, end diastolic velocity and resistivity index. RESULTS: Twenty infants were included with useable conventional spectral Doppler images in 72/100 measurements and ultrafast Doppler images in 51/100 measurements. Intraoperatively, the success rates were 53/60 (88.3%) and 41/60 (68.3%), respectively. Cerebral blood flow velocity increased after emergence for both conventional (end diastolic velocity, from 2.01 to 2.75 cm/s, p < 0.001) and ultrafast spectral Doppler (end diastolic velocity, from 0.59 to 0.94 cm/s), whereas cerebral oxygenation showed a reverse pattern with a decrease after the emergence of the infant (85% to 68%, p < 0.001). CONCLUSION: It is possible to quantify cortical blood flow velocity during general anesthesia using conventional and ultrafast spectral Doppler cerebral ultrasound. Cerebral blood flow velocity and blood pressure decreased, while regional cerebral oxygenation increased during general anesthesia. Ultrafast spectral Doppler ultrasound offers novel insights into perfusion within the cerebral cortex, unattainable through conventional spectral ultrasound. Yet, ultrafast Doppler is curtailed by a lower success rate and a more rigorous learning curve compared to conventional method.

Biomarkers for assessing pain and pain relief in the neonatal intensive care unit.

Newborns admitted to the neonatal intensive care unit (NICU) regularly undergo painful procedures and may face various painful conditions such as postoperative pain. Optimal management of pain in these vulnerable preterm and term born neonates is crucial to ensure their comfort and prevent negative consequences of neonatal pain. This entails accurate and timely identification of pain, non-pharmacological pain treatment and if needed administration of analgesic therapy, evaluation of treatment effectiveness, and monitoring of adverse effects. Despite the widely recognized importance of pain management, pain assessment in neonates has thus far proven to be a challenge. As self-report, the gold standard for pain assessment, is not possible in neonates, other methods are needed. Several observational pain scales have been developed, but these often rely on snapshot and largely subjective observations and may fail to capture pain in certain conditions. Incorporation of biomarkers alongside observational pain scores holds promise in enhancing pain assessment and, by extension, optimizing pain treatment and neonatal outcomes. This review explores the possibilities of integrating biomarkers in pain assessment in the NICU.

Current anesthesia practice for preterm infants undergoing surgery for necrotizing enterocolitis: A European survey.

STUDY OBJECTIVE: Necrotizing enterocolitis (NEC) is a life-threatening intestinal illness mostly affecting preterm infants, which commonly requires surgery. Anesthetic care for these patients is challenging, due to their prematurity and critical illness with hemodynamic instability. Currently, there are no guidelines for anesthetic care for these vulnerable patients. Therefore, this study aimed to describe current anesthesia practices across Europe for infants undergoing surgery for NEC. DESIGN: Cross-sectional survey study. PARTICIPANTS: Anesthesiologists working in centers where surgery for NEC is performed across Europe. MEASUREMENTS: A 46-item questionnaire assessing protocols for anesthesia practice, preoperative care, intraoperative care, postoperative care, and the respondent's opinion on the adequacy of anesthetic care for patients with NEC in their center. MAIN RESULTS: Out of the 173 responding anesthesiologists from 31 countries, approximately a third had a written standard protocol for anesthetic care in infants. Three quarters of the respondents screened all patients with NEC preoperatively, and a third structurally performed preoperative multidisciplinary consultation. For induction of general anesthesia, most respondents opted for intravenous anesthesia (n = 73, 43%) or a combination of intravenous and inhalation anesthesia (n = 57, 33%). For intravenous induction, they mostly used propofol (n = 58, 44%), followed by midazolam (n = 43, 33%) and esketamine (n = 42, 32%). For maintenance of anesthesia, inhalation anesthetic agents were more commonly used (solely: n = 71, 41%; in combination: n = 37, 22%), almost exclusively with sevoflurane. Postoperative analgesics mainly included paracetamol and/or morphine. Sixty percent of the respondents (n = 104) considered their anesthetic care for patients with NEC adequate. Suggestions for further improvement mainly revolved around monitoring, protocols, and collaboration. CONCLUSIONS: Anesthesia practice for infants undergoing surgery for NEC was highly variable. Most respondents considered the provided anesthetic care for patients with NEC adequate, but also recognized opportunities for further improvement, especially with regards to monitoring, protocols, and interdisciplinary collaboration.

Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial.

IMPORTANCE: Continuous morphine infusion as standard postoperative analgesic therapy in young infants is associated with unwanted adverse effects such as respiratory depression. OBJECTIVE: To determine whether intravenous paracetamol (acetaminophen) would significantly (>30%) reduce morphine requirements in neonates and infants after major surgery. DESIGN, SETTING, AND PATIENTS: Single-center, randomized, double-blind study conducted in a level 3 pediatric intensive care unit in Rotterdam, The Netherlands. Patients were 71 neonates or infants younger than 1 year undergoing major thoracic (noncardiac) or abdominal surgery between March 2008 and July 2010, with follow-up of 48 hours. INTERVENTIONS: All patients received a loading dose of morphine 30 minutes before the end of surgery, followed by continuous morphine or intermittent intravenous paracetamol up to 48 hours postsurgery. Infants in both study groups received morphine (boluses and/or continuous infusion) as rescue medication on the guidance of the validated pain assessment instruments. MAIN OUTCOME MEASURES: Primary outcome was cumulative morphine dose (study and rescue dose). Secondary outcomes were pain scores and morphine-related adverse effects. RESULTS: The cumulative median morphine dose in the first 48 hours postoperatively was 121 (interquartile range, 99-264) µg/kg in the paracetamol group (n = 33) and 357 (interquartile range, 220-605) µg/kg in the morphine group (n = 38), P < .001, with a between-group difference that was 66% (95% CI, 34%-109%) lower in the paracetamol group. Pain scores and adverse effects were not significantly different between groups. CONCLUSION AND RELEVANCE: Among infants undergoing major surgery, postoperative use of intermittent intravenous paracetamol compared with continuous morphine resulted in a lower cumulative morphine dose over 48 hours. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1438.

COMFORTneo scale: a reliable and valid instrument to measure prolonged pain in neonates?

OBJECTIVE: We studied the reliability and validity of the COMFORTneo scale, designed to measure neonatal prolonged pain. STUDY DESIGN: This prospective observational study evaluated four clinimetric properties of the COMFORTneo scale from NICU nurses' assessments of neonates' pain. Intra-rater reliability was determined from three video fragments at two time points. Inter-rater reliability and construct validity were determined in five neonates per nurse with the COMFORTneo and numeric rating scales (NRS) for pain and distress. Pain scores using N-PASS were correlated with COMFORTneo scores to further evaluate construct validity. RESULT: Intra-rater reliability: Twenty-two nurses assessed pain twice with an intraclass correlation coefficient (ICC) of 0.70. Inter-rater reliability: The ICC for 310 COMFORTneo scores together with 62 nurses was 0.93. Construct validity: Correlation between COMFORTneo and NRS pain, distress, and N-PASS was 0.34, 0.72, and 0.70, respectively. CONCLUSION: The COMFORTneo can be used to reliably and validly assess pain in NICU patients.

The influence of intensive care treatment in infancy on cortisol levels in childhood and adolescence.

BACKGROUND: Infants admitted to the intensive care unit experience numerous early-life stressors, which may have long-term effects on hypothalamic-pituitary-adrenal axis functioning. AIMS: To determine the effects of intensive care treatment and related exposure to stress, pain, and opioids in infancy on cortisol levels in childhood and adolescence. STUDY DESIGN: Cross-sectional study. SUBJECTS: Children and adolescents aged 8 to 18 years with a history of intensive care treatment in infancy and healthy controls. The intensive care treatment cohort consisted of four subgroups with varying levels of exposure to stress, pain, and opioids in infancy. They received either mechanical ventilation, extracorporeal membrane oxygenation, major surgery, or excochleation of a giant congenital melanocytic nevus. OUTCOME MEASURES: Between-group differences in stress reactivity to a study visit consisting of pain threshold testing and an MRI examination and diurnal cortisol levels, as measured in saliva. RESULTS: After adjustment for age, sex, and gestational age, the diurnal cortisol output (AUCg) in the overall intensive care group (N = 76) was 18 % (approximately 1000 nmol/L) (95 % CI [-31 %, -3 %], P = 0.022) lower than that in the control group (N = 67). Cortisol awakening response, diurnal decline, and stress reactivity neither differed significantly between the overall intensive care group and control group, nor between the intensive care subgroups and control group. CONCLUSION: Children and adolescents with a history of intensive care treatment in infancy have similar cortisol profiles to those of healthy controls, except for an 18 % lower diurnal cortisol output. The clinical relevance of this reduction is yet to be determined.

Sedation Prior to Intubation at Birth in Infants with Congenital Diaphragmatic Hernia: An International Survey on Current Practices.

INTRODUCTION: Infants with congenital diaphragmatic hernia (CDH) are commonly intubated immediately after birth. Consensus on whether to provide sedation prior to intubation in the delivery room is lacking, although avoidance of stress is especially important in this population with high risk of pulmonary hypertension. We aimed at obtaining an overview of local pharmacological interventions and at providing guidance on delivery room management. METHODS: An electronic survey was sent to international clinicians in referral centres for prenatal and postnatally diagnosed infants with CDH. This survey addressed demographic information, use of sedation and/or muscle relaxant prior to intubation, and use of pain scales in the delivery room. RESULTS: We received 93 relevant responses from 59 centres. Most centres were from Europe (n = 33, 56%), followed by North America (n = 16, 27%), Asia (n = 6, 10%), Australia (n = 2, 3%), and South America (n = 2, 3%). A total of 19% (11/59) of the centres routinely provided sedation prior to intubation in the delivery room, with midazolam and fentanyl being most often used. Methods of administration varied for all medications provided. Only 5 of 11 centres using sedation reported an adequate sedative effect prior to intubation. Muscle relaxants prior to intubation were used in 12% (7/59) of the centres, although not always in combination with sedation. CONCLUSION: This international survey shows a substantial variation in sedation practices in the delivery room and scarce use of both sedative agents and muscle relaxants prior to intubation of CDH infants. We provide guidance on developing protocols for pre-intubation medication in this population.

Risk factors for pediatric intensive care admission in children with acute asthma.

INTRODUCTION: Severe acute asthma in children is associated with substantial morbidity and may require pediatric ICU (PICU) admission. The aim of the study was to determine risk factors for PICU admission. METHODS: The study used a retrospective multicenter case-control design. The cases included children admitted to the PICU because of severe acute asthma and a history of out-patient treatment by pediatricians or pediatric pulmonologists. Controls were children with asthma without a PICU admission for severe acute asthma. The children were matched for sex, age, hospital, and time elapsed since the diagnosis of asthma. Fourteen possible risk factors were analyzed. RESULTS: Sixty-six cases were matched to 164 controls. In univariate analysis, all but one of the analyzed variables were significantly associated with PICU-hospitalization. After multivariate conditional logistic regression analysis, 4 risk factors remained significant. These included active or passive smoking, allergies, earlier hospitalization for asthma, and non-sanitized home. CONCLUSIONS: Physicians and parents should be aware of these risk factors, and efforts should be made to counteract them.

Neonatal Pain, Opioid, and Anesthetic Exposure; What Remains in the Human Brain After the Wheels of Time?

Objective: To evaluate possible negative long-term effects of neonatal exposure to pain, opioids and anesthetics in children and adolescents. Study Design: We studied five unique groups of children recruited from well-documented neonatal cohorts with a history of neonatal exposure to pain, opioids or anesthetics at different points along the continuum from no pain to intense pain and from no opioid exposure to very high opioid exposure in the presence or absence of anesthetics. We evaluated children who underwent major surgery (group 1 and 2), extracorporeal membrane oxygenation (group 3), preterm birth (group 4) and prenatal opioid exposure (group 5) in comparison to healthy controls. Neuropsychological functioning, thermal detection and pain thresholds and high-resolution structural and task-based functional magnetic resonance imaging during pain were assessed. In total 94 cases were included and compared to their own control groups. Results: Children and adolescents in groups 3 and 5 showed worse neuropsychological functioning after high opioid exposure. A thicker cortex was found in group 1 (pain, opioid and anesthetic exposure) in only the left rostral-middle-frontal-cortex compared to controls. We found no differences in other brain volumes, pain thresholds or brain activity during pain in pain related brain regions between the other groups and their controls. Conclusions: No major effects of neonatal pain, opioid or anesthetic exposure were observed in humans 8-19 years after exposure in early life, apart from neuropsychological effects in the groups with the highest opioid exposure that warrants further investigation. Studies with larger sample sizes are needed to confirm our findings and test for less pronounced differences between exposed and unexposed children.

Risk for neonatal hypoglycaemia and bradycardia after beta-blocker use during pregnancy or lactation: a systematic review and meta-analysis protocol.

INTRODUCTION: Beta-blockers are often used during pregnancy to treat diseases such as pre-existing hypertension, arrhythmias or pregnancy-related hypertension. Since beta-blockers are able to cross the placenta and can pass into breast milk, they could potentially harm the neonate. Known potential neonatal side effects of maternal beta-blocker use are hypoglycaemia and bradycardia. This systematic review and meta-analysis aims to investigate the risk for neonatal hypoglycaemia and bradycardia after exposure to beta-blockers in utero or through lactation. METHODS AND ANALYSIS: We will conduct a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic electronic search will be conducted using EMBASE, Medline, Cochrane Central Register of Trials and Web of Science from initiation to April 2021. Our primary outcome will be the risk for hypoglycaemia or bradycardia in neonates exposed to beta-blockers in utero or through lactation in comparison with unexposed neonates. All articles will be screened by title and abstract twice by different independent review authors. Next, standardised methodological quality assessment will be conducted for each included article and finally a meta-analysis will be performed. ETHICS AND DISSEMINATION: Ethical approval is not required. The results of this study will help to assess the need for postnatal glucose and heart rate monitoring of the neonate after maternal beta-blocker exposure. Our findings will be communicated to the target audience through peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42021264269.

The Risk for Neonatal Hypoglycemia and Bradycardia after Beta-Blocker Use during Pregnancy or Lactation: A Systematic Review and Meta-Analysis.

Beta-blockers are often used during pregnancy to treat cardiovascular diseases. The described neonatal side effects of maternal beta-blocker use are hypoglycemia and bradycardia, but the evidence base for these is yet to be evaluated comprehensively. Hence, this systematic review and meta-analysis was performed to evaluate the potential increased risk for hypoglycemia and bradycardia in neonates exposed to beta-blockers in utero or during lactation. A systematic search of English-language human studies was conducted until 21 April 2021. Both observational studies and randomized controlled trials investigating hypoglycemia and/or bradycardia in neonates following beta-blocker exposure during pregnancy and lactation were included. All articles were screened by two authors independently and eligible studies were included. Pair-wise and proportion-based meta-analysis was conducted and the certainty of evidence (CoE) was performed by standard methodologies. Of the 1.043 screened articles, 55 were included in this systematic review. Our meta-analysis showed a probable risk of hypoglycemia (CoE-Moderate) and possible risk of bradycardia (CoE-Low) in neonates upon fetal beta-blocker exposure. Therefore, we suggest the monitoring of glucose levels in exposed neonates until 24 h after birth. Due to the limited clinical implication, monitoring of the heart rate could be considered for 24 h. We call for future studies to substantiate our findings.

Developmental neurobiology as a guide for pharmacological management of pain in neonates.

Pain in newborn children should be prevented due to negative short- and long-term consequences. A good understanding of the development of the nociceptive system in newborns is necessary to enable optimal pain assessment, and most importantly to treat and prevent pain adequately in neonates. So far, preclinical juvenile animal studies have led to a tremendous amount of information regarding the development of the nociceptive system. In addition, they have made clear that the developmental stage of the nociceptive system may influence the mechanism of action of different classes of analgesics. Age specific analgesic therapy, based on post-menstrual age, should therefore be considered by incorporating information on the developmental stages of the nociceptive system in combination with knowledge from pharmacokinetic and -dynamic studies in neonates.