Inhaled bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.

BACKGROUND: Chronic lung disease (CLD) occurs frequently in preterm infants and is associated with respiratory morbidity. Bronchodilators have the potential effect of dilating small airways with muscle hypertrophy. Increased compliance and tidal volume, and decreased airway resistance, have been documented with the use of bronchodilators in infants with CLD. Therefore, bronchodilators are widely considered to have a role in the prevention and treatment of CLD, but there remains uncertainty as to whether they improve clinical outcomes. This is an update of the 2016 Cochrane review. OBJECTIVES: To determine the effect of inhaled bronchodilators given as prophylaxis or as treatment for chronic lung disease (CLD) on mortality and other complications of preterm birth in infants at risk for or identified as having CLD. SEARCH METHODS: An Information Specialist searched CENTRAL, MEDLINE, Embase, CINAHL and three trials registers from 2016 to May 2023. In addition, the review authors undertook reference checking, citation searching and contact with trial authors to identify additional studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials involving preterm infants less than 32 weeks old that compared bronchodilators to no intervention or placebo. CLD was defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age. Initiation of bronchodilator therapy for the prevention of CLD had to occur within two weeks of birth. Treatment of infants with CLD had to be initiated before discharge from the neonatal unit. The intervention had to include administration of a bronchodilator by nebulisation or metered dose inhaler. The comparator was no intervention or placebo. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Critical outcomes included: mortality within the trial period; CLD (defined as oxygen dependency at 28 days of life or at 36 weeks' postmenstrual age); adverse effects of bronchodilators, including hypokalaemia (low potassium levels in the blood), tachycardia, cardiac arrhythmia, tremor, hypertension and hyperglycaemia (high blood sugar); and pneumothorax. We used the GRADE approach to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included two randomised controlled trials in this review update. Only one trial provided useable outcome data. This trial was conducted in six neonatal intensive care units in France and Portugal, and involved 173 participants with a gestational age of less than 31 weeks. The infants in the intervention group received salbutamol for the prevention of CLD. The evidence suggests that salbutamol may result in little to no difference in mortality (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.50 to 2.31; risk difference (RD) 0.01, 95% CI -0.09 to 0.11; low-certainty evidence) or CLD at 28 days (RR 1.03, 95% CI 0.78 to 1.37; RD 0.02, 95% CI -0.13 to 0.17; low-certainty evidence), when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax. The one trial with usable data reported that there were no relevant differences between groups, without providing the number of events (very low-certainty evidence). Investigators in this study did not report if side effects occurred. We found no eligible trials that evaluated the use of bronchodilator therapy for the treatment of infants with CLD. We identified no ongoing studies. AUTHORS' CONCLUSIONS: Low-certainty evidence from one trial showed that inhaled bronchodilator prophylaxis may result in little or no difference in the incidence of mortality or CLD in preterm infants, when compared to placebo. The evidence is very uncertain about the effect of salbutamol on pneumothorax, and neither included study reported on the incidence of serious adverse effects. We identified no trials that studied the use of bronchodilator therapy for the treatment of CLD. Additional clinical trials are necessary to assess the role of bronchodilator agents in the prophylaxis or treatment of CLD. Researchers studying the effects of inhaled bronchodilators in preterm infants should include relevant clinical outcomes in addition to pulmonary mechanical outcomes.

Value of preclinical systematic reviews and meta-analyses in pediatric research.

Similar to systematic reviews (SRs) in clinical fields, preclinical SRs address a specific research area, furnishing information on current knowledge, possible gaps, and potential methodological flaws of study design, conduct, and report. One of the main goals of preclinical SRs is to identify aspiring treatment strategies and evaluate if currently available data is solid enough to translate to clinical trials or highlight the gaps, thus justifying the need for new studies. It is imperative to rigorously follow the methodological standards that are widely available. These include registration of the protocol and adherence to guidelines for assessing the risk of bias, study quality, and certainty of evidence. A special consideration should be made for pediatric SRs, clinical and preclinical, due to the unique characteristics of this age group. These include rationale for intervention and comparison of primary and secondary outcomes. Outcomes measured should acknowledge age-related physiological changes and maturational processes of different organ systems. It is crucial to choose the age of the animals appropriately and its possible correspondence for specific pediatric age groups. The findings of well-conducted SRs of preclinical studies have the potential to provide a reliable evidence synthesis to guide the design of future preclinical and clinical studies. IMPACT: This narrative review highlights the importance of rigorous design, conduct and reporting of preclinical primary studies and systematic reviews. A special consideration should be made for pediatric systematic reviews of preclinical studies, due to the unique characteristics of this age group.

Workplace interventions to reduce the risk of SARS-CoV-2 infection outside of healthcare settings.

BACKGROUND: Although many people infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) experience no or mild symptoms, some individuals can develop severe illness and may die, particularly older people and those with underlying medical problems. Providing evidence-based interventions to prevent SARS-CoV-2 infection has become more urgent with the potential psychological toll imposed by the coronavirus disease 2019 (COVID-19) pandemic. Controlling exposures to occupational hazards is the fundamental method of protecting workers. When it comes to the transmission of viruses, workplaces should first consider control measures that can potentially have the most significant impact. According to the hierarchy of controls, one should first consider elimination (and substitution), then engineering controls, administrative controls, and lastly, personal protective equipment. This is the first update of a Cochrane review published 6 May 2022, with one new study added. OBJECTIVES: To assess the benefits and harms of interventions in non-healthcare-related workplaces aimed at reducing the risk of SARS-CoV-2 infection compared to other interventions or no intervention. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science Core Collections, Cochrane COVID-19 Study Register, World Health Organization (WHO) COVID-19 Global literature on coronavirus disease, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and medRxiv to 13 April 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies of interventions. We included adult workers, both those who come into close contact with clients or customers (e.g. public-facing employees, such as cashiers or taxi drivers), and those who do not, but who could be infected by coworkers. We excluded studies involving healthcare workers. We included any intervention to prevent or reduce workers' exposure to SARS-CoV-2 in the workplace, defining categories of intervention according to the hierarchy of hazard controls (i.e. elimination; engineering controls; administrative controls; personal protective equipment). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were incidence rate of SARS-CoV-2 infection (or other respiratory viruses), SARS-CoV-2-related mortality, adverse events, and absenteeism from work. Our secondary outcomes were all-cause mortality, quality of life, hospitalisation, and uptake, acceptability, or adherence to strategies. We used the Cochrane RoB 2 tool to assess risk of bias, and GRADE methods to evaluate the certainty of evidence for each outcome. MAIN RESULTS: We identified 2 studies including a total of 16,014 participants. Elimination-of-exposure interventions We included one study examining an intervention that focused on elimination of hazards, which was an open-label, cluster-randomised, non-inferiority trial, conducted in England in 2021. The study compared standard 10-day self-isolation after contact with an infected person to a new strategy of daily rapid antigen testing and staying at work if the test is negative (test-based attendance). The trialists hypothesised that this would lead to a similar rate of infections, but lower COVID-related absence. Staff (N = 11,798) working at 76 schools were assigned to standard isolation, and staff (N = 12,229) working at 86 schools were assigned to the test-based attendance strategy. The results between test-based attendance and standard 10-day self-isolation were inconclusive for the rate of symptomatic polymerase chain reaction (PCR)-positive SARS-CoV-2 infection (rate ratio (RR) 1.28, 95% confidence interval (CI) 0.74 to 2.21; 1 study; very low-certainty evidence). The results between test-based attendance and standard 10-day self-isolation were inconclusive for the rate of any PCR-positive SARS-CoV-2 infection (RR 1.35, 95% CI 0.82 to 2.21; 1 study; very low-certainty evidence). COVID-related absenteeism rates were 3704 absence days in 566,502 days-at-risk (6.5 per 1000 working days) in the control group and 2932 per 539,805 days-at-risk (5.4 per 1000 working days) in the intervention group (RR 0.83, 95% CI 0.55 to 1.25). We downgraded the certainty of the evidence to low due to imprecision. Uptake of the intervention was 71% in the intervention group, but not reported for the control intervention. The trial did not measure our other outcomes of SARS-CoV-2-related mortality, adverse events, all-cause mortality, quality of life, or hospitalisation. We found seven ongoing studies using elimination-of-hazard strategies, six RCTs and one non-randomised trial. Administrative control interventions We found one ongoing RCT that aims to evaluate the efficacy of the Bacillus Calmette-Guérin (BCG) vaccine in preventing COVID-19 infection and reducing disease severity. Combinations of eligible interventions We included one non-randomised study examining a combination of elimination of hazards, administrative controls, and personal protective equipment. The study was conducted in two large retail companies in Italy in 2020. The study compared a safety operating protocol, measurement of body temperature and oxygen saturation upon entry, and a SARS-CoV-2 test strategy with a minimum activity protocol. Both groups received protective equipment. All employees working at the companies during the study period were included: 1987 in the intervention company and 1798 in the control company. The study did not report an outcome of interest for this systematic review. Other intervention categories We did not find any studies in this category. AUTHORS' CONCLUSIONS: We are uncertain whether a test-based attendance policy affects rates of PCR-positive SARS-CoV-2 infection (any infection; symptomatic infection) compared to standard 10-day self-isolation amongst school and college staff. A test-based attendance policy may result in little to no difference in absenteeism rates compared to standard 10-day self-isolation. The non-randomised study included in our updated search did not report any outcome of interest for this Cochrane review. As a large part of the population is exposed in the case of a pandemic, an apparently small relative effect that would not be worthwhile from the individual perspective may still affect many people, and thus become an important absolute effect from the enterprise or societal perspective. The included RCT did not report on any of our other primary outcomes (i.e. SARS-CoV-2-related mortality and adverse events). We identified no completed studies on any other interventions specified in this review; however, eight eligible studies are ongoing. More controlled studies are needed on testing and isolation strategies, and working from home, as these have important implications for work organisations.

Ibuprofen for acute postoperative pain in children.

BACKGROUND: Children often require pain management following surgery to avoid suffering. Effective pain management has consequences for healing time and quality of life. Ibuprofen, a frequently used non-steroidal anti-inflammatory drug (NSAID) administered to children, is used to treat pain and inflammation in the postoperative period. OBJECTIVES: 1) To assess the efficacy and safety of ibuprofen (any dose) for acute postoperative pain management in children compared with placebo or other active comparators. 2) To compare ibuprofen administered at different doses, routes (e.g. oral, intravenous, etc.), or strategies (e.g. as needed versus as scheduled). SEARCH METHODS: We used standard Cochrane search methods. We searched CENTRAL, MEDLINE, Embase, CINAHL and trials registries in August 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in children aged 17 years and younger, treated for acute postoperative or postprocedural pain, that compared ibuprofen to placebo or any active comparator. We included RCTs that compared different administration routes, doses of ibuprofen and schedules. DATA COLLECTION AND ANALYSIS: We adhered to standard Cochrane methods for data collection and analysis. Our primary outcomes were pain relief reported by the child, pain intensity reported by the child, adverse events, and serious adverse events. We present results using risk ratios (RR) and standardised mean differences (SMD), with the associated confidence intervals (CI). We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 43 RCTs that enroled 4265 children (3935 children included in this review). We rated the overall risk of bias at the study level as high or unclear for 37 studies that had one or several unclear or high risk of bias judgements across the domains. We judged six studies as having a low risk of bias across all domains. Ibuprofen versus placebo (35 RCTs) No studies reported pain relief reported by the child or a third party, or serious adverse events. Ibuprofen probably reduces child-reported pain intensity less than two hours postintervention compared to placebo (SMD -1.12, 95% CI -1.39 to -0.86; 3 studies, 259 children; moderate-certainty evidence). Ibuprofen may reduce child-reported pain intensity, two hours to less than 24 hours postintervention (SMD -1.01, 95% CI -1.24 to -0.78; 5 studies, 345 children; low-certainty evidence). Ibuprofen may result in little to no difference in adverse events compared to placebo (RR 0.79, 95% CI 0.51 to 1.23; 5 studies, 384 children; low-certainty evidence). Ibuprofen versus paracetamol (21 RCTs) No studies reported pain relief reported by the child or a third party, or serious adverse events. Ibuprofen likely reduces child-reported pain intensity less than two hours postintervention compared to paracetamol (SMD -0.42, 95% CI -0.82 to -0.02; 2 studies, 100 children; moderate-certainty evidence). Ibuprofen may slightly reduce child-reported pain intensity two hours to 24 hours postintervention (SMD -0.21, 95% CI -0.40 to -0.02; 6 studies, 422 children; low-certainty evidence). Ibuprofen may result in little to no difference in adverse events (0 events in each group; 1 study, 44 children; low-certainty evidence). Ibuprofen versus morphine (1 RCT) No studies reported pain relief or pain intensity reported by the child or a third party, or serious adverse events. Ibuprofen likely results in a reduction in adverse events compared to morphine (RR 0.58, 95% CI 0.40 to 0.83; risk difference (RD) -0.25, 95% CI -0.40 to -0.09; number needed to treat for an additional beneficial outcome (NNTB) 4; 1 study, 154 children; moderate-certainty evidence). Ibuprofen versus ketorolac (1 RCT) No studies reported pain relief or pain intensity reported by the child, or serious adverse events. Ibuprofen may result in a reduction in adverse events compared to ketorolac (RR 0.51, 95% CI 0.27 to 0.96; RD -0.29, 95% CI -0.53 to -0.04; NNTB 4; 1 study, 59 children; low-certainty evidence). AUTHORS' CONCLUSIONS: Despite identifying 43 RCTs, we remain uncertain about the effect of ibuprofen compared to placebo or active comparators for some critical outcomes and in the comparisons between different doses, schedules and routes for ibuprofen administration. This is largely due to poor reporting on important outcomes such as serious adverse events, and poor study conduct or reporting that reduced our confidence in the results, along with small underpowered studies. Compared to placebo, ibuprofen likely results in pain reduction less than two hours postintervention, however, the efficacy might be lower at two hours to 24 hours. Compared to paracetamol, ibuprofen likely results in pain reduction up to 24 hours postintervention. We could not explore if there was a different effect in different kinds of surgeries or procedures. Ibuprofen likely results in a reduction in adverse events compared to morphine, and in little to no difference in bleeding when compared to paracetamol. We remain mostly uncertain about the safety of ibuprofen compared to other drugs.

Diclofenac for acute postoperative pain in children.

BACKGROUND: Many children undergo various surgeries, which often lead to acute postoperative pain. This pain influences recovery and quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs), specifically cyclo-oxygenase (COX) inhibitors such as diclofenac, can be used to treat pain and reduce inflammation. There is uncertainty regarding diclofenac's benefits and harms compared to placebo or other drugs for postoperative pain. OBJECTIVES: To assess the efficacy and safety of diclofenac (any dose) for acute postoperative pain management in children compared with placebo, other active comparators, or diclofenac administered by different routes (e.g. oral, rectal, etc.) or strategies (e.g. 'as needed' versus 'as scheduled'). SEARCH METHODS: We used standard, extensive Cochrane search methods. We searched CENTRAL, MEDLINE, and trial registries on 11 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in children under 18 years of age undergoing surgery that compared diclofenac (delivered in any dose and route) to placebo or any active pharmacological intervention. We included RCTs comparing different administration routes of diclofenac and different strategies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were: pain relief (PR) reported by the child, defined as the proportion of children reporting 50% or better postoperative pain relief; pain intensity (PI) reported by the child; adverse events (AEs); and serious adverse events (SAEs). We presented results using risk ratios (RR), mean differences (MD), and standardised mean differences (SMD), with the associated confidence intervals (CI). MAIN RESULTS: We included 32 RCTs with 2250 children. All surgeries were done using general anaesthesia. Most studies (27) included children above age three. Only two studies had an overall low risk of bias; 30 had an unclear or high risk of bias in one or several domains. Diclofenac versus placebo (three studies) None of the included studies reported on PR or PI. We are very uncertain about the benefits and harms of diclofenac versus placebo on nausea/vomiting (RR 0.83, 95% CI 0.38 to 1.80; 2 studies, 100 children) and any reported bleeding (RR 3.00, 95% CI 0.34 to 26.45; 2 studies, 100 children), both very low-certainty evidence. None of the included studies reported SAEs. Diclofenac versus opioids (seven studies) We are very uncertain if diclofenac reduces PI at 2 to 24 hours postoperatively compared to opioids (median pain intensity 0.3 (interquartile range (IQR) 0.0 to 2.5) for diclofenac versus median 0.7 (IQR 0.1 to 2.4) in the opioid group; 1 study, 50 children; very low-certainty evidence). None of the included studies reported on PR or PI for other time points. Diclofenac probably results in less nausea/vomiting compared to opioids (41.0% in opioids, 31.0% in diclofenac; RR 0.75, 95% CI 0.58 to 0.96; 7 studies, 463 participants), and probably increases any reported bleeding (5.4% in opioids, 16.5% in diclofenac; RR 3.06, 95% CI 1.31 to 7.13; 2 studies, 222 participants), both moderate-certainty evidence. None of the included studies reported SAEs. Diclofenac versus paracetamol (10 studies) None of the included studies assessed child-reported PR. Compared to paracetamol, we are very uncertain if diclofenac: reduces PI at 0 to 2 hours postoperatively (SMD -0.45, 95% CI -0.74 to -0.15; 2 studies, 180 children); reduces PI at 2 to 24 hours postoperatively (SMD -0.64, 95% CI -0.89 to -0.39; 3 studies, 300 children); reduces nausea/vomiting (RR 0.47, 95% CI 0.25 to 0.87; 5 studies, 348 children); reduces bleeding events (RR 0.57, 95% CI 0.12 to 2.62; 5 studies, 332 participants); or reduces SAEs (RR 0.50, 95% CI 0.05 to 5.22; 1 study, 60 children). The evidence certainty was very low for all outcomes. Diclofenac versus bupivacaine (five studies) None of the included studies reported on PR or PI. Compared to bupivacaine, we are very uncertain about the effect of diclofenac on nausea/vomiting (RR 1.28, 95% CI 0.58 to 2.78; 3 studies, 128 children) and SAEs (RR 4.52, 95% CI 0.23 to 88.38; 1 study, 38 children), both very low-certainty evidence. Diclofenac versus active pharmacological comparator (10 studies) We are very uncertain about the benefits and harms of diclofenac versus any other active pharmacological comparator (dexamethasone, pranoprofen, fluorometholone, oxybuprocaine, flurbiprofen, lignocaine), and for different routes and delivery of diclofenac, due to few and small studies, no reporting of key outcomes, and very low-certainty evidence for the reported outcomes. We are unable to draw any meaningful conclusions from the numerical results. AUTHORS' CONCLUSIONS: We remain uncertain about the efficacy of diclofenac compared to placebo, active comparators, or by different routes of administration, for postoperative pain management in children. This is largely due to authors not reporting on clinically important outcomes; unclear reporting of the trials; or poor trial conduct reducing our confidence in the results. We remain uncertain about diclofenac's safety compared to placebo or active comparators, except for the comparison of diclofenac with opioids: diclofenac probably results in less nausea and vomiting compared with opioids, but more bleeding events. For healthcare providers managing postoperative pain, diclofenac is a COX inhibitor option, along with other pharmacological and non-pharmacological approaches. Healthcare providers should weigh the benefits and risks based on what is known of their respective pharmacological effects, rather than known efficacy. For surgical interventions in which bleeding or nausea and vomiting are a concern postoperatively, the risks of adverse events using opioids or diclofenac for managing pain should be considered.

Positioning for lumbar puncture in newborn infants.

BACKGROUND: Lumbar puncture is a common invasive procedure performed in newborns for diagnostic and therapeutic purposes. Approximately one in two lumbar punctures fail, resulting in both short- and long-term negative consequences for the clinical management of patients. The most common positions used to perform lumbar puncture are the lateral decubitus and sitting position, and each can impact the success rate and safety of the procedure. However, it is uncertain which position best improves patient outcomes. OBJECTIVES: To assess the benefits and harms of the lateral decubitus, sitting, and prone positions for lumbar puncture in newborn infants. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 24 January 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs involving newborn infants of postmenstrual age up to 46 weeks and 0 days, undergoing lumbar puncture for any indication, comparing different positions (i.e. lateral decubitus, sitting, and prone position) during the procedure. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) and standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CI). Our primary outcomes were successful lumbar puncture procedure at the first attempt; total number of lumbar puncture attempts; and episodes of bradycardia. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included five studies with 1476 participants. Compared to sitting position: lateral decubitus position probably results in little to no difference in successful lumbar puncture procedure at the first attempt (RR 0.99, 95% CI 0.88 to 1.12; RD 0.00, 95% CI -0.06 to 0.05; I2 = 47% and 46% for RR and RD, respectively; 2 studies, 1249 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts as specified in this review. Lateral decubitus position likely increases episodes of bradycardia (RR 1.72, 95% CI 1.08 to 2.76; RD 0.03, 95% CI 0.00 to 0.05; number needed to treat for an additional harmful outcome (NNTH) = 33; I2 = not applicable and 69% for RR and RD, respectively; 3 studies, 1279 infants, moderate-certainty evidence) and oxygen desaturation (RR 2.10, 95% CI 1.42 to 3.08; RD 0.06, 95% CI 0.03 to 0.09; NNTH = 17; I2 = not applicable and 96% for RR and RD, respectively; 2 studies, 1249 infants, moderate-certainty evidence). Lateral decubitus position results in little to no difference in time to perform the lumbar puncture compared to sitting position (I2 = not applicable; 2 studies; 1102 infants; high-certainty evidence; in one of the study median and IQR to report time to perform the lumbar puncture were 8 (5-13) and 8 (5-12) in the lateral and sitting position, respectively, I2 = not applicable; 1 study, 1082 infants; in the other study: mean difference 2.00, 95% CI -4.98 to 8.98; I2 = not applicable; 1 study, 20 infants). Lateral decubitus position may result in little to no difference in the number of episodes of apnea during the procedure (RR not estimable; RD 0.00, 95% CI -0.03 to 0.03; I2 = not applicable and 0% for RR and RD, respectively; 2 studies, 197 infants, low-certainty evidence). No studies reported apnea defined as number of infants with one or more episodes during the procedure. Compared to prone position: lateral decubitus position may reduce successful lumbar puncture procedure at first attempt (RR 0.75, 95% CI 0.63 to 0.90; RD -0.21, 95% CI -0.34 to -0.09; number needed to treat for an additional beneficial outcome = 5; I2 = not applicable; 1 study, 171 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts or episodes of apnea. Pain intensity during and after the procedure was reported using a non-validated pain scale. None of the studies comparing lateral decubitus versus prone position reported the other critical outcomes of this review. AUTHORS' CONCLUSIONS: When compared to sitting position, lateral decubitus position probably results in little to no difference in successful lumbar puncture procedure at first attempt. None of the included studies reported the total number of lumbar puncture attempts as specified in this review. Furthermore, infants in a sitting position likely experience less episodes of bradycardia and oxygen desaturation than in the lateral decubitus, and there may be little to no difference in episodes of apnea. Lateral decubitus position results in little to no difference in time to perform the lumbar puncture compared to sitting position. Pain intensity during and after the procedure was reported using a pain scale that was not included in our prespecified tools for pain assessment due to its high risk of bias. Most study participants were term newborns, thereby limiting the applicability of these results to preterm babies. When compared to prone position, lateral decubitus position may reduce successful lumbar puncture procedure at first attempt. Only one study reported on this comparison and did not evaluate adverse effects. Further research exploring harms and benefits and the effect on patients' pain experience of different positions during lumbar puncture using validated pain scoring tool may increase the level of confidence in our conclusions.

Stem cell-based interventions for the treatment of stroke in newborn infants.

BACKGROUND: Perinatal stroke refers to a diverse but specific group of cerebrovascular diseases that occur between 20 weeks of fetal life and 28 days of postnatal life. Acute treatment options for perinatal stroke are limited supportive care, such as controlling hypoglycemia and seizures. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, or regenerate injured brain tissue. Preclinical findings have culminated in ongoing human neonatal studies. OBJECTIVES: To evaluate the benefits and harms of stem cell-based interventions for the treatment of stroke in newborn infants compared to control (placebo or no treatment) or stem-cell based interventions of a different type or source. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, and three trials registries in February 2023. We planned to search the reference lists of included studies and relevant systematic reviews for studies not identified by the database searches. SELECTION CRITERIA: We attempted to include randomized controlled trials, quasi-randomized controlled trials, and cluster trials that evaluated any of the following comparisons. • Stem cell-based interventions (any type) versus control (placebo or no treatment) • Mesenchymal stem/stromal cells (MSCs) of a specifictype (e.g. number of doses or passages) or source (e.g. autologous/allogeneic or bone marrow/cord) versus MSCs of another type or source • Stem cell-based interventions (other than MSCs) of a specific type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, or induced pluripotent stem cell-derived cells) or source (e.g. autologous/allogeneic or bone marrow/cord) versus stem cell-based interventions (other than MSCs) of another type or source • MSCs versus stem cell-based interventions other than MSCs We planned to include all types of transplantation regardless of cell source (bone marrow, cord blood, Wharton's jelly, placenta, adipose tissue, peripheral blood), type of graft (autologous or allogeneic), and dose. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all-cause neonatal mortality, major neurodevelopmental disability, and immune rejection or any serious adverse event. Our secondary outcomes included all-cause mortality prior to first hospital discharge, seizures, adverse effects, and death or major neurodevelopmental disability at 18 to 24 months of age. We planned to use GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified no completed or ongoing randomized trials that met our inclusion criteria. We excluded three studies: two were phase 1 trials, and one included newborn infants with conditions other than stroke (i.e. cerebral ischemia and anemia). Among the three excluded studies, we identified the first phase 1 trial on the use of stem cells for neonatal stroke. It reported that a single intranasal application of bone marrow-derived MSCs in term neonates with a diagnosis of perinatal arterial ischemic stroke (PAIS) was feasible and apparently not associated with severe adverse events. However, the trial included only 10 infants, and follow-up was limited to three months. AUTHORS' CONCLUSIONS: No evidence is currently available to evaluate the benefits and harms of stem cell-based interventions for treatment of stroke in newborn infants. We identified no ongoing studies. Future clinical trials should focus on standardizing the timing and method of cell delivery and cell processing to optimize the therapeutic potential of stem cell-based interventions and safety profiles. Phase 1 and large animal studies might provide the groundwork for future randomized trials. Outcome measures should include all-cause mortality, major neurodevelopmental disability and immune rejection, and any other serious adverse events.

Improving rates of successful extubation: Medications.

This chapter focuses on the pharmacological management of newborn infants in the peri-extubation period to reduce the risk of re-intubation and prolonged mechanical ventilation. Drugs used to promote respiratory drive, reduce the risk of apnoea, reduce lung inflammation and avoid bronchospasm are critically assessed. When available, Cochrane reviews and randomised trials are used as the primary sources of evidence. Methylxanthines, particularly caffeine, are well studied and there is accumulating evidence to guide clinicians on the timing and dosage that may be used. Efficacy and safety for doxapram, steroids, adrenaline and salbutamol are summarised. Management of term infants, extubation following surgery, accidental and complicated extubation and the use of cuffed endotracheal tubes are presented. Overall, caffeine is the only drug with a substantial evidence base, proven to increase the likelihood of successful extubation in preterm infants; no drugs are needed to facilitate extubation in most term infants. Future studies might further define the role of caffeine in late preterm infants and evaluate medications for post-extubation stridor, bronchospasm or apnoea not responsive to methylxanthines.

Association between human chorionic gonadotropin (hCG) levels and adverse pregnancy outcomes: A systematic review and meta-analysis.

Human chorionic gonadotropin (hCG), a glycoprotein produced in the placenta, is crucial for a healthy pregnancy. We investigated the relationship between hCG levels and adverse pregnancy outcomes. We conducted a systematic review including studies measuring hCG blood levels in the first or second trimester, reporting on any of the 12 predefined adverse pregnancy outcomes with logistic regression-adjusted association estimates. The primary outcomes were placenta-associated complications, such as miscarriage, preeclampsia, intrauterine growth restriction, and preterm delivery. We searched PubMed, Embase and CINAHL Complete. The hCG levels were analysed as multiple of the median (MoM). Odds ratio (OR) and 95% confidence interval (CI) were used. Risk of bias and the certainty of evidence were assessed using ROBINS-I and GRADE, respectively. Meta-analysis also showed that hCG levels, reported as MoM ≥2/2.31/2.5, might be associated with an increased risk of preeclampsia (OR 2.08, 95% CI 1.26 to 3.44) and preterm delivery (OR 1.29, 95% CI 1.12 to 1.47), but the evidence is very uncertain. High second trimester hCG levels may be associated with preeclampsia and preterm delivery but confidence in evidence is low.

Surfactant therapy guided by tests for lung maturity in preterm infants at risk of respiratory distress syndrome.

BACKGROUND: Administration of various exogenous surfactant preparations has been shown to decrease lung injury and pneumothorax and improve survival in very preterm infants with respiratory distress syndrome (RDS). There is no consensus on the threshold for surfactant administration, to allow timely intervention and avoid over-treatment, also considering the invasiveness of the procedure and its cost. Rapid tests for lung maturity, which include the click test, lamellar body counts and stable microbubble test, might guide the identification of those infants needing surfactant administration. OBJECTIVES: To assess the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants at risk for or having RDS. Comparison 1: In preterm infants at risk for RDS, does surfactant treatment guided by rapid tests for surfactant deficiency compared to prophylactic surfactant administration to all high-risk infants minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality? Comparison 2: In preterm infants who require early respiratory support, does surfactant treatment guided by rapid tests for surfactant deficiency compared to surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality? SEARCH METHODS: We searched in October 2022 CENTRAL, PubMed, Embase and three additional trial registries. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs evaluating rapid tests after birth for surfactant deficiency in infants at high risk of RDS or requiring respiratory support. We specified two comparisons: 1)surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high-risk infants in extremely preterm (less than 28 weeks' gestation) and very preterm (28 to 32 weeks' gestation); 2)surfactant treatment guided by rapid tests for surfactant deficiency versus surfactant therapy provided to preterm infants (less than 37 weeks' gestation) with RDS diagnosed on clinical and radiologic criteria. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) and risk difference (RD), with their 95% confidence intervals (CIs) for dichotomous data. Our primary outcomes were: neonatal mortality, mortality prior to hospital discharge, bronchopulmonary dysplasia and the composite outcome bronchopulmonary dysplasia or mortality. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included three RCTs enrolling 562 newborn infants in this review. No studies compared surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high-risk infants. Comparing surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge: RR 1.25, 95% CI 0.65 to 2.41, RD 0.01, 95% CI -0.03 to 0.05, 562 participants, 3 studies; I² for RR and RD = 75% and 43%, respectively; very low-certainty evidence. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia: RR 0.90, 95% CI 0.61 to 1.32, RD -0.02, 95% CI -0.08 to 0.04, 562 participants, 3 studies; I² for RR and RD = 0%; low-certainty evidence. No studies reported the composite outcome bronchopulmonary dysplasia or mortality. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in surfactant utilization (RR 0.97, 95% CI 0.85 to 1.11, RD -0.02, 95% CI -0.10 to 0.06, 562 participants, 3 studies, I² for RR and RD = 63% and 65%, respectively, low-certainty evidence), and any pneumothorax (RR 0.53, 95% CI 0.15 to 1.92, RD -0.01, 95% CI -0.04 to 0.01, 506 participants, 2 studies, I² for RR and RD = 0%, low-certainty evidence) compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported moderate to severe neurodevelopmental impairment. We identified two large ongoing RCTs. AUTHORS' CONCLUSIONS: No studies compared surfactant treatment guided by rapid tests for surfactant deficiency to prophylactic surfactant administration to all high-risk infants. Low to very low-certainty evidence from three studies is available on surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality, the composite outcome 'bronchopulmonary dysplasia or mortality', or neurodevelopmental outcomes. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia, surfactant utilization and any pneumothorax. The findings of the two large ongoing trials identified in this review are likely to have an important impact on establishing the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants.

Positioning for lumbar puncture in newborn infants.

BACKGROUND: Lumbar puncture is a common invasive procedure performed in newborns for diagnostic and therapeutic purposes. Approximately one in two lumbar punctures fail, resulting in both short- and long-term negative consequences for the clinical management of patients. The most common positions used to perform lumbar puncture are the lateral decubitus and sitting position, and each can impact the success rate and safety of the procedure. However, it is uncertain which position best improves patient outcomes. OBJECTIVES: To assess the benefits and harms of the lateral decubitus, sitting, and prone positions for lumbar puncture in newborn infants. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 24 January 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs involving newborn infants of postmenstrual age up to 46 weeks and 0 days, undergoing lumbar puncture for any indication, comparing different positions (i.e. lateral decubitus, sitting, and prone position) during the procedure. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) and standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CI). Our primary outcomes were successful lumbar puncture procedure at the first attempt; total number of lumbar puncture attempts; and episodes of bradycardia. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included five studies with 1476 participants. Compared to sitting position: lateral decubitus position may result in little to no difference in successful lumbar puncture procedure at the first attempt (RR 0.93, 95% CI 0.85 to 1.02; RD -0.04, 95% CI -0.09 to 0.01; I2 = 70% and 72% for RR and RD, respectively; 2 studies, 1249 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts. Lateral decubitus position likely increases episodes of bradycardia (RR 1.72, 95% CI 1.08 to 2.76; RD 0.03, 95% CI 0.00 to 0.05; number needed to treat for an additional harmful outcome (NNTH) = 33; I2 = not applicable and 69% for RR and RD, respectively; 3 studies, 1279 infants, moderate-certainty evidence) and oxygen desaturation (RR 2.10, 95% CI 1.42 to 3.08; RD 0.06, 95% CI 0.03 to 0.09; NNTH = 17; I2 = not applicable and 96% for RR and RD, respectively; 2 studies, 1249 infants, moderate-certainty evidence). The evidence is very uncertain regarding the effect of lateral decubitus position on time to perform the lumbar puncture (MD 2.00, 95% CI -4.98 to 8.98; I2 = not applicable; 1 study, 20 infants, very low-certainty evidence). Lateral decubitus position may result in little to no difference in the number of episodes of apnea during the procedure (RR not estimable; RD 0.00, 95% CI -0.03 to 0.03; I2 = not applicable and 0% for RR and RD, respectively; 2 studies, 197 infants, low-certainty evidence). No studies reported apnea defined as number of infants with one or more episodes during the procedure. Compared to prone position: lateral decubitus position may reduce successful lumbar puncture procedure at first attempt (RR 0.75, 95% CI 0.63 to 0.90; RD -0.21, 95% CI -0.34 to -0.09; number needed to treat for an additional beneficial outcome = 5; I2 = not applicable; 1 study, 171 infants, low-certainty evidence). None of the studies reported the total number of lumbar puncture attempts or episodes of apnea. Pain intensity during and after the procedure was reported using a non-validated pain scale. None of the studies comparing lateral decubitus versus prone position reported the other critical outcomes of this review. AUTHORS' CONCLUSIONS: When compared to sitting position, lateral decubitus position may result in little to no difference in successful lumbar puncture procedure at first attempt. None of the included studies reported the total number of lumbar puncture attempts. Furthermore, infants in a lateral decubitus position likely experience more episodes of bradycardia and oxygen desaturation, and there may be little to no difference in episodes of apnea. The evidence is very uncertain regarding time to perform lumbar puncture. Pain intensity during and after the procedure was reported using a pain scale that was not included in our prespecified tools for pain assessment due to its high risk of bias. Most study participants were term newborns, thereby limiting the applicability of these results to preterm babies. When compared to prone position, lateral decubitus position may reduce successful lumbar puncture procedure at first attempt. Only one study reported on this comparison and did not evaluate adverse effects. Further research exploring harms and benefits and the effect on patients' pain experience of different positions during lumbar puncture using validated pain scoring tool may increase the level of confidence in our conclusions.

Methylxanthine for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Very preterm infants often require respiratory support and are therefore exposed to an increased risk of chronic lung disease and later neurodevelopmental disability. Although methylxanthines are widely used to prevent and treat apnea associated with prematurity and to facilitate extubation, there is uncertainty about the benefits and harms of different types of methylxanthines. OBJECTIVES: To assess the effects of methylxanthines on the incidence of apnea, death, neurodevelopmental disability, and other longer-term outcomes in preterm infants (1) at risk for or with apnea, or (2) undergoing extubation. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and three trial registers (November 2022). SELECTION CRITERIA: We included randomized trials in preterm infants, in which methylxanthines (aminophylline, caffeine, or theophylline) were compared to placebo or no treatment for any indication (i.e. prevention of apnea, treatment of apnea, or prevention of re-intubation). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods and GRADE to assess the certainty of evidence. MAIN RESULTS: We included 18 studies (2705 infants), evaluating the use of methylxanthine in preterm infants for: any indication (one study); prevention of apnea (six studies); treatment of apnea (five studies); and to prevent re-intubation (six studies). Death or major neurodevelopmental disability (DMND) at 18 to 24 months. Only the Caffeine for Apnea of Prematurity (CAP) study (enrolling 2006 infants) reported on this outcome. Overall, caffeine probably reduced the risk of DMND in preterm infants treated with caffeine for any indication (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.78 to 0.97; risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence). No other trials reported DMND. Results from the CAP trial regarding DMND at 18 to 24 months are less precise when analyzed based on treatment indication. Caffeine probably results in little or no difference in DMND in infants treated for prevention of apnea (RR 1.00, 95% CI 0.80 to 1.24; RD -0.00, 95% CI -0.10 to 0.09; 1 study, 423 infants; moderate-certainty evidence) and probably results in a slight reduction in DMND in infants treated for apnea of prematurity (RR 0.85, 95% CI 0.71 to 1.01; RD -0.06, 95% CI -0.13 to 0.00; NNTB 16, 95% CI 7 to > 1000; 1 study, 767 infants; moderate-certainty evidence) or to prevent re-intubation (RR 0.85, 95% CI 0.73 to 0.99; RD -0.08, 95% CI -0.15 to -0.00; NNTB 12, 95% CI 6 to >1000; 1 study, 676 infants; moderate-certainty evidence). Death. In the overall analysis of any methylxanthine treatment for any indication, methylxanthine used for any indication probably results in little or no difference in death at hospital discharge (RR 0.99, 95% CI 0.71 to 1.37; I2 = 0%; RD -0.00, 95% CI -0.02 to 0.02; I2 = 5%; 7 studies, 2289 infants; moderate-certainty evidence). Major neurodevelopmental disability at 18 to 24 months. In the CAP trial, caffeine probably reduced the risk of major neurodevelopmental disability at 18 to 24 months (RR 0.85, 95% CI 0.76 to 0.96; RD -0.06, 95% CI -0.10 to -0.02; NNTB 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence), including a reduction in the risk of cerebral palsy or gross motor disability (RR 0.60, 95% CI 0.41 to 0.88; RD -0.03, 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100; 1 study, 1810 infants; moderate-certainty evidence) and a marginal reduction in the risk of developmental delay (RR 0.88, 95% CI 0.78 to 1.00; RD -0.05, 95% CI -0.09 to -0.00; NNTB 20, 95% CI 11 to > 1000; 1 study, 1725 infants; moderate-certainty evidence). Any apneic episodes, failed apnea reduction after two to seven days (< 50% reduction in apnea) (for infants treated with apnea), and need for positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication probably reduces the occurrence of any apneic episodes (RR 0.31, 95% CI 0.18 to 0.52; I2 = 47%; RD -0.38, 95% CI -0.51 to -0.25; I2 = 49%; NNTB 3, 95% CI 2 to 4; 4 studies, 167 infants; moderate-certainty evidence), failed apnea reduction after two to seven days (RR 0.48, 95% CI 0.33 to 0.70; I2 = 0%; RD -0.31, 95% CI -0.44 to -0.17; I2 = 53%; NNTB 3, 95% CI 2 to 6; 4 studies, 174 infants; moderate-certainty evidence), and may reduce receipt of positive-pressure ventilation after institution of treatment (RR 0.61, 95% CI 0.39 to 0.96; I2 = 0%; RD -0.06, 95% CI -0.11 to -0.01; I2 = 49%; NNTB 16, 95% CI 9 to 100; 9 studies, 373 infants; low-certainty evidence). Chronic lung disease. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age) (RR 0.77, 95% CI 0.69 to 0.85; I2 = 0%; RD -0.10, 95% CI -0.14 to -0.06; I2 = 18%; NNTB 10, 95% CI 7 to 16; 4 studies, 2142 infants; high-certainty evidence). Failure to extubate or the need for re-intubation within one week after initiation of therapy. Methylxanthine used for the prevention of re-intubation probably results in a large reduction in failed extubation compared with no treatment (RR 0.48, 95% CI 0.32 to 0.71; I2 = 0%; RD -0.27, 95% CI -0.39 to -0.15; I2 = 69%; NNTB 4, 95% CI 2 to 6; 6 studies, 197 infants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Caffeine probably reduces the risk of death, major neurodevelopmental disability at 18 to 24 months, and the composite outcome DMND at 18 to 24 months. Administration of any methylxanthine to preterm infants for any indication probably leads to a reduction in the risk of any apneic episodes, failed apnea reduction after two to seven days, cerebral palsy, developmental delay, and may reduce receipt of positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age).

Doxapram for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline, and caffeine) are effective in the treatment of apnea of prematurity. Doxapram is used as a respiratory stimulant in cases refractory to the methylxanthine treatment. OBJECTIVES: To evaluate the benefits and harms of doxapram administration on the incidence of apnea and other short-term and longer-term clinical outcomes in preterm infants. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was March 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the role of doxapram in prevention and treatment of apnea of prematurity and prevention of reintubation in preterm infants (less than 37 weeks' gestation). We included studies comparing doxapram with either placebo or methylxanthines as a control group, or when doxapram was used as an adjunct to methylxanthines and compared to methylxanthines alone as a control group. We included studies of doxapram at any dose and route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were clinical apnea, need for positive pressure ventilation after initiation of treatment, failed apnea reduction after two to seven days, and failed extubation (defined as unable to wean from invasive intermittent positive pressure ventilation [IPPV] and extubate or reintubation for IPPV within one week). We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included eight RCTs enrolling 248 infants. Seven studies (214 participants) provided data for meta-analysis. Five studied doxapram for treatment of apnea in preterm infants. Three studied doxapram to prevent reintubation in preterm infants. None studied doxapram in preventing apnea in preterm infants. All studies administered doxapram intravenously as continuous infusions. Two studies used doxapram as an adjunct to aminophylline compared to aminophylline alone and one study as an adjunct to caffeine compared to caffeine alone. When used to treat apnea, compared to no treatment, doxapram may result in a slight reduction in failed apnea reduction (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.20 to 1.05; 1 study, 21 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 0.31, 95% CI 0.01 to 6.74; 1 study, 21 participants; very low-certainty evidence). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in both groups; risk difference [RD] 0.00, 95% CI -0.17 to 0.17; 1 study, 21 participants; low-certainty evidence). Compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed apnea reduction (RR 1.35, 95% CI 0.53 to 3.45; 4 studies, 84 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 2.40, 95% CI 0.11 to 51.32; 2 studies, 37 participants; very-low certainty evidence; note 1 study recorded 0 events in both groups. Thus, the RR and CIs were calculated from 1 study rather than 2). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in all groups; RD 0.00, 95% CI -0.15 to 0.15; 37 participants; 2 studies; low-certainty evidence). As adjunct therapy to methylxanthine, the evidence is very uncertain about the effect of doxapram on failed apnea reduction after two to seven days (RR 0.08, 95% CI 0.01 to 1.17; 1 study, 10 participants; very low-certainty evidence). No studies reported on clinical apnea, chronic lung disease at 36 weeks' postmenstrual age (PMA), death at any time during initial hospitalization, long-term neurodevelopmental outcomes in the three comparisons, and need for positive pressure ventilation and side effects when used as adjunct therapy to methylxanthine. In studies to prevent reintubation, when compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed extubation (RR 0.43, 95% CI 0.10 to 1.83; 1 study, 25 participants; very low-certainty evidence). As adjunct therapy to methylxanthine, doxapram may result in a slight reduction in 'clinical apnea' after initiation of treatment (RR 0.36, 95% CI 0.13 to 0.98; 1 study, 56 participants; low-certainty evidence). Doxapram may result in little to no difference in failed extubation (RR 0.92, 95% CI 0.52 to 1.62; 1 study, 56 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on side effects causing cessation of therapy (RR 6.42, 95% CI 0.80 to 51.26; 2 studies, 85 participants; very low-certainty evidence). No studies reported need for positive pressure ventilation, chronic lung disease at 36 weeks' PMA, long-term neurodevelopmental outcomes in the three comparisons; failed extubation when compared to no treatment; and clinical apnea, death at any time during initial hospitalization, and side effects when compared to no treatment or alternative treatment. We identified two ongoing studies, one conducted in Germany and one in multiple centers in the Netherlands and Belgium. AUTHORS' CONCLUSIONS: In treating apnea of prematurity, doxapram may slightly reduce failure in apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for positive pressure ventilation when compared to no treatment or alternative treatment and about failed apnea reduction when used as alternative or adjunct therapy to methylxanthine. For use to prevent reintubation, doxapram may reduce apnea episodes when administered in adjunct to methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about doxapram's effect on death when used as adjunct therapy to methylxanthine and about failed extubation when used as alternative or adjunct therapy to methylxanthine. There is a knowledge gap about the use of doxapram as a therapy to prevent apnea. More studies are needed to clarify the role of doxapram in the treatment of apnea of prematurity, addressing concerns about long-term outcomes. The ongoing studies may provide useful data.

Caffeine versus other methylxanthines for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Methylxanthines, including caffeine, theophylline, and aminophylline, work as stimulants of the respiratory drive, and decrease apnea of prematurity, a developmental disorder common in preterm infants. In particular, caffeine has been reported to improve important clinical outcomes, including bronchopulmonary dysplasia (BPD) and neurodevelopmental disability. However, there is uncertainty regarding the efficacy of caffeine compared to other methylxanthines. OBJECTIVES: To assess the effects of caffeine compared to aminophylline or theophylline in preterm infants at risk of apnea, with apnea, or in the peri-extubation phase. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Epistemonikos, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in February 2023. We also checked the reference lists of relevant articles to identify additional studies. SELECTION CRITERIA: Studies: randomized controlled trials (RCTs) and quasi-RCTs Participants: infants born before 34 weeks of gestation for prevention and extubation trials, and infants born before 37 weeks of gestation for treatment trials Intervention and comparison: caffeine versus theophylline or caffeine versus aminophylline. We included all doses and duration of treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR), risk difference (RD), and 95% confidence intervals (CI) for categorical data, and mean, standard deviation, and mean difference for continuous data. We used the GRADE approach to evaluate the certainty of evidence. MAIN RESULTS: We included 22 trials enrolling 1776 preterm infants. The indication for treatment was prevention of apnea in three studies, treatment of apnea in 13 studies, and extubation management in three studies. In three studies, there were multiple indications for treatment, and in one study, the indication for treatment was unclear. In 19 included studies, the infants had a mean gestational age between 28 and 32 weeks and a mean birth weight between 1000 g and 1500 g. One study's participants had a mean gestational age of more than 32 weeks, and two studies had participants with a mean birth weight of 1500 g or more. Caffeine administrated for any indication may result in little to no difference in all-cause mortality prior to hospital discharge compared to other methylxanthines (RR 1.12, 95% CI 0.68 to 1.84; RD 0.02, 95% CI -0.05 to 0.08; 2 studies, 396 infants; low-certainty evidence). Only one study enrolling 79 infants reported components of the outcome moderate to severe neurodevelopmental disability at 18 to 26 months. The evidence is very uncertain about the effect of caffeine on cognitive developmental delay compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.37; RD -0.12, 95% CI -0.24 to 0.01; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on language developmental delay compared to other methylxanthines (RR 0.76, 95% CI 0.37 to 1.58; RD -0.07, 95% CI -0.27 to 0.12; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on motor developmental delay compared to other methylxanthines (RR 0.50, 95% CI 0.13 to 1.96; RD -0.07, 95% CI -0.21 to 0.07; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on visual and hearing impairment compared to other methylxanthines. At 24 months of age, visual impairment was seen in 8 out of 11 infants and 10 out of 11 infants in the caffeine and other methylxanthines groups, respectively. Hearing impairment was seen in 2 out of 5 infants and 1 out of 1 infant in the caffeine and other methylxanthines groups, respectively. No studies reported the outcomes cerebral palsy, gross motor disability, and mental development. Compared to other methylxanthines, caffeine may result in little to no difference in BPD/chronic lung disease, defined as 28 days of oxygen exposure at 36 weeks' postmenstrual age (RR 1.40, 95% CI 0.92 to 2.11; RD 0.04, 95% CI -0.01 to 0.09; 3 studies, 481 infants; low-certainty evidence). The evidence is very uncertain about the effect of caffeine on side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of methylxanthines compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.32; RD -0.29, 95% CI -0.57 to -0.02; 1 study, 30 infants; very low-certainty evidence). Caffeine may result in little to no difference in duration of hospital stay compared to other methylxanthines (median (interquartile range): caffeine 43 days (27.5 to 61.5); other methylxanthines 39 days (28 to 55)). No studies reported the outcome seizures. AUTHORS' CONCLUSIONS: Although caffeine has been shown to improve important clinical outcomes, in the few studies that compared caffeine to other methylxanthines, there might be little to no difference in mortality, bronchopulmonary dysplasia, and duration of hospital stay. The evidence is very uncertain about the effect of caffeine compared to other methylxanthines on long-term development and side effects. Although caffeine or other methylxanthines are widely used in preterm infants, there is little direct evidence to support the choice of which methylxanthine to use. More research is needed, especially on extremely preterm infants born before 28 weeks of gestation. Data from four ongoing studies might provide more evidence on the effects of caffeine or other methylxanthines.

Superoxide dismutase for bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring enzyme which provides a defense against such oxidant injury. Providing supplementary SOD has been tested in clinical trials to prevent BPD in preterm infants. OBJECTIVES: To determine the efficacy and safety of SOD in the prevention and treatment of BPD on mortality and other complications of prematurity in infants at risk for, or having BPD. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, and three trials registers on 22 September 2022 together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: Randomized, quasi-randomized and cluster-randomized controlled trials (RCTs) where the participants were preterm infants who had developed, or were at risk of developing BPD, and who were randomly allocated to receive either SOD (in any form, by any route, any dose, anytime) or placebo, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality, mortality prior to discharge, and BPD or death at 36 weeks' postmenstrual age. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for the dichotomous outcomes. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included three RCTs (380 infants) on SOD administration in preterm infants at risk for BPD, and no studies in preterm infants with evolving BPD / early respiratory insufficiency. The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days (RR 1.09, 95% CI 0.94 to 1.26; RD 0.06, 95% CI -0.05 to 0.16, 1 study, 302 infants; I2 for RR and RD not applicable), BPD defined as oxygen at 36 weeks' postmenstrual age (RR 0.96, 95% CI 0.72 to 1.29; RD -0.01, 95% CI -0.11 to 0.09, 2 studies, 335 infants; I2 for RR and RD = 0%), neonatal mortality (RR 0.98, 95% CI 0.57 to 1.68; RD -0.00, 95% CI -0.08 to 0.07, 2 studies, 335 infants; I2 for RR and RD = 0%), and mortality prior to discharge (RR 1.20, 95% CI 0.53 to 2.71; RD 0.04, 95% CI -0.14 to 0.23, 2 studies, 78 infants; I2 for RR and RD = 0%). No studies reported BPD or death at 36 weeks' postmenstrual age. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage (RR 0.95, 95% CI 0.78 to 1.15; RD -0.03, 95% CI -0.15 to 0.08, 2 studies, 335 infants; I2for RR = 0%, I2 for RD = 8%), and severe retinopathy of prematurity (ROP) (RR 0.97, 95% CI 0.57 to 1.65; RD -0.01, 95% CI -0.10 to 0.09, 1 study, 244 infants; I2 for RR and RD not applicable). No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. Certainty of evidence was very low for all outcomes. We identified no ongoing trials. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality and mortality prior to discharge compared to placebo. No studies reported BPD or death at 36 weeks' postmenstrual age and need for supplemental oxygen. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage and severe retinopathy of prematurity. No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. The effects of SOD in preterm infants has not been reported in any trial in the last few decades, considering that the most recent trial on SOD in preterm infants was conducted in 1997/1998, and no new studies are ongoing. In the light of the limited available evidence, new data from preclinical and observational studies are needed to justify the conduction of new RCTs. Observational studies might report how SOD is administered, including indication, dose and association with relevant outcomes such as mortality, BPD and long-term neurodevelopment.

AMSTAR 2 is only partially applicable to systematic reviews of non-intervention studies: a meta-research study.

OBJECTIVES: A measurement tool to assess systematic reviews 2 (AMSTAR 2) was originally developed for systematic reviews (SRs) of health-care interventions. The aim of this study was to assess the applicability of AMSTAR 2 to SRs of non-intervention studies. STUDY DESIGN AND SETTING: This was a meta-research study. We used 20 SRs for each of the following four types of SRs: Diagnostic Test Accuracy reviews, Etiology and/or Risk reviews, Prevalence and/or Incidence reviews, and Prognostic reviews (80 in total). Three authors applied AMSTAR 2 independently to each included SRs. Then, the authors assessed the applicability of each item to that SR type and any SR type. RESULTS: Researchers unanimously indicated that 7 of 16 AMSTAR 2 items were applicable for all four specific SR types and any SR type (items 2, 5, 6, 7, 10, 14 and 16), but 8 of 16 items for any SR type. These items could cover generic SR methods that do not depend on a specific SR type. CONCLUSION: AMSTAR 2 is only partially applicable for non-intervention SRs. There is a need to adapt/extend AMSTAR 2 for SRs of non-intervention studies. Our study can help to further define generic methodological aspects shared across SR types and methodological expectations for non-intervention SRs.

Pharmacological interventions for the management of pain and discomfort during lumbar puncture in newborn infants.

BACKGROUND: Lumbar puncture (LP) is a common invasive procedure, most frequently performed to diagnose infection. Physicians perform LP in newborn infants with the help of an assistant using a strict aseptic technique; it is important to monitor the infant during all the steps of the procedure. Without adequate analgesia, LP can cause considerable pain and discomfort. As newborns have increased sensitivity to pain, it is crucial to adequately manage the procedural pain of LP in this population. OBJECTIVES: To assess the benefits and harms, including pain, discomfort, and success rate, of any pharmacological intervention during lumbar puncture in newborn infants, compared to placebo, no intervention, non-pharmacological interventions, or other pharmacological interventions. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, and three trial registries in December 2022. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs comparing drugs used for pain management, sedation, or both, during LP. We considered the following drugs suitable for inclusion. • Topical anesthetics (e.g. eutectic mixture of local anesthetics [EMLA], lidocaine) • Opioids (e.g. morphine, fentanyl) • Alpha-2 agonists (e.g. clonidine, dexmedetomidine) • N-Methyl-D-aspartate (NMDA) receptor antagonists (e.g. ketamine) • Other analgesics (e.g. paracetamol) • Sedatives (e.g. benzodiazepines such as midazolam) DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) or standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CIs). Our main outcomes were successful LP on first attempt, total number of LP attempts, episodes of bradycardia, pain assessed with validated scales, episodes of desaturation, number of episodes of apnea, and number of infants with one or more episodes of apnea. We used the GRADE approach to evaluate the certainty of the evidence. MAIN RESULTS: We included three studies (two RCTs and one quasi-RCT) that enrolled 206 newborns. One study included only term infants. All studies assessed topical treatment versus placebo or no intervention. The topical anesthetics were lidocaine 4%, lidocaine 1%, and EMLA. We identified no completed studies on opioids, non-steroidal anti-inflammatory drugs, alpha-2 agonists, NMDA receptor antagonists, other analgesics, sedatives, or head-to-head comparisons (drug A versus drug B). Based on very low-certainty evidence from one quasi-RCT of 100 LPs in 76 infants, we are unsure if topical anesthetics (lidocaine), compared to no anesthesia, has an effect on the following outcomes. • Successful LP on first attempt (first-attempts success in 48% of LPs in the lidocaine group and 42% of LPs in the control group) • Number of attempts per LP (mean 1.9 attempts, [standard error of the mean 0.2] in the lidocaine group, and mean 2.1 attempts [standard error of the mean 2.1] in the control group) • Episodes of bradycardia (0% of LPs in the lidocaine group and 4% of LPs in the control group) • Episodes of desaturation (0% of LPs in the lidocaine group and 8% of LPs in the control group) • Occurrence of apnea (RR 3.24, 95% CI 0.14 to 77.79; risk difference [RD] 0.02, 95% CI -0.03 to 0.08). Topical anesthetics compared to placebo may reduce pain assessed with the Neonatal Facial Coding System (NFCS) score (SMD -1.00 standard deviation (SD), 95% CI -1.47 to -0.53; I² = 98%; 2 RCTs, 112 infants; low-certainty evidence). No studies in this comparison reported total number of episodes of apnea. We identified three ongoing studies, which will assess the effects of EMLA, lidocaine, and fentanyl. Three studies are awaiting classification. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effect of topical anesthetics (lidocaine) compared to no anesthesia on successful lumbar puncture on first attempt, the number of attempts per lumbar puncture, episodes of bradycardia, episodes of desaturation, and occurrence of apnea. Compared to placebo, topical anesthetics (lidocaine or EMLA) may reduce pain assessed with the NFCS score. One ongoing study will assess the effects of systemic treatment.

Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation - an overview of systematic reviews.

BACKGROUND: Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) may contribute to neonatal morbidity and mortality and result in long-term neurodevelopmental sequelae. Appropriate pain and sedation management in ventilated preterm infants may decrease the risk of GMH-IVH; however, it might be associated with harms. OBJECTIVES: To summarize the evidence from systematic reviews regarding the effects and safety of pharmacological interventions related to pain and sedation management in order to prevent GMH-IVH in ventilated preterm infants. METHODS: We searched the Cochrane Library August 2022 for reviews on pharmacological interventions for pain and sedation management to prevent GMH-IVH in ventilated preterm infants (< 37 weeks' gestation). We included Cochrane Reviews assessing the following interventions administered within the first week of life: benzodiazepines, paracetamol, opioids, ibuprofen, anesthetics, barbiturates, and antiadrenergics. Primary outcomes were any GMH-IVH (aGMH-IVH), severe IVH (sIVH), all-cause neonatal death (ACND), and major neurodevelopmental disability (MND). We assessed the methodological quality of included reviews using the AMSTAR-2 tool. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included seven Cochrane Reviews and one Cochrane Review protocol. The reviews on clonidine and paracetamol did not include randomized controlled trials (RCTs) matching our inclusion criteria. We included 40 RCTs (3791 infants) from reviews on paracetamol for patent ductus arteriosus (3), midazolam (3), phenobarbital (9), opioids (20), and ibuprofen (5). The quality of the included reviews was high. The certainty of the evidence was moderate to very low, because of serious imprecision and study limitations. Germinal matrix hemorrhage-intraventricular hemorrhage (any grade) Compared to placebo or no intervention, the evidence is very uncertain about the effects of paracetamol on aGMH-IVH (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.38 to 2.07; 2 RCTs, 82 infants; very low-certainty evidence); midazolam may result in little to no difference in the incidence of aGMH-IVH (RR 1.68, 95% CI 0.87 to 3.24; 3 RCTs, 122 infants; low-certainty evidence); the evidence is very uncertain about the effect of phenobarbital on aGMH-IVH (RR 0.99, 95% CI 0.83 to 1.19; 9 RCTs, 732 infants; very low-certainty evidence); opioids may result in little to no difference in aGMH-IVH (RR 0.85, 95% CI 0.65 to 1.12; 7 RCTs, 469 infants; low-certainty evidence); ibuprofen likely results in little to no difference in aGMH-IVH (RR 0.99, 95% CI 0.81 to 1.21; 4 RCTs, 759 infants; moderate-certainty evidence). Compared to ibuprofen, the evidence is very uncertain about the effects of paracetamol on aGMH-IVH (RR 1.17, 95% CI 0.31 to 4.34; 1 RCT, 30 infants; very low-certainty evidence). Compared to midazolam, morphine may result in a reduction in aGMH-IVH (RR 0.28, 95% CI 0.09 to 0.87; 1 RCT, 46 infants; low-certainty evidence). Compared to diamorphine, the evidence is very uncertain about the effect of morphine on aGMH-IVH (RR 0.65, 95% CI 0.40 to 1.07; 1 RCT, 88 infants; very low-certainty evidence). Severe intraventricular hemorrhage (grade 3 to 4) Compared to placebo or no intervention, the evidence is very uncertain about the effect of paracetamol on sIVH (RR 1.80, 95% CI 0.43 to 7.49; 2 RCTs, 82 infants; very low-certainty evidence) and of phenobarbital (grade 3 to 4) (RR 0.91, 95% CI 0.66 to 1.25; 9 RCTs, 732 infants; very low-certainty evidence); opioids may result in little to no difference in sIVH (grade 3 to 4) (RR 0.98, 95% CI 0.71 to 1.34; 6 RCTs, 1299 infants; low-certainty evidence); ibuprofen may result in little to no difference in sIVH (grade 3 to 4) (RR 0.82, 95% CI 0.54 to 1.26; 4 RCTs, 747 infants; low-certainty evidence). No studies on midazolam reported this outcome. Compared to ibuprofen, the evidence is very uncertain about the effects of paracetamol on sIVH (RR 2.65, 95% CI 0.12 to 60.21; 1 RCT, 30 infants; very low-certainty evidence). Compared to midazolam, the evidence is very uncertain about the effect of morphine on sIVH (grade 3 to 4) (RR 0.08, 95% CI 0.00 to 1.43; 1 RCT, 46 infants; very low-certainty evidence). Compared to fentanyl, the evidence is very uncertain about the effect of morphine on sIVH (grade 3 to 4) (RR 0.59, 95% CI 0.18 to 1.95; 1 RCT, 163 infants; very low-certainty evidence). All-cause neonatal death Compared to placebo or no intervention, the evidence is very uncertain about the effect of phenobarbital on ACND (RR 0.94, 95% CI 0.51 to 1.72; 3 RCTs, 203 infants; very low-certainty evidence); opioids likely result in little to no difference in ACND (RR 1.12, 95% CI 0.80 to 1.55; 5 RCTs, 1189 infants; moderate-certainty evidence); the evidence is very uncertain about the effect of ibuprofen on ACND (RR 1.00, 95% CI 0.38 to 2.64; 2 RCTs, 112 infants; very low-certainty evidence). Compared to midazolam, the evidence is very uncertain about the effect of morphine on ACND (RR 0.31, 95% CI 0.01 to 7.16; 1 RCT, 46 infants; very low-certainty evidence). Compared to diamorphine, the evidence is very uncertain about the effect of morphine on ACND (RR 1.17, 95% CI 0.43 to 3.19; 1 RCT, 88 infants; very low-certainty evidence). Major neurodevelopmental disability Compared to placebo, the evidence is very uncertain about the effect of opioids on MND at 18 to 24 months (RR 2.00, 95% CI 0.39 to 10.29; 1 RCT, 78 infants; very low-certainty evidence) and at five to six years (RR 1.6, 95% CI 0.56 to 4.56; 1 RCT, 95 infants; very low-certainty evidence). No studies on other drugs reported this outcome. AUTHORS' CONCLUSIONS: None of the reported studies had an impact on aGMH-IVH, sIVH, ACND, or MND. The certainty of the evidence ranged from moderate to very low. Large RCTs of rigorous methodology are needed to achieve an optimal information size to assess the effects of pharmacological interventions for pain and sedation management for the prevention of GMH-IVH and mortality in preterm infants. Studies might compare interventions against either placebo or other drugs. Reporting of the outcome data should include the assessment of GMH-IVH and long-term neurodevelopment.

Opioids for procedural pain in neonates.

BACKGROUND: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. OBJECTIVES: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence): with one study reporting a concerning increase in severe apnea (RR 7.44, 95% CI 0.42 to 132.95; 31 participants, 1 study; very low-certainty). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). AUTHORS' CONCLUSIONS: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. The evidence is very uncertain about the effect of opioids on episodes of bradycardia, hypotension or severe apnea. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.