Abstract

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.

Abstract

BACKGROUND Intraventricular haemorrhage (IVH) is a major complication of preterm birth. Large haemorrhages are associated with a high risk of disability and hydrocephalus. Instability of blood pressure and cerebral blood in the newborn flow are postulated as causative factors. Another mechanism may involve reperfusion damage from oxygen free radicals. It has been suggested that phenobarbital stabilises blood pressure and may protect against free radicals. This is an update of a review first published in 2001 and updated in 2007 and 2013. OBJECTIVES To assess the benefits and harms of the postnatal administration of phenobarbital in preterm infants at risk of developing IVH compared to control (i.e. no intervention or placebo). SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL and clinical trial registries in January 2022. A new, more sensitive search strategy was developed, and searches were conducted without date limits. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs in which phenobarbital was given within the first 24 hours of life to preterm infants identified as being at risk of IVH because of gestational age below 34 weeks, birth weight below 1500 g or respiratory failure. Phenobarbital was compared to no intervention or placebo. We excluded infants with serious congenital malformations. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were all grades of IVH and severe IVH (i.e. grade III and IV); secondary outcomes were ventricular dilation or hydrocephalus, hypotension, pneumothorax, hypercapnia, acidosis, mechanical ventilation, neurodevelopmental impairment and death. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS We included 10 RCTs (792 infants). The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH of any grade compared with control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.84 to 1.19; risk difference (RD) 0.00, 95% CI -0.06 to 0.07; I² for RD = 65%; 10 RCTs, 792 participants; low certainty evidence) and in severe IVH (RR 0.88, 95% CI 0.64 to 1.21; 10 RCTs, 792 participants; low certainty evidence). The evidence is very uncertain about the effect of phenobarbital on posthaemorrhagic ventricular dilation or hydrocephalus (RR 0.62, 95% CI 0.31 to 1.26; 4 RCTs, 271 participants; very low certainty evidence), mild neurodevelopmental impairment (RR 0.57, 95% CI 0.15 to 2.17; 1RCT, 101 participants; very low certainty evidence), and severe neurodevelopmental impairment (RR 1.12, 95% CI 0.44 to 2.82; 2 RCTs, 153 participants; very low certainty evidence). Phenobarbital may result in little to no difference in death before discharge (RR 0.88, 95% CI 0.64 to 1.21; 9 RCTs, 740 participants; low certainty evidence) and mortality during study period (RR 0.98, 95% CI 0.72 to 1.33; 10 RCTs, 792 participants; low certainty evidence) compared with control. We identified no ongoing trials. AUTHORS' CONCLUSIONS The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH (any grade or severe) compared with control (i.e. no intervention or placebo). The evidence is very uncertain about the effects of phenobarbital on ventricular dilation or hydrocephalus and on neurodevelopmental impairment. The evidence suggests that phenobarbital results in little to no difference in death before discharge and all deaths during the study period compared with control. Since 1993, no randomised studies have been published on phenobarbital for the prevention of IVH in preterm infants, and no trials are ongoing. The effects of postnatal phenobarbital might be assessed in infants with both neonatal seizures and IVH, in both randomised and observational studies. The assessment of benefits and harms should include long-term outcomes.

Abstract

BACKGROUND Recombinant human erythropoietin (rhEPO) lost its role in minimizing red blood cell transfusion in very preterm infants after it had been associated with severe retinopathy of prematurity (ROP). Previous systematic reviews did not stratify ROP by gestation and birth weight (BW). OBJECTIVES The aim of this study was to investigate the effect of early prophylactic rhEPO on ROP in a stratified meta-analysis of randomized controlled trials (RCTs). METHODS The databases EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched in January 2022 and complemented by citation searching. RCTs comparing early rhEPO treatment with no treatment or placebo were selected if they were published in a peer-reviewed journal and reported ROP outcomes. Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW. Data were extracted and analyzed using the standard methods of the Cochrane Neonatal Review Group. Pre-specified outcomes were "ROP stage ≥3" (primary outcome) and "any ROP." RESULTS Fourteen RCTs, comprising 2,040 infants of <29 weeks of GA, were included for meta-analysis. Data syntheses showed no effects of rhEPO on ROP stage ≥3 or on any ROP, neither in infants of <29 weeks GA, nor in infants of <1,000 g BW, nor in any GA strata. The risk ratio (95% confidence interval) for ROP stage ≥3 in infants of <29 weeks of GA was 1.13 (0.84, 1.53), p = 0.41 (quality of evidence: moderate). CONCLUSIONS The present meta-analysis detected no effects of early rhEPO on ROP in any comparison, but most stratified analyses were limited by low statistical power.

Abstract

Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs (n = 5359) were included, of which six were new (n = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes. CONCLUSION There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings. WHAT IS KNOWN • Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects. • Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants. WHAT IS NEW • Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation. • EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs. How might it impact clinical practice in the foreseeable future? • Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias.

Abstract

A meta-analysis update of randomized controlled trials investigating recombinant human erythropoietin suggests improved neurodevelopmental outcome in preterm infants. There was substantial heterogeneity, which could be ascribed to a single trial. Exclusion of this trial featuring a high risk of bias abolished heterogeneity and any effects of recombinant human erythropoietin treatment.

Abstract

OBJECTIVE Previous systematic review has shown the safety and efficiency of EPO (erythropoietin) for neonatal hypoxic-ischemic encephalopathy (HIE). To date, the evidence is limited that EPO is beneficial to therapeutic hypothermia as an adjuvant. There has not a brief discussion about the neuroprotection effects of EPO without hypothermia. To evaluate the long-term prognosis of HIE treated with EPO alone, we carried out this study that can be a supplement to the previous meta-analysis. MATERIALS AND METHODS 7 databases (including PubMed, EMBASE, Cochrane, CKNI, CBM, WanFang, and VIP) and the ClinicalTrials.gov were retrieved from inception to 1 March 2020. The inclusion criteria were RCTs with EPO treatment without hypothermia. The outcomes were tested by using the Bayley Scales of Infant Development (BSID), including the Bayley Mental Development Index Score (MDI) and the Bayley Psychomotor Development Index Score (PDI). This meta-analysis was done to compare the Risk Ratio (RR) for the scores of BSID less than 70 after over 6 months of follow-up. RESULTS 11 RCTs (1099 newborns) were included, excluding deaths and lost visits, and 917 patients finally were performed the statistical analysis. In neonatal HIE infants, investigation results showed a lower risk of cognitive impairment and psychomotor disability with EPO monotherapy. The pooled event rates of MDI <70 saw a reduction of 36% (95% CI 24%-54%) compared to the control group. There was a decrease of 37% (95% CI 24%-56%) of Psychomotor abnormal (PDI <70) in the EPO group. CONCLUSIONS EPO administration alone could improve the scores of mental and psychomotor in neonates with HIE. However, the level of evidence is low to moderate for the insufficient sample size, so large-scale, multicenter clinical trials are still needed.

Abstract

The aim of this meta-analysis was conducted to assess the effects of different doses of prophylactic rhEPO on neurodevelopmental outcomes and provide reference for rational drug use. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Five RCTs, comprising 2282 infants, were included in this meta-analysis. Overall, prophylactic rhEPO administration reduced the incidence of infants with an MDI <70, with an odds ratio (95% confidence interval) of 0.55 (0.38-0.79), P <0.05. The low-dose rhEPO subgroup was superior to the placebo subgroup, with an OR (95% CI) of 0.47 (0.25-0.87), P <0.05. However, high-dose rhEPO subgroup had no significant impact on MDI <70 in infants <28 weeks' gestational age. The definitions of the secondary outcome showed that there was no significant effect of rhEPO on cerebral palsy. For neonatal complications, although four studies showed that there were no differences in the pooled results of BPD and ICH events between rhEPO treatment and placebo, the ICH events were significantly lower in the low-dose rhEPO (OR 0.36; 95% CI 0.23-0.59). In addition, in the pooled results of NEC and ROP events, there were significant differences between the two groups (OR 0.63; 95% CI 0.43-0.93) (OR 0.80; 95% CI 0.65-0.98). And the NEC events were significantly lower in the low-dose rhEPO (OR 0.45; 95% CI 0.27-0.73). Sustained low-dose prophylactic early erythropoietin might be more superior than high-dose for improvement of neurological outcomes and several neonatal complications in preterm infants.

Abstract

BACKGROUND In the 1960s and 1970s, pulmonary haemorrhage (PH) occurred mainly in full-term infants with pre-existing illness with an incidence of 1.3 per 1000 live births. Risk factors for PH included severity of illness, intrauterine growth restriction, patent ductus arteriosus (PDA), coagulopathy and the need for assisted ventilation. Presently, PH occurs in 3% to 5% of preterm ventilated infants with severe respiratory distress syndrome (RDS) who often have a PDA and have received surfactant. The cause of PH is thought to be due to rapid lowering of intrapulmonary pressure, which facilitates left to right shunting across a PDA and an increase in pulmonary blood flow. Retrospective case reports and one prospective uncontrolled study have shown promising results for surfactant in treating PH. OBJECTIVES To evaluate the effect of surfactant treatment compared to placebo or no intervention on mortality and morbidities in neonates with PH. SEARCH METHODS For this update The Cochrane Library, Issue 2, 2012; MEDLINE; EMBASE; CINAHL; Clinicaltrials.gov; Controlled-trials.com; proceedings (2000 to 2011) of the Annual Meetings of the Pediatric Academic Societies (Abstracts2View) and Web of Science were searched on 8 February 2012. SELECTION CRITERIA Randomised or quasi-randomised controlled trials that evaluated the effect of surfactant in the treatment of PH in intubated term or preterm (< 37 weeks) neonates with PH. Infants were included up to 44 weeks' postmenstrual age. The interventions studied were intratracheal instillation of surfactant (natural or synthetic, regardless of dose) versus placebo or no intervention. DATA COLLECTION AND ANALYSIS If studies were identified by the literature search, the planned analyses included risk ratio, risk difference, number needed to treat to benefit or to harm for dichotomous outcomes, and mean difference for continuous outcomes, with their 95% confidence intervals. A fixed-effect model would be used for meta-analyses. The risk of bias for included trials would be assessed. Heterogeneity tests, including the I(2) statistic, would be performed to assess the appropriateness of pooling the data and the results would be reported. MAIN RESULTS No trials were identified. AUTHORS' CONCLUSIONS No randomised or quasi-randomised trials that evaluated the effect of surfactant in PH were identified. Therefore, no conclusions from such trials can be drawn. In view of the promising results from studies with less strict study designs than a randomised controlled trial, there is reason to conduct further trials of surfactant for the treatment of PH in neonates.

Abstract

BACKGROUND Head position during care may affect cerebral haemodynamics and contribute to the development of germinal matrix-intraventricular haemorrhage (GM-IVH) in very preterm infants. Turning the head toward one side may occlude jugular venous drainage while increasing intracranial pressure and cerebral blood volume. It is suggested that cerebral venous pressure is reduced and hydrostatic brain drainage improved if the infant is cared for in the supine 'head midline' position. OBJECTIVES To assess whether head midline position is more effective than other head positions for preventing (or preventing extension) of GM-IVH in very preterm infants (< 32 weeks' gestation at birth). SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), MEDLINE via PubMed (1966 to 12 September 2019), Embase (1980 to 12 September 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 12 September 2019). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing caring for very preterm infants in a supine head midline position versus a prone or lateral decubitus position, or undertaking a strategy of regular position change, or having no prespecified position. We included trials enrolling infants with existing GM-IVH and planned to assess extension of haemorrhage in a subgroup of infants. We planned to analyse horizontal (flat) versus head elevated positions separately for all body positions. DATA COLLECTION AND ANALYSIS We used standard methods of Cochrane Neonatal. For each of the included trials, two review authors independently extracted data and assessed risk of bias. The primary outcomes were GM-IVH, severe IVH, and neonatal death. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data; and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS Three RCTs, with a total of 290 infants (either < 30 weeks' gestational age or < 1000 g body weight), met the inclusion criteria. Two trials compared supine midline head position versus head rotated 90 degrees with the cot flat. One trial compared supine midline head position versus head rotated 90 degrees with the bed tilted at 30 degrees . We found no trials that compared supine versus prone midline head position. Meta-analysis of three trials (290 infants) did not show an effect on rates of GM-IVH (RR 1.11, 95% confidence interval (CI) 0.78 to 1.56; I(2) = 0%) and severe IVH (RR 0.71, 95% CI 0.37 to 1.33; I(2) = 0%). Neonatal mortality (RR 0.49, 95% CI 0.25 to 0.93; I(2) = 0%; RD -0.09, 95% CI -0.16 to -0.01) and mortality until hospital discharge (typical RR 0.50, 95% CI 0.28 to 0.90; I(2) = 0%; RD -0.10, 95% CI -0.18 to -0.02) were lower in the supine midline head position. The certainty of the evidence was very low for all outcomes because of limitations in study design and imprecision of estimates. We identified one ongoing study. AUTHORS' CONCLUSIONS We found few trial data on the effects of head midline position on GM-IVH in very preterm infants. Although meta-analyses suggest that mortality might be reduced, the certainty of the evidence is very low and it is unclear whether any effect is due to cot tilting (a co-intervention in one trial). Further high-quality RCTs would be needed to resolve this uncertainty.

Abstract

OBJECTIVE The aim of this systematic review and meta-analysis study was to determine the pooled estimate of the effect of antenatal magnesium sulfate (MgSO4) on intraventricular hemorrhage (IVH) in premature infants. METHODS Two review authors independently searched all randomized clinical trials from international databases, including Medline (PubMed), Web of Sciences, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Research Registers of ongoing trials (ClinicalTrials.gov), from January 1989 to August 2017. Two independent review authors were responsible for data collection. After extracting the necessary information from the evaluated articles, metaanalysis of the data was performed using Stata version 14. Also, sources of heterogeneity among studies were determined by Meta regression. RESULTS In this study, among 126 articles that were extracted from primary studies, 7 papers that evaluated the effect of MgSO4 on IVH were eligible for inclusion in the meta-analysis. The results of the meta-analysis showed that pooled relative risk (95% confidence interval [CI]) was 0.80 (95% CI, 0.63 to 1.03) for the effect of MgSO4 on IVH. RESULTS of this study showed that although MgSO4 had a protective effect on IVH in premature infants, this effect was not statistically significant. Further studies are needed to determine the best dosage, timing, and gestational age to achieve the optimum effect of MgSO4 on IVH. SYSTEMATIC REVIEW REGISTRATION International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42019119610.