Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants: a network meta-analysis.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Cyclooxygenase inhibitors (COX-I) may prevent PDA-related complications. Controversy exists on which COX-I drug is the most effective and has the best safety profile in preterm infants. OBJECTIVES: To compare the effectiveness and safety of prophylactic COX-I drugs and 'no COXI prophylaxis' in preterm infants using a Bayesian network meta-analysis (NMA). SEARCH METHODS: Searches of Cochrane CENTRAL via Wiley, OVID MEDLINE and Embase via Elsevier were conducted on 9 December 2021. We conducted independent searches of clinical trial registries and conference abstracts; and scanned the reference lists of included trials and related systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled preterm or low birth weight infants within the first 72 hours of birth without a prior clinical or echocardiographic diagnosis of PDA and compared prophylactic administration of indomethacin or ibuprofen or acetaminophen versus each other, placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. We used the GRADE NMA approach to assess the certainty of evidence derived from the NMA for the following outcomes: severe intraventricular haemorrhage (IVH), mortality, surgical or interventional PDA closure, necrotizing enterocolitis (NEC), gastrointestinal perforation, chronic lung disease (CLD) and cerebral palsy (CP). MAIN RESULTS: We included 28 RCTs (3999 preterm infants). Nineteen RCTs (n = 2877) compared prophylactic indomethacin versus placebo/no treatment, 7 RCTs (n = 914) compared prophylactic ibuprofen versus placebo/no treatment and 2 RCTs (n = 208) compared prophylactic acetaminophen versus placebo/no treatment. Nine RCTs were judged to have high risk of bias in one or more domains.We identified two ongoing trials on prophylactic acetaminophen. Bayesian random-effects NMA demonstrated that prophylactic indomethacin probably led to a small reduction in severe IVH (network RR 0.66, 95% Credible Intervals [CrI] 0.49 to 0.87; absolute risk difference [ARD] 43 fewer [95% CrI, 65 fewer to 16 fewer] per 1000; median rank 2, 95% CrI 1-3; moderate-certainty), a moderate reduction in mortality (network RR 0.85, 95% CrI 0.64 to 1.1; ARD 24 fewer [95% CrI, 58 fewer to 16 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and surgical PDA closure (network RR 0.40, 95% CrI 0.14 to 0.66; ARD 52 fewer [95% CrI, 75 fewer to 30 fewer] per 1000; median rank 2, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic indomethacin resulted in trivial difference in NEC (network RR 0.76, 95% CrI 0.35 to 1.2; ARD 16 fewer [95% CrI, 42 fewer to 13 more] per 1000; median rank 2, 95% CrI 1-3; high-certainty), gastrointestinal perforation (network RR 0.92, 95% CrI 0.11 to 3.9; ARD 4 fewer [95% CrI, 42 fewer to 137 more] per 1000; median rank 1, 95% CrI 1-3; moderate-certainty) or CP (network RR 0.97, 95% CrI 0.44 to 2.1; ARD 3 fewer [95% CrI, 62 fewer to 121 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty) and may result in a small increase in CLD (network RR 1.10, 95% CrI 0.93 to 1.3; ARD 36 more [95% CrI, 25 fewer to 108 more] per 1000; median rank 3, 95% CrI 1-3; low-certainty). Prophylactic ibuprofen probably led to a small reduction in severe IVH (network RR 0.69, 95% CrI 0.41 to 1.14; ARD 39 fewer [95% CrI, 75 fewer to 18 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and moderate reduction in surgical PDA closure (network RR 0.24, 95% CrI 0.06 to 0.64; ARD 66 fewer [95% CrI, from 82 fewer to 31 fewer] per 1000; median rank 1, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic ibuprofen may result in moderate reduction in mortality (network RR 0.83, 95% CrI 0.57 to 1.2; ARD 27 fewer [95% CrI, from 69 fewer to 32 more] per 1000; median rank 2, 95% CrI 1-4; low-certainty) and leads to trivial difference in NEC (network RR 0.73, 95% CrI 0.31 to 1.4; ARD 18 fewer [95% CrI, from 45 fewer to 26 more] per 1000; median rank 1, 95% CrI 1-3; high-certainty), or CLD (network RR 1.00, 95% CrI 0.83 to 1.3; ARD 0 fewer [95% CrI, from 61 fewer to 108 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty). The evidence is very uncertain on effect of ibuprofen on gastrointestinal perforation (network RR 2.6, 95% CrI 0.42 to 20.0; ARD 76 more [95% CrI, from 27 fewer to 897 more] per 1000; median rank 3, 95% CrI 1-3; very low-certainty). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (network RR 1.17, 95% CrI 0.04 to 55.2; ARD 22 more [95% CrI, from 122 fewer to 1000 more] per 1000; median rank 4, 95% CrI 1-4; very low-certainty), mortality (network RR 0.49, 95% CrI 0.16 to 1.4; ARD 82 fewer [95% CrI, from 135 fewer to 64 more] per 1000; median rank 1, 95% CrI 1-4; very low-certainty), or CP (network RR 0.36, 95% CrI 0.01 to 6.3; ARD 70 fewer [95% CrI, from 109 fewer to 583 more] per 1000; median rank 1, 95% CrI 1-3; very low-certainty). In summary, based on ranking statistics, both indomethacin and ibuprofen were equally effective (median ranks 2 respectively) in reducing severe IVH and mortality. Ibuprofen (median rank 1) was more effective than indomethacin in reducing surgical PDA ligation (median rank 2). However, no statistically-significant differences were observed between the COX-I drugs for any of the relevant outcomes. AUTHORS' CONCLUSIONS: Prophylactic indomethacin probably results in a small reduction in severe IVH and moderate reduction in mortality and surgical PDA closure (moderate-certainty), may result in a small increase in CLD (low-certainty) and results in trivial differences in NEC (high-certainty), gastrointestinal perforation (moderate-certainty) and cerebral palsy (low-certainty). Prophylactic ibuprofen probably results in a small reduction in severe IVH and moderate reduction in surgical PDA closure (moderate-certainty), may result in a moderate reduction in mortality (low-certainty) and trivial differences in CLD (low-certainty) and NEC (high-certainty). The evidence is very uncertain about the effect of acetaminophen on any of the clinically-relevant outcomes.

Do Single-Family Rooms Increase Parental Presence, Involvement, and Maternal Well-Being in Neonatal Intensive Care?

Objectives of this study were to determine whether single-family room (SFR) design enhances parental presence, involvement, and maternal well-being during neonatal intensive care hospitalization. An observational cohort including mothers of infants was randomly assigned to receive care in a tertiary-level open-bay (OB) (n = 35) or SFR (n = 36). Mothers were asked to complete daily diaries documenting parental presence, involvement in care, and questionnaires examining maternal well-being. Mother and father mean presence (standard deviation) was significantly higher in the SFR-17.4 (5.2) and 13.6 (6.8)-compared to OB-11.9 (6.3) and 4.6 (3.7) hours/day. Total time spent in care activities did not differ for mothers, except SFR mothers spent more time expressing breast milk (EBM). SFR fathers had greater involvement with care activities. There were no other significant differences. The SFR was associated with greater maternal presence, but not greater involvement in care activities except for EBM, nor improved maternal well-being. The SFR appears to have greater impact on fathers' involvement in care and comforting activities, although the amount of time involved remained quite low compared with mothers. Further studies examining ways to enhance parental involvement in the neonatal intensive care unit are warranted.

Caregiver Presence and Involvement in a Canadian Neonatal Intensive Care Unit: An Observational Cohort Study.

BACKGROUND: Presence in the neonatal intensive care unit (NICU) is a vital step for caregivers initiating involvement, such as skin-to-skin contact, holding or singing/reading to their newborn. Little is known about caregiver presence and involvement in Canadian NICU's context by caregiver type (mother, father, other), and the association between maternal presence and key maternal and newborn characteristics. PURPOSE: The primary objective was to examine the presence and involvement of family caregivers in the NICU. The secondary objective was to examine the relationship between maternal presence and maternal and newborn characteristics. DESIGN AND METHODS: A prospective observational cohort study in an open bay setting of an Eastern Canadian NICU. Presence (physically present at the newborn's bedside) and involvement (e.g., skin-to-skin, singing/reading) were tracked daily by families in the NICU until discharge. Demographic information was also collected. RESULTS: Participants included 142 mothers and their newborns. Mothers were present 8.7 h/day, fathers were present 4.1 h/day, and other caregivers were present 1.8 h/day in the NICU in the first 34 days. Mothers were involved in care activities 50% of the time they were present in the NICU, whereas fathers and other caregivers were spending 20% and 6% of their time respectively. Regression identified maternal age, distance to home, parity, birthweight, and length of stay to be statistically significant variables related to maternal presence. CONCLUSIONS: There is variation in presence and involvement by caregiver type. Targeted interventions to maintain and increase mothers, fathers and other caregivers' presence and involvement in care throughout their stay in the NICU are recommended.

Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to prevent or treat a PDA. There are concerns regarding adverse effects of NSAIDs in preterm infants. Controversy exists on whether early targeted treatment of a hemodynamically significant (hs) PDA improves clinical outcomes. OBJECTIVES: To assess the effectiveness and safety of early treatment strategies versus expectant management for an hs-PDA in reducing mortality and morbidity in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 6) in the Cochrane Library; MEDLINE via PubMed (1966 to 31 May 2019), Embase (1980 to 31 May 2019), and CINAHL (1982 to 31 May 2019). An updated search was run on 2 October 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCT) and quasi-randomized trials. SELECTION CRITERIA: We included RCTs in which early pharmacological treatment, defined as treatment initiated within the first seven days after birth, was compared to no intervention, placebo or other non-pharmacological expectant management strategies for treatment of an hs-PDA in preterm (< 37 weeks' postmenstrual age) or low birth weight (< 2500 grams) infants. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal. Our primary outcome was all-cause mortality during hospital stay. We used the GRADE approach to assess the certainty of evidence for selected clinical outcomes. MAIN RESULTS: We included 14 RCTs that enrolled 910 infants. Seven RCTs compared early treatment (defined as treatment initiated by seven days of age) versus expectant management and seven RCTs compared very early treatment (defined as treatment initiated by 72 hours of age) versus expectant management. No difference was demonstrated between early treatment versus expectant management (no treatment initiated within the first seven days after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (6 studies; 500 infants; typical RR 0.80, 95% CI 0.46 to 1.39; typical RD -0.02; 95% CI -0.07 to 0.03; moderate-certainty evidence), or other important outcomes such as surgical PDA ligation (4 studies; 432 infants; typical RR 1.08, 95% CI 0.65 to 1.80; typical RD -0.03; 95% CI -0.09 to 0.03; very low-certainty evidence), chronic lung disease (CLD) (4 studies; 339 infants; typical RR 0.90, 95% CI 0.62 to 1.29; typical RD -0.03; 95% CI -0.10 to 0.03; moderate-certainty evidence), severe intraventricular hemorrhage (IVH) (2 studies; 171 infants; typical RR 0.83,95% CI 0.32 to 2.16; typical RD -0.01; 95% CI -0.08 to 0.06; low-certainty evidence), and necrotizing enterocolitis (NEC) (5 studies; 473 infants; typical RR 2.34,95% CI 0.86 to 6.41; typical RD 0.04; 95% CI 0.01 to 0.08; low-certainty evidence). Infants receiving early treatment in the first seven days after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (2 studies; 232 infants; typical RR 2.30, 95% CI 1.86 to 2.83; typical RD 0.57; 95% CI 0.48 to 0.66; low-certainty evidence). No difference was demonstrated between very early treatment versus expectant management (no treatment initiated within the first 72 hours after birth) for an hs-PDA for the primary outcome of 'all-cause mortality' (7 studies; 384 infants; typical RR 0.94, 95% CI 0.58 to 1.53; typical RD -0.03; 95% CI -0.09 to 0.04; moderate-certainty evidence) or other important outcomes such as surgical PDA ligation (5 studies; 293 infants; typical RR 0.88, 95% CI 0.36 to 2.17; typical RD -0.01; 95% CI -0.05 to 0.02; moderate-certainty evidence), CLD (7 studies; 384 infants; typical RR 0.83, 95% CI 0.63 to 1.08; typical RD -0.05; 95% CI -0.13 to 0.04; low-certainty evidence), severe IVH (4 studies, 240 infants; typical RR 0.64, 95% CI 0.21 to 1.93; typical RD -0.02; 95% CI -0.07 to 0.04; moderate-certainty evidence), NEC (5 studies; 332 infants; typical RR 1.08, 95% CI 0.53 to 2.21; typical RD 0.01; 95% CI -0.04 to 0.06; moderate-certainty evidence) and neurodevelopmental impairment (1 study; 79 infants; RR 0.27, 95% CI 0.03 to 2.31 for moderate/severe cognitive delay at 18 to 24 months; RR 0.54, 95% CI 0.05 to 5.71 for moderate/severe motor delay at 18 to 24 months; RR 0.54, 95% CI 0.10 to 2.78 for moderate/severe language delay at 18 to 24 months; low-certainty evidence). Infants receiving very early treatment in the first 72 hours after birth were more likely to receive any PDA pharmacotherapy compared to expectant management (4 studies; 156 infants; typical RR 1.64, 95% CI 1.31 to 2.05; typical RD 0.69; 95% CI 0.60 to 0.79; very low-certainty evidence). Very early treatment, however, shortened the duration of hospitalization compared to expectant management (4 studies; 260 infants; MD -5.35 days; 95% CI -9.23 to -1.47; low-certainty evidence). AUTHORS' CONCLUSIONS: Early or very early pharmacotherapeutic treatment of an hs-PDA probably does not reduce mortality in preterm infants (moderate-certainty evidence). Early pharmacotherapeutic treatment of hs-PDA may increase NSAID exposure (low-certainty evidence) without likely reducing CLD (moderate-certainty evidence), severe IVH or NEC (low-certainty evidence). We are uncertain whether very early pharmacotherapeutic treatment of hs-PDA also increases NSAID exposure (very low-certainty evidence). Very early treatment probably does not reduce surgical PDA ligation, severe IVH or NEC (moderate-certainty evidence), and may not reduce CLD or neurodevelopmental impairment (low-certainty evidence). Additional large trials that specifically include preterm infants at the highest risk of PDA-attributable morbidity, are adequately powered for patient-important outcomes and are minimally contaminated by open-label treatment are required to explore if early targeted treatment of hs-PDA improves clinical outcomes. There are currently two trials awaiting classification and two ongoing trials exploring this question.

Comparative effectiveness of catheter ablation devices in the treatment of atrial fibrillation: a network meta-analysis.

Atrial fibrillation (AF) ablation is most commonly performed using radiofrequency (RF) and cryoballoon (CB) catheters. Ablation Index is a novel lesion-quality marker associated with improved outcomes in RF ablation. Due to lack of direct comparative evidence between the latest generations of technologies, there is uncertainty regarding the best treatment option. Aim: To conduct a network meta-analysis to evaluate the comparative effectiveness of RF with Ablation Index to other catheter ablation devices in the treatment of AF. Methods: Searches for randomized and nonrandomized prospective comparative studies of ablation catheters were conducted in multiple databases. The outcome of interest was 12-month freedom from atrial arrhythmias after a single ablation procedure. Studies were grouped as high-, low- and unclear-quality based on study design and balanced baseline patient characteristics. Bayesian hierarchical network meta-analysis was conducted and results presented as relative risk ratios with 95% credible intervals (CrIs). Results: 12 studies evaluating five different catheter ablation devices were included. Radiofrequency ablation with Ablation Index was associated with statistically significantly greater probability of 12-month freedom from atrial arrhythmias than Arctic Front (relative risk: 1.77; 95% CrI: 1.21-2.87), Arctic Front Advance™ (1.41; 1.06-2.47), THERMOCOOL™ (1.34; 1.17-1.48) and THERMOCOOL SMARTTOUCH™ (1.09; 1-1.3). Results were robust in multiple sensitivity analyses. Conclusion: Radiofrequency catheter with Ablation Index is superior to currently available options for 12-month freedom from atrial arrhythmias after AF ablation. This study provides decision-makers with robust, pooled, comparative evidence of the latest ablation technologies.

The burden of osteoporosis in four Latin American countries: Brazil, Mexico, Colombia, and Argentina.

Objective: Osteoporosis is under-diagnosed and under-treated worldwide. Information on the burden of osteoporosis in Latin American countries is limited. This study aimed to estimate the economic burden of osteoporosis in adults aged 50-89 years in Brazil, Mexico, Colombia, and Argentina. Methods: Analyses were conducted using a burden of illness model. Where possible, country-specific model inputs were informed by a systematic review and expert opinion. Osteoporosis-related fracture costs were calculated for hospitalizations, testing, surgeries, prescription drugs, and patient productivity losses. Costs were expressed in 2018 USD for the annual burden, annual burden per 1,000 at risk, and projected 5-year burden. No discounting was applied. Results: Over 840,000 osteoporosis-related fractures were predicted to occur in 2018, amounting to a total annual cost of ∼1.17 billion USD. The total projected 5-year cost was ∼6.25 billion USD. Annual costs were highest in Mexico (411 million USD), followed by Argentina (360 million USD), Brazil (310 million USD), and Colombia (94 million USD). The average burden per 1,000 at risk was greatest in Argentina (32,583 USD), followed by Mexico (16,671 USD), Colombia (8,240 USD), and Brazil (6,130 USD). Conclusions: Over the next 5 years, ∼4,485,352 fractures are anticipated to occur in Brazil, Mexico, Colombia, and Argentina. To control and prevent these fractures, stakeholders must work together to close the care gap. Efforts to identify individuals at high fracture risk, initiate treatment, and improve long-term treatment persistence will be essential in minimizing the financial and patient burden of osteoporosis in Latin America.