Advances and limitations for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment.

Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.

BACKGROUND: Infants born preterm (before 37 weeks' gestation) have poorer outcomes than infants at term, particularly if born before 32 weeks. Early cord clamping has been standard practice over many years, and enables quick transfer of the infant to neonatal care. Delayed clamping allows blood flow between the placenta, umbilical cord and baby to continue, and may aid transition. Keeping baby at the mother's side enables neonatal care with the cord intact and this, along with delayed clamping, may improve outcomes. Umbilical cord milking (UCM) is proposed for increasing placental transfusion when immediate care for the preterm baby is needed. This Cochrane Review is a further update of a review first published in 2004 and updated in 2012. OBJECTIVES: To assess the effects on infants born at less than 37 weeks' gestation, and their mothers of: 1) delayed cord clamping (DCC) compared with early cord clamping (ECC) both with immediate neonatal care after cord clamping; 2) DCC with immediate neonatal care with cord intact compared with ECC with immediate neonatal care after cord clamping; 3) DCC with immediate neonatal care after cord clamping compared with UCM; 4) UCM compared with ECC with immediate neonatal care after cord clamping. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 November 2017), and reference lists of retrieved studies. We updated the search in November 2018 and added nine new trial reports to the awaiting classification section to be assessed at the next update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing delayed with early clamping of the umbilical cord (with immediate neonatal care after cord clamping or with cord intact) and UCM for births before 37 weeks' gestation. Quasi-RCTs were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Random-effects are used in all meta-analyses. Review authors assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: This update includes forty-eight studies, involving 5721 babies and their mothers, with data available from 40 studies involving 4884 babies and their mothers. Babies were between 24 and 36+6 weeks' gestation at birth and multiple births were included. The data are mostly from high-income countries. Delayed clamping ranged between 30 to 180 seconds, with most studies delaying for 30 to 60 seconds. Early clamping was less than 30 seconds and often immediate. UCM was mostly before cord clamping but some were milked after cord clamping. We undertook subgroup analysis by gestation and type of intervention, and sensitivity analyses by low risk of selection and attrition bias.All studies were high risk for performance bias and many were unclear for other aspects of risk of bias. Certainty of the evidence using GRADE was mostly low, mainly due to imprecision and unclear risk of bias.Delayed cord clamping (DCC) versus early cord clamping (ECC) both with immediate neonatal care after cord clamping (25 studies, 3100 babies and their mothers)DCC probably reduces the number of babies who die before discharge compared with ECC (average risk ratio (aRR) 0.73, 95% confidence interval (CI) 0.54 to 0.98, 20 studies, 2680 babies (moderate certainty)).No studies reported on 'Death or neurodevelopmental impairment' in the early years'.DCC may make little or no difference to the number of babies with severe intraventricular haemorrhage (IVH grades 3 and 4) (aRR 0.94, 95% CI 0.63 to 1.39, 10 studies, 2058 babies, low certainty) but slightly reduces the number of babies with any grade IVH (aRR 0.83, 95% CI 0.70 to 0.99, 15 studies, 2333 babies, high certainty).DCC has little or no effect on chronic lung disease (CLD) (aRR 1.04, 95% CI 0.94 to 1.14, 6 studies, 1644 babies, high certainty).Due to insufficient data, we were unable to form conclusions regarding periventricular leukomalacia (PVL) (aRR 0.58, 95% CI 0.26 to 1.30, 4 studies, 1544 babies, low certainty) or maternal blood loss of 500 mL or greater (aRR 1.14, 95% CI 0.07 to 17.63, 2 studies, 180 women, very low certainty).We identified no important heterogeneity in subgroup or sensitivity analyses.Delayed cord clamping (DCC) with immediate neonatal care with cord intact versus early cord clamping (ECC) (one study, 276 babies and their mothers)There are insufficient data to be confident in our findings, but DCC with immediate neonatal care with cord intact may reduce the number of babies who die before discharge, although the data are also compatible with a slight increase in mortality, compared with ECC (aRR 0.47, 95% CI 0.20 to 1.11, 1 study, 270 babies, low certainty). DCC may also reduce the number of babies who die or have neurodevelopmental impairment in early years (aRR 0.61, 95% CI 0.39 to 0.96, 1 study, 218 babies, low certainty). There may be little or no difference in: severe IVH; all grades IVH; PVL; CLD; maternal blood loss ≥ 500 mL, assessed as low certainty mainly due to serious imprecision.Delayed cord clamping (DCC) with immediate neonatal care after cord clamping versus umbilical cord milking (UCM) (three studies, 322 babies and their mothers) and UCM versus early cord clamping (ECC) (11 studies, 1183 babies and their mothers)There are insufficient data for reliable conclusions about the comparative effects of UCM compared with delayed or early clamping (mostly low or very low certainty). AUTHORS' CONCLUSIONS: Delayed, rather than early, cord clamping may reduce the risk of death before discharge for babies born preterm. There is insufficient evidence to show what duration of delay is best, one or several minutes, and therefore the optimum time to clamp the umbilical cord remains unclear. Whilst the current evidence supports not clamping the cord before 30 seconds at preterm births, future trials could compare different lengths of delay. Immediate neonatal care with the cord intact requires further study, and there are insufficient data on UCM.The nine new reports awaiting further classification may alter the conclusions of the review once assessed.

Kangaroo mother care to reduce morbidity and mortality in low birthweight infants.

BACKGROUND: Kangaroo mother care (KMC), originally defined as skin-to-skin contact between a mother and her newborn, frequent and exclusive or nearly exclusive breastfeeding, and early discharge from hospital, has been proposed as an alternative to conventional neonatal care for low birthweight (LBW) infants. OBJECTIVES: To determine whether evidence is available to support the use of KMC in LBW infants as an alternative to conventional neonatal care before or after the initial period of stabilization with conventional care, and to assess beneficial and adverse effects. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches in CENTRAL (Cochrane Central Register of Controlled Trials; 2016, Issue 6), MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), LILACS (Latin American and Caribbean Health Science Information database), and POPLINE (Population Information Online) databases (all from inception to June 30, 2016), as well as the WHO (World Health Organization) Trial Registration Data Set (up to June 30, 2016). In addition, we searched the web page of the Kangaroo Foundation, conference and symposia proceedings on KMC, and Google Scholar. SELECTION CRITERIA: Randomized controlled trials comparing KMC versus conventional neonatal care, or early-onset KMC versus late-onset KMC, in LBW infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Twenty-one studies, including 3042 infants, fulfilled inclusion criteria. Nineteen studies evaluated KMC in LBW infants after stabilization, one evaluated KMC in LBW infants before stabilization, and one compared early-onset KMC with late-onset KMC in relatively stable LBW infants. Sixteen studies evaluated intermittent KMC, and five evaluated continuous KMC. KMC versus conventional neonatal care: At discharge or 40 to 41 weeks' postmenstrual age, KMC was associated with a statistically significant reduction in the risk of mortality (risk ratio [RR] 0.60, 95% confidence interval [CI] 0.39 to 0.92; eight trials, 1736 infants), nosocomial infection/sepsis (RR 0.35, 95% CI 0.22 to 0.54; five trials, 1239 infants), and hypothermia (RR 0.28, 95% CI 0.16 to 0.49; nine trials, 989 infants; moderate-quality evidence). At latest follow-up, KMC was associated with a significantly decreased risk of mortality (RR 0.67, 95% CI 0.48 to 0.95; 12 trials, 2293 infants; moderate-quality evidence) and severe infection/sepsis (RR 0.50, 95% CI 0.36 to 0.69; eight trials, 1463 infants; moderate-quality evidence). Moreover, KMC was found to increase weight gain (mean difference [MD] 4.1 g/d, 95% CI 2.3 to 5.9; 11 trials, 1198 infants; moderate-quality evidence), length gain (MD 0.21 cm/week, 95% CI 0.03 to 0.38; three trials, 377 infants) and head circumference gain (MD 0.14 cm/week, 95% CI 0.06 to 0.22; four trials, 495 infants) at latest follow-up, exclusive breastfeeding at discharge or 40 to 41 weeks' postmenstrual age (RR 1.16, 95% CI 1.07 to 1.25; six studies, 1453 mothers) and at one to three months' follow-up (RR 1.20, 95% CI 1.01 to 1.43; five studies, 600 mothers), any (exclusive or partial) breastfeeding at discharge or at 40 to 41 weeks' postmenstrual age (RR 1.20, 95% CI 1.07 to 1.34; 10 studies, 1696 mothers; moderate-quality evidence) and at one to three months' follow-up (RR 1.17, 95% CI 1.05 to 1.31; nine studies, 1394 mothers; low-quality evidence), and some measures of mother-infant attachment and home environment. No statistically significant differences were found between KMC infants and controls in Griffith quotients for psychomotor development at 12 months' corrected age (low-quality evidence). Sensitivity analysis suggested that inclusion of studies with high risk of bias did not affect the general direction of findings nor the size of the treatment effect for main outcomes. Early-onset KMC versus late-onset KMC in relatively stable infants: One trial compared early-onset continuous KMC (within 24 hours post birth) versus late-onset continuous KMC (after 24 hours post birth) in 73 relatively stable LBW infants. Investigators reported no significant differences between the two study groups in mortality, morbidity, severe infection, hypothermia, breastfeeding, and nutritional indicators. Early-onset KMC was associated with a statistically significant reduction in length of hospital stay (MD 0.9 days, 95% CI 0.6 to 1.2). AUTHORS' CONCLUSIONS: Evidence from this updated review supports the use of KMC in LBW infants as an alternative to conventional neonatal care, mainly in resource-limited settings. Further information is required concerning the effectiveness and safety of early-onset continuous KMC in unstabilized or relatively stabilized LBW infants, as well as long-term neurodevelopmental outcomes and costs of care.

Kangaroo mother care to reduce morbidity and mortality in low birthweight infants.

BACKGROUND: Kangaroo mother care (KMC), originally defined as skin-to-skin contact between a mother and her newborn, frequent and exclusive or nearly exclusive breastfeeding, and early discharge from hospital, has been proposed as an alternative to conventional neonatal care for low birthweight (LBW) infants. OBJECTIVES: To determine whether there is evidence to support the use of KMC in LBW infants as an alternative to conventional neonatal care. SEARCH METHODS: The standard search strategy of the Cochrane Neonatal Group was used. This included searches in MEDLINE, EMBASE, LILACS, POPLINE, CINAHL databases (all from inception to March 31, 2014) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2014) In addition, we searched the web page of the Kangaroo Foundation, conference and symposia proceedings on KMC, and Google scholar. SELECTION CRITERIA: Randomized controlled trials comparing KMC versus conventional neonatal care, or early onset KMC (starting within 24 hours after birth) versus late onset KMC (starting after 24 hours after birth) in LBW infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Eighteen studies, including 2751 infants, fulfilled inclusion criteria. Sixteen studies evaluated KMC in LBW infants after stabilization, one evaluated KMC in LBW infants before stabilization, and one compared early onset KMC with late onset KMC in relatively stable LBW infants. Thirteen studies evaluated intermittent KMC and five evaluated continuous KMC. At discharge or 40-41 weeks' postmenstrual age, KMC was associated with a reduction in the risk of mortality (typical risk ratio (RR) 0.60, 95% confidence interval (CI) 0.39 to 0.92; eight trials, 1736 infants), nosocomial infection/sepsis (typical RR 0.45, 95% CI 0.27 to 0.76), hypothermia (typical RR 0.34, 95% CI 0.17 to 0.67), and length of hospital stay (typical mean difference 2.2 days, 95% CI 0.6 to 3.7). At latest follow up, KMC was associated with a decreased risk of mortality (typical RR 0.67, 95% CI 0.48 to 0.95; 11 trials, 2167 infants) and severe infection/sepsis (typical RR 0.56, 95% CI 0.40 to 0.78). Moreover, KMC was found to increase some measures of infant growth, breastfeeding, and mother-infant attachment. There were no significant differences between KMC infants and controls in neurodevelopmental and neurosensory impairment at one year of corrected age. Sensitivity analysis suggested that the inclusion of studies with high risk of bias did not affect the general direction of findings or the size of the treatment effect for the main outcomes. AUTHORS' CONCLUSIONS: The evidence from this updated review supports the use of KMC in LBW infants as an alternative to conventional neonatal care mainly in resource-limited settings. Further information is required concerning effectiveness and safety of early onset continuous KMC in unstabilized or relatively stabilized LBW infants, long term neurodevelopmental outcomes, and costs of care.

Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study.

BACKGROUND AND OBJECTIVES: Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA. METHODS: In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points. RESULTS: Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported. DISCUSSION: Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA. TRIAL REGISTRATION INFORMATION: This trial is registered with ClinicalTrials.gov (NCT03921528). CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

An Epithelioid Hemangioma Camouflaged As Radial Aneurysm.

Epithelioid hemangioma (EH) is an uncommon benign vascular lesion usually present as subcutaneous nodules in the head and neck area. Sometimes, these lesions can occur in the peripheral arteries, and when they do, they can be mistaken for aneurysmal dilatations of that respective vessel. We report a case of a 43-year-old male who underwent surgical recession of a radial aneurysm, which after anatomopathological examination, revealed an EH.

Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.

BACKGROUND: Optimal timing for clamping the umbilical cord at preterm birth is unclear. Early clamping allows for immediate transfer of the infant to the neonatologist. Delaying clamping allows blood flow between the placenta, the umbilical cord and the baby to continue. The blood which transfers to the baby between birth and cord clamping is called placental transfusion. Placental transfusion may improve circulating volume at birth, which may in turn improve outcome for preterm infants. OBJECTIVES: To assess the short- and long-term effects of early rather than delaying clamping or milking of the umbilical cord for infants born at less than 37 completed weeks' gestation, and their mothers. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 May 2011). We updated this search on 26 June 2012 and added the results to the awaiting classification section. SELECTION CRITERIA: Randomised controlled trials comparing early with delayed clamping of the umbilical cord and other strategies to influence placental transfusion for births before 37 completed weeks' gestation. DATA COLLECTION AND ANALYSIS: Three review authors assessed eligibility and trial quality. MAIN RESULTS: Fifteen studies (738 infants) were eligible for inclusion. Participants were between 24 and 36 weeks' gestation at birth. The maximum delay in cord clamping was 180 seconds. Delaying cord clamping was associated with fewer infants requiring transfusions for anaemia (seven trials, 392 infants; risk ratio (RR) 0.61, 95% confidence interval (CI) 0.46 to 0.81), less intraventricular haemorrhage (ultrasound diagnosis all grades) 10 trials, 539 infants (RR 0.59, 95% CI 0.41 to 0.85) and lower risk for necrotising enterocolitis (five trials, 241 infants, RR 0.62, 95% CI 0.43 to 0.90) compared with immediate clamping. However, the peak bilirubin concentration was higher for infants allocated to delayed cord clamping compared with immediate clamping (seven trials, 320 infants, mean difference 15.01 mmol/L, 95% CI 5.62 to 24.40). For most other outcomes (including the primary outcomes infant death, severe (grade three to four) intraventricular haemorrhage and periventricular leukomalacia) there were no clear differences identified between groups; but for many there was incomplete reporting and wide CIs. Outcome after discharge from hospital was reported for one small study; there were no significant differences between the groups in mean Bayley II scores at age seven months (corrected for gestation at birth (58 children)).No studies reported outcomes for the women. AUTHORS' CONCLUSIONS: Providing additional placental blood to the preterm baby by either delaying cord clamping for 30 to 120 seconds, rather than early clamping, seems to be associated with less need for transfusion, better circulatory stability, less intraventricular haemorrhage (all grades) and lower risk for necrotising enterocolitis. However, there were insufficient data for reliable conclusions about the comparative effects on any of the primary outcomes for this review.

Gestational age at birth and morbidity, mortality, and growth in the first 4 years of life: findings from three birth cohorts in Southern Brazil.

BACKGROUND: We assessed anthropometric status, breastfeeding duration, morbidity, and mortality outcomes during the first four years of life according to gestational age, in three population-based birth cohorts in the city of Pelotas, Southern Brazil. METHODS: Total breastfeeding duration, neonatal mortality, infant morbidity and mortality, and anthropometric measures taken at 12 and 48 months were evaluated in children of different gestational ages born in 1982, 1993 and 2004 in Southern Brazil. RESULTS: Babies born <34 weeks of gestation and those born between 34-36 weeks presented increased morbidity and mortality, were breastfed for shorter periods, and were more likely to be undernourished at 12 months of life, in comparison with the 39-41 weeks group. Children born with 37 weeks were more than twice as likely to die in the first year of life, and were also at increased risk of hospitalization and underweight at 12 months of life. Post-term infants presented an increased risk of neonatal mortality. CONCLUSION: The increased risks of morbidity and mortality among preterm (<37 weeks of gestation) and post-term (>41 weeks) are well known. In our population babies born at 37 also present increased risk. As the proportion of preterm and early term babies has increased markedly in recent years, this is a cause for great concern.

Kangaroo mother care to reduce morbidity and mortality in low birthweight infants.

BACKGROUND: Kangaroo mother care (KMC), originally defined as skin-to-skin contact between a mother and her newborn, frequent and exclusive or nearly exclusive breastfeeding, and early discharge from hospital, has been proposed as an alternative to conventional neonatal care for low birthweight (LBW) infants. OBJECTIVES: To determine whether there is evidence to support the use of KMC in LBW infants as an alternative to conventional neonatal care. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Group was used. This included searches of MEDLINE, EMBASE, LILACS, POPLINE, CINAHL databases (from inception to January 31, 2011), and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2011). In addition, we searched the web page of the Kangaroo Foundation, conference and symposia proceedings on KMC, and Google scholar. SELECTION CRITERIA: Randomized controlled trials comparing KMC versus conventional neonatal care, or early onset KMC (starting within 24 hours after birth) versus late onset KMC (starting after 24 hours after birth) in LBW infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Sixteen studies, including 2518 infants, fulfilled inclusion criteria. Fourteen studies evaluated KMC in LBW infants after stabilization, one evaluated KMC in LBW infants before stabilization, and one compared early onset KMC with late onset KMC in relatively stable LBW infants. Eleven studies evaluated intermittent KMC and five evaluated continuous KMC. At discharge or 40 - 41 weeks' postmenstrual age, KMC was associated with a reduction in the risk of mortality (typical risk ratio (RR) 0.60, 95% confidence interval (CI) 0.39 to 0.93; seven trials, 1614 infants), nosocomial infection/sepsis (typical RR 0.42, 95% CI 0.24 to 0.73), hypothermia (typical RR 0.23, 95% CI 0.10 to 0.55), and length of hospital stay (typical mean difference 2.4 days, 95% CI 0.7 to 4.1). At latest follow up, KMC was associated with a decreased risk of mortality (typical RR 0.68, 95% CI 0.48 to 0.96; nine trials, 1952 infants) and severe infection/sepsis (typical RR 0.57, 95% CI 0.40 to 0.80). Moreover, KMC was found to increase some measures of infant growth, breastfeeding, and mother-infant attachment. AUTHORS' CONCLUSIONS: The evidence from this updated review supports the use of KMC in LBW infants as an alternative to conventional neonatal care mainly in resource-limited settings. Further information is required concerning effectiveness and safety of early onset continuous KMC in unstabilized LBW infants, long term neurodevelopmental outcomes, and costs of care.

Umbilical Cord Management for Newborns <34 Weeks' Gestation: A Meta-analysis.

CONTEXT: The International Liaison Committee on Resuscitation prioritized scientific review of umbilical cord management strategies at preterm birth. OBJECTIVE: To determine the effects of umbilical cord management strategies (including timing of cord clamping and cord milking) in preterm infants <34 weeks' gestation. DATA SOURCES: Cochrane Central Register of Controlled Trials, Medline, PubMed, Embase, CINAHL, and trial registries were searched through July 2019 for randomized controlled trials assessing timing of cord clamping and/or cord milking. STUDY SELECTION: Two authors independently assessed trial eligibility, extracted data, appraised risk of bias, and assessed evidence certainty (GRADE). DATA EXTRACTION: We identified 42 randomized controlled trials (including 5772 infants) investigating 4 different comparisons of cord management interventions. RESULTS: Compared to early cord clamping, delayed cord clamping (DCC) and intact-cord milking (ICM) may slightly improve survival; however, both are compatible with no effect (DCC: risk ratio: 1.02, 95% confidence interval: 1.00 to 1.04, n = 2988 infants, moderate certainty evidence; ICM: risk ratio: 1.02, 95% confidence interval: 0.98 to 1.06, n = 945 infants, moderate certainty evidence). DCC and ICM both probably improve hematologic measures but may not affect major neonatal morbidities. LIMITATIONS: For many of the included comparisons and outcomes, certainty of evidence was low. Our subgroup analyses were limited by few researchers reporting subgroup data. CONCLUSIONS: DCC appears to be associated with some benefit for infants born <34 weeks. Cord milking needs further evidence to determine potential benefits or harms. The ideal cord management strategy for preterm infants is still unknown, but early clamping may be harmful.

Caesarean sections and the prevalence of preterm and early-term births in Brazil: secondary analyses of national birth registration.

OBJECTIVES: To investigate whether the high rates of caesarean sections (CSs) in Brazil have impacted on the prevalence of preterm and early-term births. DESIGN: Individual-level, cross-sectional analyses of a national database. SETTING: All hospital births occurring in the country in 2015. PARTICIPANTS: 2 903 716 hospital-delivered singletons in 3157 municipalities, representing >96% of the country's births. PRIMARY AND SECONDARY OUTCOME MEASURES: CS rates and gestational age distribution (<37, 37-38, 39-41 and 42 or more weeks' gestation). Outcomes were analysed according to maternal education, measured in years of schooling and municipal CS rates. Analyses were also adjusted for maternal age, marital status and parity. RESULTS: Prevalence of CS was 55.5%, preterm prevalence (<37 weeks' gestation) was 10.1% and early-term births (37-38 weeks of gestation) represented 29.8% of all births, ranging from 24.9% among women with <4 years of schooling to 39.8% among those with >12 years of education. The adjusted prevalence ratios of preterm and early-term birth were, respectively, 1.215 (1.174-1.257) and 1.643 (1.616-1.671) higher in municipalities with≥80% CS compared with those <30%. CONCLUSIONS: Brazil faces three inter-related epidemics: a CS epidemic; an epidemic of early-term births, associated with the high CS rates; and an epidemic of preterm birth, also associated with CS but mostly linked to poverty-related risk factors. The high rates of preterm and early-term births produce an excess of newborns at higher risk of short-term morbidity and mortality, as well as long-term developmental problems. Compared with high-income countries, there is an annual excess of 354 000 preterm and early-term births in Brazil.

Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy.

PURPOSE: Epidermal growth factor receptor (EGFR) expression is observed in 50%-70% of colorectal carcinomas and is associated with poor prognosis. The aim of this study was to determine the EGFR expression rate in locally advanced rectal cancer and to analyze whether EGFR expression predicts tumor response to preoperative radiotherapy. METHODS AND MATERIALS: Between December 1997 and October 2000, 45 patients were included. Treatment consisted of preoperative pelvic radiotherapy and, in 21 patients, 2 courses of 5-fluorouracil leucovorin. Surgical resection was performed 4-8 weeks later. Immunohistochemistry for EGFR was determined at the preradiation diagnostic biopsy and in the resected specimens. Immunostaining was performed using EGFR monoclonal antibody (Biogenex, MU 207-UC). Immunohistochemical staining was evaluated according to extension and intensity. We defined positive staining (EGFR+) as extension of 5% or more. RESULTS: Preoperative treatment resulted in pathologic complete remission in 7 patients (15%), downstaging in 13 patients (29%), and no response in 25 patients (56%). EGFR+ was observed in 29 of 45 tumors (64%) and was associated with neither clinical tumor stage nor clinical nodal stage. The overall response rate was 34% in EGFR+ patients vs. 62% in those who were EGFR- (p = 0.07). Only 1 of the 7 pathologic complete remission patients was EGFR+ (p = 0.003). CONCLUSIONS: EGFR is expressed in a significant number of locally advanced rectal tumors. EGFR expression is an indicator for poor response to preoperative radiotherapy in advanced rectal carcinoma.

Posterior fontanelle sonography: an acoustic window into the neonatal brain.

BACKGROUND AND PURPOSE: Sonographic brain studies are classically performed through the anterior fontanelle, but visualization of posterior supratentorial and infratentorial structures is poor with this approach. Posterior fontanelle sonography is recommended for better assessment of these structures. Our purpose was 1) to determine whether sonography of the brain through the posterior fontanelle (PF) improves visualization of brain lesions when added to the routine anterior fontanelle (AF) approach and 2) to describe standardized PF coronal and sagittal sections. METHODS: In this prospective study (conducted from February 1999 to January 2001), PF sonography was added to AF sonography in 165 consecutive premature neonates with a birth weight of < 2000 g. Sonograms were recorded in digital format for re-evaluation at the end of the study. Lesions were grouped as congenital, infectious, hemorrhagic, or hypoxic-ischemic. The chi2 test for paired data and the kappa coefficient were used to compare diagnoses with AF alone and diagnoses with AF plus PF. RESULTS: PF sonography was performed in 164 of 165 patients. Results were normal in 86 and abnormal in 78. The single posterior fossa malformation detected in this series was best delineated with the PF approach. PF sonography increased the diagnostic rate of grade II hemorrhage by 32%. Cerebellar hemorrhage (two patients) and cerebellar abscesses (one patient) were diagnosed by using the PF approach. PF sonography did not contribute to the diagnosis of periventricular leukomalacia. CONCLUSION: Study of the neonatal brain with the addition of PF sonography afforded greater accuracy in detecting intraventricular hemorrhage compared with AF sonography alone, especially when the ventricle was not dilated. The PF approach better defines posterior fossa malformations.

[Etiology of hospital-acquired infections in Spanish hospitals (EPINE, 1990-1999)]. / Etiología de las infecciones hospitalarias en España (EPINE, 1990-1999).

BACKGROUND: Clinical and demographic characteristics of patients, their interaction with pathogens and antimicrobial therapies are prompting changes in the epidemiology of hospital-acquired infections (HI). The knowledge of the etiology of hospital-acquired infections is valuable for the treatment of infected patients and for the prevention of HI. PATIENTS AND METHOD: We analyzed a series of 10 annual prevalence studies during the period 1990-1999 (EPINE project) in Spanish hospitals. Estimate of prevalence of infection was calculated by means of the percent distribution of every organism regarding overall identified organisms and infections. RESULTS: 40,550 HI were identified among 484,013 patients (HI prevalence = 8.4%; 95% CI, 8.3-8.5%). Gram-positive organism predominated steadily in bloodstream and surgical wound infections, while gram-negative bacilli predominated in respiratory and urinary tract infections. There was an increase in HI infections by Acinetobacter baumannii (from 1.9% in 1990 to 3.6% in 1999; P < 0.001) and Candida albicans (from 2.4 to 3.2%; P < 0.001), as well as an increase in both HI and community-acquired infections by methicillin-resistant Staphylococcus aureus [HI: from 4.7 to 40.2% (P < 0.001); community-acquired: from 2.7 to 15.6% (P < 0.001)]. CONCLUSIONS: We observed some changes in the etiology of infections over the last decade: rates of methicillin-resistant S. aureus hospital-acquired and community-acquired infections increased steadily and their initial rates multiplied by 8 and 6, respectively. Rates of HI caused by yeasts and A. baumannii increased also.

[Antimicrobial use in Spanish hospitals (EPINE, 1990-1999)]. / Utilización de los antimicrobianos en los hospitales españoles (EPINE, 1990-1999).

BACKGROUND: Monitoring of antimicrobial use and knowledge of prescription habits are some of the strategies recommended to contain the resistance to antimicrobials in hospitals. METHOD: We analyzed a series of 10 annual studies of prevalence during the period 1990-1999 (EPINE project) in Spanish hospitals. Estimates of antimicrobial use were calculated as the percent distribution of every antimicrobial related to the overall antimicrobials prescribed. RESULTS: Among 484,013 hospitalized patients, 34 to 36% were receiving antimicrobials (antibiotics > 90%). Amoxicillin-clavulanate use increased from 3.8% in 1990 up to 14.8% in 1999 (P < 0.01). Significant increases were also observed in the use of carbapenems (0.9 to 2.7%; P < 0.01), glycopeptides (1.7 to 3.7%; P < 0.01) and quinolones (8.5 to 11.3%; P < 0.01) though to a lesser degree. Conversely, the use of aminoglycosides decreased over the decade studied (15.8 to 9.4%; P < 0.01). CONCLUSIONS: Even though the use of antimicrobials has increased over the last decade, current figures are within the ranges observed in other countries. The pattern of antibiotics use has changed during this period: while the use of aminoglycosides decreased, that of -lactams plus -lactamase inhibitors, quinolones and carbapenems increased.

Administración de surfactante profiláctico por vía orofaríngea previo al pinzamiento de cordón umbilical en el recién nacido de muy bajo peso en la maternidad del Hospital Universitario / Prophylactic oropharyngeal surfactant administration before cord clamping in very low birth weight newborns at the University Children Hospital Maternity Department / Administração de surfactante profilático por via orofaríngea antes do clampeamento do cordão umbilical em recém-nascidos de baixo peso extremo na Maternidade do Hospital Pediátrico Universitário

Resumen: En la era de la búsqueda de estrategias ventilatorias mínimamente invasivas, la administración profiláctica de surfactante con técnicas sencillas, que no requieren elevada destreza y que pueden ser realizadas en ámbitos de baja complejidad, deben ser investigadas para potencialmente disminuir la morbilidad y mortalidad del pretérmino. Se reporta el uso de surfactante en la orofaringe de cuatro recién nacidos de muy bajo peso (promedio de peso de 1.236 g y 28 semanas de edad gestacional), y concomitante colocación de presión positiva continua por pieza nasal antes de la primera inspiración extrauterina manteniendo el cordón intacto. No se registraron efectos adversos y la aspiración gástrica posterior demostró que el surfactante fue inspirado a los pulmones del recién nacido. La administración de surfactante orofaríngeo es una técnica innovadora, segura, factible y reproducible. A la vez que minimizamos los riesgos de posible iatrogenia por la técnica utilizada, facilitamos una transición cardiovascular más estable, manteniendo la circulación fetoplacentaria.

Summary: In the era of minimally invasive ventilatory procedures, the prophylactic administration of surfactant using simple techniques that can be performed in low complexity settings, should be researched as a tool to potentially reduce preterm morbidity and mortality. We report the use of oropharyngeal surfactant in 4 very low birth weight newborns (average birth weight 1236g and 28 weeks of gestational age) and of continuous positive airway pressure before the first intrauterine inspiration and keeping an intact umbilical cord. No adverse effects happened, and the aspiration of gastric residual confirmed that surfactant had reached the lungs. The administration of oropharyngeal surfactant is an innovative, safe, feasible and reproducible technique. It minimizes the risks of possible iatrogenesis due to the technique used, and it also facilitates a more stable cardiovascular transition, maintaining the fetus' placental circulation.

Resumo: Na era da procura de técnicas ventilatórias minimamente invasivas, a administração profilática de surfactante utilizando técnicas simples, que não requerem muita destreza e que pode ser realizada em contextos de baixa complexidade, deve ser pesquisada para reduzir potencialmente a morbidade e mortalidade dos pré-termos. Reportamos o uso de surfactante na orofaringe em 4 recém-nascidos com baixo peso ao nascimento (peso médio de 1,236 g e 28 semanas de idade gestacional), e colocação concomitante de pressão positiva contínua por adaptador nasal, antes da primeira inspiração extrauterina e mantendo o cordão umbilical intacto. Não houve efeitos adversos e o aspirado gástrico subsequente mostrou que o surfactante foi inspirado e observado nos pulmões dos recém-nascidos. O surfactante de administração orofaríngea é uma técnica inovadora, segura, viável e reprodutível. Minimiza os riscos iatrogênicos eventuais devido à técnica utilizada, à vez que proporciona uma transição cardiovascular mais estável porque mantém a circulação da placenta fetal.

Intubación al nacer con tubo nasal corto en la transición a la vida extrauterina en recién nacidos de muy bajo peso / Intubation with a short nasal tube at birth during the transition to extrauterine life in very low birth weight infants

Describimos cambios recientes en el cuidado convencional al nacer en recién nacidos de muy bajo peso al nacer y la utilización de un tubo nasal corto para apoyar la ventilación inicial en este nuevo contexto. Reportamos nuestra experiencia con los tres primeros casos en que usamos esta técnica simple para administrar nCPAP a recién nacidos durante el alumbramiento mientras existe función placentaria antes de cortar el cordón.

We describe recent changes in conventional care at birth of very low birth weight infants and the use of a short nasal tube to support ventilation. We report our experience in the first three cases with this simple technique to deliver nCPAP to newborn infants during the third stage of labour, while the placenta is still functioning and before cutting the cord