Urinary stress incontinence and other maternal outcomes 2 years after caesarean or vaginal birth for twin pregnancy: a multicentre randomised trial.

OBJECTIVE: Does planned caesarean compared with planned vaginal birth lower the risk of problematic urinary stress, faecal, or flatal incontinence? DESIGN: Women between 320/7 and 386/7 weeks of gestation with a twin pregnancy were randomised to planned caesarean or planned vaginal birth. SETTING: The trial took place at 106 centres in 25 countries. POPULATION: A total of 2305 of the 2804 women enrolled in the study completed questionnaires at 2 years (82.2% follow-up): 1155 in the planned caesarean group and 1150 in the planned vaginal birth group. METHODS: A structured self-administered questionnaire completed at 2 years postpartum. MAIN OUTCOME MEASURES: The primary maternal outcome of the Twin Birth Study was problematic urinary stress, or fecal, or flatal incontinence at 2 years RESULTS: Women in the planned caesarean group had lower problematic urinary stress incontinence rates compared with women in the planned vaginal birth group [93/1147 (8.11%) versus 140/1143 (12.25%); odds ratio, 0.63; 95% confidence interval, 0.47-0.83; P = 0.001]. Among those with problematic urinary stress incontinence, quality of life (measured using the Incontinence Impact Questionnaire, IIQ-7) was not different for planned caesarean versus planned vaginal birth groups [mean (SD): 18.4 (21.0) versus 19.1 (21.5); P = 0.82]. There were no differences in problematic faecal or flatal incontinence, or in other maternal outcomes. CONCLUSIONS: Among women with a twin pregnancy and no prior history of urinary stress incontinence, a management strategy of planned caesarean compared with planned vaginal birth reduces the risk of problematic urinary stress incontinence at 2 years postpartum. Our findings show that the prevalence but not the severity of urinary stress incontinence was associated with mode of birth. FUNDING: Canadian Institutes of Health Research (CIHR) (grant no. MCT-63164). TWEETABLE ABSTRACT: For women with twins, planned caesarean compared with planned vaginal birth is associated with decreased prevalence but not severity of urinary stress incontinence at 2 years.

Maternal outcomes at 3 months after planned caesarean section versus planned vaginal birth for twin pregnancies in the Twin Birth Study: a randomised controlled trial.

OBJECTIVE: To compare outcomes at 3 months post partum for women randomised to give birth by planned caesarean section (CS) or by planned vaginal birth (VB) in the Twin Birth Study (TBS). DESIGN: We invited women in the TBS to complete a 3-month follow-up questionnaire. SETTING: Two thousand and eight hundred and four women from 25 countries. POPULATION: Two thousand and five hundred and seventy women (92% response rate). METHODS: Women randomised between 13 December 2003 and 4 April 2011 in the TBS completed a questionnaire and outcomes were compared using an intention-to-treat approach. MAIN OUTCOME AND MEASURES: Breastfeeding, quality of life, depression, fatigue and urinary incontinence. RESULTS: We found no clinically important differences between groups in any outcome. In the planned CS versus planned VB groups, breastfeeding at any time after birth was reported by 84.4% versus 86.4% (P = 0.13); the mean physical and mental Short Form (36) Health Survey (SF-36) quality of life scores were 51.8 versus 51.6 (P = 0.65) and 46.7 versus 46.0 (P = 0.09), respectively; the mean Multidimensional Assessment of Fatigue score was 20.3 versus 20.8 (P = 0.14); the frequency of probable depression on the Edinburgh Postnatal Depression Scale was 14.0% versus 14.8% (P = 0.57); the rate of problematic urinary incontinence was 5.5% versus 6.4% (P = 0.31); and the mean Incontinence Impact Questionnaire-7 score was 20.5 versus 20.4 (P = 0.99). Partner relationships, including painful intercourse, were similar between the groups. CONCLUSION: For women with twin pregnancies randomised to planned CS compared with planned VB, outcomes at 3 months post partum did not differ. The mode of birth was not associated with problematic urinary incontinence or urinary incontinence that affected the quality of life. Contrary to previous studies, breastfeeding at 3 months was not increased with planned VB. TWEETABLE ABSTRACT: Planned mode of birth for twins doesn't affect maternal depression, wellbeing, incontinence or breastfeeding.

Evaluation of species-specific PCR, Bruker MS, VITEK MS and the VITEK 2 system for the identification of clinical Enterococcus isolates.

The purpose of this investigation was to compare the performance of species-specific polymerase chain reaction (PCR), matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and phenotypic identification systems for the identification of Enterococcus species. A total of 132 clinical isolates were investigated by the following: (1) a multiplex real-time PCR assay targeting ddl Enterococcus faecium, ddl Enterococcus faecalis, vanC1 and vanC2/C3 genes, and a high-resolution melting (HRM) analysis of the groESL gene for the differentiation of Enterococcus casseliflavus and Enterococcus gallinarum; (2) Bruker MS; (3) VITEK MS; and (4) the VITEK 2 system. 16S rRNA gene sequencing was used as a reference method in the study. The 132 isolates were identified as 32 E. faecalis, 63 E. faecium, 16 E. casseliflavus and 21 E. gallinarum. The multiplex PCR, Bruker MS and VITEK MS were able to identify all the isolates correctly at the species level. The VITEK 2 system could identify 131/132 (99.2 %) and 121/132 (91.7 %) of the isolates at the genus and species levels, respectively. The HRM-groESL assay identified all (21/21) E. gallinarum isolates and 81.3 % (13/16) of the E. casseliflavus isolates. The PCR methods described in the present study are effective in identifying the enterococcal species. MALDI-TOF MS is a rapid, reliable and cost-effective identification technique for enterococci. The VITEK 2 system is less efficient at detecting non-faecalis and non-faecium Enterococcus species.

Screening for vancomycin-resistant enterococci: an efficient and economical laboratory-developed test.

A laboratory-developed test (Lab Assay), combining enrichment broth and real-time polymerase chain reaction (PCR) for vancomycin-resistant enterococci (VRE) screening, was developed and evaluated in this study. A total of 1,765 faecal or rectal swabs sent to the laboratory for VRE screening were investigated in parallel by Lab Assay and the Roche LightCycler VRE detection kit-based method. The diagnostic values for Lab Assay were as follows: 100% sensitivity, 79.92% specificity, 1.94% positive predictive value and 100% negative predictive value, which were comparable to the results from the LightCycler kit-based assay. The detection limit of Lab Assay was 10(0) to 10(1) colony-forming units (CFU)/ml of inoculum in broth for both VanA-type and VanB-type VRE. The PCR method developed in this study was approved to be applicable on both the Applied Biosystems 7500 Fast Real-Time PCR System and the LightCycler(®) 480 Real-Time PCR System. The flexibility in choosing PCR systems makes it possible that the PCR assay could be fully compatible with the DNA extraction's platform, providing an integrated workflow. Furthermore, the material cost is saved at 7EUR per sample when Lab Assay replaces the commercial kit-based method in our routine screening for VRE. Therefore, the laboratory-developed broth-PCR method is an efficient and economical assay for VRE screening.

Metabolism of Klebsiella pneumoniae freeze-dried cultures for the design of BOD bioassays.

AIMS: The survival rate of freeze-dried cultures is not enough information for technological applications of micro-organisms. There could be serious metabolic/structural damage in the survivors, leading to a delay time that can jeopardize the design of a rapid biochemical oxygen demand (BOD) metabolic-based bioassay. Therefore, we will study the metabolic activity (as ferricyanide reduction activity) and the survival rate (as colony-forming units, CFU) of different Klebsiella pneumoniae freeze-dried cultures looking for stable metabolic conditions after 35days of storage. METHOD AND RESULTS: Here, we tried several simple freeze-drying processes of Kl. pneumoniae. Electrochemical measurements of ferrocyanide and survival rates obtained with the different freeze-dried cultures were used to choose the best freeze-drying process that leads to a rapid metabolic-based bioassay. CONCLUSIONS: The use of milk plus monosodium glutamate was the best choice to obtain a Kl. pneumoniae freeze-dried culture with metabolic stable conditions after storage at -20°C without the need of vacuum storage and ready to use after 20min of rehydration. We also demonstrate that the viability and the metabolic activity are not always directly correlated. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that the use of this Kl. pneumoniae freeze-dried culture is appropriate for the design of a rapid BOD bioassay.

The Early External Cephalic Version (ECV) 2 Trial: an international multicentre randomised controlled trial of timing of ECV for breech pregnancies.

OBJECTIVE: To investigate whether initiating external cephalic version (ECV) earlier in pregnancy might increase the rate of successful ECV procedures, and be more effective in decreasing the rate of non-cephalic presentation at birth and of caesarean section. DESIGN: An unblinded multicentred randomised controlled trial. SETTING: A total of 1543 women were randomised from 68 centres in 21 countries. POPULATION: Women with a singleton breech fetus at a gestational age of 33(0/7) weeks (231 days) to 35(6/7) weeks (251 days) of gestation were included. METHODS: Participants were randomly assigned to having a first ECV procedure between the gestational ages of 34(0/7) (238 days) and 35(6/7) weeks of gestation (early ECV group) or at or after 37(0/7) (259 days) weeks of gestation (delayed ECV group). MAIN OUTCOME MEASURES: The primary outcome was the rate of caesarean section; the secondary outcome was the rate of preterm birth. RESULTS: Fewer fetuses were in a non-cephalic presentation at birth in the early ECV group (314/765 [41.1%] versus 377/768 [49.1%] in the delayed ECV group; relative risk [RR] 0.84, 95% CI 0.75, 0.94, P=0.002). There were no differences in rates of caesarean section (398/765 [52.0%] versus 430/768 [56.0%]; RR 0.93, 95% CI 0.85, 1.02, P=0.12) or in risk of preterm birth (50/765 [6.5%] versus 34/768 [4.4%]; RR 1.48, 95% CI 0.97, 2.26, P=0.07) between groups. CONCLUSION: External cephalic version at 34-35 weeks versus 37 or more weeks of gestation increases the likelihood of cephalic presentation at birth but does not reduce the rate of caesarean section and may increase the rate of preterm birth.

Delta-1-tetrahydrocannabinol: structure of a major metabolite.

triangle up(1)-Tetrahydrocannabinol, the major psychotomimetically active compound of Cannabis, was metabolized in vitro by the 10, OOOg supernatant from rabbit liver. By mass and nuclear magnetic resonance spectrometry, the major metabolite was identified as 7-hydroxy-triangle up(1)-tetrahydrocannabinol. The latter compound of Cannabis, was metabolized in vitro by the 10,OOOg supernatant from

Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants.

BACKGROUND: A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gastrointestinal tract. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin, with fewer side effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants. To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants. SEARCH STRATEGY: Randomized or quasi-randomized controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1996 - August 2007), CINAHL (1982 - August 2007), EMBASE (1980 - August 2007), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - April 2005) or on their website (to August 2007). No language restrictions were applied. SELECTION CRITERIA: 1) DESIGN: Randomized or quasi-randomized controlled trials2) POPULATION: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) with a clinically or echocardiographically diagnosed PDA3) INTERVENTION: Administration of ibuprofen (orally or intravenously) for the closure of PDA4) OUTCOMES: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ductal ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), chronic lung disease (CLD), sepsis, pulmonary hemorrhage, pulmonary hypertension, duration of supplementary oxygen, duration of mechanical ventilation, duration of hospital stay, and serum creatinine levels following treatment. DATA COLLECTION AND ANALYSIS: At least two review authors worked independently at each step of the original review, then compared results and resolved differences. The current update was conducted by one review author (AO). Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of follow up. Weighted treatment effects, calculated using RevMan 4.2.10, included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared test (I(2)) were performed to assess the appropriateness of pooling the data. MAIN RESULTS: No studies using mefenamic acid were identified. Sixteen studies enrolling 876 infants were identified. Four additional trials were identified for this update and two studies published as abstracts were now available as full articles. One study compared ibuprofen to placebo, but the results were not reported unblinded to intervention group. Fifteen studies including 740 infants compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.99 (95% CI 0.78, 1.27); typical RD 0.00 (95% CI -0.06, 0.06)]. There were no statistically significant differences in mortality, reopening of the ductus, need for surgical duct ligation, duration of ventilator support, duration of supplementary oxygen, pulmonary hemorrhage, pulmonary hypertension, CLD, IVH, PVL, NEC, intestinal perforation, gastrointestinal bleed, time to full enteral feeds, time to regain birth weight, ROP, sepsis, duration of hospitalization. Ibuprofen treatment was associated with statistically significantly lower serum creatinine levels after treatment (6 trials, 336 infants; WMD - 8.2 (95% CI -13.3, -3.2) mmol/L and lower incidence of 'decreased urine output' [3 trials, 336 infants; typical RR; 0.22 (95% CI 0.09, 0.51); typical RD -0.12 (95% CI -0.18, -0.06); NNT 8 (95% CI 6,17)]. There was moderate heterogeneity of treatment effect for the outcomes 'time to regain birth weight' and 'decreased urine output". Heterogeneity was not noted for other outcomes. For several of these outcomes, the sample size was small and the estimates imprecise. There are not enough data available regarding the effectiveness of oral ibuprofen compared with indomethacin to close a PDA [3 trials, 69 infants; typical RR 1.41 (95% CI 0.68, 2.93); typical RD 0.10 (95% CI -0.10, 0.30)]. Pulmonary hypertension was noted in one infant receiving ibuprofen to close a PDA enrolled in a trial in this review and an additional report of such a case was identified from the literature. AUTHORS' CONCLUSIONS: No statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing a PDA was found. Ibuprofen compared with indomethacin reduces the risk of oliguria and is associated with lower serum creatinine levels following treatment. Pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen and one infant receiving ibuprofen for treatment in this review developed pulmonary hypertension. One additional case of pulmonary hypertension following treatment with ibuprofen to close a PDA was identified from the literature. The available data support the use of either drug for the treatment of a PDA. As both drugs are equally effective in closing a PDA, the clinician needs to weigh the potential side effects of one drug vs. the other when making a decision which drug to use. The most urgent research question to be answered is whether ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age and at the age of school entry.

Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants.

BACKGROUND: Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or treatment with indomethacin, has not been well established. OBJECTIVES: To compare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - July 2007), CINAHL (1982 - July 2007), EMBASE (1980 - July 2007); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002) or on line from May 2002 -July 2007. No language restrictions were applied. SELECTION CRITERIA: All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA. DATA COLLECTION AND ANALYSIS: Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data. MAIN RESULTS: Only one study, trial B in the report of Gersony 1983, was found eligible. No additional studies were identified in the literature searches performed in July 2007. The trial compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity stage III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)]. AUTHORS' CONCLUSIONS: The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants. It should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care.

Continuous negative extrathoracic pressure or continuous positive airway pressure for acute hypoxemic respiratory failure in children.

BACKGROUND: Acute hypoxemic respiratory failure (AHRF) is an important cause of mortality and morbidity in children. Positive pressure ventilation is currently the standard care, however, it does have complications. Continuous negative extrathoracic pressure ventilation (CNEP) or continuous positive airway pressure (CPAP) ventilation delivered via non-invasive approaches (Ni-CPAP) have shown certain beneficial effects in animal and uncontrolled human studies. OBJECTIVES: The primary objective was to assess the effectiveness of CNEP or Ni-CPAP in pediatric patients with AHRF from non-cardiogenic causes. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 3); MEDLINE (January 1966 to July 2007); EMBASE (1980 to July 2007); CINAHL (1982 to July 2007); and published abstracts from the meetings of the American Thoracic Society and Pediatric Critical Care Meetings (1992 to 2007). SELECTION CRITERIA: Randomized or quasi-randomized clinical trials of either CNEP or Ni-CPAP versus standard therapy (including positive pressure ventilation) involving children (at least 1 month old and less than 18 years of age at the time of randomization) who met the criteria for diagnosis of AHRF with at least one of the outcomes reported were included. DATA COLLECTION AND ANALYSIS: Risks of bias of the included study was assessed using: concealment of allocation, blinding of intervention, completeness of follow up and blinding of outcome measurements. Data on relevant outcomes were abstracted and the effect size was estimated by calculating relative risk (RR) with 95% confidence intervals (CI) and risk difference (RD). MAIN RESULTS: One eligible study published in an abstract format was identified. It studied 33 infants (18 controls, 15 receiving CNEP) with a clinical diagnosis of bronchiolitis and fraction of inspired oxygen (FiO(2)) > 40% were studied. This allowed a reduction in the FiO(2) (< 30% within one hour of initiation of therapy) in four patients in the CNEP group compared to none in the control group (RR 10.7, 95% CI 0.6 to 183.9). One infant required CPAP and one infant required nasal CPAP in the control group while all infants in the CNEP group were managed without intubation (RR for both outcomes 0.40, 95% CI 0.02 to 9.06). AUTHORS' CONCLUSIONS: There is a lack of well designed, controlled experiments of non-invasive modes of respiratory support in children with AHRF. Reduction of in-hospital mortality is an important outcome and even a small reduction would be beneficial. Studies assessing other outcomes such as avoidance of intubation and its associated complications, reduction in hospital stay and improvement in patient comfort are also valuable in gauging the overall impact of these strategies.

Pregnancy and lactation in a woman with classical galactosaemia heterozygous for p.Q188R and p.R333W.

A 31-year old patient who is compound heterozygous for the two galactose-1-phosphate uridyltransferase mutations p.Q188R and p.R333W delivered two healthy boys after uneventful spontaneous pregnancies. The patient chose to breast-feed her first baby and her galactose metabolites in blood and urine were monitored closely. A temporary increase in her galactose-1-phosphate (gal-1-P) levels with a maximum of 0.30 mmol/L on day 2 after delivery was observed. Galactose-1-phosphate was normalized 10 days after delivery. At the time of weaning, 8 months after delivery, her menses returned and she had normal sex steroid levels. She became pregnant again 2 months later. The second baby was also breast-fed. This time an increase in her gal-1-P values could be seen for 3 weeks with a maximum gal-1-P level of of 0.25 mmol/L at day 7. Only minor changes in her urine galactitol values were noted during the study period but the values stayed in the range of treated galactosaemia patients. We thus report that breast-feeding has been possible with only small adverse effects on the levels of galactose metabolites in a patient with classical galactosaemia.

The Control of Hypertension In Pregnancy Study pilot trial.

OBJECTIVE: To determine whether 'less tight' (versus 'tight') control of nonsevere hypertension results in a difference in diastolic blood pressure (dBP) between groups. DESIGN: Randomised controlled trial (ISRCTN#57277508). SETTING: Seventeen obstetric centres in Canada, Australia, New Zealand, and UK. POPULATION: Inclusion: pregnant women, dBP 90-109 mmHg, pre-existing/gestational hypertension; live fetus(es); and 20-33(+6) weeks. Exclusion: systolic blood pressure > or = 170 mmHg and proteinuria, contraindication, or major fetal anomaly. METHODS: Randomisation to less tight (target dBP, 100 mmHg) or tight (target dBP, 85 mmHg) blood pressure control. MAIN OUTCOME MEASURES: Primary: mean dBP at 28, 32 and 36 weeks. Secondary: clinician compliance and women's satisfaction. Other: serious perinatal and maternal complications. RESULTS: A total of 132 women were randomised to less tight (n = 66; seven had no study visit) or tight control (n= 66; one was lost to follow up; seven had no study visit). Mean dBP was significantly lower with tight control: -3.5 mmHg, 95% credible interval (-6.4, -0.6). Clinician compliance was 79% in both groups. Women were satisfied with their care. With less tight (versus tight) control, the rates of other treatments and outcomes were the following: post-randomisation antenatal antihypertensive medication use: 46 (69.7%) versus 58 (89.2%), severe hypertension: 38 (57.6%) versus 26 (40.0%), proteinuria: 16 (24.2%) versus 20 (30.8%), serious maternal complications: 3 (4.6%) versus 2 (3.1%), preterm birth: 24 (36.4%) versus 26 (40.0%), birthweight: 2675 +/- 858 versus 2501 +/- 855 g, neonatal intensive care unit (NICU) admission: 15 (22.7%) versus 22 (34.4%), and serious perinatal complications: 9 (13.6%) versus 14 (21.5%). CONCLUSION: The CHIPS pilot trial confirms the feasibility and importance of a large definitive trial to determine the effects of less tight control on serious perinatal and maternal complications.

Venepuncture versus heel lance for blood sampling in term neonates.

BACKGROUND: Heel lance has been the conventional method of blood sampling in neonates for screening tests. Neonates undergoing this procedure experience pain. Despite various studies evaluating the role of pharmacological and non-pharmacological interventions to date, there are no effective and practical methods to alleviate pain from heel lance. OBJECTIVES: To determine whether venepuncture or heel lance is less painful and more effective for blood sampling in term neonates. SEARCH STRATEGY: Systematic search was performed in accordance with the Cochrane Neonatal Collaborative Review Group. Randomized controlled trials which compared pain response to venepuncture vs. heel lance were identified using MEDLINE (1966 - June 2007), EMBASE (1980 - June 2007), CINAHL (1982 - June 2007), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), reference lists of identified trials and personal files. No language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials which compared pain response to venepuncture vs. heel lance were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding the primary outcome of pain response to venepuncture vs. heel lance as assessed by validated pain measures were abstracted. Secondary outcomes included the need of repeat blood sampling, bruising/hematoma at local site, and parental perception of their own anxiety and infant's pain. All data were analysed using RevMan 4.2.10. When possible, meta-analyses were performed using relative risk (RR) and risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, number needed to treat (NNT) was calculated. Weighted mean difference (WMD) was used for continuous data. When present, statistically significant between study heterogeneity was reported including the I squared (I(2) ) test. MAIN RESULTS: Five trials were eligible for inclusion in the review (including one additional trial identified in this update). Pain assessments were made using validated pain measures including Neonatal Infant Pain Scale (NIPS), Neonatal Facial Action Coding System (NFCS), Premature Infant Pain Profile (PIPP) score and cry characteristics. Two trials did not report on outcomes for all enrolled infants (not intention to treat analyses). Despite the many different pain measures used, all studies showed statistically significantly lower pain scores for venepuncture as compared to heel lance. A meta-analysis of the NIPS scores during the first minute of the procedure (reported in two studies) was statistically significantly lower in the venepuncture group compared to the heel lance group [typical WMD -1.84 (95% CI -2.61, -1.06)]. There was no statistically significant heterogeneity for this outcome (p = 0.22; I(2) 33.3%). The typical RR for requiring more than one skin puncture for venepuncture vs. heel lance (reported in 4 studies) was 0.30 (95% CI 0.18, 0.49). The RD was -0.31 (95% CI -0.41, -0.22). For this outcome there was statistically significant between study heterogeneity (for RR, p = 0.02, I(2 )74.3%; for RD, p < 0.00001, I(2) 96.6%). The number needed to treat (NNT) to avoid one repeat skin puncture was 3 (95% CI 2, 5). In one study, maternal anxiety was noted to be higher in the venepuncture group as compared to heel lance group prior to the procedure; however, after observing the procedure, mothers rated their infant's pain to be lower in the venepuncture group. AUTHORS' CONCLUSIONS: Venepuncture, when performed by a skilled phlebotomist, appears to be the method of choice for blood sampling in term neonates. For each three venepunctures instead of heel lance, the need for one additional skin puncture can be avoided.Further well designed randomized controlled trials need to be conducted. The interventions should be compared in settings where several individuals perform the venepuncture and/or the heel lance.

Interventions for non-oliguric hyperkalaemia in preterm neonates.

BACKGROUND: Non-oliguric hyperkalaemia of the newborn is defined as a plasma potassium level > 6.5 mmol/L in the absence of acute renal failure. Hyperkalaemia is a common complication in the first 48 hours of life in very low birth weight (birth weight < 1500 g) and/or very preterm newborns (< 32 weeks gestational age). OBJECTIVES: To determine the effectiveness and safety of interventions for non-oliguric hyperkalaemia [for the purpose of this review defined as serum potassium > 6.0 mmol/L ( the clinical setting in which interventions would likely be introduced prior to reaching a grossly abnormal level) and a urine output > 0.5 ml/kg/hour] in preterm or very low birth weight (VLBW) infants during their first 72 hours of life. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006) was searched to identify relevant randomised and quasi-randomised controlled trials. The following data bases were searched in June 2006; MEDLINE from 1966, EMBASE from 1980, CINAHL from 1982. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials conducted in preterm and/or VLBW neonates with a diagnosis of non-oliguric hyperkalaemia. The interventions included were those aimed at redistributing serum potassium (sodium bicarbonate or insulin and glucose) or increasing the elimination of potassium from the body [diuretics (any type) or ion exchange resins (any type), or exchange transfusion, or peritoneal dialysis, or salbutamol, or albuterol] or counteracting potential arrhythmias from hyperkalaemia (calcium) vs. placebo or no intervention; or comparing any two of these interventions. The primary outcome measure was 'All cause mortality during initial hospital stay'. Secondary outcomes included common adverse outcomes seen in infants born preterm. DATA COLLECTION AND ANALYSIS: The standard review methods of the Cochrane Neonatal Review Group were used. All studies identified as potentially relevant by the literature search were assessed for inclusion in the review by the two authors. The statistical methods included relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for dichotomous and weighed mean difference (WMD) for continuous outcomes reported with 95% confidence intervals (CI). A fixed effects model was used for meta-analysis. Heterogeneity was assessed using the I squared (I(2 )) statistic. MAIN RESULTS: Three randomized trials, enrolling 74 preterm infants (outcome data available on 71 infants) evaluated interventions for hyperkalemia. Urine output was ascertained only in one study (Hu 1999). In none of the trials could we ascertain that allocation to the comparison groups was concealed. The sample sizes of the three trials were very small with 12 (Malone 1991), 19 (Singh 2002) and 40 infants enrolled (Hu 1999). The intervention and the outcomes assessments could not be blinded to the clinical staff in two trials (Hu 1999; Malone 1991). In one study (Malone 1991), glucose and insulin, compared to cation-exchange resin, caused a reduction in all cause mortality that was of borderline statistical significance: RR 0.18 (95% CI 0.03, 1.15); RD -0.66 (95% CI -1.09, -0.22); NNTB 2 (95% CI 1, 5)]. In the study of Hu (Hu 1999), the incidence of intraventricular haemorrhage > grade 2 was significantly reduced [RR 0.30 (95% CI; 0.10, 0.93); RD -0.35 (95% CI; -0.62, -0.08); NNTB 3 (95% CI; 2, 13). Albuterol inhalation vs. saline inhalation changed serum K+ from baseline at 4 hours [WMD -0.69 mmol/L (95% CI; -0.87, -0.51)] and at 8 hours [WMD -0.59 mmol/L (95% CI; -0.78, -0.40)] after initiation of treatment. No differences were noted in mortality or other clinical outcomes (Singh 2002). No serious side effects were noted with either the combination of insulin and glucose or albuterol inhalation. Other interventions that we listed in our objectives have not been studied to date. AUTHORS' CONCLUSIONS: In view of the limited information from small studies of uncertain quality, no firm recommendations for clinical practice can be made. It appears that the combination of insulin and glucose is preferred over treatment with rectal cation-resin for hyperkalaemia in preterm infants. Both the combination of insulin and glucose and albuterol inhalation deserve further study. The two interventions could possibly be tested against each other. The effectiveness of other potentially effective interventions for non-oliguric hyperkalaemia (diuretics, exchange transfusion, peritoneal dialysis and calcium) have not been tested in randomized controlled trials.

Sildenafil for pulmonary hypertension in neonates.

BACKGROUND: Persistent pulmonary hypertension in neonates (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN is assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly and may not be appropriate in resource-poor settings. Approximately 30% of patients fail to respond to iNO. High concentrations of phosphodiesterases in the pulmonary vasculature has led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone. OBJECTIVES: To assess the efficacy and safety of Sildenafil in the treatment of persistent pulmonary hypertension in neonates. SEARCH STRATEGY: MEDLINE, EMBASE, CINAHL databases were searched from their inception until March 2007; the Cochrane Central Register of Controlled Trials, the Cochrane Library, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of Sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route and duration of administration in neonates with PPHN, were included if the trial reported any of the pre-specified outcomes. DATA COLLECTION AND ANALYSIS: The methodological quality of the trials was assessed regarding how bias at study entry, study intervention and outcomes measurement was minimized. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and weighted mean difference (MD) as appropriate. The I-squared (I(2)) test of heterogeneity was applied. MAIN RESULTS: Two small eligible trials (one full article and one abstract) were identified. The methodological quality of the trial presented in the full article was good. Information provided in the abstract was limited. The total number of enrolled patients in the two studies was 37. Both studies were performed in resource-limited settings where iNO and high frequency ventilation are not available. Both studies reported statistically significant improvement in oxygenation (reduction in oxygenation index) in the Sildenafil group. One study reported what would be, if replicated, a strongly protective effect on mortality (RR 0.17, 95% CI 0.03, 1.09) favoring the Sildenafil group. However, this result needs to be replicated in larger studies. No clinically important side effects were reported. AUTHORS' CONCLUSIONS: The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials. Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN.

Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates.

BACKGROUND: Chronic lung disease remains a common complication among preterm infants. There is increasing evidence that inflammation plays an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties, corticosteroids are an attractive intervention strategy. However, there are growing concerns regarding short and long-term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects. OBJECTIVES: To determine the impact of inhaled corticosteroids administered to ventilated very low birth weight preterm neonates in the first two weeks of life for the prevention of chronic lung disease (CLD). SEARCH STRATEGY: Randomized and quasi-randomized trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - July 2007), EMBASE (1980 - July 2007), CINAHL (1982 - July 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 - April 2007). SELECTION CRITERIA: Randomized controlled trials of inhaled corticosteroid therapy initiated within the first 2 weeks of life in ventilated preterm infants with birth weight <1500 grams were included in this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including chronic lung disease at 28 days or 36 weeks postmenstrual age (PMA), mortality, combined outcome of death or CLD at 28 days of age and at 36 weeks PMA, the need for systemic corticosteroids, failure to extubate within 14 days and adverse effects of corticosteroids were evaluated. All data were analyzed using RevMan 4.2.10. When possible, meta-analysis was performed using relative risk (RR), risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, the number needed to treat (NNT) was calculated. MAIN RESULTS: Three additional trials were identified for inclusion in this update. Eleven trials assessing the impact of inhaled corticosteroid for the prevention of CLD were identified. Four trials were excluded. The present review includes data analyses based on seven qualifying trials. There was no statistically significant effect of inhaled steroids on CLD either at 28 days [typical RR 1.05 (95% CI 0.84, 1.32); typical RD 0.02 (95% CO -0.07, 0.11)] or at 36 weeks PMA [typical RR 0.97 (95% CI 0.62, 1.52); typical RD 0.00 (95% CI -0.07, 0.06)], when analyzed either for all randomized infants or among survivors. No statistically significant differences were noted for mortality or for the combined outcome of mortality and CLD either at 28 days of age or at 36 weeks PMA. There were no statistically significant differences in adverse events between groups. AUTHORS' CONCLUSIONS: Based on this updated review, there is no evidence from the trials reviewed that early administration (in the first two weeks of life) of inhaled steroids to ventilated preterm neonates was effective in reducing the incidence of CLD. Currently, use of inhaled steroids in this population cannot be recommended. Studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short-term and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.

Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants.

BACKGROUND: Chronic lung disease (CLD) remains a serious and common problem among very low birth weight infants despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Due to their anti-inflammatory properties, corticosteroids have been widely used to treat or prevent CLD. However, the use of systemic steroids has been associated with serious short and long-term adverse effects. Administration of corticosteroids topically through the respiratory tract might result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects. OBJECTIVES: To determine the effect of inhaled versus systemic corticosteroids administered to ventilator dependent preterm neonates with birth weight < 1500 g or gestational age < 32 weeks after two weeks of life for the treatment of evolving CLD. SEARCH STRATEGY: Randomized and quasi-randomized trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - June 2007), EMBASE (1980 - June 2007), CINAHL (1982 - June 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies website (1990 - April 2007). SELECTION CRITERIA: Randomized or quasi-randomized trials comparing inhaled versus systemic corticosteroid therapy (irrespective of the dose and duration of therapy) starting after the first two weeks of life in ventilator dependent very low birth weight preterm infants. DATA COLLECTION AND ANALYSIS: Data were extracted regarding clinical outcomes including CLD at 28 days or 36 weeks postmenstrual age (PMA), mortality, combined outcome of death or CLD at 28 days of age or 36 weeks PMA, other pulmonary outcomes and adverse effects. All data were analyzed using RevMan 4.2.10. When appropriate, meta-analysis was performed using relative risk (RR), risk difference (RD), and weighted mean difference (WMD) along with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to treat (NNT) was calculated. MAIN RESULTS: Data from one additional trial were available for inclusion in this update. Thus, five trials comparing inhaled versus systemic corticosteroids in the treatment of CLD were identified. Two trials were excluded as both included non-ventilator dependent patients and three trials qualified for inclusion in this review. Halliday et al (Halliday 2001) randomized infants at < 72 hours, while Rozycki et al (Rozycki 2003) and Suchomski et al (Suchomski 2002) randomized at 12 - 21 days. The data from the two trials of Rozycki et al and Suchmoski et al are combined using meta-analytic techniques. The data from the trial by Halliday et al are reported separately, as outcomes were measured over different time periods from the age at randomization. In none of the trials was there a statistically significant difference between the groups in the incidence of CLD at 36 weeks PMA among all randomized infants. The estimates for the trial by Halliday et al (Halliday 2001) were RR 1.10 (95% CI 0.82, 1.47), RD 0.03 (95% CI -0.08, 0.15); number of infants (n = 292). For the trials by Rozycki et al (Rozycki 2003) and Suchomski et al (Suchomski 2002) the typical RR was 1.02 (95% CI 0.83, 1.25) and the typical RD 0.01 (95% CI -0.11, 0.14); (number of infants = 139 ). There were no statistically significant differences between the groups in either trial for oxygen dependency at 28 days of age, death by 28 days or 36 weeks PMA, the combined outcome of death by or CLD at 28 days or 36 weeks PMA, duration of intubation, duration of oxygen dependence, or adverse effects. Information on the long-term neurodevelopmental outcomes was not available. AUTHORS' CONCLUSIONS: This review found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator dependent preterm infants. Neither inhaled steroids nor systemic steroids can be recommended as standard treatment for ventilated preterm infants. There was no evidence of difference in effectiveness or side-effect profiles for inhaled versus systemic steroids. A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing side-effects. To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcome, should be addressed in future studies.

Surfactant for meconium aspiration syndrome in full term/near term infants.

BACKGROUND: Surfactant replacement therapy has been proven beneficial in the prevention and treatment of neonatal respiratory distress syndrome (RDS). The deficiency of surfactant or surfactant dysfunction may contribute to respiratory failure in a broader group of disorders, including meconium aspiration syndrome (MAS). OBJECTIVES: To evaluate the effect of surfactant administration in the treatment of term/near-term infants with MAS. SEARCH STRATEGY: Searches were made using The Cochrane Library (Issue 4, 2006), MEDLINE and EMBASE (1985 to December 2006), previous reviews including cross-references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching. No language restrictions were applied. Authors were directly contacted to provide additional data. SELECTION CRITERIA: Randomised controlled trials which evaluated the effect of surfactant administration in term infants with meconium aspiration syndrome are included in the analyses. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality, treatment with extracorporeal membrane oxygenation (ECMO), pneumothorax, duration of assisted ventilation, duration of supplemental oxygen, intraventricular haemorrhage (any grade and severe IVH), and chronic lung disease, and were excerpted from the reports of the clinical trails by the review authors. Data analyses were done in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Four randomised controlled trials met inclusion criteria. The meta-analysis of 4 trials enrolling 326 infants showed no statistically significant effect on mortality (typical relative risk 0.98 (95% CI 0.41, 2.39), typical risk difference 0.00 (95% CI -0.05, 0.05). The risk of requiring extracorporeal membrane oxygenation was significantly reduced in a meta-analysis of two trials (n = 208); (typical relative risk 0.64, 95% CI 0.46, 0.91; typical risk difference -0.17, 95% CI -0.30, -0.04); number needed to treat to benefit 6 (95% CI 3, 25). One trial (n = 40) reported a statistically significant reduction in the length of hospital stay [mean difference - 8 days (95% CI -14, -3 days)]. There were no statistically significant reductions in any other outcomes studied (duration of assisted ventilation, duration of supplemental oxygen, pneumothorax, pulmonary interstitial emphysema, air leaks, chronic lung disease, need for oxygen at discharge or intraventricular haemorrhage). AUTHORS' CONCLUSIONS: In infants with MAS, surfactant administration may reduce the severity of respiratory illness and decrease the number of infants with progressive respiratory failure requiring support with ECMO. The relative efficacy of surfactant therapy compared to, or in conjunction with, other approaches to treatment including inhaled nitric oxide, liquid ventilation, surfactant lavage and high frequency ventilation remains to be tested.

Women's views of their experiences in the CHIPS (Control of Hypertension in Pregnancy Study) Pilot Trial.

BACKGROUND: Satisfaction with maternity care is strongly related to the patient-caregiver relationship and involvement in the decision-making process. We sought to compare women's views about their care in a randomized trial of 'less tight' vs. 'tight' control of non-proteinuric pre-existing or gestational hypertension in pregnancy. METHODS: In the CHIPS Pilot Trial, women completed a postpartum questionnaire to assess their likes and dislikes about their blood pressure (BP) management and trial participation. Comparisons were descriptive. RESULTS: Baseline information was similar for the 'less tight' and 'tight' control groups. Of 132 women, 126 (95.5%) from 17 centers completed a postpartum questionnaire, usually within days of delivery. At least 90% of women in both groups were satisfied with their care, and would be willing to participate again or recommend participation to a friend. Women in both the 'less tight' and 'tight' groups were satisfied with BP management (98.4% vs. 95.1%), and the frequency of tests of maternal and fetal well being. Half of women in both groups perceived that their BP was too high and that caregivers thought that their BP was too high. More women in the 'less tight' (vs. the 'tight') control group took less medication than expected (71.7% vs. 38.2%). More women in the 'tight' (vs. the 'less tight') group took more medication than they expected (60.0% vs. 22.2%). At least 60% of all women used home BP monitoring. CONCLUSION: In the CHIPS Pilot Trial, while women stated that they were satisfied with their BP management and care, a surprising 50% in both groups thought that their BP was too high. The majority of women used home BP monitoring, the role of which must be further defined in hypertensive pregnancies.

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

BACKGROUND: Hematocrit falls after birth in preterm infants due to physiological factors and blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anemia. PRIMARY OBJECTIVE: To assess the effectiveness and safety of late initiation of EPO (initiated at 8 days after birth or later) in reducing the use of red blood cell transfusions in preterm and/or low birth weight infants. SECONDARY OBJECTIVES: Subgroup analyses of low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and within these subgroups analyses of the use of low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron, in reducing the use of red blood cell transfusions in these infants. SEARCH STRATEGY: MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005/April 2006 and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006). No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomized controlled trials of late initiation of EPO treatment (started at eight days of age or later) vs. placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. For inclusion the studies needed to provide information on at least one outcome of interest. DATA COLLECTION AND ANALYSIS: Data were abstracted by the two authors on pre-tested data collection forms. Data were entered by one review author (AO) and checked for accuracy by the other (SA). Data were analysed using RevMan 4.2.8. The statistical methods included relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes reported with their 95% confidence intervals (CI). A fixed effects model was used for meta-analyses. Heterogeneity tests including the I squared (I(2)) statistic were performed to assess the appropriateness of pooling the data. MAIN RESULTS: Twenty-eight studies enrolling 1302 preterm infants in 21 countries were included. The quality of the trials varied. Most trials were of small sample size. Only one study clearly stated that infants were excluded if they had received red blood cell transfusion prior to study entry (Samanci 1996). A total of 19 studies including 912 infants reported on the primary outcome of "Use of one or more red cell transfusions". The meta-analysis showed a significant effect [typical RR; 0.66 (95% CI; 0.59, 0.74); typical RD -0.21 (95% CI; -0.26, -0.16); typical NNTB of 5 (95% CI 4, 6)]. There was statistically significant heterogeneity [for RR (p < 0.00001), I(2 )= 74.0% and for RD (p = 0.0006), I(2 )=58.9%]. Similar results were obtained in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was a significant reduction in the total volume (ml/kg) of blood transfused per infant (four studies enrolling 177 infants) [typical WMD = -7 ml (95% CI -12, -3)] and in the number of transfusions per infant (nine studies enrolling 567 infants); [typical WMD -0.78 (-0.97, -0.59)]. The effect size was less in a post hoc analyses of high quality studies compared to studies in which the quality was uncertain and in studies that used strict guidelines for red blood cell transfusions vs. studies that did not. There were no significant differences in mortality, retinopathy of prematurity, sepsis, intraventricular haemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, SIDS, neutropenia, hypertension, or length of hospital stay. Long-term neurodevelopmental outcomes were not reported. AUTHORS' CONCLUSIONS: Late administration of EPO reduces the use of one or more red blood cell transfusions, the number of red blood cell transfusions per infant and the total volume of red blood cell transfused per infant. The clinical importance of the results for the latter two outcomes is marginal (< 1 transfusion per infant and 7 ml/kg of transfused red blood cells). Any donor exposure is likely not avoided as most studies included infants who had received red cell transfusions prior to trial entry. Late EPO does not significantly reduce or increase any of many important neonatal adverse outcomes including mortality and retinopathy of prematurity. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when red blood cell requirements are most likely to be required and cannot be prevented by late EPO treatment.