Randomized controlled trial of magnesium sulfate in women at risk of preterm delivery-neonatal cardiovascular effects.

OBJECTIVE: Use of antenatal magnesium sulfate (MgSO(4)) may reduce cerebral palsy in infants born very preterm. Low systemic blood flow in the first day in very preterm infants has been associated with cerebral injury and adverse motor outcome. The aim was to determine the effect of MgSO(4) on systemic blood flow in preterm infants. STUDY DESIGN: Randomized trial of MgSO(4) versus saline placebo given to mothers at risk of delivery before 30 weeks gestation. Echocardiographic monitoring performed at 3 to 5, 10 to 12 and 24 h. RESULT: A total of 48 infants were exposed to MgSO(4) and 39 to placebo. Infants exposed to MgSO(4) were significantly more likely to receive volume expansion (42% versus 21%). Inotrope use did not differ significantly (40% versus 26%). There was no significant difference in mean lowest superior vena cava (SVC) flow or right ventricular output (RVO), or incidence of low SVC flow or RVO in the first 24 h. Infants exposed to MgSO(4) had a significantly higher heart rate and were more likely to have low SVC flow at 10 to 12 h but not other times. CONCLUSION: Antenatal MgSO(4) produced no consistent cardiovascular effects in the infant in the first 24 h. There is no evidence from this study to suggest the mechanism by which antenatal MgSO(4) prevents cerebral palsy is through a cardiovascular effect in the newborn.

Prebiotics in infants for prevention of allergic disease and food hypersensitivity.

BACKGROUND: The composition of the intestinal microflora may be different in individuals with atopic eczema from those without this condition, and such differences may precede the development of eczema. Prebiotics are nondigestible food components that benefit the host by selectively stimulating the growth or activity of non-pathogenic bacteria in the colon. Prebiotics (commonly oligosaccharides) added to infant feeds have the potential to prevent sensitisation of infants to dietary allergens. OBJECTIVES: To determine the effect of prebiotics given to infants for the prevention of allergic disease or food hypersensitivity. SEARCH STRATEGY: This included searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (1966 - February 2007), EMBASE, PREMEDLINE, abstracts of conference proceedings and citations of published articles, and expert informants. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared the use of a prebiotic to no prebiotic; or the use a specific prebiotic compared to a different prebiotic. DATA COLLECTION AND ANALYSIS: Assessment of trial quality, data extraction and synthesis of data were performed using standard methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Seven studies were eligible for inclusion. Only two studies reported an allergic disease outcome for 432 infants. Study quality was reasonable, although Moro 2006 reported 20% post-randomisation losses. Moro 2006 enrolled hydrolysed formula fed infants at high risk of allergy and reported a significant reduction in eczema in infants up to six months of age (RR 0.42, 95% CI 0.21, 0.84). Ziegler 2007 enrolled formula fed infants who were not selected on the basis of risk for allergy and reported no significant difference in eczema up to four months of age (RR 1.62, 95% CI 0.62, 4.26). Meta-analysis of the two studies found no significant difference in eczema, but significant heterogeneity was detected. Differences were potentially attributable to differences in infant risk, prebiotic formulation or measurement of eczema. Analysis of five studies reporting measures of infant growth found no consistent adverse effects. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the role of prebiotic supplementation of infant formula for prevention of allergic disease and food hypersensitivity. One small trial of prebiotic oligosaccharides with excess losses reported a reduction in eczema in high risk formula fed infants. Further trials are needed to determine whether this finding persists over a longer period of time, applies to other manifestations of allergic disease, is associated with reductions in allergen sensitisation, and is reproducible.

Probiotics in infants for prevention of allergic disease and food hypersensitivity.

BACKGROUND: The composition of the intestinal microflora may be different in individuals with atopic eczema from those without this condition, and such differences may precede the development of eczema. Probiotics are live bacteria that colonize the gastrointestinal tract and provide a health benefit to the host. Probiotics added to infant feeds have the potential to prevent sensitisation of infants to dietary allergens. OBJECTIVES: To determine the effect of probiotics given to infants for the prevention of allergic disease or food hypersensitivity. SEARCH STRATEGY: This included searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (1966 - February 2007), EMBASE, PREMEDLINE, abstracts of conference proceedings and citations of published articles, and expert informants. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compare the use of a probiotic to no probiotic; or the use a specific probiotic compared to a different probiotic; or a probiotic with added prebiotic to control. DATA COLLECTION AND ANALYSIS: Assessment of trial quality, data extraction and synthesis of data were performed using standard methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Twelve studies were eligible for inclusion. Allergic disease and / or food hypersensitivity outcomes were assessed by 6 studies enrolling 2080 infants, but outcomes for only 1549 infants were reported. Studies generally had adequate randomisation, allocation concealment and blinding of treatment. However, the findings of this review should be treated with caution due to excess losses in patient follow-up (17% to 61%). Meta-analysis of five studies reporting the outcomes of 1477 infants found a significant reduction in infant eczema (typical RR 0.82, 95% CI 0.70, 0.95). However, there was significant and substantial heterogeneity between studies. One study reported that the difference in eczema between groups persisted to 4 years age. When the analysis was restricted to studies reporting atopic eczema (confirmed by skin prick test or specific IgE), the findings were no longer significant (typical RR 0.80, 95% CI 0.62, 1.02). All studies reporting significant benefits used probiotic supplements containing L. rhamnosus and enrolled infants at high risk of allergy. No other benefits were reported for any other allergic disease or food hypersensitivity outcome. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the addition of probiotics to infant feeds for prevention of allergic disease or food hypersensitivity. Although there was a reduction in clinical eczema in infants, this effect was not consistent between studies and caution is advised in view of methodological concerns regarding included studies. Further studies are required to determine whether the findings are reproducible.

The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow.

BACKGROUND: Low systemic blood flow (SBF) is common in extremely premature infants in the first day after birth and has been associated with peri / intraventricular haemorrhage (PIVH), necrotising enterocolitis (NEC), mortality and developmental impairment. OBJECTIVES: To determine the effect of specific inotropes on morbidity and mortality in preterm infants with low systemic blood flow SEARCH STRATEGY: Searches were made of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006 ), MEDLINE (1966 - April 2006), EMBASE (1980 - April 2006) and CINAHL (1982 - April 2006), supplemented by searches of abstracts of conference proceedings, citations of reviews and expert informants. SELECTION CRITERIA: Random and quasi-random controlled trials of inotropes enrolling preterm infants with low systemic or organ blood flow in the neonatal period. DATA COLLECTION AND ANALYSIS: Independent assessment of trial eligibility, quality and data extraction by each review author. Synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration. MAIN RESULTS: No studies that compared an inotrope to no treatment in preterm infants with low SBF were found. One study (Osborn 2002a) was found that compared dobutamine versus dopamine. The study was of adequate methodology. It enrolled 42 infants < 30 weeks gestation and < 12 hours after birth with low SVC flow. The trial compared the effect of dobutamine versus dopamine titrated 10 to 20 mug/kg/min with the goal of increasing and maintaining SVC flow > 40 ml/kg/min. No significant difference was reported in mortality to discharge (RR 1.41, 95% CI 0.79, 2.52), PIVH (RR 1.01, 95% 0.52, 1.97), grade 3 or 4 PIVH (RR 0.39, 95% CI 0.12, 1.31) or NEC. At three years, there was no significant difference in cerebral palsy, deafness, Developmental quotient > 2 sd below norm or combined disability (RR 0.10, 95% CI 0.01, 1.56). Surviving infants treated with dobutamine had a significantly higher development quotient (MD 35.00, 95% CI 17.68, 52.32). There was no significant difference in death or disability at the latest time reported (RR 0.95, 95% CI 0.66, 1.38). For secondary outcomes, there was no significant difference in periventricular leucomalacia, renal impairment, pulmonary haemorrhage, retinopathy of prematurity or CLD at 36 weeks. There was no significant difference in treatment failure. Dobutamine produced a significantly greater increase in SVC flow at the highest dose reached (MD 13.10, 95% CI 2.87, 23.33), whereas dopamine produced a significantly greater increase in mean BP at 10 and 20 mug/kg/min and at the highest dose reached (MD -7.20, 95% CI -11.41, -2.99). AUTHORS' CONCLUSIONS: In preterm infants with low systemic blood flow, there is some evidence that dobutamine is better than dopamine at increasing and maintaining systemic blood flow. The only eligible trial did not demonstrate any consistent differences in clinical outcomes. However, this study was not sufficiently powered to prove or disprove effects on clinical outcomes. It is unclear what is the most effective strategy for improving the cardiovascular status of immature infants in the first day. Further trials are needed to determine effective strategies for preventing and improving low systemic and organ blood flow.

Postnatal thyroid hormones for preterm infants with transient hypothyroxinaemia.

BACKGROUND: Extremely premature infants are at risk of transient hypothyroxinaemia in the first weeks after birth. These low thyroid hormone levels are associated with an increased incidence of neonatal morbidity, mortality and longer term developmental impairments. Thyroid hormone therapy might prevent these problems. OBJECTIVES: To determine the evidence for thyroid hormone therapy in preterm infants with transient hypothyroxinaemia (low thyroid hormone level, normal TSH) for improvement of neonatal outcomes and neurodevelopment. SEARCH STRATEGY: Searches were performed of The Cochrane Central Register of Controlled (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), PREMEDLINE (March 2006), EMBASE (1980 - March 2006), previous reviews including cross references, abstracts and conference proceedings, supplemented by requests to expert informants. SELECTION CRITERIA: Trials enrolling preterm infants with transient hypothyroxinaemia (low thyroid hormone level, normal TSH level) in the neonatal period, using random or quasi-random patient allocation to thyroid hormone therapy compared to control (placebo or no treatment). DATA COLLECTION AND ANALYSIS: Independent assessment of trial quality and data extraction by each review author. Synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Only one study was eligible. Chowdhry (1984) enrolled 23 infants < 1250 g and 25 - 28 weeks gestation with transient hypothyroxinaemia (serum total T4

Postnatal thyroid hormones for respiratory distress syndrome in preterm infants.

BACKGROUND: Preterm infants with respiratory distress syndrome are at increased risk of adverse neonatal and developmental outcomes. In animal research, thyroid hormones stimulate surfactant production and reduce the incidence and severity of respiratory distress when given antenatally. OBJECTIVES: To determine whether thyroid hormone therapy used postnatally in preterm infants with suspected respiratory distress syndrome results in clinically important improvements in respiratory morbidity and subsequent improvements in neonatal and long term outcomes. SEARCH STRATEGY: Searches were performed of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), PREMEDLINE (March 2006), EMBASE (1980 - March 2006), previous reviews including cross references, abstracts and conference proceedings, supplemented by requests to expert informants. SELECTION CRITERIA: Trials that enrolled preterm infants with suspected respiratory distress syndrome and allocated infants thyroid hormone treatment compared to control commenced in the first 48 hours after birth. DATA COLLECTION AND ANALYSIS: Independent assessment of trial quality and data extraction by each author. Synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Two studies enrolled preterm infants with respiratory distress. Amato (1988) allocated infants to L-thyroxine 50 mug/dose at 1 and at 24 hours or no treatment. Amato (1989) allocated infants to L-triiodothyronine 50 mug/day in two divided doses for two days or no treatment. Both studies had methodological concerns including quasi-random methods of patient allocation, no blinding of treatment or measurement and substantial post allocation losses. Neither study reported any significant benefits in neonatal morbidity or mortality from use of thyroid hormones. Meta-analysis of two studies (80 infants) found no significant difference in mortality to discharge (typical RR 1.00, 95% CI 0.47, 2.14). Amato 1988 reported no significant difference in use of mechanical ventilation (RR 0.64, 95% CI 0.38, 1.09). No significant effects were found in use of mechanical ventilation, duration of mechanical ventilation, air leak, CLD at 28 days in survivors, patent ductus arteriosus, intraventricular haemorrhage or necrotising enterocolitis. Neurodevelopment was not reported. AUTHORS' CONCLUSIONS: There is no evidence from controlled clinical trials that postnatal thyroid hormone treatment reduces the severity of respiratory distress syndrome, neonatal morbidity or mortality in preterm infants with respiratory distress syndrome.

Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants.

BACKGROUND: Observational studies have shown an association between transiently low thyroid hormone levels in preterm infants in the first weeks of life (transient hypothyroxinaemia) and abnormal neurodevelopmental outcome. Thyroid hormone replacement might prevent this. OBJECTIVES: To determine whether prophylactic thyroid hormones given to preterm infants without congenital hypothyroidism result in clinically important changes in neonatal and long term outcomes. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), EMBASE, PREMEDLINE, and searches of abstracts of conference proceedings, citations of published articles and expert informants. SELECTION CRITERIA: All trials using random or quasi-random patient allocation in which prophylactic thyroid hormone treatment was compared to control in premature infants. DATA COLLECTION AND ANALYSIS: Assessment of trial quality, data extraction and synthesis of data, using relative risk (RR) and weighted mean difference (WMD), were performed using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Four studies enrolling 318 infants were included. All studies enrolled preterm infants on the basis of gestational age criteria. All studies commenced treatment in the first 48 hours, but used different regimens, dose and durations of treatment. All four studies used thyroxine (T4). Valerio 2004 incorporated one arm with an early short course of T3, then T4 for 6 weeks. Only two studies with neurodevelopmental follow-up were of good methodology (van Wassenaer 1997; Vanhole 1997). All studies were small with the largest (van Wassenaer 1997) enrolling 200 infants.No significant difference was found in neonatal morbidity, mortality or neurodevelopmental outcome in infants who received thyroid hormones compared to control. van Wassenaer 1997 reported no significant difference in abnormal mental development at 6, 12, 24 months (RR 0.67, 95% CI 0.28, 1.56) or five years (RR 0.66, 95% CI 0.22, 1.99) or cerebral palsy assessed at five years (RR 0.72, 95% CI 0.28, 1.84). Meta-analysis of two studies (van Wassenaer 1997, Vanhole 1997) found no significant difference in the Bayley MDI (WMD -1.14, 95% CI -5.46, 3.19) and PDI (WMD 0.22, 95% CI -4.80, 5.24) at 7 - 12 months. van Wassenaer 1997 reported no significant difference in the Bayley MDI (MD -3.50, 95% CI -11.21, 4.21) and PDI (MD 3.10, 95% CI -3.31, 9.51) at 24 months, IQ scores at 5 years (MD -2.10, 95% CI -7.91, 3.71) and children in special schooling at 10 years (RR 0.88, 95% CI 0.43, 1.83). Meta-analysis of all four trials found no significant difference in mortality to discharge (typical RR 0.76, 95% CI 0.46 to 1.24). van Wassenaer 1997 reported no significant difference in death or cerebral palsy at five years (RR 0.70, 95% CI 0.43 to 1.14). No significant differences were reported for neonatal morbidities, including the need for mechanical ventilation, duration of mechanical ventilation, air leak, CLD in survivors at 28 days or 36 weeks, intraventricular haemorrhage, severe intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus, sepsis, necrotising enterocolitis or retinopathy of prematurity. AUTHORS' CONCLUSIONS: This review does not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality, neonatal morbidity or improve neurodevelopmental outcomes. An adequately powered clinical trial of thyroid hormone supplementation with the goal of preventing the postnatal nadir of thyroid hormone levels seen in very preterm infants is required.

Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants.

BACKGROUND: Allergies and food reactions are common and may be associated with foods including adapted cow's milk formula. Formulas containing hydrolysed proteins have been used to treat infants with allergy or food intolerance. However, it is unclear whether hydrolysed formula can be advocated for prevention of allergy and food intolerance in infants without evidence of allergy or food intolerance. OBJECTIVES: To determine the effect of feeding hydrolysed formulas on allergy and food intolerance in infants and children compared to adapted cow's milk or human breast milk. If hydrolysed formulas are effective, to determine what type of hydrolysed formula is most effective including extensively and partially hydrolysed formulas. To determine which infants benefit, including infants at low or high risk of allergy and infants receiving early, short term or prolonged formula feeding. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. The review was updated with searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966-March 2006), EMBASE (1980-March 2006) and CINAHL (1982-March 2006) and previous reviews including cross references. SELECTION CRITERIA: Randomised and quasi-randomised trials that compare the use of a hydrolysed infant formula to human milk or cow's milk formula. Trials with >80% follow up of participants were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Eligibility of studies for inclusion, methodological quality and data extraction were assessed independently by each review author. Primary outcomes included clinical allergy, specific allergies and food intolerance. Meta-analysis was conducted using a fixed effects model. MAIN RESULTS: Two trials compared early, short term hydrolysed formula to human milk feeding. No significant difference in infant allergy or childhood cow's milk allergy (CMA) were reported. No eligible trial compared prolonged hydrolysed formula to human milk feeding. Two trials compared early, short term hydrolysed formula to cow's milk formula feeding. No significant benefits were reported. One large quasi-random study reported a reduction in infant CMA of borderline significance in low risk infants (RR 0.62, 95% CI 0.38, 1.00). Ten eligible studies compared prolonged feeding with hydrolysed formula versus cow's milk formula in high risk infants. Meta-analysis found a significant reduction in infant allergy (seven studies, 2514 infants; typical RR 0.79, 95% CI 0.66, 0.94), but not in the incidence of childhood allergy (two studies, 950 infants; typical RR 0.85, 95% CI 0.69, 1.05). There was no significant difference in infant eczema (eight studies, 2558 infants, typical RR 0.84, 95% CI 0.68, 1.04), childhood eczema incidence (two studies, 950 infants, typical RR 0.83, 95% CI 0.63, 1.10), childhood eczema prevalence (one study, 872 infants; RR 0.66, 95% CI 0.43, 1.02), or infant or childhood asthma, rhinitis and food allergy. One study reported a significant reduction in infants with CMA with confirmed atopy (RR 0.36, 95% CI 0.15, 0.89). Subgroup analysis of trials blinded to formula found no significant difference in infant allergy (four studies, 2156 infants; typical RR 0.87, 95% CI 0.69, 1.08) or childhood allergy incidence (one study, 872 infants; RR 0.91, 95% CI 0.73, 1.14). No eligible trial examined the effect of prolonged hydrolysed formula feeding on allergy beyond early childhood. There is evidence that preterm or low birthweight infants fed a hydrolysed preterm formula have significantly reduced weight gain, but not in other growth parameters (head circumference or length). Studies in term infants report no adverse effects on growth. Subgroup analysis of trials of partially hydrolysed versus cow's milk formula found a significant reduction in infant allergy (six studies, 1391 infants; typical RR 0.79, 95% CI 0.65, 0.97) but not childhood allergy, or infant or childhood asthma, eczema or rhinitis. Methodological concerns were the same as for the overall analysis. Analysis of trials of extensively hydrolysed formula versus cow's milk formula found no significant differences in allergy or food intolerance. Infants fed extensively hydrolysed formula compared with partially hydrolysed formula had a significant reduction in food allergy (two studies, 341 infants; typical RR 0.43, 95% CI 0.19, 0.99), but there was no significant difference in all allergy or any other specific allergy incidence. Comparing extensively hydrolysed casein containing formula with cow's milk formula, one study (431 infants) reported a significant reduction in childhood allergy incidence (RR 0.72, 95% CI 0.53, 0.97). Meta-analysis found a significant reduction in infant eczema (three studies, 1237 infants; typical RR 0.71, 95% CI 0.51, 0.97). One study reported a significant reduction in childhood eczema incidence (RR 0.66, 95% CI 0.44, 0.98) and prevalence (RR 0.50, 95% CI 0.27, 0.92). AUTHORS' CONCLUSIONS: There is no evidence to support feeding with a hydrolysed formula for the prevention of allergy compared to exclusive breast feeding. In high risk infants who are unable to be completely breast fed, there is limited evidence that prolonged feeding with a hydrolysed formula compared to a cow's milk formula reduces infant and childhood allergy and infant CMA. In view of methodological concerns and inconsistency of findings, further large, well designed trials comparing formulas containing partially hydrolysed whey, or extensively hydrolysed casein to cow's milk formulas are needed.

Soy formula for prevention of allergy and food intolerance in infants.

BACKGROUND: Allergies and food reactions in infants and children are common and may be associated with a variety of foods including adapted cow's milk formula. Soy based formulas have been used to treat infants with allergy or food intolerance. However, it is unclear whether they can help prevent allergy and food intolerance in infants without clinical evidence of allergy or food intolerance. OBJECTIVES: To determine the effect of feeding adapted soy formula compared to human milk, cow's milk formula or a hydrolysed protein formula on preventing allergy or food intolerance in infants without clinical evidence of allergy or food intolerance. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. Updated searches were performed of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966-March 2006), EMBASE (1980-March 2006), CINAHL (1982-March 2006) and previous reviews including cross references. SELECTION CRITERIA: Randomised and quasi-randomised trials that compare the use of an adapted soy formula to human milk, an adapted cow's milk or a hydrolysed protein formula for feeding infants without clinical allergy or food intolerance in the first six months of life. Only trials with > 80% follow up of participants and reported in group of assignment were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Eligibility of studies for inclusion, methodological quality and data extraction were assessed independently by each review author. Primary outcomes included clinical allergy, specific allergies and food intolerance. Where no heterogeneity of treatment effect was found, the fixed effect model was used for meta-analysis. Where significant or apparent heterogeneity was found, results were reported using the random effects model and potential causes of the heterogeneity were sought. MAIN RESULTS: Three eligible studies enrolling high risk infants with a history of allergy in a first degree relative were included. No eligible study enrolled infants fed human milk. No study examined the effect of early, short term soy formula feeding. All compared prolonged soy formula to cow's milk formula feeding. One study was of adequate methodology and without unbalanced allergy preventing co-interventions in treatment groups. One study with unclear allocation concealment and 19.5% losses reported a significant reduction in infant allergy, asthma and allergic rhinitis. However, no other study reported any significant benefits from the use of a soy formula. Meta-analysis found no significant difference in childhood allergy incidence (2 studies; typical RR 0.73, 95% CI 0.37, 1.44). No significant difference was reported in one study in infant asthma (RR 1.10, 95% CI 0.86, 1.40), infant eczema (RR 1.20, 95% CI 0.95, 1.52), childhood eczema prevalence (RR 1.10, 95% CI 0.73, 1.68), infant rhinitis (RR 0.94, 95% CI 0.76, 1.16) or childhood rhinitis prevalence (RR 1.20, 95% CI 0.73, 2.00). Meta-analysis found no significant difference in childhood asthma incidence (3 studies, 728 infants; typical RR 0.71, 95% CI 0.26, 1.92), childhood eczema incidence (2 studies, 283 infants; typical RR 1.57, 95% CI 0.90, 2.75) or childhood rhinitis incidence (2 studies, 283 infants; typical RR 0.69, 95% CI 0.06, 8.00). One study reported no significant difference in infant CMPI (RR 1.09, 95% CI 0.45, 2.62), infant CMA (RR 1.09, 95% CI 0.24, 4.86), childhood soy protein allergy incidence (RR 3.26, 95% CI 0.36, 29.17) and urticaria. No study compared soy formula to hydrolysed protein formula. AUTHORS' CONCLUSIONS: Feeding with a soy formula cannot be recommended for prevention of allergy or food intolerance in infants at high risk of allergy or food intolerance. Further research may be warranted to determine the role of soy formulas for prevention of allergy or food intolerance in infants unable to be breast fed with a strong family history of allergy or cow's milk protein intolerance.

Home visits during pregnancy and after birth for women with an alcohol or drug problem.

BACKGROUND: One potential method of improving outcome for pregnant or postpartum women with a drug or alcohol problem is with home visits. OBJECTIVES: To determine the effects of home visits during pregnancy and/or after birth for pregnant women with a drug or alcohol problem. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Trials Register (30 April 2004), CENTRAL (The Cochrane Library, Issue 2, 2004), MEDLINE (1966 to April 2004), EMBASE (1980 to week 16, 2004), CINAHL (1982 to April 2004), PsycINFO (1974 to April 2004), citations from previous reviews and trials, and contacted expert informants. SELECTION CRITERIA: Studies using random or quasi-random allocation of pregnant or postpartum women with a drug or alcohol problem to home visits. Trials enrolling high-risk women of whom more than 50% were reported to use drugs or alcohol were also eligible. DATA COLLECTION AND ANALYSIS: Assessments of trials were performed independently by all review authors. Statistical analyses were performed using fixed and random-effects models where appropriate. MAIN RESULTS: Six studies (709 women) compared home visits after birth with no home visits. None provided a significant antenatal component of home visits. The visitors included community health nurses, pediatric nurses, trained counsellors, paraprofessional advocates, midwives and lay African-American women. Most studies had methodological limitations, particularly large losses to follow up. There were no significant differences in continued illicit drug use (2 studies, 248 women; relative risk (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.20), continued alcohol use (RR 1.08, 95% CI 0.83 to 1.41) failure to enrol in a drug treatment program (2 studies, 211 women; RR 0.45 95% CI 0.10 to 1.94). There was no significant difference in the Bayley MDI (3 studies, 199 infants; weighted mean difference 2.89, 95% CI -1.17 to 6.95) or Psychomotor Index (WMD 3.14, 95% CI -0.03 to 6.32). Other outcomes reported by one study only included breastfeeding at six months (RR 1.00, 95% CI 0.81 to 1.23), incomplete six-month infant vaccination schedule (RR 1.07, 95% CI 0.58 to 1.96), non-accidental injury and non-voluntary foster care (RR 0.16, 95% CI 0.02 to 1.23), failure to use postpartum contraception (RR 0.41, 95% CI 0.20 to 0.82), child behavioural problems (RR 0.46, 95% CI 0.21 to 1.01), and involvement with child protective services (RR 0.38, 95% CI 0.20 to 0.74). AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the routine use of home visits for women with a drug or alcohol problem. Further large, high-quality trials are needed, and women's views on home visiting need to be assessed.

Sedatives for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This update included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE 1966-March 2005 and abstracts of conference proceedings. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included treatment failure (failure to achieve symptom control or use of additional drug treatment), seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Six studies enrolling a total of 305 patients met inclusion criteria (Coyle 2002; Finnegan 1984; Kahn 1969; Kaltenbach 1986; Khoo 1995; Madden 1977); however, two (Finnegan 1984; Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological concerns included the use of quasi-random allocation methods in four studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbitone compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care given to infants was significantly reduced (MD -162.1 mins/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or hospital stay. Comparing phenobarbitone with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment reported by treatment group of allocation were available. No trials were eligible that assessed clonidine for NAS. In infants treated with an opiate, a small quasi-random study reported a reduced severity of withdrawal. Infants were weaned from an opiate more quickly which allowed earlier hospital discharge and reduced hospital costs. These findings may reflect the low dose of opiate used for initial treatment and the policy of discharging infants home on phenobarbitone but not morphine. AUTHORS' CONCLUSIONS: In newborn infants with NAS, there is no evidence that phenobarbitone compared with supportive care alone reduces treatment failure; however, phenobarbitone may reduce the daily duration of supportive care needed. Phenobarbitone, compared to diazepam, reduces treatment failure. In infants treated with an opiate, the addition of phenobarbitone may reduce withdrawal severity. Further trials are required to determine if this finding is applicable when a higher initial dose of opiate is used, and determine the effects of phenobabritone on infant development. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS. Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial. This review should be taken in conjunction with the review "Opiate treatment for opiate withdrawal in newborn infants" (Osborn 2002a) which indicates that an opiate is the preferred initial therapy for NAS.

Opiate treatment for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using an opiate, compared to a sedative or non-pharmacological treatment, for treatment of NAS due to withdrawal from opiates. SEARCH STRATEGY: The previous review was updated with additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), MEDLINE (1966-December 2004) and EMBASE (1980-December 2004) supplemented by searches of conference abstracts and citation lists of published articles. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to opiate or control. Control could include an opiate, sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included control of symptoms, seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using relative risk (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Seven studies enrolling a total of 585 infants met inclusion criteria (Carin 1983; Finnegan 1984; Jackson 2004; Kaltenbach 1986; Kandall 1983; Khoo 1995; Madden 1977); however, two (Finnegan 1984; Kaltenbach 1986) may be sequential reports that include some identical patients. The studies enrolled infants of mothers who had used opiates with or without other drugs during pregnancy. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies; sizeable, largely unexplained differences in reported numbers allocated to each group in four studies; and imbalances in group characteristics after randomisation in one study. Opiate (morphine) vs supportive care only: One study (Khoo 1995) found no significant effect on treatment failure (RR 1.29, 95% CI 0.41, 4.07), a significant increase in hospital stay (MD 15.0 days, 95% CI 8.9, 21.1) and significant reductions in time to regain birthweight (MD -2.8 days, 95% -5.3, -0.3) and duration of supportive care (MD -197.2 minutes/day, 95% CI -274.2, -120.3). Opiate vs phenobarbitone: Meta-analysis of four studies found no significant difference in treatment failure (typical RR 0.76, 95% CI 0.51, 1.11). One of these studies (Finnegan 1984) reported that opiate treatment resulted in a significant reduction in treatment failure among infants of mothers who had used only opiates; however, as this was a post-hoc analysis, this result should be interpreted with caution. One study (Jackson 2004) reported a significant reduction in duration of treatment and admission to the nursery for infants receiving morphine compared to phenobarbitone. One study (Kandall 1983) reported a reduction in seizures, of borderline statistical significance, with the use of opiate. Opiate vs diazepam: Meta-analysis of two studies found a significant reduction in treatment failure (RR 0.43, 95% CI 0.23, 0.80) with the use of opiate. No study reported neurodevelopment by allocated treatment group. AUTHORS' CONCLUSIONS: Opiates, as compared to supportive care only, appear to reduce the time to regain birth weight and reduce the duration of supportive care, but increase the duration of hospital stay; there is no evidence of effect on treatment failure. When compared to phenobarbitone, opiates may reduce the incidence of seizures but, overall, there is no evidence of effect on treatment failure. One study reported a reduction in duration of treatment and nursery admission for infants on morphine. When compared to diazepam, opiates reduce the incidence of treatment failure. A post-hoc analysis generates the hypothesis that treatment effects may vary according to whether the population includes infants born to all opiate users (i.e. with or without other drug exposure) or is restricted to infants of mothers who used opiates only. In view of the methodologic limitations of the included studies the conclusions of this review should be treated with caution.

Soy formula for prevention of allergy and food intolerance in infants.

BACKGROUND: Allergies and food reactions in infants and children are common and may be associated with foods including adapted cow's milk formulas. Soy based formulas have been used to treat infants with allergy or food intolerance. However, it is unclear whether they can be advocated for the prevention of allergy and food intolerance in infants without clinical evidence of allergy or food intolerance. OBJECTIVES: In infants without clinical evidence of allergy or food intolerance, to determine whether feeding them an adapted soy formula compared to human milk, cow's milk formula or a hydrolysed protein formula prevents allergy or food intolerance. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used including searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2003), MEDLINE (1966 - January 2004), EMBASE (1980 - January 2004), CINAHL (1982 - December 2003) and previous reviews including cross references. SELECTION CRITERIA: Randomised and quasi-randomised trials that compare the use of an adapted soy formula to human milk, an adapted cow's milk or a hydrolysed protein formula for infant feeding in the first 6 months. Only trials with > 80% follow up of participants and reported in group of assignment were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Eligibility of studies for inclusion, methodological quality and data extraction were assessed independently by each reviewer. Primary outcomes included clinical allergy, specific allergies and food intolerance. Meta-analysis was conducted using a fixed effects model where no heterogeneity of treatment effect existed, and a random effects model when heterogeneity was found. MAIN RESULTS: Five eligible studies were found, all enrolling infants at high risk of allergy on the basis of a family history of allergy in a first degree relative. All studies compared use of a soy to a cow's milk formula. Two studies also included a group fed a formula containing hydrolysed protein. No eligible study enrolled infants fed human milk. No study examined the effect of early, short term soy formula feeding. Three studies were of good methodology and did not have unbalanced allergy-preventing co-interventions in the treatment groups. Comparing soy to cow's milk formula, one study with unclear allocation concealment and 19.5% losses to follow up reported a reduction in cumulative incidence of childhood allergy, asthma and allergic rhinitis. No other study reported a significant benefit for any allergy or food intolerance. Analysis found no significant difference in allergy cumulative incidence in infancy (one study: RR 1.02, 95% CI 0.69, 1.49) or childhood (3 studies: typical RR 0.73, 95% CI 0.37, 1.44) and no significant difference in cumulative incidence or period prevalence of any specific allergy or food intolerance in infancy or childhood. Analysis of studies comparing soy to a hydrolysed formula found a significant increase in infant (one study: RR 1.67, 95% CI 1.03, 2.69) and childhood allergy cumulative incidence (one study: RR 1.55, 95% CI 1.02, 2.35), infant eczema cumulative incidence (2 studies: typical RR 2.34, 95% CI 1.51, 3.62) and childhood food allergy period prevalence (one study: RR 1.81, 95% CI 1.09, 3.02). REVIEWERS' CONCLUSIONS: Feeding with a soy formula should not be recommended for the prevention of allergy or food intolerance in infants at high risk of allergy or food intolerance.

Early volume expansion for prevention of morbidity and mortality in very preterm infants.

BACKGROUND: Reduced perfusion of organs such as the brain, heart, kidneys and the gastrointestinal tract may lead to acute dysfunction and be associated with permanent injury. Various strategies have been used to provide cardiovascular support to preterm infants including inotropes, corticosteroids and volume expansion. OBJECTIVES: In very preterm infants, does early volume expansion reduce morbidity and mortality. If volume expansion is effective, what type of volume expansion is most effective. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. See Review Group details for more information. This was supplemented by additional searches of the Oxford Database of Perinatal Trials, and updated search performed of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library Issue 1, 2004), MEDLINE (1996-January 2004), EMBASE (1980-January 2004), previous reviews including cross references (all articles referenced), abstracts and conferences (Perinatal Society of Australia and New Zealand, and Pediatric Academic Societies and American Academy of Pediatrics meetings 1998-2003). SELECTION CRITERIA: Randomised trials of early volume expansion with normal saline, fresh frozen plasma, albumin, plasma substitutes or blood compared to no treatment or another form of volume expansion in preterm infants < 32 weeks gestation or < 1500g were included. Volume expansion was defined as at least 10 mls/kg given in the first 72 hours of life. DATA COLLECTION AND ANALYSIS: Standard methods of the Neonatal Review Group with use of relative risk (RR), risk difference (RD) and weighted mean difference (WMD). The fixed effects model using RevMan 4.1 was used for meta-analysis. Data from individual studies were only eligible for inclusion if a least 80% of infants were reported for that outcome. MAIN RESULTS: Seven studies were included. Five studies, four with data for mortality, compared volume to no treatment. Most studies enrolled very preterm infants on the basis of gestation or birthweight. Two studies comparing different types of volume expansion enrolled very preterm infants with hypotension. No study enrolled infants on the basis of low blood flow. One study examined the effect of volume expansion on blood flow but in normotensive very preterm infants. Comparing volume and no treatment, 4 studies with a total of 940 very preterm infants reported no significant difference in mortality (RR 1.11, 95% CI 0.88, 1.40). The large NNNI 1996 study reported no significant difference in severe disability (RR 0.80, 95% CI 0.52, 1.23), cerebral palsy (RR 0.76, 95% CI 0.48, 1.20) and combined death or severe disability (RR 1.00, 95% CI 0.80, 1.24). Although one small study (Beverley 1985) reported reduced P/IVH with volume expansion, this was not supported by any other study. No significant difference was reported in grade 3-4 P/IVH and combined death or grade 3-4 P/IVH. One study (NNNI 1996) reported no significant difference in the incidence of hypotension. The finding of decreased necrotising enterocolitis and increased sepsis in infants who received fresh frozen plasma compared to a gelatin-based plasma substitute or no treatment in one study should be treated with caution. No significant differences in mortality or disability were found in this study. Comparing albumin and saline in hypotensive infants, one study (Lynch 2002) reported a significant increase in mean BP and reduced incidence of treatment failure (persistent hypotension). The other study (So 1997) and the meta-analysis of the two studies found no significant difference in treatment failure (RR 0.75, 95% CI 0.53, 1.06) or in any other clinical outcome. REVIEWERS' CONCLUSIONS: There is no evidence from randomised trials to support the routine use of early volume expansion in very preterm infants without cardiovascular compromise. There is insufficient evidence to determine whether infants with cardiovascular compromise benefit from volume expansion. There is insufficient evidence to determine what type of volume expansion should be used in preterm infants (if at all) or for the use of early red cell transfusions. The significance of the finding of a significant increase in blood pressure in hypotensive preterm infants in one trial comparing albumin and saline is unclear, but the overall meta-analyses found no other significant clinical benefit in using albumin compared to saline.

Adrenaline for prevention of morbidity and mortality in preterm infants with cardiovascular compromise.

BACKGROUND: Inotropes are widely used in preterm infants to treat cardiovascular compromise, which may result from early adaptive problems of the transitional circulation, perinatal asphyxia or sepsis. Sustained hypotension and poor organ blood flow are associated with brain injury including peri/intraventricular haemorrhage and subsequent poor neurodevelopmental outcomes. Adrenaline (epinephrine) infusions are used in preterm infants with clinical cardiovascular compromise. OBJECTIVES: To determine the effectiveness and safety of adrenaline compared to no treatment or other inotropes in reducing mortality and morbidity in preterm infants with cardiovascular compromise. SEARCH STRATEGY: Randomised controlled trials were identified by searching MEDLINE (1966-August 2003), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003) and EMBASE (1980 - 2003), supplemented with searches of reference lists of published trials and abstracts of conference proceedings. SELECTION CRITERIA: Randomised controlled trials of preterm newborn infants that compared adrenaline to no treatment or other inotropic agents (including dopamine, dobutamine, noradrenaline or isoprenaline). DATA COLLECTION AND ANALYSIS: Data were extracted and analysed independently by two reviewers. Treatment effects on the following outcomes were to be determined: mortality in the newborn period, long term neurodevelopmental outcomes, radiological evidence of brain injury, short term haemodynamic changes, adverse drug effects and short term neonatal outcomes. Study authors were contacted for additional information. Studies were analysed for methodological quality using the criteria of the Cochrane Neonatal Review Group. MAIN RESULTS: One ongoing study (Pellicer 2003) was identified. One study comparing adrenaline with dopamine infusion was included but was published in abstract form only (Phillipos 1996). It enrolled hypotensive, predominantly preterm infants in the first 24 hours. Only infants >1750g are included in this review (report for infants <=1750g appears incomplete). The study was reported as being randomised and double blinded, but methods were not reported. Both adrenaline and dopamine significantly increased heart rate and mean BP, with no statistically significant effect on left or right ventricular outputs. No other clinical outcomes were reported. No studies were identified that compared adrenaline to other inotropes, placebo or no treatment. REVIEWER'S CONCLUSIONS: There are insufficient data on the use of adrenaline infusions in preterm infants with cardiovascular compromise to make recommendations for practice. There is a need for larger trials to determine whether adrenaline is effective in reducing morbidity and mortality in preterm infants with cardiovascular compromise.

Clinical detection of low upper body blood flow in very premature infants using blood pressure, capillary refill time, and central-peripheral temperature difference.

OBJECTIVE: To determine the accuracy of blood pressure (BP), capillary refill time (CRT), and central-peripheral temperature difference (CPTd) for detecting low upper body blood flow in the first day after birth. METHODS: A prospective, two centre cohort study of 128 infants born at < 30 weeks gestation. Invasive BP (n = 108), CRT (n = 128), and CPTd (n = 46) were performed immediately before echocardiographic measurement of superior vena cava (SVC) flow at three, 5-10, and 24 hours after birth. RESULTS: Forty four (34%) infants had low SVC flow (< 41 ml/kg/min) in the first day, 13/122 (11%) at three hours, 39/126 (31%) at 5-10 hours, and 4/119 (3%) at 24 hours. CPTd did not detect infants with low flows. Combining all observations in the first 24 hours, CRT > or = 3 seconds had 55% sensitivity and 81% specificity, mean BP < 30 mm Hg had 59% sensitivity and 77% specificity, and systolic BP < 40 mm Hg had 76% sensitivity and 68% specificity for detecting low SVC flow. Combining a mean BP < 30 mm Hg and/or central CRT > or = 3 seconds increases the sensitivity to 78%. CONCLUSIONS: Low upper body blood flow is common in the first day after birth and strongly associated with peri/intraventricular haemorrhage. BP and CRT are imperfect bedside tests for detecting low blood flow in the first day after birth.

Effect of early targeted indomethacin on the ductus arteriosus and blood flow to the upper body and brain in the preterm infant.

OBJECTIVE: To determine if indomethacin given to preterm infants with a large ductus arteriosus (DA) in the first hours of life results in maintained or improved brain and upper body blood (superior vena cava (SVC)) flow. STUDY DESIGN: A randomised, double blind trial of indomethacin v placebo. Echocardiography was performed on 111 infants born at < 30 weeks gestation at 3 and/or 10 hours after birth. Infants were eligible if the DA diameter was > 1.6 mm. Infants were randomised to receive indomethacin 0.2 mg/kg or placebo. Crossover occurred if the DA was still > 1.6 mm. Echocardiography was performed one hour after each treatment. RESULTS: Seventy (63%) infants had a DA > 1.6 mm, with 35 randomised to receive indomethacin and 35 to receive placebo. At one hour there was no difference in DA constriction (indomethacin -20% v placebo -15%), change in SVC flow (-1% v -9%), for right ventricular output (RVO). Two hours after indomethacin, 62 infants had uncontrolled observations, at which time significant ductal constriction had occurred. At this time, infants of > or = 27 weeks gestation had significantly greater increases in SVC flow and RVO than infants of < 27 weeks gestation. Infants with failed ductal constriction had significantly lower initial SVC flow and developed more late grade 3/4 peri/intraventricular haemorrhage (P/IVH). Initial SVC flow, but not ductal constriction, was a significant predictor of late grade 3/4 P/IVH in adjusted analysis. CONCLUSIONS: Indomethacin had minimal effect on ductal constriction and blood flow at one hour compared with placebo. Failure of ductal constriction is associated with low SVC flow and subsequent late severe P/IVH.

Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants.

BACKGROUND: Allergies and food reactions are common and may be associated with foods including adapted cow's milk formulas. Formulas containing hydrolysed proteins have been used to treat infants with allergy or food intolerance, and have been advocated for prevention of allergy and food intolerance in infants. OBJECTIVES: To determine whether use of hydrolysed formulas for infant feeding prevents allergy and food intolerance. If hydrolysed formulas are effective, to determine what type of hydrolysed formula is most effective including extensively and partially hydrolysed formulas. To determine which infants benefit including infants at low or high risk of allergy and infants receiving early, short term or prolonged formula feeding. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used including searches of the Cochrane Controlled Trials Register (2003, Issue 1), MEDLINE (1966 - January 2003), EMBASE (1980 - January 2003) and CINAHL (1982 - January 2003) and previous reviews including cross references. SELECTION CRITERIA: Randomised and quasi-randomised trials that compare the use of a hydrolysed infant formula to human milk or cow's milk formula. Trials with >80% follow up of participants were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Eligibility of studies for inclusion, methodological quality and data extraction were assessed independently by each reviewer. Primary outcomes included clinical allergy, specific allergies and food intolerance. Meta-analysis was conducted using a fixed effects model. MAIN RESULTS: Eighteen trials met criteria for inclusion. No eligible trials compared prolonged hydrolysed formula to human milk feeding. Two trials compared early, short term hydrolysed formula to human milk feeding and reported no significant difference in infant allergy or childhood cow's milk allergy (CMA). Two trials compared early, short term hydrolysed formula to cow's milk formula feeding with no significant benefits reported. One large quasi-random study reported a reduction in infant CMA of borderline significance in low risk infants (RR 0.62, 95% CI 0.38, 1.00).Seven studies compared prolonged feeding of hydrolysed formula to cow's milk formula without using co-interventions for allergy prevention. Meta-analysis of 4 studies (386 infants) found a significant reduction in allergy incidence in infancy (typical RR 0.63, 95% CI 0.47, 0.85; RD -0.15, 95% CI -0.25, -0.06). One study reported a significant reduction in allergy incidence in childhood (RR 0.54, 95% CI 0.36, 0.81). Significant reductions were found in asthma prevalence in childhood, eczema incidence in infancy and prevalence in childhood, food allergy prevalence in childhood, and CMA incidence in infancy. All studies enrolled infants at high risk of allergy. Only three trials comparing prolonged hydrolysed formula feeding to cow's milk formula feeding were considered of good methodology. Only one of these trials demonstrated a benefit into childhood (5 years of age). No eligible trials examined the effects of prolonged hydrolysed formula feeding on allergy beyond early childhood. Costs were not reported. Three trials compared prolonged feeding with an extensive to a partially hydrolysed formula and reported no significant difference in allergy incidence in infancy. REVIEWER'S CONCLUSIONS: There is no evidence to support feeding with a hydrolysed formula for the prevention of allergy in preference to exclusive breast feeding. In high risk infants who are unable to be completely breast fed, there is evidence that prolonged feeding with a hydrolysed compared to a cow's milk formula reduces infant and childhood allergy and infant CMA. Further trials are required to determine if significant clinical benefits persist beyond 5 years of age and if there is any additional benefit from use of an extensive compared to a partially hydrolysed formula. Incremental costs of formula and the effect on compliance should be measured.

Sedatives for opiate withdrawal in newborn infants.

BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002) and MEDLINE 1966-2002. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence, with > 80% follow up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. Primary outcomes included treatment failure (failure to achieve symptom control or use of additional drug treatment), seizure occurrence, mortality and neurodevelopment. Treatment effect was expressed using (RR), risk difference (RD), mean difference (MD) and weighted mean difference (WMD). Meta-analysis was performed using a fixed effect model. MAIN RESULTS: Five studies enrolling a total of 285 patients met inclusion criteria (Finnegan 1984, Kahn 1969, Kaltenbach 1986, Khoo 1995, Madden 1977); however, two (Finnegan 1984, Kaltenbach 1986) may be sequential reports that include some identical patients. Methodological concerns included the use of quasi-random rather than random patient allocation methods in three studies, and sizeable, largely unexplained differences in reported numbers allocated to each group in three studies. Phenobarbital compared to supportive care alone has not been shown to reduce treatment failure or time to regain birthweight (one study). However, the duration of supportive care required to be given to infants each day was significantly reduced (MD -162.1 minutes/day, 95% CI -249.2, -75.1). Comparing phenobarbital to diazepam, meta-analysis of two studies found that phenobarbital produced a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). There was no significant difference in duration of treatment or duration of hospital stay. Comparing phenobarbital with chlorpromazine, one study found no significant difference in treatment failure rate. No data for neurodevelopment were available, reported by treatment group as allocated. No trials were eligible that assessed clonidine for NAS. REVIEWER'S CONCLUSIONS: In newborn infants with NAS, there is no evidence that phenobarbital, compared with supportive care alone, reduces treatment failure; however, phenobarbital may reduce the daily duration of supportive care needed. Phenobarbital, compared to diazepam, reduces treatment failure. There is insufficient evidence to support the use of chlorpromazine or clonidine in newborn infants with NAS. Clonidine and chlorpromazine should only be used in the context of a randomised clinical trial. The results of this review, taken in conjunction with the related review, Opiate treatment for opiate withdrawal in newborn infants (Osborn 2002), indicate that treatment with opiates is the preferred initial therapy for NAS. It is hypothesised that this is particularly true for infants whose mothers have used only opiates during pregnancy. If a sedative is used, phenobarbital is preferred to diazepam. The results of an ongoing trial of the addition of phenobarbital to an opiate are awaited.