Arne Ohlsson

Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants.

BACKGROUND The prophylactic administration of indomethacin reduces the frequency of patent ductus arteriosus and severe intraventricular hemorrhage in very-low-birth-weight infants (those with birth weights below 1500 g). Whether prophylaxis with indomethacin confers any long-term benefits that outweigh the risks of drug-induced reductions in renal, intestinal, and cerebral blood flow is not known. METHODS Soon after they were born, we randomly assigned 1202 infants with birth weights of 500 to 999 g (extremely low birth weight) to receive either indomethacin (0.1 mg per kilogram of body weight) or placebo intravenously once daily for three days. The primary outcome was a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months. Secondary long-term outcomes were hydrocephalus necessitating the placement of a shunt, seizure disorder, and microcephaly within the same time frame. Secondary short-term outcomes were patent ductus arteriosus, pulmonary hemorrhage, chronic lung disease, ultrasonographic evidence of intracranial abnormalities, necrotizing enterocolitis, and retinopathy. RESULTS Of the 574 infants with data on the primary outcome who were assigned to prophylaxis with indomethacin, 271 (47 percent) died or survived with impairments, as compared with 261 of the 569 infants (46 percent) assigned to placebo (odds ratio, 1.1; 95 percent confidence interval, 0.8 to 1.4; P=0.61). Indomethacin reduced the incidence of patent ductus arteriosus (24 percent vs. 50 percent in the placebo group; odds ratio, 0.3; P<0.001) and of severe periventricular and intraventricular hemorrhage (9 percent vs. 13 percent in the placebo group; odds ratio, 0.6; P=0.02). No other outcomes were altered by the prophylactic administration of indomethacin. CONCLUSIONS In extremely-low-birth-weight infants, prophylaxis with indomethacin does not improve the rate of survival without neurosensory impairment at 18 months, despite the fact that it reduces the frequency of patent ductus arteriosus and severe periventricular and intraventricular hemorrhage.

Meta-analysis of Enteral Nutrition as a Primary Treatment of Active Crohn's Disease

BACKGROUND/AIMS The efficacy of enteral nutrition as primary therapy of active Crohns disease is controversial. The aim of the study was to compare by meta-analysis the likelihood of clinical response to liquid diet therapy vs. corticosteroids and to assess the importance of formula composition to efficacy. METHODS Randomized controlled trials comparing exclusive enteral nutrition with corticosteroids and elemental with nonelemental formulas were identified through a combination of computerized and hand-searching techniques. Rates of clinical remission of active Crohns disease, based on the intention-to-treat principle, were extracted from the studies by two independent reviewers. Odds ratios for likelihood of clinical response were calculated. RESULTS In eight trials comprising 413 patients, enteral nutrition was inferior to corticosteroids (pooled odds ratio, 0.35; 95% confidence interval, 0.23-0.53). In five trials comprising 134 patients, there was no difference in the efficacy of elemental versus nonelemental formulas (pooled odds ratio, 0.87; 95% confidence interval, 0.41-1.83). CONCLUSIONS Corticosteroids are more effective than enteral nutrition in the treatment of active Crohns disease. Limited sample size precludes definitive conclusions about the importance of formula composition in the efficacy of enteral nutrition; however, data analyzed in this study do not support an advantage to elemental feedings compared with a polymeric formulation.

Determinants of Preterm Birth Rates in Canada from 1981 through 1983 and from 1992 through 1994

BACKGROUND The rates of preterm birth have increased in many countries, including Canada, over the past 20 years. However, the factors underlying the increase are poorly understood. METHODS We used data from the Statistics Canada live-birth and stillbirth data bases to determine the effects of changes in the frequency of multiple births, registration of births occurring very early in gestation, patterns of obstetrical intervention, and use of ultrasonographic dating of gestational age on the rates of preterm birth in Canada from 1981 through 1983 and from 1992 through 1994. All births in 9 of the 12 provinces and territories of Canada were included. Logistic-regression analysis and Poisson regression analysis were used to estimate changes between the two three-year periods, after adjustment for the above-mentioned determinants of the likelihood of preterm births. RESULTS Preterm births increased from 6.3 percent of live births in 1981 through 1983 to 6.8 percent in 1992 through 1994, a relative increase of 9 percent (95 percent confidence interval, 7 to 10 percent). Among singleton births, preterm births increased by 5 percent (95 percent confidence interval, 3 to 6 percent). Multiple births increased from 1.9 percent to 2.1 percent of all live births; the rates of preterm birth among live births resulting from multiple gestations increased by 25 percent (95 percent confidence interval, 21 to 28 percent). Adjustment for the determinants of the likelihood of preterm birth reduced the increase in the rate of preterm birth to 3 percent among all live births and 1 percent among singleton births. CONCLUSIONS The recent increase in preterm births in Canada is largely attributable to changes in the frequency of multiple births, obstetrical intervention, and the use of ultrasound-based estimates of gestational age.

Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis

Abstract Objective To review outcomes in randomised controlled trials comparing hydralazine against other antihypertensives for severe hypertension in pregnancy. Study design Meta-analysis of randomised controlled trials (published between 1966 and September 2002) of short acting antihypertensives for severe hypertension in pregnancy. Independent data abstraction by two reviewers. Data were entered into RevMan software for analysis (fixed effects model, relative risk and 95% confidence interval); in a secondary analysis, risk difference was also calculated. Results Of 21 trials (893 women), eight compared hydralazine with nifedipine and five with labetalol. Hydralazine was associated with a trend towards less persistent severe hypertension than labetalol (relative risk 0.29 (95% confidence interval 0.08 to 1.04); two trials), but more severe hypertension than nifedipine or isradipine (1.41 (0.95 to 2.09); four trials); there was significant heterogeneity in outcome between trials and differences in methodological quality. Hydralazine was associated with more maternal hypotension (3.29 (1.50 to 7.23); 13 trials); more caesarean sections (1.30 (1.08 to 1.59); 14 trials); more placental abruption (4.17 (1.19 to 14.28); five trials); more maternal oliguria (4.00 (1.22 to 12.50); three trials); more adverse effects on fetal heart rate (2.04 (1.32 to 3.16); 12 trials); and more low Apgar scores at one minute (2.70 (1.27 to 5.88); three trials). For all but Apgar scores, analysis by risk difference showed heterogeneity between trials. Hydralazine was associated with more maternal side effects (1.50 (1.16 to 1.94); 12 trials) and with less neonatal bradycardia than labetalol (risk difference -0.24 (-0.42 to -0.06); three trials). Conclusions The results are not robust enough to guide clinical practice, but they do not support use of hydralazine as first line for treatment of severe hypertension in pregnancy. Adequately powered clinical trials are needed, with a comparison of labetalol and nifedipine showing the most promise.

Preterm birth and low birth weight among in vitro fertilization singletons: A systematic review and meta-analyses

Our objective was to determine the risks of preterm birth (PTB) and low birth weight (LBW) in singletons conceived through in vitro fertilization (IVF)+/-intracytoplasmic sperm injection (ICSI) compared to spontaneously conceived singletons after matching or controlling for at least maternal age. The MOOSE guidelines for meta-analysis of observational studies were followed. Medline and Embase were searched using comprehensive search strategies. Bibliographies of identified articles were reviewed. English language studies examining LBW or PTB in singletons conceived by IVF or IVF/intracytoplasmic sperm injection, compared with spontaneously conceived singletons, that matched or controlled for at least maternal age. Two reviewers independently assessed titles, abstracts, full articles and study quality and extracted data. Dichotomous data were meta-analyzed using relative risks (RR) as measures of effect size with a random effects model and for continuous data weighted mean difference was calculated. Seventeen studies were included with 31,032 singletons conceived through IVF (+/-ICSI) and 81,119 spontaneously conceived singletons. After matching or controlling for maternal age and often other factors, compared to spontaneously conceived singletons, IVF singletons had increased risks of our two primary outcomes, PTB (RR 1.84, 95% CI 1.54, 2.21) and LBW (<2500 g, RR 1.60, 95% CI 1.29, 1.98). Singletons conceived through IVF or IVF/ICSI were at increased risk for late PTB (32-36 weeks, RR 1.52, 95% CI 1.01, 2.30), moderate PTB <32-33 weeks (RR 2.27, 95% CI 1.73, 2.97), very LBW (<1500 g, RR 2.65, 95% CI 1.83, 3.84), and intrauterine growth restriction (RR 1.45, 95% CI 1.04, 2.00), lower birth weights (-97 g, 95% CI -161 g, -33 g) and shorter mean gestations (-0.6 weeks, 95% CI -0.9 weeks, -0.4 weeks). In conclusion, IVF singletons have significantly increased risks of PTB, LBW and other adverse perinatal outcomes compared to spontaneously conceived singletons after matching or controlling for maternal age at least.

Neonatal follow-up of very low birthweight/extremely low birthweight infants to school age : a critical overview

ABSTRACT. Neonatal follow‐up studies of school age children, published in the last decade, were critically reviewed. Nine studies examined extremely low birthweight infants (≤1000 g) and 16 involved very low birthweight infants (≤1500 8). The majority of children had age appropriate I.Q. scores, however, there was a greater variability of test scores. There was an increased need for special education or remedial therapy. Visual‐motor integration deficits were frequently reported. Behavioural difficulties were described. Fine and gross motor incoordination was identified. There was no conclusive correlation between perinatal course and school outcome. Gender did appear to influence outcome, in the small percent of studies which examined this variable, with females generally faring better. Low socioeconomic status was the most frequently reported predictor of poor outcome. Identified methodological limitations included heterogeneous samples, lack of control groups, high attrition, variable diagnostic criteria and lack of consensus regarding correction for prematurity.

Survival Without Disability to Age 5 Years After Neonatal Caffeine Therapy for Apnea of Prematurity

CONTEXT Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age. OBJECTIVE To determine whether neonatal caffeine therapy has lasting benefits or newly apparent risks at early school age. DESIGN, SETTING, AND PARTICIPANTS Five-year follow-up from 2005 to 2011 in 31 of 35 academic hospitals in Canada, Australia, Europe, and Israel, where 1932 of 2006 participants (96.3%) had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between 1999 and 2004. A total of 1640 children (84.9%) with birth weights of 500 to 1250 g had adequate data for the main outcome at 5 years. MAIN OUTCOME MEASURES Combined outcome of death or survival to 5 years with 1 or more of motor impairment (defined as a Gross Motor Function Classification System level of 3 to 5), cognitive impairment (defined as a Full Scale IQ<70), behavior problems, poor general health, deafness, and blindness. RESULTS The combined outcome of death or disability was not significantly different for the 833 children assigned to caffeine from that for the 807 children assigned to placebo (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95% CI, 0.65-1.03; P = .09). The rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness did not differ significantly between the 2 groups. The incidence of cognitive impairment was lower at 5 years than at 18 months and similar in the 2 groups (4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-1.55; P = .89). CONCLUSION Neonatal caffeine therapy was no longer associated with a significantly improved rate of survival without disability in children with very low birth weights who were assessed at 5 years.

Intention to Become Pregnant and Low Birth Weight and Preterm Birth: A Systematic Review

Increased stress, psychosocial problems, economic disadvantages, and lack of prenatal care are proposed to explain discrepancies in the outcome of unintended pregnancies. Studies of maternal intention and pregnancy outcomes have yielded varied results. Objective is to review studies of the risk of low birth weight (LBW)/preterm births (PTB) associated with unintended pregnancies ending in a live birth. We reviewed studies reporting on maternal intentions and outcomes from Medline, Embase, CINAHL, and bibliographies of identified articles. An unintended pregnancy was further classified as mistimed (not intended at that time) or unwanted (not desired at any time). Studies reporting an association between pregnancy intention and any of the outcomes were included. Study quality was assessed for biases in selection, exposure assessment, confounder adjustment, analyses, outcomes assessment, and attrition. Unadjusted and adjusted data from included studies were extracted by two reviewers. There were significantly increased odds of LBW among unintended pregnancies [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.25, 1.48] ending in a live birth. Within the unintended category, mistimed (OR 1.31, 95% CI 1.13, 1.52) and unwanted (OR 1.51, 95% CI 1.29, 1.78) pregnancies were associated with LBW. There were statistically significantly increased odds of PTB among unintended (OR 1.31, 95% CI 1.09, 1.58), and unwanted (OR 1.50, 95% CI 1.41, 1.61) but not for mistimed (OR 1.36, 95% CI 0.96, 1.93) pregnancies. Unintended, unwanted, and mistimed pregnancies ending in a live birth are associated with a significantly increased risk of LBW and PTB.

The efficacy of sucrose for relieving procedural pain in neonates—a systematic review and meta-analysis

Abstract The objective was to determine the efficacy and optimal dose of sucrose for relieving procedural pain in neonates. Data were obtained using MEDLINE, EMBASE, Reference Update and personal files and assessed for quality of the methods. Data from all randomized controlled trials where term and preterm neonates received a heelstick or venipuncture were examined for the efficacy of different sucrose doses (0.18 g, 0.24 g, 0.48 g or 0.50 g, 1.0 g) and water (placebo). The primary outcome was the proportion of time crying during 3 min after the painful stimulus. Data were combined across studies using a random effects model, adapted for use with single groups, producing a point estimate and 95% confidence interval (CI). Thirteen trials were identified; eight were rejected as data were inappropriate, non‐extractable, or the primary outcome was not measured. Five studies provided data on 271 infants. The proportion of time crying did not differ between 0.18 g of sucrose and water (p > 0.05) but was significantly lower in all other sucrose groups. There were no differences in proportion of time crying between term and preterm neonates. Sucrose reduced the proportion of time crying during painful procedures in neonates. The 0.18 g dose of sucrose was ineffective. Doses of 0.24 g (2 ml of 12% sucrose solution) were most effective. A dose of 0.50 g provided no additional benefit.

Perinatal Outcomes of Singleton Pregnancies Achieved by In Vitro Fertilization: A Systematic Review and Meta-Analysis

Abstract Objective : To determine whether the incidence of adverse obstetric outcomes is higher in singleton pregnancies achieved by in vitro fertilization (IVF) than in spontaneously conceived singletons matched for maternal age. Methods : We used comprehensive search strategies to search MEDLINE and EMBASE databases. We selected case-control and cohort studies that compared singleton pregnancies conceived by IVF or intracytoplasmic sperm injection (ICSI) with spontaneously conceived singletons (matched for maternal age [case-control studies] or controlled for maternal age [cohort studies]). Two reviewers independently assessed titles, abstracts, and study quality and extracted data. Statistical analysis was performed with Review Manager for Windows (Version 4.2, Oxford, UK). We performed meta-analysis of dichotomous data, using odds ratios (ORs) as measures of effect size, with a random effects model. We followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analysis of observational studies. Results : Singleton pregnancies resulting from IVF have increased rates of poor obstetric outcome, compared with spontaneously conceived singletons matched for maternal age, with increases in perinatal mortality (OR 2.40; 95% confidence interval [CI] 1.59-3.63), preterm birth at Conclusions : IVF singleton pregnancies have increased rates of poor obstetric outcome, compared with spontaneously conceived singletons matched for maternal age.