Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes

Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
American journal of obstetrics and gynecology (Impact Factor: 4.7). 12/2007; 197(5):486.e1-10. DOI: 10.1016/j.ajog.2007.04.019
Source: PubMed


The objective of the study was to determine whether indomethacin used as a tocolytic agent is associated with adverse neonatal outcomes.
We used published guidelines of the Metaanalysis of Observational Studies in Epidemiology Group (MOOSE) to perform the metaanalysis. The search strategy used included computerized bibliographic searches of MEDLINE (1966-2005), PubMed (1966-2005), abstracts published in Obstetrics and Gynecology (1991-2005), abstracts published in Pediatric Research (1991-2005), and references of published manuscripts. Study inclusion criteria were publication in English, more than 30 deliveries less than 37 weeks' gestation, and meeting diagnostic criteria for individual neonatal outcomes. Exclusion criteria included case reports, case series, and multiple publications from the same author. Metaanalysis was performed using random effects model if there were more than 2 observational studies for a specific outcome. Eggers test was performed to exclude publication bias. Sensitivity analysis was performed to evaluate the effect of antenatal steroid exposure, gestation, and recent antenatal indomethacin exposure (duration of 48 hours or more between the last dose and delivery).
Fifteen retrospective cohort studies and 6 case-controlled studies met inclusion criteria. Antenatal indomethacin was associated with an increased risk of periventricular leukomalacia (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3-3.1). Recent exposure to antenatal indomethacin was associated with necrotizing enterocolitis (OR, 2.2; 95% CI; 1.1-4.2). Antenatal indomethacin was not associated with intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia, and mortality.
Antenatal indomethacin may be associated with an increased risk of periventricular leukomalacia and necrotizing enterocolitis in premature infants and therefore should be used judiciously for tocolysis.

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    • "Another meta- analysis of fifteen retrospective studies and six case controlled studies found a statistically significant association between periventriclar leukomalacia and administration of antenatal indomethacin in premature infants [29]. In addition, the same study showed a statistically significant association between necrotizing enterocolitis and administration of antenatal indomethacin within 72 hours prior to delivery in premature infants. "
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The aims of this study were 1) to examine the social competence of a regional cohort of children born very preterm and full term comparison children at age four years, 2) to identify infant clinical factors and socio-familial characteristics associated with poor social competence amongst children born very preterm, and 3) to examine the predictive validity of social competence problems amongst both very preterm and full term preschoolers in relation to school academic functioning and behavioural adjustment at age 6 years. At age 4, children were assessed using a range of parent and/or teacher completed questionnaires, spanning emotional regulation, behavioural adjustment and interpersonal social behaviour. Measures included the Emotion Regulation Checklist, the Infant-Toddler Symptoms Checklist, the Strengths and Difficulties Questionnaire, the Behaviour Rating Inventory of Executive Functioning “ Preschool version and the Penn Interactive Peer Play Scale. In addition, as part of a structured research assessment, children completed a battery of false belief tasks and a short form version of the Weschler Preschool and Primary Scales of Intelligence. Two years later at age 6, school teachers qualitatively rated children's behavioural adjustment and academic achievement in math, reading, spelling and language comprehension compared to their classroom peers. Results showed that relative to their full term peers, some children born very preterm tended to score less well across several areas of social competence. Specifically, parent report showed that children born very preterm were more likely to be characterised by higher levels of emotional dysregulation (p=.002) as well as a range of behavioural adjustment problems, spanning inhibitory control problems (p=.03), hyperactivity/inattention (p=.01), conduct problems (p=.01) and emotional symptoms (p=.008). While elevated rates of behavioural adjustment difficulties were also evident amongst very preterm children within the preschool environment, group differences were not statistically significant. However, a statistical trend towards elevated risk of inhibitory control problems amongst very preterm children in the preschool environment was noted (p=.09). Further, children born very preterm were at around a four-fold risk of emotional regulation difficulties of clinical significance,as well as being around 1.5 times more likely to exhibit clinically significant externalising and internalising behavioural difficulties and interpersonal social problems at age 4 years. In contrast, the interpersonal social behaviours and the extent of social cognitive understanding were largely similar across both groups. This pattern of findings remained largely unchanged following statistical control for the selection effects of family socio-economic status. Amongst children born very preterm, significant infant clinical and sociofamilial predictors of both emotional dysregulation and externalizing behaviour were male gender (p=.008/p=.006), neonatal indomethacin (p=.002/p=.005) and elevated maternal anxiety (p=.009/p=.002). Emotional dysregulation was also predicted by low socio-economic status (p=.002). In contrast, internalising behaviour was predicted only by low birth weight (p=.03). Finally, across both groups significant associations were found between overall social competence problems at age 4 years and later school adjustment with those very preterm and full term preschoolers characterised by poor social competence being at elevated risk of a range of behavioural adjustment difficulties and poor academic functioning in reading, spelling and math at age 6 years (corrected). Links between poor social competence and later behavioural adjustment remained across both groups following statistical control for child IQ, while associations with academic functioning were largely attenuated. By age 4 years a number of very preterm children are beginning to display elevated levels of emotional dysregulation, hyperactivity/inattention, conduct problems and emotional symptoms. Further, a substantial proportion of very preterm children may be at risk of developing clinically significant difficulties with these most pronounced in terms of emotional regulation abilities. Children's abilities to regulate their emotions and behaviour represent important building blocks for their later social and emotional functioning. Further, these abilities will likely influence the extent to which children are able to successfully transition to school. 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