GASTROINTESTINAL BLEEDING ASSOCIATED WITH PHARMACOLOGIC TREATMENT OF PATENT DUCTUS ARTERIOSUS IN PRETERM NEONATES

ABSTRACT Objectives. A persistently patent ductus arteriosus (PDA) is a major complication of prematurity. A prompt PDA closure is crucial to reduce related risk of morbidity and mortality. Cycloxygenase inhibitors (COXi) are the a therapy of choice for PDA. However, the use of COXi is characterized by a high risk of gastrointestinal bleeding. Recently paracetamol was proposed as alternative treatment to reduce side effects of the COX-inhibitors therapy for PDA. We performed a systematic review and meta-analysis of all the available evidence to assess the risk of gastrointestinal bleeding during the treatment of PDA with paracetamol vs. COXi. Methods We conducted electronic searches in Medline, Scopus, and ISI web of Knowledge databases, using the following medical subject headings and terms: paracetamol, acetaminophen, and patent ductus arteriosus. Additionally, we performed electronic and manual screening of conference abstracts from international meetings of relevant organizations and manual search of the reference lists of all eligible articles. We considered eligible all studies comparing paracetamol vs. COXi (i.e. ibuprofen or indomethacin), or vs. placebo, for the treatment of PDA. Data regarding safety were collected and analyzed. Results Sixteen studies were included: two randomized controlled trials (RCTs) and 14 uncontrolled studies. Quality of selected studies is poor. A meta-analysis of RCT demonstrated a reduction of the risk of gastrointestinal bleeding in subjects receiving paracetamol vs. COXi (2/125 vs 9/125, RR 0.2, 0.1-1.0 95%CI). No data on gastrointestinal bleeding were reported by uncontrolled studies. Contemporarily, the meta-analysis of the data on the efficacy do not demonstrate any difference between the two therapeutic options on ductal closure (Arch Dis Child Fetal Neonatal Ed 2015; fetalneonatal-2014-307312). Conclusions The use of paracetamol may reduce the risk of gastrointestinal bleeding in preterm neonates receiving pharmacologic treatment for PDA. These results should be interpreted with caution taking into account the non-optimal quality of the studies analyzed and the limited number of neonates treated with paracetamol so far

Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis.

OBJECTIVES: We performed a systematic review and meta-analysis of all the available evidence to assess the efficacy and safety of paracetamol for the treatment of patent ductus arteriosus (PDA) in neonates, and to explore the effects of clinical variables on the risk of closure. DATA SOURCE: MEDLINE, Scopus and ISI Web of Knowledge databases, using the following medical subject headings and terms: paracetamol, acetaminophen and patent ductus arteriosus. Electronic and manual screening of conference abstracts from international meetings of relevant organisations. Manual search of the reference lists of all eligible articles. STUDY SELECTION: Studies comparing paracetamol versus ibuprofen, indomethacin, placebo or no intervention for the treatment of PDA. DATA EXTRACTION: Data regarding efficacy and safety were collected and analysed. RESULTS: Sixteen studies were included: 2 randomised controlled trials (RCTs) and 14 uncontrolled studies. Quality of selected studies is poor. A meta-analysis of RCTs does not demonstrate any difference in the risk of ductal closure (Mantel-Haenszel model, RR 1.07, 95% CI 0.87 to 1.33 and RR 1.03, 95% CI 0.92 to 1.16, after 3 and 6 days of treatment, respectively). Proportion meta-analysis of uncontrolled studies demonstrates a pooled ductal closure rate of 49% (95% CI 29% to 69%) and 76% (95% CI 61% to 88%) after 3 and 6 days of treatment with paracetamol, respectively. Safety profiles of paracetamol and ibuprofen are similar. CONCLUSIONS: Efficacy and safety of paracetamol appear to be comparable with those of ibuprofen. These results should be interpreted with caution, taking into account the non-optimal quality of the studies analysed and the limited number of neonates treated with paracetamol so far

An Observational, Prospective, Multicenter, Registry-Based Cohort Study Comparing Conservative and Medical Management for Patent Ductus Arteriosus.

No consensus has been reached on which patent ductus arteriosus (PDAs) in preterm infants require treatment and if so, how, and when they should be treated. A prospective, multicenter, cohort study was conducted to compare the effects of conservative approaches and medical treatment options on ductal closure at discharge, surgical ligation, prematurity-related morbidities, and mortality. Infants between 24(0/7) and 28(6/7) weeks of gestation from 24 neonatal intensive care units were enrolled. Data on PDA management and patients' clinical characteristics were recorded prospectively. Patients with moderate-to-large PDA were compared. Among the 1,193 enrolled infants (26.7 ± 1.4 weeks and 926 ± 243 g), 649 (54%) had no or small PDA, whereas 544 (46%) had moderate-to-large PDA. One hundred thirty (24%) infants with moderate-to-large PDA were managed conservatively, in contrast to 414 (76%) who received medical treatment. Eighty (62%) of 130 infants who were managed conservatively did not receive any rescue treatment and the PDA closure rate was 53% at discharge. There were no differences in the rates of late-onset sepsis, necrotizing enterocolitis (NEC), retinopathy of prematurity, intraventricular hemorrhage (≥Grade 3), surgical ligation, and presence of PDA at discharge between conservatively-managed and medically-treated infants (p > 0.05). Multivariate analysis including perinatal factors showed that medical treatment was associated with increased risk for mortality (OR 1.68, 95% Cl 1.01-2.80, p = 0.046), but decreased risk for BPD or death (BPD/death) (OR 0.59, 95%Cl 0.37-0.92, p = 0.022). The preferred treatment options were ibuprofen (intravenous 36%, oral 31%), and paracetamol (intravenous 26%, oral 7%). Infants who were treated with oral paracetamol had higher rates of NEC and mortality in comparison to other treatment options. Infants treated before postnatal day 7 had higher rates of mortality and BPD/death than infants who were conservatively managed or treated beyond day 7 (p = 0.009 and 0.007, respectively). In preterm infants born at <29 weeks of gestation with moderate-to-large PDA, medical treatment did not show any reduction in the rates of open PDA at discharge, surgical or prematurity-related secondary outcomes. In addition to the high incidence of spontaneous closure of PDA in the first week of life, early treatment (<7 days) was associated with higher rates of mortality and BPD/death

PREMM: Preterm early massage by the mother: Protocol of a randomised controlled trial of massage therapy in very preterm infants

© 2016 Lai et al.Background: Preterm infants follow an altered neurodevelopmental trajectory compared to their term born peers as a result of the influence of early birth, and the altered environment. Infant massage in the preterm infant has shown positive effects on weight gain and reduced length of hospital stay. There is however, limited current evidence of improved neurodevelopment or improved attachment, maternal mood or anxiety.The aim of this study is to investigate the effects of infant massage performed by the mother in very preterm (VPT) infants.Effects on the infant will be assessed at the electrophysiological, neuroradiological and clinical levels. Effects on maternal mood, anxiety and mother-infant attachment will also be measured. Methods/Design: A randomised controlled trial to investigate the effect of massage therapy in VPT infants. Sixty VPT infants, born at 28 to 32weeks and 6days gestational age, who are stable, off supplemental oxygen therapy and have normal cranial ultrasounds will be recruited and randomised to an intervention (infant massage) group or a control (standard care) group. Ten healthy term born infants will be recruited as a reference comparison group. The intervention group will receive standardised massage therapy administered by the mother from recruitment, until term equivalent age (TEA). The control group will receive care as usual (CAU). Infants and their mothers will be assessed at baseline, TEA, 12months and 24months corrected age (CA), with a battery of clinical, neuroimaging and electrophysiological measures, as well as structured questionnaires, psychoanalytic observations and neurodevelopmental assessments. Discussion: Optimising preterm infant neurodevelopment is a key aim of neonatal research, which could substantially improve long-term outcomes and reduce the socio-economic impact of VPT birth. This study has the potential to give insights into the mother-baby relationship and any positive effects of infant massageon neurodevelopment. An early intervention such as massage that is relatively easy to administer and could alter the trajectory of preterm infant brain development, holds potential to improve neurodevelopmental outcomes in this vulnerable population. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12612000335897. Date registered: 22/3/2012

Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR-ROP study): a prospective, multicentre study in 69 neonatal intensive care units

Background To evaluate the prevalence, risk factors and treatment of retinopathy of prematurity (ROP) in Turkey and to establish screening criteria for this condition. Methods A prospective cohort study (TR-ROP) was performed between 1 April 2016 and 30 April 2017 in 69 neonatal intensive care units (NICUs). Infants with a birth weight (BW)=1500 g or gestational age (GA) 1500 g or GA> 32 weeks with an unstable clinical course were included in the study. Predictors for the development of ROP were determined by logistic regression analyses. Results The TR-ROP study included 6115 infants: 4964 (81%) with a GA 32 weeks. Overall, 27% had any stage of ROP and 6.7% had severe ROP. A lower BW, smaller GA, total days on oxygen, late-onset sepsis, frequency of red blood cell transfusions and relative weight gain were identified as independent risk factors for severe ROP in infants with a BW=1500 g. Of all infants, 414 needed treatment and 395 (95.4%) of the treated infants had a BW <= 1500 g. Sixty-six (16%) of the treated infants did not fulfil the Early Treatment for Retinopathy of Prematurity requirements for treatment. Conclusions Screening of infants with a GA <= 34 weeks or a BW<1700 g appears to be appropriate in Turkey. Monitoring standards of neonatal care and conducting quality improvement projects across the country are recommended to improve neonatal outcomes in Turkish NICUs