Prophylactic Use Of Indomethacin Research Articles

Evaluation of Health-Related Values and Preferences of Adults Who Were Preterm Infants and Parents of Preterm Infants Concerning Use of Prophylactic Cyclooxygenase Inhibitor Drugs

There is wide variability in the use of prophylactic cyclooxygenase inhibitor (COX-I) drugs to prevent morbidity and mortality in preterm infants. Parents of preterm infants are rarely involved in this decision-making process. To explore the health-related values and preferences of adults who were preterm infants and families of preterm infants concerning the prophylactic use of indomethacin, ibuprofen, and acetaminophen initiated within the first 24 hours after birth. This cross-sectional study used direct choice experiments conducted in 2 phases of virtual video-conferenced interviews between March 3, 2021, and February 10, 2022: (1) a pilot feasibility study and (2) a formal study of values and preferences, using a predefined convenience sample. Participants included adults born very preterm (gestational age <32 weeks) or parents of very preterm infants currently in the neonatal intensive care unit (NICU) or having graduated from the NICU in the last 5 years. Relative importance of clinical outcomes, willingness to use each of the COX-Is when presented as the only option, preference for using prophylactic hydrocortisone vs indomethacin, willingness to use any of the COX-Is when all 3 options are available, and relative importance of having family values and preferences included in decision-making. Of 44 participants enrolled, 40 were included in the formal study (31 parents and 9 adults born preterm). The median gestational age of the participant or the participant's child at birth was 26.0 (IQR, 25.0-28.8) weeks. Death (median score, 100 [IQR, 100-100]) and severe intraventricular hemorrhage (IVH) (median score, 90.0 [IQR, 80.0-100]) were rated as the 2 most critical outcomes. Based on direct choice experiments, most participants were willing to consider prophylactic indomethacin (36 [90.0%]) or ibuprofen (34 [85.0%]), but not acetaminophen (4 [10.0%]) when offered as the only option. Among participants who initially chose indomethacin (n = 36), if prophylactic hydrocortisone was offered as a potential therapy with the caveat that both cannot be used simultaneously, only 12 of 36 (33.3%) preferred to remain with indomethacin. Variability in preference was noted when all 3 COX-I options were available, indomethacin (19 [47.5%]) being the most preferred option followed by ibuprofen (16 [40.0%]), while the remainder opted for no prophylaxis (5 [12.5%]). The findings of this cross-sectional study of former preterm infants and parents of preterm infants suggest that there was minimal variability in how participants valued the main outcomes, with death and severe IVH being rated as the 2 most important undesirable outcomes. While indomethacin was the most preferred form of prophylaxis, variability was noted in the choice of COX-I interventions when participants were presented with the benefits and harms of each drug.

Indomethacin for symptomatic patent ductus arteriosus in preterm infants.

Symptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored. To determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA. We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. We included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants. We used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding. We included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision. High-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.

Indomethacin for symptomatic patent ductus arteriosus in preterm infants

Background Symptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored. Objectives To determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA. Search methods We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. Selection criteria We included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants. Data collection and analysis We used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding. Main results We included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision. Authors' conclusions High-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.

Association between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants

To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants. Retrospective cohort study using prospectively collected data for infants with gestational ages < 29 weeks or birth weights of 401-1000 g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Prespecified subgroup analyses were performed. Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus after the first day of life was less common among 2587 infants who received prophylactic indomethacin compared with 5244 who did not (21.0% vs 36.1%, P < .001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72-1.10), death (OR 0.80, 95% CI 0.64-1.01), or death or BPD (OR 0.87, 95% CI 0.71-1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a patent ductus arteriosus after the first day of life. Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death. ClinicalTrials.gov: NCT00063063.

Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants.

To determine the effect of concomitant administration of prophylactic indomethacin and early enteral feeds on the risk of spontaneous intestinal perforation (SIP) in extremely low-birth-weight (ELBW) infants, and to describe the variation in prophylactic indomethacin use in Canada. A retrospective cohort study of 4268 ELBW infants born at <30 weeks' gestation admitted to Canadian neonatal units between 2010 and 2014 was conducted. Prophylactic indomethacin (I+ or I-, administered within 24 h) and early feeding (E+ or E-, initiated in the first 2 days) exposures were studied concurrently and independently. The primary outcomes were SIP and death before discharge. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. Compared with the I-/E+ reference group (n=1829), infants in I+/E+ (n=285; aOR 2.92, 95% CI 1.41 to 6.08) and I+/E- (n=213; aOR 2.84, 95% CI 1.35 to 5.98) groups had higher odds of SIP, whereas those in the I-/E- group had similar odds (n=1941; aOR 1.37, 95% CI 0.88 to 2.14). Odds of SIP were higher in the indomethacin exposed group (I+) compared with the unexposed (I-) group when controlled for early feeding (aOR 2.43, 95% CI 1.41 to 4.19), but not in the early feeding group when controlled for indomethacin. The use of prophylactic indomethacin ranged from 0% usage in 13 sites to 78% use in one site. Prophylactic indomethacin was associated with increased odds of SIP independently from early feeding in this cohort; however, early enteral feeding was not associated with SIP. Marked variation in the use of prophylactic indomethacin was identified.

Prophylactic indomethacin and intestinal perforation in extremely low birth weight infants.

Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP. This was a cohort study of 15,751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP. Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49-1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37-0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36-0.777, P = .0011). The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.

Proximal Femoral Resection for the Painful Dislocated Hip in Cerebral Palsy

Painful hip displacement is difficult to treat in severe cerebral palsy. Proximal femoral resection (PFR) is an excellent procedure for pain relief but has a high rate of heterotopic ossification (HO). Indomethacin is the gold standard therapy used for prevention in hip and acetabular surgery. There is no evidence of its benefit in this complex patient group. Forty-one consecutive patients with severe cerebral palsy underwent 52 primary PFRs for severe pain in 2 pediatric orthopaedic units in London, UK. Twenty-one patients received a prophylactic postoperative dose of indomethacin for the prevention of HO. Notes and radiographs were reviewed independently by 2 orthopaedic trainees. The mean age of patients was 14.3 and 14.8 years in the group administered with and administered without indomethacin, respectively, and mean follow-up was 4.5 and 4.3 years. Five patients in each group developed HO. One patient in the indomethacin group was offered reexcision for HO but declined. Two in the nonindomethacin group were offered reexcision and one accepted and made a good recovery. There was no difference in pain relief between the groups and no correlation between the degree of HO and level of postoperative pain. This study does not support the use of prophylactic indomethacin in severe cerebral palsy patients undergoing PFR. We also question the importance of HO in the outcome of this procedure. Level III.

Prophylactic Indomethacin Worsens Short-Term Respiratory Outcomes in Extremely Low-Birth-Weight Infants

To compare the effects of prophylactic indomethacin versus expectant management on short-term respiratory outcomes in extremely low-birth-weight (ELBW) infants. This was a retrospective cohort study of ELBW infants with gestational age less than 28 weeks, born at a level III neonatal intensive care unit from 2004 to 2009. Patients were grouped based on whether they received prophylactic indomethacin or expectant treatment. The key outcome was the cumulative number of days of mechanical ventilation. Other outcomes were cumulative number of days supplemental oxygen and continuous positive airway pressure (CPAP) were required; duration of hospital stay; mortality; and other morbidities such as necrotizing enterocolitis and intraventricular hemorrhage. Multivariable linear regression was performed with treatment group and seven covariates, defined a priori, as predictor variables and cumulative number of days of mechanical ventilation as the outcome. There were 144 infants in the prophylaxis group and 221 infants in the expectant treatment group. At baseline, the Score for Neonatal Acute Physiology-Perinatal Extension, incidence of respiratory distress syndrome, and usage of antenatal corticosteroids were significantly higher in the prophylaxis group. The cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP were significantly higher in the prophylaxis group. On multivariable linear regression, after adjusting for confounders, use of prophylactic indomethacin (unstandardized β coefficient = 12.4; 95% confidence interval [CI]: 6.6, 18.1; p < 0.001), birth weight (β = -0.025; 95% CI: -0.05, -0.001; p = 0.043), and gestation (β = -4.5; 95% CI: -7.24, -1.8; p = 0.001) were the independent predictors of cumulative number of days of mechanical ventilation. ELBW infants who received prophylactic indomethacin had significantly longer cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP. Prophylactic indomethacin is an independent predictor of cumulative number of days of mechanical ventilation.

1151 International Survey on the Use of Prophylactic Indomethacin in Extremely Pre-Term Infants

BackgroundProphylactic trials with indomethacin have consistently revealed short term benefits like a decreased need for PDA ligation (RR 0.51), decreased incidence of pulmonary haemorrhage (RR 0.35), and serious IVH (RR...

Intercenter Differences in Bronchopulmonary Dysplasia or Death Among Very Low Birth Weight Infants

To determine (1) the magnitude of clustering of bronchopulmonary dysplasia (36 weeks) or death (the outcome) across centers of the Eunice Kennedy Shriver National Institute of Child and Human Development National Research Network, (2) the infant-level variables associated with the outcome and estimate their clustering, and (3) the center-specific practices associated with the differences and build predictive models. Data on neonates with a birth weight of <1250 g from the cluster-randomized benchmarking trial were used to determine the magnitude of clustering of the outcome according to alternating logistic regression by using pairwise odds ratio and predictive modeling. Clinical variables associated with the outcome were identified by using multivariate analysis. The magnitude of clustering was then evaluated after correction for infant-level variables. Predictive models were developed by using center-specific and infant-level variables for data from 2001 2004 and projected to 2006. In 2001-2004, clustering of bronchopulmonary dysplasia/death was significant (pairwise odds ratio: 1.3; P < .001) and increased in 2006 (pairwise odds ratio: 1.6; overall incidence: 52%; range across centers: 32%-74%); center rates were relatively stable over time. Variables that varied according to center and were associated with increased risk of outcome included lower body temperature at NICU admission, use of prophylactic indomethacin, specific drug therapy on day 1, and lack of endotracheal intubation. Center differences remained significant even after correction for clustered variables. Bronchopulmonary dysplasia/death rates demonstrated moderate clustering according to center. Clinical variables associated with the outcome were also clustered. Center differences after correction of clustered variables indicate presence of as-yet unmeasured center variables.

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Persistent patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Prostaglandin synthetase inhibitors such as indomethacin promote PDA closure but also have potential side effects. The effect of the prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA would be exposed to indomethacin, warrants particular scrutiny. To determine the effect of prophylactic indomethacin on mortality and morbidity in preterm infants. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 5, 2010), MEDLINE, EMBASE and CINAHL (until April 2010), conference proceedings, and previous reviews. Randomised or quasi-randomised controlled trials that compared prophylactic indomethacin versus placebo or no drug in preterm infants. The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two review authors. Nineteen eligible trials in which 2872 infants participated were identified. Most participants were very low birth weight, but the largest single trial restricted participation to extremely low birth weight infants (N = 1202). The trials were generally of good quality.The incidence of symptomatic PDA [typical relative risk (RR) 0.44, 95% confidence interval (CI) 0.38 to 0.50] and PDA surgical ligation (typical RR 0.51, 95% CI 0.37,0.71) was significantly lower in treated infants. Prophylactic indomethacin also significantly reduced the incidence of severe intraventricular haemorrhage (typical RR 0.66, 95% CI 0.53 to 0.82). Meta-analyses found no evidence of an effect on mortality (typical RR 0.96, 95% CI 0.81 to 1.12) or on a composite of death or severe neurodevelopmental disability assessed at 18 to 36 months old (typical RR 1.02, 95% CI 0.90, 1.15). Prophylactic indomethacin has short-term benefits for preterm infants including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.

Cochrane Review: Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

AbstractBackgroundPatent ductus arteriosus (PDA) and intraventricular haemorrhage (IVH) are both associated with increased mortality and morbidity in preterm infants. Indomethacin has been used successfully to treat symptomatic PDA and may also prevent or limit IVH in the neonatal period. There are however potential unwanted side effects of indomethacin, in particular a potential for reduced organ perfusion that might outweigh any clinical benefits. The prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA or IVH would be exposed to indomethacin, warrants particular scrutiny.ObjectivesThis review examines the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with PDA and IVH in preterm infants.Search strategyAn initial literature search was conducted in three computerised databases: MEDLINE; EMBASE; and the Oxford Database of Perinatal Trials in October 1994. The search was updated in February 1997 and October 2001.Selection criteriaStrict selection criteria were applied to clinical trials: the population had to be newborn preterm infants (less than 37 completed weeks gestation); the intervention had to be prophylactic intravenous indomethacin; the trial had to be randomised and controlled; and at least one of several prespecified outcomes had to be reported in the results.Data collection and analysisThe methodological quality of each study was assessed using explicit criteria. Data on relevant outcome measures were extracted and, where appropriate, the results of individual trials were combined using meta‐analysis techniques to provide a pooled estimate of effect.Main resultsNineteen eligible trials randomising 2872 infants were identified.There is no evidence of difference in mortality at latest follow‐up between infants receiving prophylactic indomethacin and controls, pooled relative risk (RR) = 0.96 [95% CI 0.81 to 1.12].There is no evidence to suggest prophylactic indomethacin is associated with any reduction in long‐term neurosensory impairment, ie no significant difference in rates of cognitive delay, cerebral palsy, blindness or deafness.The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled RR = 0.44 [0.38 to 0.50] but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin reduces the need for surgical PDA ligation [RR = 0.51 (0.37,0.71)].Prophylactic indomethacin significantly reduces the incidence of Grade 3 and 4 intraventricular haemorrhage, pooled RR = 0.66 [0.53 to 0.82].There is no evidence of difference in rates of necrotising enterocolitis, excessive clinical bleeding or sepsis. Increased incidence of oliguria is seen with prophylactic indomethacin [RR = 1.90 (1.45,2.47] but this is not associated with major renal impairment.Authors' conclusionsProphylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus, the need for duct ligation and severe intraventricular haemorrhage. There is no evidence to suggest either benefit or harm in longer term outcomes including neurodevelopment. Depending on clinical circumstances and personal preferences, there may be a role for prophylactic indomethacin in some infants on some neonatal units.Plain Language SummaryProphylactic intravenous indomethacin for preventing mortality and morbidity in preterm infantsPatent ductus arteriosus (PDA) occurs when an artery near the heart and lungs, which should close off soon after birth, stays open. Babies born too early (preterm) with PDA are at increased risk of severe illness and death. Indomethacin has been given to very small babies within 24 hours of birth to help close a PDA, at the same time reducing the risk of bleeding into the head ‐ intraventricular hemorrhage (IVH). The review found that giving indomethacin to preterm babies reduced their risk of both PDA and IVH. Indomethacin may also reduce blood flow in some organs including the brain but this does not seem to cause any serious lasting adverse effects. However, giving prophylactic indomethacin has no effect on the development of the babies in the longer term ‐ development is neither better nor worse than the development of babies who have not received the treatment ‐ suggesting its use may be limited to achieving short‐term benefits only.

Can Early Echocardiographic Findings Predict Patent Ductus Arteriosus?

Background: Prophylactic treatment with prostaglandin synthetase inhibitors (PSI) is potentially harmful. Moreover, long-term benefits of prophylactic use of indomethacin or ibuprofen are not proven. Early treatment of a high-risk population is alternative to the routine prophylactic use of PSI, but it remains unclear which newborn is at greatest risk for patent ductus arteriosus (PDA). Objective: Evaluation of the prognostic value of early echocardiographic studies with respect to PDA in later life. Methods: Sixty preterm infants with a mean birth weight of 1,087 g and mean gestational age of 28.5 weeks were included in a prospective study. Cardiac scans were performed in all newborns on entry into the study (within 12–48 h after birth) and further in case of clinical suspicion of PDA or obligatorily on the 7th and 28th days of life. There was no prophylactic or treatment use of any PSI during the study period. Newborns were divided into 2 cohorts: with significant left to right shunt requiring surgical ligation of PDA (n = 16) or without significant PDA during follow-up (control group, n = 44). Results: On entry, the mean internal diameter of the ductus arteriosus (2.6 vs. 0.91 mm/kg; p < 0.01), mean cardiac index across aortic valve (2.96 vs. 2.37 l/min/m²; p < 0.01) and early filling peak velocity (43.1 vs. 33.7; p = 0.01) were significantly higher in babies who later needed surgical ligation of PDA. There was no difference in the mean values of the other echocardiographic parameters studied. An early ductal diameter of >1.5 mm/kg predicted symptomatic PDA with a sensitivity of 94% and a specificity of 73%, and its positive predictive value equaled 57% and negative predictive value amounted to 97%. Conclusions: Early echocardiographic studies possess negative predictive value and may decrease unnecessary surgical ligation of PDA in very low birth weight infants.

Indomethacin Therapy for Patent Ductus Arteriosus in Premature Infants

Patent ductus arteriosus (PDA) occurs in 18–77% of very low-birth-weight (VLBW) infants [10]. This wide variation in incidence of PDA is mainly attributable to a difference in gestational age distribution in the studied VLBW population; the lower the gestational age, the higher the risk for symptomatic PDA in these infants, and they are also less likely to respond to medical therapy. Since the reports of the first successful treatment of PDA with indomethacin in 1976 [3, 5, 9], a large number of studies have attempted to seek the best strategy for indomethacin use. Prophylactic use of indomethacin has been shown to reduce the incidence of symptomatic PDA and grade III and IV intraventricular hemorrhage (IVH), but it has not shown any significant difference in mortality or long-term neurodevelopmental outcomes compared to a control group [4]. Prophylactic use of indomethacin has not been widely used primarily because of spontaneous closure of ductus in a significant proportion of VLBW infants and potential adverse effects of indomethacin. Rather than prophylactically treating all VLBW infants, indomethacin treatment could be limited to VLBW infants with asymptomatic PDA. Cooke et al. [3] conducted a meta-analysis on three randomized controlled trials in which asymptomatic PDA was treated with indomethacin, placebo, or no intervention. Indomethacin significantly reduced the incidence of symptomatic PDA and duration of supplemental oxygen. However, there was no effect on mortality, chronic lung disease, IVH, or length of ventilation. Long-term neurodevelopmental outcomes were not reported in these studies. Again, asymptomatic PDA may close in time, and one may question the justification for indomethacin treatment for all asymptomatic PDA. For symptomatic PDA, there is agreement regarding the need for treatment, and indomethacin has been the drug of choice. However, the optimal treatment strategy for indomethacin has not been clearly established with regard to appropriate dose, duration, and when to subject patients to surgical ligation, particularly for extremely low-birth-weight infants [2]. Ductal closure would certainly be dependent on indomethacin blood level. It would also be influenced by gestational age, postnatal age, and ductal size and flow. Pharmacokinetic data for indomethacin indicate that preterm infants less than 1000 g have lower indomethacin plasma levels compared to larger premature infants, possibly due to their relatively large extracellular fluid space and lower serum protein concentration [16]. It has been noted that prostaglandin levels rise 24–72 hours after the last dose of indomethacin [13], coinciding with the time for a risk of PDA reopening. In most trials, short courses of indomethacin have been studied. It thus appears that to achieve and maintain ductal closure, a prolonged course of indomethacin exposure may be more successful than a short course. Sangem et al. [12] examined neonatal outcomes in premature infants with multiple courses of indomethacin. Of 259 infants with persistent PDA, the ductus closed in 224 (84%) with either the first or the second course of indomethacin. Among the remaining 35 infants, 11 had a surgical ligation and 23 received the third course of indomethacin with a closure rate of 43%. Overall closure rate for PDA by indomethacin was 234 of 258 (91%). This result is similar to that of a study by Sperandio et al. [14], in which incremental doses of indomethacin were given to 129 infants of gestational age \33 weeks and with symptomatic PDA. In this study, following the initial three doses K.-S. Lee (&) University of Chicago Comer Children’s Hospital, 5841 South Maryland Avenue, Chicago, IL 60637, USA e-mail: klee@uchicago.edu

The Classic: A New Periacetabular Osteotomy for the Treatment of Hip Dysplasias

A new periacetabular osteotomy of the pelvis has been used for the treatment of residual hip dysplasias in adolescents and adults. The identification of the joint capsule is performed through a Smith-Petersen approach, which also permits all osteotomies to be performed about the acetabulum. This osteotomy does not change the diameter of the true pelvis, but allows an extensive acetabular reorientation including medial and lateral displacement. Preparations and injections of the vessels of the hip joint on cadavers have shown that the osteotomized fragment perfusion after correction is sufficient. Because the posterior pillar stays mechanically intact the acetabular fragment can be stabilized sufficiently using two screws. This stability allows patients to partially bear weight after osteotomy without immobilization. Since 1984, 75 periacetabular osteotomies of the hip have been performed. The corrections are 31° for the vertical center-edge (VCE) angle of Wiberg and 26° for the corresponding angle of Lequesne and de Seze in the sagittal plane. Complications have included two intraarticular osteotomies, a femoral nerve palsy that resolved, one nonunion, and ectopic bone formation in four patients prior to the prophylactic use of indomethacin. Thirteen patients required screw removal. There was no evidence of vascular impairment of the osteotomized fragment.

Indometacina profiláctica en el prematuro extremo

Indomethacin has been useful in the treatment of patent ductus arteriosus. During the last 10 years, it has been used prophylactically to decrease the incidences of intraventricular haemorrhage and patent ductus arteriosus. Objetive: To compare 2 prophylactic protocols with a non prophylactic group. Patient and Methods: Very low birthweight newborn (VLBW) less than 1 500 g and/or less than 32 weeks gestational age, were included. A historical group without prophylaxis n = 74, born 1994-1996, group I n = 71 born 1997-99 and group 2 n = 83 born 1999-2001 were studied. Congenital heart disease, severe asphyxia, genetic disorders and major malformations were factors of exclusion. Group I were given indomethacin 0.1mg/kg iv over 30 minutes at 6, 30 and 54 hours of life. Group 2 recieved a single dose at 6 hours. All patients were evaluated with CNS ultrasound at 3, 10 and 30 days of life, with echocardiography at 7 days. Results: There were no differences in patient characteristics between the studied groups. The historic group presented PDA in 14 (18.9%), 4 requiring surgical closure and IVH in 13 (17.5%). In group 16 (8.4%) presented PDA with no surgical treatment necessary, IVH en 9.8%. In group 2, 6 (8.4%) had PDA and 13 (15.7%) had IVH. The incidence of PDA can be decreased using 3 doses or a single dose of indomethacin, 55.5% and 61.9% respectively (p < 0.01). However IVH is only reduced with 3 doses 44% vs 10.28% respectively. Conclusions: Early prophylactic use of indomethacin can decrease the incidence of PDA, a single dose is as effective as 3 doses. However to reduce the incidence of IVH 3 doses are needed. Thus the choice of which protocol should be based on therapeutic goals, the reduction in cerebral plasma flow is the main mechanism of preventing haemorrhage. These results should encourage a randomised controlled trial.

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

A patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants and increases the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD) and death. The standard treatment to close a PDA is indomethacin. Its use is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has been shown to be effective in closing a PDA without reducing blood flow velocity to the brain, gut or kidneys. To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) in the prevention of PDA in preterm infants. Randomized controlled trials comparing prophylactic ibuprofen use with placebo/no intervention/indomethacin were identified by searching the Cochrane Controlled Trial Register (The Cochrane Library, Issue 4, 2002), MEDLINE (1966-November 2002), CINAHL (1982-November 2002), EMBASE (1980-November 2002), reference lists of published trials and abstracts published in Pediatric Research (1990-2002). No language restrictions were applied. Randomized or quasi-randomized controlled trials comparing use of ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) for the prevention of PDA in preterm and/or low birth weight infants. Data regarding the clinical outcomes including presence of PDA on day three and day seven, need for surgical ligation, need for rescue treatment with cyclo-oxygenase inhibitors, IVH, mortality, renal and gastrointestinal complications were extracted. Meta-analyses were performed using RevMan 4.1 and treatment estimates were reported as weighted mean difference (WMD), typical relative risk (RR), typical risk difference (RD) and, if statistically significant, number needed to treat (NNT) or number needed to harm (NNH), along with their 95% confidence intervals (CI). Four trials (n = 623) were included in the review. There was a statistically significant decrease in the incidence of PDA on day three in the ibuprofen group [typical RR 0.36 (95% CI 0.26, 0.49); typical RD -0.29 (95% CI -0.37, -0.21); NNT 3 (95% CI 3, 5); 3 trials, n = 488]. There was a significant increase in the serum creatinine levels in the ibuprofen group [WMD 0.11 mg/dl (95% CI 0.06, 0.17); 2 trials, n = 438]. There were no statistically significant differences in mortality, grade 3 or 4 IVH, CLD at 28 days or 36 weeks, need for surgical closure of PDA, NEC, GI hemorrhage, time to reach full feeds and urine output. One trial (Gournay 2002) (n = 135) reported on three infants in the ibuprofen group who developed pulmonary hypertension responsive to nitric oxide treatment. Prophylactic use of ibuprofen reduces the incidence of PDA. However, further trials, which address potential adverse effects including pulmonary hypertension, are needed. Such trials should include long-term neurodevelopmental outcomes. Trials comparing the effectiveness of prophylactic use of indomethacin versus ibuprofen may be warranted with particular reference to IVH, need for surgical ligation and neurodevelopmental outcome.

Cost-effectiveness of prophylactic indomethacin in very-low-birth-weight infants.

To perform cost-effectiveness analysis to facilitate the decision-making process surrounding use of indomethacin in preterm infants to lower the incidence of patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), and death. A MEDLINE literature search from 1966 to July 2000 was performed to identify relevant randomized, controlled trials (RCTs), as well as cohort and retrospective case-control studies. A decision tree was built representing the choice to use or not use indomethacin, and the potential outcome costs. Probabilities of being in each chance node were obtained from this search. Where data probabilities were not clear, a sensitivity analysis was conducted. There was no difference in the expected survival per year; however, there was a significant difference when effectiveness was measured as quality-adjusted life years (QALYs), resulting in 11 and 10 years for the indomethacin and control groups, respectively. The indomethacin treatment cost was $95,157 and that of the control groups was $99,955. The cost effectiveness per life expectancy of being in the indomethacin and control groups was $7142 and $7727, respectively. The sensitivity analysis for PDA closure and prevention of IVH for infants eventually developing PDA versus those without PDA showed no difference. The cost-effectiveness analysis per QALY was $8443 for the indomethacin treatment and $9168 for the control group. The prophylactic use of indomethacin is less costly and more effective within an important range of certainty. However, this analysis does not include several potentially confounding factors, such as antenatal steroid use or indomethacin-induced renal toxicity. Depending on the frequency with which these factors arise, economic projections may be considerably altered against the early use of indomethacin.

Management of Symptomatic Patent Ductus Arteriosus in Very Low-Birth-Weight Infants

A retrospective study of 39 infants under 30 weeks' gestation was carried out to analyze the incidence, management, and morbidity resulting from symptomatic patent ductus arteriosus. Symptomatic patent ductus arteriosus developed in 21 (53.8%) infants. Eleven (52.3%) infants underwent surgical closure of the ductus. The infants in this group had lower birth weight and severe respiratory distress syndrome and higher morbidity, compared with the medically managed group. The infants who responded to medical management did not have higher morbidity compared with the control group who did not sustain symptomatic patent ductus arteriosus. Indomethacin treatment was not effective in infants with a birth weight less than 800 gm. Our findings indicate that the higher morbidity seen in the symptomatic patent ductus arteriosus group may be due to respiratory distress syndrome, surgery, and birth weight under 800 gm. Prophylactic use of indomethacin may have a doubtful value in this group.

A New Periacetabular Osteotomy for the Treatment of Hip Dysplasias Technique and Preliminary Results

A new periacetabular osteotomy of the pelvis has been used for the treatment of residual hip dysplasias in adolescents and adults. The identification of the joint capsule is performed through a Smith-Petersen approach, which also permits all osteotomies to be performed about the acetabulum. This osteotomy does not change the diameter of the true pelvis, but allows an extensive acetabular reorientation including medial and lateral displacement. Preparations and injections of the vessels of the hip joint on cadavers have shown that the osteotomized fragment perfusion after correction is sufficient. Because the posterior pillar stays mechanically intact the acetabular fragment can be stabilized sufficiently using two screws. This stability allows patients to partially bear weight after osteotomy without immobilization. Since 1984, 75 periacetabular osteotomies of the hip have been performed. The corrections are 31 degrees for the vertical center-edge (VCE) angle of Wiberg and 26 degrees for the corresponding angle of Lequesne and de Seze in the sagittal plane. Complications have included two intraarticular osteotomies, a femoral nerve palsy that resolved, one nonunion, and ectopic bone formation in four patients prior to the prophylactic use of indomethacin. Thirteen patients required screw removal. There was no evidence of vascular impairment of the osteotomized fragment.