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The role of prophylactic indomethacin in extremely low birth weight (ELBW) infants.

Three Part Question

In [ELBW (<1000 g) preterm infants] does [prophylactic indomethacin given on the day of birth] decrease [symptomatic and surgical ligations of patent ductus arteriosus (PDA) and grade III/IV intraventricular haemorrhage (IVH)] without serious side effects?

Clinical Scenario

A 900g preterm infant is ventilator dependent on day five due to significant PDA and IVH. Indomethacin is contraindicated due to probable necrotising enterocolitis and thrombocytopenia. Fluid restriction and diuretics did not improve the clinical condition and PDA ligation seemed the only option. I had earlier worked in an intensive care unit that gave prophylactic indomethacin to all ELBW infants to decrease the incidence of PDA and IVH. I wanted to explore the evidence to recommend similar guideline in the current unit.

Search Strategy

Primary source: The Cochrane library (2004, Issue 1) Secondary sources: Medline 1966-2004, EMBASE 1974-2004 and CINHAL 1982-2004 using the Dialog Datastar.
Primary source: The search term 'prophylactic indomethacin'. Hits: systematic reviews (8), Controlled trials (27) and Economic evaluation (1).
Secondary sources: The search term [({indomethacin} AND {prophylaxis} AND {ductus arteriosus OR patent ductus arteriosus OR patent arterial duct}] Filter meta-analyses and randomised controlled trials. Limit to human and english language. Hits: Medline (4), EMBASE (8) and CINAHL (3).

Search Outcome

2 relevant randomised controlled trials (see table).

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Schmidt B et al (TIPP)
1202 ELBW infants (500-999 g). 601 infants randomised to indomethacin grp (0.1 mg/kg every 24 hrs for 3 days starting between 2 and 6 hrs of age) and 601 infants to placebo grp (equal volume of normal saline)RCT (1b)Symptomatic PDAIndomethacin grp: 142/601 (24%), Placebo grp: 301/601 (50%) (RR 0.47; 95%CI 0.40, 0.56) Calculated RRR=52%, ARR=26%, NNT=4Echocardiographic confirmation of PDA not attempted before prophylactic indomethacin.
PDA ligationIndomethacin grp: 40/601 (7%), Placebo grp: 74/601 (13%) (RR 0.54, 95% CI 0.37, 0.78), Calculated RRR=47%, ARR=6%, NNT=17
All IVHIndomethacin grp: 236/601 (40%), Placebo grp: 234/601 (39%) (RR 1.01, 95%CI 0.88, 1.16)
Grade III/IV IVHIndomethacin grp :52/601 (9%) Placebo grp: 75/601 (13%) (RR 0.69, 95% CI, 0.50,0.97), Calculated RRR=31%, ARR=4%, NNT=25
Diminished urine outputIndomethacin grp: 44/601 (8%) Placebo grp: 22/601 (4%) (RR 2.0, 95%CI 1.21,3.29), Calculated ARI=4%, NNH=25
Supapannachart S
30 VLBW infants (630-1230 g). 15 infants were randomised to the prophylactic indomethacin grp (intravenous, initially 0.2 mg/kg, then 0.1mg/kg x 2 doses 12 hrs apart) and 15 infants to placebo grp (equal volume of saline)RCT (1)Symptomatic PDAIndomethacin grp: 4/15, Placebo grp: 12/15 (RR 0.33, 95 % CI 0.14, 0.80)Small sample size. The population data on ELBW not available for scrutiny. Echocardiographic confirmation of PDA not attempted before the prophylactic indomethacin.
Symptomatic PDA in subgroup ELBW and VLBWSignificantly less in ELBW only (data not available for scrutiny)
PDA ligationIndomethacin grp: 1/15, Placebo grp: 5/15 (RR 0.20, 95% CI 0.03, 1.51) (The results are likely to be the same in ELBW infants)
All IVHIndomethacin grp: 5/15, Placebo grp: 5/15 (RR 1.0, 95%CI, 0.36,2.75)
Side effectsNo significant permanent side effects (data not available for scrutiny).


ELBW infants have significant mortality and morbidity due to PDA and IVH posing difficult challenge to the neonatologists. Prophylactic indomethacin is shown to prevent the development of symptomatic PDA and may also prevent or limit IVH in the neonatal period. There is however concerns regarding adverse side effects of indomethacin particularly for reduced organ perfusion. By targeting a group of ELBW infants rather than treating all VLBW infants, prophylactic indomethacin would be restricted, limiting the possibility of significant side effects to those with greater chance of benefit. The primary search yielded 1 systematic review (Fowlie PW et al, 2002) addressing the efficacy of prophylactic indomethacin for preventing mortality and morbidity in preterm infants <37 weeks and < 1750 g. A critical appraisal of the review revealed 2 RCT's that included ELBW infants as the study group (Schmidt B et al and Supapannachart et al). Supapannachart et al study group consisted of infants < 1250 g; their data however included subanalysis of ELBW infants. Relative risk reduction (RRR), absolute risk reduction (ARR), number needed to treat (NNT), absolute risk increase (ARI) and number needed to harm (NNH) were calculated from the available population data. The indomethacin dose used in the 2 studies was different. Both RCT's showed significant reduction in symptomatic and surgical ligations of PDA. However the systematic review by Fowlie PW et al did not show improved long-term morbidity and mortality and long-term adverse effects but showed a trend towards increased incidence of necrotising enterocolitis and mild renal impairment. Further trials are needed to assess more precisely the effects, both beneficial and harmful in ELBW infants

Clinical Bottom Line

Intravenous indomethacin within the first 24 hrs decreases the incidence of symptomatic PDA (NNT 4), surgical ligation (NNT 17) and grade III/IV IVH (NNT 25) without major side effects (impaired renal function, NNH 25) in ELBW infants. The recommended indomethacin dose (TIPP study) is intravenous, 0.1 mg/kg every 24 hours for 3 days. Based on the current evidence prophylactic indomethacin may be used in neonatal units with high prevalence of symptomatic PDA and IVH. Further trials are needed of prophylactic indomethacin in ELBW infants to assess precisely the effects, beneficial and harmful.


  1. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, Solimano A, Vincer M, Wright LL Trial of Indomethacin Prophylaxis in Preterms Investigators. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001;344(26):1966-72
  2. Supapannachart-S, Khowsathit-P, Patchakpati-B Indomethacin prophylaxis for patent ductus arteriosus (PDA) in infants with a birth weight of less than 1250 grams J Med Assoc Thai 1999; 82 Suppl 1: S87-92
  3. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants (Cochrane Review). In : The Cochrane Library, Issue 1, 2004.