University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• Twin A born at 30 wks. weighs 1450 gms. and requires supplemental O2 via nasal cannula. Twin B weighs 1250 gms. and is intubated shortly after birth for respiratory distress. What is the evidence to support the use of prophylactic intravenous indomethacin for the prevention of intraventricular hemorrhage?

Clinical Bottom Lines

1. IV indomethacin (0.2 mg/kg times one within 12 hrs. of birth, followed by 9.1 mg/kg every 12 hrs. times 2) decreases the incidence (P<.002) of Grade 2-4 intraventricular hemorrhages in oxygen requiring premature infants weighing between 500 and 1300 gms.  The NNT to prevent one hemorrhage is 5.
2. Oliguria was a statistically significant side effect of indomethacin administration but it was transient in nature.  There was also a trend toward an increased incidence of ROP (>stage 3) in infants weighing 900-1300 gms. who received indomethacin prophylaxis.
3. Mortality was unaffected and long-term neurodevelopmental outcome data was still being collected at the time of publication.

Summary of Key Evidence

1. 199 premature infants with at least some oxygen requirement and weighing less than or equal to 1300 gms. were randomized to receive either IV indomethacin or placebo.  Exclusion criteria included terminal conditions, prestudy Grade 2-4 IVH, major congenital malformations or infection, and hemostatic abnormalities.
2. Patients had a cranial ultrasound prior to randomization, daily for the first three days, weekly for the first two weeks, and then at least every two weeks until there was resolution or stabilization of the bleed.  The radiologist was blinded to the patient's study assignment.
3. 46% of the placebo arm had final IVH grade between 2-4 as compared to only 23% in the indomethacin group (P<.02).  The impact was most pronounced for Grade 2 IVH but the indomethacin group did also have fewer Grade 3-4 hemorrhages (in terms of absolute numbers).
4. The reduction in risk for Grade 2-4 IVH was seen in both the 500-899 gms. and the 900-1300 gms. groups (P<.05).
5. 10 out of 14 of the placebo group who started with Grade 1 IVH subsequently extended to Grade 2-4.  6 out of 14 of the indomethacin group extended.
6. Oliguria (defined as urine output <1ml/kg/hr) was noted in 40 of the indomethacin treated patients compared with 20 placebo treated patients (P,.001).  15% of the indomethacin group weighing 900-1300 had ROP >or =to stage 3 as opposed to 3% of the placebo group (P<.07).

Additional Comments

• Indomethacin is thought to exert its protective effect by attenuating the prostaglandin mediated cerebral vasodilatation in response to hypoxia, hypercarbia, and blood pressure fluctuations.  It is also postulated that indomethacin may decrease the production of tissue damaging free radicals.
• Previous studies have shown a statistically significant decrease in serum prostaglandins after administration of indomethacin to neonates 600-1250 gms.
• Other potential side effects of indomethacin include: increase in serum creatinine, decreased plasma sodium, and interference with platelet aggregation.

Citation

1. Ment et al. Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants. Journal of Pediatrics Dec 1985 pgs. 937-942.
2. Bada et al. Indomethacin reduces the risk of severe intraventricular hemorrhage. Journal of Pediatrics Oct 1989 pgs.631-636.
3. Donn et al. The Michigan Manual  1997  pgs. 131-135.

CAT Author: Brett Hofmann, MD

CAT Appraisers: <Reviewers>, MD

Date appraised: December 7, 1998