Early Indomethacin and NEC

Neonatal Necrotizing Enterocolitis With Intestinal Perforation in Extremely Premature Infants Receiving Early Indomethacin Treatment for Patent Ductus Arteriosus .
Fujii AM, Brown E, Mirochnick M, et al. Journal of Perinatology (2002) 22, 535-540.

Background: Survival of extremely premature infants (<27 weeks' gestational age) has improved over the past two decades. Indomethacin prophylaxis was used in these infants, who have the highest mortality and morbidity rates, to reduce the incidence of intraventricular hemorrhage and patent ductus arteriosus (PDA).

Methods: Medical records of 65 extremely premature infants born at our institution between 1995 and 2001 were reviewed retrospectively to determine whether treatment of PDA with indomethacin in the first 48 hours of life reduces the need for PDA ligation or increases neonatal morbidity, when compared to treatment begun later.

Results: Thirty infants in the early treatment group (ETG) were treated during the first 48 hours after birth, and 32 infants in the standard treatment group (STG) were managed expectantly for PDA. Three infants died in the first hours of life and were eliminated from further analysis. ETG infants were 24.9±1.1 (mean±SD) weeks' gestation with a birth weight of 678±143 g. STG infants were 25.3±1.1 weeks (NS) and 730±125 g (NS). Hemodynamically significant PDA was diagnosed or confirmed by echocardiography in 19 ETG patients and 17 STG patients. Of the patients with hemodynamically significant PDA, 1 (5%) ETG patient and 6 (35%) STG patients underwent surgical ligation (p=0.033). Necrotizing enterocolitis (NEC) with intestinal perforation was the most serious morbidity and occurred in 20% of infants in the ETG, but in no STG infant (p=0.011).Four of the six infants in the ETG with NEC and intestinal perforation died. The overall mortality rate for all infants studied was 28%.

Conclusions: We conclude that in extremely premature infants, use of indomethacin during the first 48 hours of life was associated with a reduced need for PDA ligation, but an increased risk of NEC with intestinal perforation.

Comment: Please note that the incidence of NEC was no different between the ETG and the STG. This agrees with the findings of the TIPP trial (see 1-042 on our web site). It was only when they looked at NEC with GI perforation that the early treatment group was at increased risk. These results differed from a previous report by Schmidt et al (NEJM 2001; 44:1966) which found no increase in NEC or NEC with perforation with early indomethacin treatment. In the present study, half of the babies in the ETG who had GI perforations were also treated with early high-dose postnatal corticosteroids. We know from other reports that early dexamethasone treatment in VLBW premature infants is also associated with GI perforations (see 2-036 and 2-030 on our web site). It is likely that the early postnatal steroid treatment is at least partly responsible for the increase in GI perforations seen in ETG in this study. It is also possible that the combination of early postnatal steroids and early indomethacin in these infants is especially risky for GI perforations. Another alternative is the use of IV ibuprofen for early PDA treatment. This drug has been shown to have fewer problems with NEC and renal side effects than indomethacin (see 1-018).

Date:        27 Oct 2002
Time:        08:30:59

I think your last remark re. Ibuprofen "This drug has been shown to have fewer problems with NEC and renal side effects than indomethacin" - is not well established yet and much more research is needed to prove its safety.

UserName:    Yoram A Bental
Institution: Sanz Medical Center, Laniado Hospital
telephone:   972-9-8604650
email:       yabental@laniado.org.il

Date: 11 Jul 2005
Time: 09:16:14

Currently, we are conducting a controled prospective randomised trial including 200 extreme low birth weight infant (100 in each arm)to assess the benifits and outcome of using oral ibuprofen in treatment od PDA. We will publish the intial data once we achieved 50% of the patients recruitmints.
Dr Husam salama
Women Hospital. Doha. Qatar

UserName: Dr husam salama
Institution: Hamad Medical corporation. Doha, Qatar
telephone: 0974-4678552
email: hus3038@yahoo.com

We have seen GI perforation that may be associated with early indomethacin, but it is probably not NEC. There is not extensive intestinal involvement, but rather a discrete area with perforation. These infants do not tend to be as sick as those with NEC with perforation. They usually had not been fed. It is really a different phenomena than NEC with perforation.

UserName: David J. Burchfield, MD
Institution: University of Florida
telephone: 352-392-4195
email: burchdj@peds.ufl.edu

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