Neonatal Necrotizing Enterocolitis With Intestinal Perforation in Extremely Premature Infants Receiving Early Indomethacin Treatment for Patent Ductus Arteriosus

Abstract

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). 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. 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%. 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.

Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis

“…Hence, in both our and in Pumberger's study, postnatal dexamethasone did not confound the risk of IIP. Contrary to our findings, Fujii et al 6 reported an increased incidence of NEC and NEC-associated perforation in infants treated with indomethacin for intraventricular hemorrhage prophylaxis compared with infants who received indomethacin later for PDA closure. None of these infants were reported to have developed IIP.…”

“…9,10 Before 1996, postnatal indomethacin administration at our center was used only to treat PDA, 7 but subsequently its use increased following reports that administration of indomethacin to very low birth weight infants within 6 to 12 h after birth was associated with a reduced rate of severe intraventricular hemorrhage. 9,10 With increased frequency and early use of indomethacin several reports linking indomethacin exposure to IIP 6,[11][12][13] and/or to NEC 6,14 emerged. Most of these retrospective studies did not carefully differentiate between IIP and NEC nor did they assess the relationship between prenatal indomethacin exposure and neonatal gut injury.…”

“…1,2 Indomethacin exposure has been implicated as one of the risk factors for neonatal gut-injury in very low birth weight infants. [3][4][5][6] Exposure to indomethacin can occur prenatally [3][4][5] and/or postnatally. 6,7 Indomethacin is used for tocolysis and acts via inhibition of prostaglandin synthetase.…”

“…[3][4][5][6] Exposure to indomethacin can occur prenatally [3][4][5] and/or postnatally. 6,7 Indomethacin is used for tocolysis and acts via inhibition of prostaglandin synthetase. 8 Postnatally, indomethacin has been used to effect closure of a patent ductus arteriosus (PDA) 7 or to prevent severe intraventricular hemorrhage in very low birth weight infants.…”

Indomethacin prophylaxis or expectant treatment of patent ductus arteriosus in extremely low birth weight infants?

“…8,9,20 In our study, NEC with and without intestinal perforation occurred with a low frequency similar to that reported by Schmidt et al 5 for indomethacin prophylaxis and placebo group. Spontaneous intestinal perforation, now recognized as a clinical entity distinct from NEC, is strongly associated with early postnatal indomethacin exposure.…”