Understanding Clinical Literature Relevant to Spontaneous Intestinal Perforations

Spontaneous intestinal perforation (SIP) has emerged as a disease of extremely low-birth-weight (ELBW) infants over the last two decades. Several risk factors have been associated with this disease including early postnatal steroids (EPS; use within the first week of life), early use of indomethacin (EUI; use within the first 3 postnatal days), and the synergistic combination of the two. These two risk factors are thought to play a causal role in the etiology of SIP through their effects on ileal trophism and motility. Two infectious agents (Candida and Staphylococcus epidermidis) are commonly grown from peritoneal cultures of patients with SIP. It is less clear whether these infections play a causal role or if they represent comorbitities of perforation. Chorioamnionitis is thought to be a risk factor for SIP, as is the stress and elevated cortisol that accompanies it. Recent analyses suggest that antenatal indomethacin may also be a risk factor for SIP, particularly when given close to birth. These latter variables are more challenging to rank in importance compared with EPS and EUI, which have been repeatedly associated with SIP in both retrospective cohorts and randomized controlled trials. Because neonatal care of the ELBW infant is commonly standardized, the habitual combination of any of these risk factors potentially amplifies the risk of SIP. Many of these factors are medicines, thus SIP risk is exacerbated by select forms of polypharmacy. Our challenge lies in understanding how these drug interactions lead to harm.