Jo-Anna B. Hudson ¹ wardha shabbir ² Lamia Hayawi ³ Monica Lik Man Chan ⁴ Nicholas Barrowman ³ Lindsey Sikora ⁵ Emanuela Ferretti ^4,6*

• ¹ Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
• ² Department of Family Medicine, College of Human Medicine, Michigan State University, East Lansing, Michigan, United States
• ³ CHEO Research Institute, University of Ottawa, Ottawa, Ontario, Canada
• ⁴ Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
• ⁵ University of Ottawa, Ottawa, Ontario, Canada
• ⁶ Children's Hospital of Eastern Ontario (CHEO), Ottawa, Ontario, Canada

Acquired spontaneous intestinal perforation or SIP occurs most commonly in the extreme premature infant population. As the incidence is rising, understanding modifiable factors such as common medication exposures become important for individualizing care.The primary outcome was SIP in premature infants with exposure to indomethacin, ibuprofen or acetaminophen. The systematic review and meta-analysis were conducted following the Cochrane methodology and PRISMA guidelines.While the point estimates from all three RCTs showed an increase in the risk of SIP with indomethacin exposure compared to no medication, the pooled estimate was not statistically significant. There is no statistically significant association for the risk of SIP for indomethacin with treatment use over prophylactic use and when holding feeds. Ibuprofen conferred less risk than indomethacin and its route of administration did not alter the risk profile. There was not enough evidence to draw conclusions about risk of SIP and acetaminophen exposure.In studies of infants exposed to either Indomethacin or Ibuprofen in the last 40 years, the incidence of SIP is still commonly within 2-8 %. Moving forward modifiable factors like medication exposure will help guide care to minimize risk where possible.