Association of Intrapartum Drugs with Spontaneous Intestinal Perforation: A Single-Center Retrospective Review

Abstract

Objective Spontaneous intestinal perforation (SIP) occurs commonly in extremely low gestational age newborns (ELGANs; <30 weeks' GA). Early, concurrent neonatal use of indomethacin (Neo_IN) and hydrocortisone (Neo_HC) is a known risk for SIP. Mothers in premature labor often receive indomethacin (Mat_IN) for tocolysis and steroids (Mat_S) for fetal maturation. Coincidentally, ELGANs may receive Neo_IN or Neo_HC within the first week of life. There are limited data on the effect of combined exposures to maternal and neonatal medications. We hypothesized that proximity exposure to these medications may increase the risk of SIP.

Study Design We reviewed the medical records of ELGANs from June 2014 to December 2019 at a single level III neonatal intensive care unit. We compared antenatal and postnatal indomethacin and steroid use between neonates with and without SIP. For analysis, chi-square, Student's t-test, Fisher's exact test, and Mann–Whitney U tests were used.

Results Among 417 ELGANs, SIP was diagnosed in 23, predominantly in neonates < 26 weeks' GA (n = 21/126, 16.7%). Risk factors analysis focused on this GA cohort in which SIP was most prevalent. Mat_IN administration within 2 days of delivery increased SIP risk (odds ratio: 3; 95% confidence interval: 1.25–7.94; p = 0.036). Neo_HC was not independently associated with SIP (p = 0.38). A higher proportion of SIP group had close temporal exposure of Mat_IN and Neo_HC compared with the non-SIP group, though not statistically significant (14 vs. 7%, p = 0.24).

Conclusion Peripartum Mat_IN was associated with increased risk for SIP in this small study sample. Larger studies are needed to further delineate SIP risk from the interaction of peripartum maternal medication with early postnatal therapies and disease pathophysiology.

Key Points

• Perinatal indomethacin is associated with SIP in preterm infants born at less than 26 weeks.

• Temporal proximity of prenatal/postnatal medication exposure matters.

• Indomethacin and Hydrocortisone the risks, benefits, and timing related to SIP.

Keywords

extremely low birth weight - spontaneous intestinal perforation - indomethacin - hydrocortisone - betamethasone - magnesium - neonate

Authors' Contribution

No outside honorarium, grant, or other forms of payment was provided to anyone to produce the manuscript. Drs. Mantle, Yang, Chan, and Yoder contributed to the conception and design of the study, data collection and analysis, and manuscript preparation; Dr. Judkins contributed to conception and design as well as manuscript review. Ms. Chanthavong contributed to data collection. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Ethical Approval

The University of Utah institutional review board approved this study with a waiver of parental consent. Trained research staff abstracted the required maternal and neonatal data via electronic medical records. Information was stored on a dual encrypted, password-protected database for analysis.

Publication History

Received: 06 August 2020

Accepted: 06 October 2021

Accepted Manuscript online:
19 October 2021

Article published online:
28 November 2021

• References

• 1 Fisher JG, Jones BA, Gutierrez IM. et al. Mortality associated with laparotomy-confirmed neonatal spontaneous intestinal perforation: a prospective 5-year multicenter analysis. J Pediatr Surg 2014; 49 (08) 1215-1219
• 2 Vongbhavit K, Underwood MA. Intestinal perforation in the premature infant. J Neonatal Perinatal Med 2017; 10 (03) 281-289
• 3 Durell J, Hall NJ, Drewett M, Paramanantham K, Burge D. Emergency laparotomy in infants born at <26 weeks gestation: a neonatal network-based cohort study of frequency, surgical pathology and outcomes. Arch Dis Child Fetal Neonatal Ed 2017; 102 (06) F504-F507
• 4 Rattray BN, Kraus DM, Drinker LR, Goldberg RN, Tanaka DT, Cotten CM. Antenatal magnesium sulfate and spontaneous intestinal perforation in infants less than 25 weeks gestation. J Perinatol 2014; 34 (11) 819-822
• 5 Gordon PV, Swanson JR, Clark R. Antenatal indomethacin is more likely associated with spontaneous intestinal perforation rather than NEC. Am J Obstet Gynecol 2008; 198 (06) 725 , author reply 725–726
• 6 Sood BG, Lulic-Botica M, Holzhausen KA. et al. The risk of necrotizing enterocolitis after indomethacin tocolysis. Pediatrics 2011; 128 (01) e54-e62
• 7 Rovers JFJ, Thomissen IJC, Janssen LCE. et al. The relationship between antenatal indomethacin as a tocolytic drug and neonatal outcomes: a retrospective cohort study. J Matern Fetal Neonatal Med 2021; 34 (18) 2945-2951
• 8 Norton ME, Merrill J, Cooper BA, Kuller JA, Clyman RI. Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 1993; 329 (22) 1602-1607
• 9 Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Am J Obstet Gynecol 2015; 212 (04) 505
• 10 Sharma R, Hudak ML, Tepas III JJ. et al. Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis. J Perinatol 2010; 30 (12) 786-793
• 11 Watterberg KL, Gerdes JS, Cole CH. et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004; 114 (06) 1649-1657
• 12 Stavel M, Wong J, Cieslak Z, Sherlock R, Claveau M, Shah PS. Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants. J Perinatol 2017; 37 (02) 188-193
• 13 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J Perinatol 2006; 26 (02) 93-99
• 14 Gordon PV, Herman AC, Marcinkiewicz M, Gaston BM, Laubach VE, Aschner JL. A neonatal mouse model of intestinal perforation: investigating the harmful synergism between glucocorticoids and indomethacin. J Pediatr Gastroenterol Nutr 2007; 45 (05) 509-519
• 15 Blakely ML, Lally KP, McDonald S. et al; NEC Subcommittee of the NICHD Neonatal Research Network. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005; 241 (06) 984-989 , discussion 989–994
• 16 Hwang H, Murphy JJ, Gow KW, Magee JF, Bekhit E, Jamieson D. Are localized intestinal perforations distinct from necrotizing enterocolitis?. J Pediatr Surg 2003; 38 (05) 763-767
• 17 Kelleher J, Salas AA, Bhat R. et al; GDB Subcommittee, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Prophylactic indomethacin and intestinal perforation in extremely low birth weight infants. Pediatrics 2014; 134 (05) e1369-e1377
• 18 Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009; 113 (03) 585-594
• 19 Shah J, Singhal N, da Silva O. et al; Canadian Neonatal Network. Intestinal perforation in very preterm neonates: risk factors and outcomes. J Perinatol 2015; 35 (08) 595-600
• 20 Moss TJ, Doherty DA, Nitsos I, Harding R, Newnham JP. Pharmacokinetics of betamethasone after maternal or fetal intramuscular administration. Am J Obstet Gynecol 2003; 189 (06) 1751-1757
• 21 Tsatsaris V, Cabrol D, Carbonne B. Pharmacokinetics of tocolytic agents. Clin Pharmacokinet 2004; 43 (13) 833-844
• 22 Reinebrant HE, Pileggi-Castro C, Romero CL. et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2015; (06) CD001992
• 23 Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing the neonatal safety of indomethacin tocolysis: a systematic review with meta-analysis. Obstet Gynecol 2005; 106 (01) 173-179
• 24 Carlin A, Norman J, Cole S, Smith R. Tocolytics and preterm labour. BMJ 2009; 338: b195
• 25 Amin SB, Sinkin RA, Glantz JC. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol 2007; 197 (05) 486
• 26 Attridge JT, Clark R, Gordon PV. New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with spontaneous intestinal perforation. J Perinatol 2006; 26 (11) 667-670
• 27 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol 2006; 26 (03) 185-188
• 28 Wadhawan R, Oh W, Vohr BR. et al. Spontaneous intestinal perforation in extremely low birth weight infants: association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age. Arch Dis Child Fetal Neonatal Ed 2013; 98 (02) F127-F132
• 29 Lichtenberger LM, Bhattarai D, Phan TM, Dial EJ, Uray K. Suppression of contractile activity in the small intestine by indomethacin and omeprazole. Am J Physiol Gastrointest Liver Physiol 2015; 308 (09) G785-G793
• 30 Morris IP, Goel N, Chakraborty M. Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis. Eur J Pediatr 2019; 178 (08) 1171-1184
• 31 Paquette L, Friedlich P, Ramanathan R, Seri I. Concurrent use of indomethacin and dexamethasone increases the risk of spontaneous intestinal perforation in very low birth weight neonates. J Perinatol 2006; 26 (08) 486-492
• 32 Stark AR, Carlo WA, Tyson JE. et al; National Institute of Child Health and Human Development Neonatal Research Network. Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. N Engl J Med 2001; 344 (02) 95-101