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Antenatal indomethacin is more likely associated with spontaneous intestinal perforation rather than NEC
Letters to the Editors
www. AJOG.org
Antenatal indomethacin is more likely associated with spontaneous intestinal perforation rather than NEC TO THE EDITORS: The manuscript by Amin et al1 represents an excellent use of the metanalysis of observational studies in epidemiology (MOOSE) consensus strategy. We congratulate them on their systematic approach to a challenging topic. They were also thorough in addressing the limitations and strengths of their data. However, they may have overlooked a caveat that strengthens their speculation that the intestinal disease acquired by recent antenatal indomethacin (AI)– exposed infants is that of spontaneous intestinal perforation (SIP) rather than necrotizing enterocolitis (NEC).1 All recent AI exposure studies were performed from 1993 to 2003, a period when SIP was not widely recognized as distinct from NEC. These same studies were within the postsurfactant era and should have been reasonably homogeneous. However, they were not uniform in their mean birthweights. We stratified these same 5 studies by birthweights of the indomethacin-exposed cohort and displayed the individual odds ratios and confidence intervals for each (Figure 1). What is evident is that the 2 studies with the smallest birthweights drive the summary finding. Recent data from a national database demonstrate that SIP occurs predominantly in lower birthweights (less than 1000 g), whereas NEC occurs over a much larger birthweight range.2 Thus, based on the birthweight data we have available to us, SIP seems more likely associated with recent AI exposure. There are other reasons to believe that this would be true. Indomethacin has also been demonstrated to be associated with SIP in the early postnatal period2 and is known to increase the risk of SIP further when given in combination with early postnatal steroids.3 Most recently, a mouse model of the harmful synergism between indomethacin and steroids has been published,4 demonstrating that the 2 agents together diminish all 3 forms of intestinal nitric oxide synthetase, making the neonatal mouse ileum vulnerable to perforation in part through perturbations of motility (rather than ischemia, as is often believed).
Most of the risk factors associated with SIP have been postnatal, but this list includes elevated cortisol levels associated with chorioamnionitis.3 Thus, at least 1 postnatal risk factor starts in utero. AI could be another such risk factor, particularly in extremely premature infants whose mothers have chorioamnionitis. Obviously, we need better data, but the study by Amin et al1 should give us pause. f Phillip V. Gordon, MD, PhD Department of Pediatrics Ochsner Health System New Orleans, LA Jonathan R. Swanson, MD Department of Pediatrics University of Virginia Charlottesville, VA [email protected] Reese Clark, MD Pediatrix Medical Group, Inc Greenville, SC REFERENCES 1. Amin SB, Sinkin RA, Glantz JC. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol 2007;197: 486.e1-10. 2. 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;26:93-9. 3. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: A multicenter trial. Pediatrics 2004;114:1649-57. 4. Gordon PV, Herman AC, Marcinkiewicz 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;45:509-19. © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.01.026
REPLY
FIGURE 1
Odds ratio for AI vs NEC stratified by birthweight 1250 Abbassi et al. n = 136
1150 Birth Weight 1050 (mean)
Vermillion et al. n = 225
Souter et al. n = 65 Norton et al. n = 114
950 850
Major et al. n = 723
Random Effects Odds Ratio
750
0
1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 Odds Ratio
We thank Dr Philip Gordon et al1 for their letter in response to our recent paper, “Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes,” and appreciate their insight regarding the association between lower birthweight and spontaneous intestinal perforation (SIP).2 We concur that the 2 studies with infants of the smallest birthweights drive the summary findings of the association of necrotizing enterocolitis after recent exposure to antenatal indomethacin.1 We also agree with the authors’ comments regarding the increase risk of SIP following postnatal indomethacin exposure in combination with early postnatal steroids.3 Although these associations strengthen the speculation that the intestinal disJUNE 2008 American Journal of Obstetrics & Gynecology
725
www. AJOG.org
Antenatal indomethacin is more likely associated with spontaneous intestinal perforation rather than NEC TO THE EDITORS: The manuscript by Amin et al1 represents an excellent use of the metanalysis of observational studies in epidemiology (MOOSE) consensus strategy. We congratulate them on their systematic approach to a challenging topic. They were also thorough in addressing the limitations and strengths of their data. However, they may have overlooked a caveat that strengthens their speculation that the intestinal disease acquired by recent antenatal indomethacin (AI)– exposed infants is that of spontaneous intestinal perforation (SIP) rather than necrotizing enterocolitis (NEC).1 All recent AI exposure studies were performed from 1993 to 2003, a period when SIP was not widely recognized as distinct from NEC. These same studies were within the postsurfactant era and should have been reasonably homogeneous. However, they were not uniform in their mean birthweights. We stratified these same 5 studies by birthweights of the indomethacin-exposed cohort and displayed the individual odds ratios and confidence intervals for each (Figure 1). What is evident is that the 2 studies with the smallest birthweights drive the summary finding. Recent data from a national database demonstrate that SIP occurs predominantly in lower birthweights (less than 1000 g), whereas NEC occurs over a much larger birthweight range.2 Thus, based on the birthweight data we have available to us, SIP seems more likely associated with recent AI exposure. There are other reasons to believe that this would be true. Indomethacin has also been demonstrated to be associated with SIP in the early postnatal period2 and is known to increase the risk of SIP further when given in combination with early postnatal steroids.3 Most recently, a mouse model of the harmful synergism between indomethacin and steroids has been published,4 demonstrating that the 2 agents together diminish all 3 forms of intestinal nitric oxide synthetase, making the neonatal mouse ileum vulnerable to perforation in part through perturbations of motility (rather than ischemia, as is often believed).
Most of the risk factors associated with SIP have been postnatal, but this list includes elevated cortisol levels associated with chorioamnionitis.3 Thus, at least 1 postnatal risk factor starts in utero. AI could be another such risk factor, particularly in extremely premature infants whose mothers have chorioamnionitis. Obviously, we need better data, but the study by Amin et al1 should give us pause. f Phillip V. Gordon, MD, PhD Department of Pediatrics Ochsner Health System New Orleans, LA Jonathan R. Swanson, MD Department of Pediatrics University of Virginia Charlottesville, VA [email protected] Reese Clark, MD Pediatrix Medical Group, Inc Greenville, SC REFERENCES 1. Amin SB, Sinkin RA, Glantz JC. Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol 2007;197: 486.e1-10. 2. 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;26:93-9. 3. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: A multicenter trial. Pediatrics 2004;114:1649-57. 4. Gordon PV, Herman AC, Marcinkiewicz 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;45:509-19. © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.01.026
REPLY
FIGURE 1
Odds ratio for AI vs NEC stratified by birthweight 1250 Abbassi et al. n = 136
1150 Birth Weight 1050 (mean)
Vermillion et al. n = 225
Souter et al. n = 65 Norton et al. n = 114
950 850
Major et al. n = 723
Random Effects Odds Ratio
750
0
1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 Odds Ratio
We thank Dr Philip Gordon et al1 for their letter in response to our recent paper, “Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes,” and appreciate their insight regarding the association between lower birthweight and spontaneous intestinal perforation (SIP).2 We concur that the 2 studies with infants of the smallest birthweights drive the summary findings of the association of necrotizing enterocolitis after recent exposure to antenatal indomethacin.1 We also agree with the authors’ comments regarding the increase risk of SIP following postnatal indomethacin exposure in combination with early postnatal steroids.3 Although these associations strengthen the speculation that the intestinal disJUNE 2008 American Journal of Obstetrics & Gynecology
725