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Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort analysis
YJPSU-59651; No of Pages 4 Journal of Pediatric Surgery xxx (xxxx) xxx
Contents lists available at ScienceDirect
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Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort analysis☆ Sam M. Han a, Charles R. Hong a, Jamie Knell a, Erika M. Edwards b, Kate A. Morrow c, Roger F. Soll b, Biren P. Modi a, Jeffrey D. Horbar b, Tom Jaksic a,⁎ a b c
Department of Surgery and Center for Advanced Intestinal Rehabilitation, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA University of Vermont and Vermont Oxford Network, Burlington, VT, USA Vermont Oxford Network, Burlington, VT, USA
a r t i c l e
i n f o
Article history: Received 4 February 2020 Accepted 20 February 2020 Available online xxxx Key words: Necrotizing enterocolitis Prematurity Infant NICU Primary peritoneal drainage
a b s t r a c t Objective: We sought to describe changes in the incidence and mortality of necrotizing enterocolitis (NEC) and associated surgical management strategies for very low birth weight (VLBW) infants. Methods: Data were prospectively collected on VLBW infants (≤1500 g or b 29 weeks) born 2006 to 2017 and admitted to 820 U.S. centers. NEC was defined by the presence of at least one clinical and one radiographic finding. Trends analyses were performed to assess changes in incidence and mortality over time. Results: Of 473,895 VLBW infants, 36,130 (7.6%) were diagnosed with NEC, of which 21,051 (58.3%) had medical NEC and 15,079 (41.7%) had surgical NEC. Medical NEC decreased from 5.3% to 3.0% (p b 0.0001). Surgical NEC decreased from 3.4% to 3.1% (p = 0.06). Medical NEC mortality decreased from 20.7% to 16.8% (p = 0.003), while surgical NEC mortality decreased from 36.6% to 31.6% (p b 0.0001). In the surgical cohort, the use of primary peritoneal drainage (PPD) versus initial laparotomy rose from 23.2% to 46.8%. Conclusion: The incidence and mortality of both medical and surgical NEC have decreased over time. Changes in surgical management during this time period included the increased utilization of primary peritoneal drainage. Type of study: Prognosis study. Level of evidence: Level II. © 2020 Elsevier Inc. All rights reserved.
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in preterm infants [1–3]. Lower birth weights are associated with a higher frequency and greater severity of disease [4,5]. Hence, the continued improvement in the overall survival of extremely low birth weight neonates may be hypothesized to result in an increase in NEC frequency and severity [6,7]. Interestingly recent data suggest a contrary trend [8,9]. Factors which may be responsible for this observation include human milk feeding, antenatal corticosteroid use, delayed enteral feeding, and pre- and probiotic administration [10–13]. However, multicenter studies analyzing outcome trends remain sparse and do not differentiate between medical and surgical NEC. We conducted a multicenter cohort study with the primary aim of quantifying the incidence and mortality for medical and surgical NEC over the last 12 years. Changes in surgical management strategies were also analyzed.
☆ Disclosures: None. ⁎ Corresponding author at: Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA 02115, USA. Tel.: +1 617 355 9600; fax: +1 617 730 0477. E-mail address: [email protected] (T. Jaksic).
1. Methods Vermont Oxford Network (VON) is a nonprofit, voluntary worldwide collaboration dedicated to improving the quality, safety and value of neonatal intensive care. Data on VLBW infants of birth weight 401–1500 g or 22 to 29 weeks’ gestational age, born within participating VON member hospitals or transferred to participating centers within 28 days of birth, are prospectively collected. These data are accrued until infants are discharged from the hospital, die, or reach 1 year of age in the hospital. This study was performed as an ongoing partnership between VON and the Boston Children's Hospital Department of Surgery. The Committee on Human Research at the University of Vermont determined that the use of the deidentified VON Research Repository (#15-143) did not constitute human subjects' research, and the Boston Children's Hospital Institutional Review Board (#P00002185) exempted the study based upon the use of deidentified data. 1.1. Study design For this cohort study, data were collected on VLBW infants born from January 1, 2006 to December 31, 2017 in 820 participating
https://doi.org/10.1016/j.jpedsurg.2020.02.046 0022-3468/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046
2
S.M. Han et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
along with mortality rates for infants receiving either initial PPD or laparotomy.
Table 1 Patient characteristics. Medical NEC N (%) / N; median (IQR)
Surgical NEC N (%) / N; median (IQR)
Male Cesarean Delivery Multiple Gestation Antenatal Steroids Small for Gestational Age Gestational Age (weeks)
21,051 (55.6%) 14,637 (69.6%) 21,050 (24.4%) 20,915 (80.8%) 21,047 (14.1%) 21,051; 26 (25, 28)
15,079 (58.9%) 15,075 (68.2%) 15,079 (24.9%) 14,939 (79.9%) 15,070 (11.0%) 15,079; 25 (24, 27)
Birth Weight (g) 401–500 g 501–750 g 751–1000 g 1001–1250 g 1251–1500 g APGAR 1 min APGAR 5 min
21,051 (3.3%) 21,051 (30.8%) 21,051 (29.8%) 21,051 (19.9%) 21,051 (14.4%) 20,849; 5 (3, 7) 20,850; 7 (6, 8)
15,079 (4.9%) 15,079 (42.5%) 15,079 (30.2%) 15,079 (13.4%) 15,079 (7.5%) 14,893; 4 (2, 6) 14,901; 7 (5, 8)
United States VON member centers. Infants diagnosed with medical and surgical NEC were included in the analysis. As per the VON Manual of Operations, NEC was clinically defined by the presence of at least one physical finding (biliary gastric aspirate or emesis, abdominal distention, or occult/gross blood in the stool in the absence of an anal fissure) and at least one radiographic finding (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum) [14]. Surgical NEC was defined by specific procedure codes as per the VON Manual of Operations. Following a diagnosis of NEC, these included the use of primary peritoneal drainage (PPD), laparotomy, intestinal diversion, or bowel resection [14]. The VON Manual of Operations defines spontaneous intestinal perforation (SIP) as a single focal defect without significant bowel pathology seen at the time of laparotomy or postmortem examination. In this report those with SIP were included in the NEC group, consistent with prior VON studies, as NEC and SIP would not be definitively differentiated in patients receiving only PPD. Neonates with a length of stay of 3 or fewer days and those with major congenital anomalies as listed in the VON Manual of Operations (e.g. open spinal dysraphism, major cardiac defects, and chromosomal anomalies) were excluded. The primary outcomes of interest were deemed to be changes in the incidence and mortality of medical and surgical NEC over the 12-year period of data collection. The utilization of PPD and laparotomy for infants with surgical NEC was also monitored over the 12-year period,
1.2. Statistical analysis Data were presented as percentages or median (interquartile range) where applicable. Trend analyses were conducted using logistic regression to examine yearly changes in NEC incidence and mortality over time. Statistical models adjusted for year of birth, SGA, birth weight, and clustering of infants within hospitals. Trends over the 12-year period in the incidence of medical and surgical NEC, and mortality in these groups, were reported as P values testing the trend from 2006 to 2017. All analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Cary, NC). 2. Results Of 473,895 VLBW infants studied during the 12-year period, 36,130 (7.6%) were diagnosed with NEC during their hospitalization. Surgical NEC was identified in 15,079 (41.7%) of those neonates. Patient characteristics are shown in Table 1. There was a higher preponderance of males with both medical (55.5%) and surgical NEC (58.9%) when compared to VLBW infants without NEC (49.8%). Medical NEC had a higher percentage of patients weighing b1001 g (63.9%) when compared to those without NEC (37.9%). Surgical NEC had an even greater rate of extremely low birth weight infants weighing b 1001 g (77.6%) when compared to both groups. The change in incidence for medical and surgical NEC is depicted in Fig. 1. The overall incidence was determined to be 7.6% over the 12year period; however, both medical and surgical NEC incidence decreased over time. For medical NEC, the incidence fell from 5.3% in 2006 to 3.0% in 2017 (p b 0.001). The incidence of surgical NEC decreased from 3.4% in 2006 to 3.1% in 2017 (p = 0.06). Infants with both medical and surgical NEC had significantly higher overall mortality rates when compared to VLBW neonates without NEC (Table 2). Those with surgical NEC had a mortality rate of 34.9% compared to 20.3% in infants with medical NEC and 4.8% in those without NEC. Trend analyses indicated significant decreases in mortality for both medical (p = 0.003) and surgical NEC (p b 0.0001) from 2006 to 2017 (Fig. 2). Mortality decreased from 20.7% in 2006 to 16.8% in 2017 among infants with medical NEC, and from 36.6% in 2006 to 31.6% in 2017 for neonates with surgical NEC.
Fig. 1. Incidence of medical and surgical NEC over time. The rate of medical NEC (gray) fell from 5.3% in 2006 down to 3.0% in 2017 with year over year trends analyses demonstrating a decreasing incidence over time (p b 0.0001). The incidence of surgical NEC (black) decreased from 3.4% in 2006 to 3.1% in 2017 (p = 0.06).
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046
S.M. Han et al. / Journal of Pediatric Surgery xxx (xxxx) xxx Table 2 Patient outcomes.
Mortality Length of Stay (days)
No NEC N (%) / N; median (IQR)
Medical NEC N (%) / N; median (IQR)
Surgical NEC N (%) /N; median (IQR)
436,442 (4.8%) 415,136; 59 (41, 84)
20,885 (20.3%) 16,601; 92 (67, 122)
14,991 (34.9%) 9742; 128 (102, 165)
The median birth weight and gestational age for VLBW infants with medical and surgical NEC for each of the 12 years were compared to infants without NEC. For medical NEC, the median birth weight decreased from 910 g in 2006 to 860 g in 2017. A similar decrease in birth weight was seen in the surgical NEC population, from 790 g in 2006 to 735 g in 2017. The median birth weight for VLBW infants without NEC, however, remained similar: 1120 g in 2006 and 1126 in 2017. The median gestational age appeared consistent for all three groups during the study
3
period: 28–29 weeks for infants without NEC, 26–27 weeks for medical NEC, and 25–26 weeks for surgical NEC. Surgical NEC patients were divided into infants receiving PPD and those who underwent laparotomy. Those receiving both PPD and laparotomy were included in the PPD group. Rates of PPD utilization more than doubled from 23.2% in 2006 to 47.3% in 2017. Those receiving only laparotomy fell from 49.7% in 2006 to 40.0% in 2017 as depicted in Fig. 3. Mortality rates among infants with surgical NEC were assessed based on treatment modality (Table 3). Data revealed a near congruent decrease in mortality for both the PPD group and the laparotomy group. Mortality in VLBW infants receiving PPD dropped from 46.5% in 2006 to 35.2% in 2017, while mortality in those undergoing laparotomy decreased from 40.0% in 2006 to 31.7% in 2017. 3. Discussion This study of 473,895 VLBW neonates demonstrates that the overall incidence of NEC fell from 9% in 2006 to 6% in 2017. Year over year trend
Fig. 2. Mortality in VLBW infants with medical NEC and surgical NEC over time. Medical NEC (gray) mortality declined from 20.6% in 2006 to 16.5% in 2017, while surgical NEC (black) mortality fell from 36.4% in 2006 to 31.3% in 2017. Trends analyses revealed a significant decrease in both medical (p = 0.003) and surgical NEC (p b 0.0001) over time.
Fig. 3. Change in Primary Peritoneal Drainage (PPD) versus Laparotomy over time. PPD utilization (gray) increased from 23.2% in 2006 to 46.8% in 2017, while laparotomy only (black) declined from 49.7% in 2006 to 40.0% in 2017.
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046
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S.M. Han et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
Table 3 Mortality rate (%) among infants with surgical NEC based on treatment modality.
Any PPD Laparotomy
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
46.5 40.0
50.8 39.9
47.2 39.5
44.0 38.0
40.3 34.6
43.7 32.0
34.6 31.2
36.7 33.8
31.6 34.3
37.2 30.6
34.2 36.9
35.2 31.7
analyses (Fig. 1) show decreases in medical NEC (p b 0.0001) and surgical NEC (p = 0.06) incidence. In 2010, a review from the National Institute of Child Health and Human Development Neonatal Research Network Data found the incidence of NEC in VLBW infants to be stable at 10% [6,15]. However, a more recent study of 58,555 VLBW infants conducted by the Pediatrix Medical Group paralleled our overall findings [16]. It showed a decline in NEC incidence from 7% to 4% over a seven-year period ending in 2013. Unfortunately, no previous investigations that report the separate incidences of medical and surgical NEC over time are available for comparison. The current analysis (Fig. 2) reveals a 4.1% (20.6 to 16.5% [p = 0.003]) and 5.1% (36.4 to 31.3% [p b 0.0001]) decrease in the all-cause mortality of medical and surgical NEC, respectively. Over the study period the median birth weight for VLBW infants with medical and surgical NEC also decreased. This suggests that the effective reduction in NEC mortality may be even more pronounced than reflected by our data. Reported mortality rates for infants with NEC vary widely, ranging from 10 to 40% [1,6,17]. A prior multicenter VON investigation showed the mortality of VLBW infants with NEC to be 28% in neonates born between 2005 and 2006 [4]. In a subsequent larger VON study, analyzing data from 2006 to 2010, surgical NEC mortality was 35% compared to 21% for medical NEC [5]. Recent large United States cohort studies examining NEC trends over time have largely focused on incidence rather than mortality. A Swedish study, however, examining data from 1987 to 2009, described a significant reduction in NEC mortality over that interval [18]. Although it is important to stress that no causative links can be made based upon our study design, changes in medical and nutritional management have transpired over the timeframe of the data collection. These included the increased utilization of antenatal steroids and more frequent administration of human milk [6,8,10,13]. A systematic review of 10 randomized control trials determined that treatment with antenatal corticosteroids was associated with a reduction in NEC [RR 0.50 (95% CI: 0.32, 0.78)] [13]. It has also been established that formula fed infants have a greater risk of NEC [RR 1.87 (95% CI: 1.23, 2.85)] even when compared to donor human milk [10]. Human milk feeding was one of the key drivers identified by the Pediatrix 100,000 Babies Campaign that may have contributed to the observed decrease in NEC incidence following a quality improvement initiative [19]. The proportion of surgical NEC patients receiving initial PPD doubled (23.2% to 47.3%) over the 12 years of the current study (Fig. 3). The reasons why this occurred cannot be elucidated based upon our data. Interestingly, mortality rates in the PPD and laparotomy groups decreased in an almost parallel fashion over the study period (Table 3). One possible explanation for this observation is that factors other than the actual selection of initial surgical therapy were the important drivers for reducing the overall surgical NEC mortality. The use of a prospectively collected, very large neonatal database remains a key strength; however, there are significant study limitations to consider. Hospital participation in the database is voluntary, and despite capturing a substantial percentage of all VLBW neonates born in the United States, this is not a true population-based study. Further
cause and effect relationships between changes in management and outcomes measures cannot be determined based upon our data. The reasons management decisions were made were not recorded; hence, any imputed associations require confirmation with specifically designed studies. 4. Conclusions In this large, 12-year analysis of very low birth weight neonates born in the United States, there was a significant reduction in the incidence of NEC over time. The mortality of infants with medical NEC and surgical NEC also declined over the period of investigation. While the use of primary peritoneal drainage (PPD) became proportionately more frequent over time, it is of note that the mortality rates of the primary peritoneal drainage and laparotomy groups both declined substantially. Further studies seeking to confirm and explain these salutary findings are required. References [1] Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364(3):255–64. [2] Robinson JR, Rellinger EJ, Hatch LD, et al. Surgical necrotizing enterocolitis. Semin Perinatol 2017;41(1):70–9. https://doi.org/10.1053/j.semperi.2016.09.020. [3] Henry MC, Lawrence Moss R. Surgical therapy for necrotizing enterocolitis: bringing evidence to the bedside. Semin Pediatr Surg 2005;14:181–90. [4] Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009 Jun;44(6):1072–5. [5] Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg 2014;218(6):1148–55. [6] Knell J, Han SM, Jaksic T, et al. Current status of necrotizing enterocolitis. Curr Probl Surg 2019 Jan;56(1):11–38. [7] Frost BL, Modi BP, Jaksic T, et al. New medical and surgical insights into neonatal necrotizing enterocolitis: a review. JAMA Pediatr 2017 Jan 1;171(1):83–8. [8] Stoll BJ, Hansen NI, Bell EF, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 2015;314(10):1039–51. [9] Horbar JD, Edwards EM, Greenberg LT, et al. Variation in performance of neonatal intensive care units in the United States. JAMA Pediatr 2017 Mar 6;171(3): e164396. [10] Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2019 Jul 19;7: CD002971. [11] Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2017;8(8):CD001241. [12] Grev J, Berg M, Soll R. Maternal probiotic supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2018 Dec 12;12: CD012519. [13] Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017 Mar 21;3:CD004454. [14] Vermont Oxford Network. Manual of operations: part 2 data definitions and infant data forms, version 19. Burlington, VT; 2015. [15] Patel RM, Kandefer S, Walsh MC, et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med 2015;372(4):331–40. [16] Ellsbury DL, Clark RH, Ursprung R, et al. A multifaceted approach to improving outcomes in the NICU: the pediatrix 100 000 babies campaign. Pediatrics 2016;137(4). [17] Lin HC, Wu SF, Underwood M. Necrotizing enterocolitis. N Engl J Med 2011;364: 1878–9. [18] Ahle M, Drott P, Andersson RE. Epidemiology and trends of necrotizing enterocolitis in Sweden: 1987–2009. Pediatrics 2013 Aug;132(2):e443–51. [19] Talavera MM, Bixler G, Cozzi C, et al. Quality improvement initiative to reduce the necrotizing enterocolitis rate in premature infants. Pediatrics 2016 May;137(5) pii: e20151119.
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort analysis☆ Sam M. Han a, Charles R. Hong a, Jamie Knell a, Erika M. Edwards b, Kate A. Morrow c, Roger F. Soll b, Biren P. Modi a, Jeffrey D. Horbar b, Tom Jaksic a,⁎ a b c
Department of Surgery and Center for Advanced Intestinal Rehabilitation, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA University of Vermont and Vermont Oxford Network, Burlington, VT, USA Vermont Oxford Network, Burlington, VT, USA
a r t i c l e
i n f o
Article history: Received 4 February 2020 Accepted 20 February 2020 Available online xxxx Key words: Necrotizing enterocolitis Prematurity Infant NICU Primary peritoneal drainage
a b s t r a c t Objective: We sought to describe changes in the incidence and mortality of necrotizing enterocolitis (NEC) and associated surgical management strategies for very low birth weight (VLBW) infants. Methods: Data were prospectively collected on VLBW infants (≤1500 g or b 29 weeks) born 2006 to 2017 and admitted to 820 U.S. centers. NEC was defined by the presence of at least one clinical and one radiographic finding. Trends analyses were performed to assess changes in incidence and mortality over time. Results: Of 473,895 VLBW infants, 36,130 (7.6%) were diagnosed with NEC, of which 21,051 (58.3%) had medical NEC and 15,079 (41.7%) had surgical NEC. Medical NEC decreased from 5.3% to 3.0% (p b 0.0001). Surgical NEC decreased from 3.4% to 3.1% (p = 0.06). Medical NEC mortality decreased from 20.7% to 16.8% (p = 0.003), while surgical NEC mortality decreased from 36.6% to 31.6% (p b 0.0001). In the surgical cohort, the use of primary peritoneal drainage (PPD) versus initial laparotomy rose from 23.2% to 46.8%. Conclusion: The incidence and mortality of both medical and surgical NEC have decreased over time. Changes in surgical management during this time period included the increased utilization of primary peritoneal drainage. Type of study: Prognosis study. Level of evidence: Level II. © 2020 Elsevier Inc. All rights reserved.
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in preterm infants [1–3]. Lower birth weights are associated with a higher frequency and greater severity of disease [4,5]. Hence, the continued improvement in the overall survival of extremely low birth weight neonates may be hypothesized to result in an increase in NEC frequency and severity [6,7]. Interestingly recent data suggest a contrary trend [8,9]. Factors which may be responsible for this observation include human milk feeding, antenatal corticosteroid use, delayed enteral feeding, and pre- and probiotic administration [10–13]. However, multicenter studies analyzing outcome trends remain sparse and do not differentiate between medical and surgical NEC. We conducted a multicenter cohort study with the primary aim of quantifying the incidence and mortality for medical and surgical NEC over the last 12 years. Changes in surgical management strategies were also analyzed.
☆ Disclosures: None. ⁎ Corresponding author at: Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Fegan 3, Boston, MA 02115, USA. Tel.: +1 617 355 9600; fax: +1 617 730 0477. E-mail address: [email protected] (T. Jaksic).
1. Methods Vermont Oxford Network (VON) is a nonprofit, voluntary worldwide collaboration dedicated to improving the quality, safety and value of neonatal intensive care. Data on VLBW infants of birth weight 401–1500 g or 22 to 29 weeks’ gestational age, born within participating VON member hospitals or transferred to participating centers within 28 days of birth, are prospectively collected. These data are accrued until infants are discharged from the hospital, die, or reach 1 year of age in the hospital. This study was performed as an ongoing partnership between VON and the Boston Children's Hospital Department of Surgery. The Committee on Human Research at the University of Vermont determined that the use of the deidentified VON Research Repository (#15-143) did not constitute human subjects' research, and the Boston Children's Hospital Institutional Review Board (#P00002185) exempted the study based upon the use of deidentified data. 1.1. Study design For this cohort study, data were collected on VLBW infants born from January 1, 2006 to December 31, 2017 in 820 participating
https://doi.org/10.1016/j.jpedsurg.2020.02.046 0022-3468/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046
2
S.M. Han et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
along with mortality rates for infants receiving either initial PPD or laparotomy.
Table 1 Patient characteristics. Medical NEC N (%) / N; median (IQR)
Surgical NEC N (%) / N; median (IQR)
Male Cesarean Delivery Multiple Gestation Antenatal Steroids Small for Gestational Age Gestational Age (weeks)
21,051 (55.6%) 14,637 (69.6%) 21,050 (24.4%) 20,915 (80.8%) 21,047 (14.1%) 21,051; 26 (25, 28)
15,079 (58.9%) 15,075 (68.2%) 15,079 (24.9%) 14,939 (79.9%) 15,070 (11.0%) 15,079; 25 (24, 27)
Birth Weight (g) 401–500 g 501–750 g 751–1000 g 1001–1250 g 1251–1500 g APGAR 1 min APGAR 5 min
21,051 (3.3%) 21,051 (30.8%) 21,051 (29.8%) 21,051 (19.9%) 21,051 (14.4%) 20,849; 5 (3, 7) 20,850; 7 (6, 8)
15,079 (4.9%) 15,079 (42.5%) 15,079 (30.2%) 15,079 (13.4%) 15,079 (7.5%) 14,893; 4 (2, 6) 14,901; 7 (5, 8)
United States VON member centers. Infants diagnosed with medical and surgical NEC were included in the analysis. As per the VON Manual of Operations, NEC was clinically defined by the presence of at least one physical finding (biliary gastric aspirate or emesis, abdominal distention, or occult/gross blood in the stool in the absence of an anal fissure) and at least one radiographic finding (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum) [14]. Surgical NEC was defined by specific procedure codes as per the VON Manual of Operations. Following a diagnosis of NEC, these included the use of primary peritoneal drainage (PPD), laparotomy, intestinal diversion, or bowel resection [14]. The VON Manual of Operations defines spontaneous intestinal perforation (SIP) as a single focal defect without significant bowel pathology seen at the time of laparotomy or postmortem examination. In this report those with SIP were included in the NEC group, consistent with prior VON studies, as NEC and SIP would not be definitively differentiated in patients receiving only PPD. Neonates with a length of stay of 3 or fewer days and those with major congenital anomalies as listed in the VON Manual of Operations (e.g. open spinal dysraphism, major cardiac defects, and chromosomal anomalies) were excluded. The primary outcomes of interest were deemed to be changes in the incidence and mortality of medical and surgical NEC over the 12-year period of data collection. The utilization of PPD and laparotomy for infants with surgical NEC was also monitored over the 12-year period,
1.2. Statistical analysis Data were presented as percentages or median (interquartile range) where applicable. Trend analyses were conducted using logistic regression to examine yearly changes in NEC incidence and mortality over time. Statistical models adjusted for year of birth, SGA, birth weight, and clustering of infants within hospitals. Trends over the 12-year period in the incidence of medical and surgical NEC, and mortality in these groups, were reported as P values testing the trend from 2006 to 2017. All analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Cary, NC). 2. Results Of 473,895 VLBW infants studied during the 12-year period, 36,130 (7.6%) were diagnosed with NEC during their hospitalization. Surgical NEC was identified in 15,079 (41.7%) of those neonates. Patient characteristics are shown in Table 1. There was a higher preponderance of males with both medical (55.5%) and surgical NEC (58.9%) when compared to VLBW infants without NEC (49.8%). Medical NEC had a higher percentage of patients weighing b1001 g (63.9%) when compared to those without NEC (37.9%). Surgical NEC had an even greater rate of extremely low birth weight infants weighing b 1001 g (77.6%) when compared to both groups. The change in incidence for medical and surgical NEC is depicted in Fig. 1. The overall incidence was determined to be 7.6% over the 12year period; however, both medical and surgical NEC incidence decreased over time. For medical NEC, the incidence fell from 5.3% in 2006 to 3.0% in 2017 (p b 0.001). The incidence of surgical NEC decreased from 3.4% in 2006 to 3.1% in 2017 (p = 0.06). Infants with both medical and surgical NEC had significantly higher overall mortality rates when compared to VLBW neonates without NEC (Table 2). Those with surgical NEC had a mortality rate of 34.9% compared to 20.3% in infants with medical NEC and 4.8% in those without NEC. Trend analyses indicated significant decreases in mortality for both medical (p = 0.003) and surgical NEC (p b 0.0001) from 2006 to 2017 (Fig. 2). Mortality decreased from 20.7% in 2006 to 16.8% in 2017 among infants with medical NEC, and from 36.6% in 2006 to 31.6% in 2017 for neonates with surgical NEC.
Fig. 1. Incidence of medical and surgical NEC over time. The rate of medical NEC (gray) fell from 5.3% in 2006 down to 3.0% in 2017 with year over year trends analyses demonstrating a decreasing incidence over time (p b 0.0001). The incidence of surgical NEC (black) decreased from 3.4% in 2006 to 3.1% in 2017 (p = 0.06).
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046
S.M. Han et al. / Journal of Pediatric Surgery xxx (xxxx) xxx Table 2 Patient outcomes.
Mortality Length of Stay (days)
No NEC N (%) / N; median (IQR)
Medical NEC N (%) / N; median (IQR)
Surgical NEC N (%) /N; median (IQR)
436,442 (4.8%) 415,136; 59 (41, 84)
20,885 (20.3%) 16,601; 92 (67, 122)
14,991 (34.9%) 9742; 128 (102, 165)
The median birth weight and gestational age for VLBW infants with medical and surgical NEC for each of the 12 years were compared to infants without NEC. For medical NEC, the median birth weight decreased from 910 g in 2006 to 860 g in 2017. A similar decrease in birth weight was seen in the surgical NEC population, from 790 g in 2006 to 735 g in 2017. The median birth weight for VLBW infants without NEC, however, remained similar: 1120 g in 2006 and 1126 in 2017. The median gestational age appeared consistent for all three groups during the study
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period: 28–29 weeks for infants without NEC, 26–27 weeks for medical NEC, and 25–26 weeks for surgical NEC. Surgical NEC patients were divided into infants receiving PPD and those who underwent laparotomy. Those receiving both PPD and laparotomy were included in the PPD group. Rates of PPD utilization more than doubled from 23.2% in 2006 to 47.3% in 2017. Those receiving only laparotomy fell from 49.7% in 2006 to 40.0% in 2017 as depicted in Fig. 3. Mortality rates among infants with surgical NEC were assessed based on treatment modality (Table 3). Data revealed a near congruent decrease in mortality for both the PPD group and the laparotomy group. Mortality in VLBW infants receiving PPD dropped from 46.5% in 2006 to 35.2% in 2017, while mortality in those undergoing laparotomy decreased from 40.0% in 2006 to 31.7% in 2017. 3. Discussion This study of 473,895 VLBW neonates demonstrates that the overall incidence of NEC fell from 9% in 2006 to 6% in 2017. Year over year trend
Fig. 2. Mortality in VLBW infants with medical NEC and surgical NEC over time. Medical NEC (gray) mortality declined from 20.6% in 2006 to 16.5% in 2017, while surgical NEC (black) mortality fell from 36.4% in 2006 to 31.3% in 2017. Trends analyses revealed a significant decrease in both medical (p = 0.003) and surgical NEC (p b 0.0001) over time.
Fig. 3. Change in Primary Peritoneal Drainage (PPD) versus Laparotomy over time. PPD utilization (gray) increased from 23.2% in 2006 to 46.8% in 2017, while laparotomy only (black) declined from 49.7% in 2006 to 40.0% in 2017.
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046
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S.M. Han et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
Table 3 Mortality rate (%) among infants with surgical NEC based on treatment modality.
Any PPD Laparotomy
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
46.5 40.0
50.8 39.9
47.2 39.5
44.0 38.0
40.3 34.6
43.7 32.0
34.6 31.2
36.7 33.8
31.6 34.3
37.2 30.6
34.2 36.9
35.2 31.7
analyses (Fig. 1) show decreases in medical NEC (p b 0.0001) and surgical NEC (p = 0.06) incidence. In 2010, a review from the National Institute of Child Health and Human Development Neonatal Research Network Data found the incidence of NEC in VLBW infants to be stable at 10% [6,15]. However, a more recent study of 58,555 VLBW infants conducted by the Pediatrix Medical Group paralleled our overall findings [16]. It showed a decline in NEC incidence from 7% to 4% over a seven-year period ending in 2013. Unfortunately, no previous investigations that report the separate incidences of medical and surgical NEC over time are available for comparison. The current analysis (Fig. 2) reveals a 4.1% (20.6 to 16.5% [p = 0.003]) and 5.1% (36.4 to 31.3% [p b 0.0001]) decrease in the all-cause mortality of medical and surgical NEC, respectively. Over the study period the median birth weight for VLBW infants with medical and surgical NEC also decreased. This suggests that the effective reduction in NEC mortality may be even more pronounced than reflected by our data. Reported mortality rates for infants with NEC vary widely, ranging from 10 to 40% [1,6,17]. A prior multicenter VON investigation showed the mortality of VLBW infants with NEC to be 28% in neonates born between 2005 and 2006 [4]. In a subsequent larger VON study, analyzing data from 2006 to 2010, surgical NEC mortality was 35% compared to 21% for medical NEC [5]. Recent large United States cohort studies examining NEC trends over time have largely focused on incidence rather than mortality. A Swedish study, however, examining data from 1987 to 2009, described a significant reduction in NEC mortality over that interval [18]. Although it is important to stress that no causative links can be made based upon our study design, changes in medical and nutritional management have transpired over the timeframe of the data collection. These included the increased utilization of antenatal steroids and more frequent administration of human milk [6,8,10,13]. A systematic review of 10 randomized control trials determined that treatment with antenatal corticosteroids was associated with a reduction in NEC [RR 0.50 (95% CI: 0.32, 0.78)] [13]. It has also been established that formula fed infants have a greater risk of NEC [RR 1.87 (95% CI: 1.23, 2.85)] even when compared to donor human milk [10]. Human milk feeding was one of the key drivers identified by the Pediatrix 100,000 Babies Campaign that may have contributed to the observed decrease in NEC incidence following a quality improvement initiative [19]. The proportion of surgical NEC patients receiving initial PPD doubled (23.2% to 47.3%) over the 12 years of the current study (Fig. 3). The reasons why this occurred cannot be elucidated based upon our data. Interestingly, mortality rates in the PPD and laparotomy groups decreased in an almost parallel fashion over the study period (Table 3). One possible explanation for this observation is that factors other than the actual selection of initial surgical therapy were the important drivers for reducing the overall surgical NEC mortality. The use of a prospectively collected, very large neonatal database remains a key strength; however, there are significant study limitations to consider. Hospital participation in the database is voluntary, and despite capturing a substantial percentage of all VLBW neonates born in the United States, this is not a true population-based study. Further
cause and effect relationships between changes in management and outcomes measures cannot be determined based upon our data. The reasons management decisions were made were not recorded; hence, any imputed associations require confirmation with specifically designed studies. 4. Conclusions In this large, 12-year analysis of very low birth weight neonates born in the United States, there was a significant reduction in the incidence of NEC over time. The mortality of infants with medical NEC and surgical NEC also declined over the period of investigation. While the use of primary peritoneal drainage (PPD) became proportionately more frequent over time, it is of note that the mortality rates of the primary peritoneal drainage and laparotomy groups both declined substantially. Further studies seeking to confirm and explain these salutary findings are required. References [1] Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364(3):255–64. [2] Robinson JR, Rellinger EJ, Hatch LD, et al. Surgical necrotizing enterocolitis. Semin Perinatol 2017;41(1):70–9. https://doi.org/10.1053/j.semperi.2016.09.020. [3] Henry MC, Lawrence Moss R. Surgical therapy for necrotizing enterocolitis: bringing evidence to the bedside. Semin Pediatr Surg 2005;14:181–90. [4] Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009 Jun;44(6):1072–5. [5] Hull MA, Fisher JG, Gutierrez IM, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg 2014;218(6):1148–55. [6] Knell J, Han SM, Jaksic T, et al. Current status of necrotizing enterocolitis. Curr Probl Surg 2019 Jan;56(1):11–38. [7] Frost BL, Modi BP, Jaksic T, et al. New medical and surgical insights into neonatal necrotizing enterocolitis: a review. JAMA Pediatr 2017 Jan 1;171(1):83–8. [8] Stoll BJ, Hansen NI, Bell EF, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 2015;314(10):1039–51. [9] Horbar JD, Edwards EM, Greenberg LT, et al. Variation in performance of neonatal intensive care units in the United States. JAMA Pediatr 2017 Mar 6;171(3): e164396. [10] Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2019 Jul 19;7: CD002971. [11] Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2017;8(8):CD001241. [12] Grev J, Berg M, Soll R. Maternal probiotic supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2018 Dec 12;12: CD012519. [13] Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017 Mar 21;3:CD004454. [14] Vermont Oxford Network. Manual of operations: part 2 data definitions and infant data forms, version 19. Burlington, VT; 2015. [15] Patel RM, Kandefer S, Walsh MC, et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med 2015;372(4):331–40. [16] Ellsbury DL, Clark RH, Ursprung R, et al. A multifaceted approach to improving outcomes in the NICU: the pediatrix 100 000 babies campaign. Pediatrics 2016;137(4). [17] Lin HC, Wu SF, Underwood M. Necrotizing enterocolitis. N Engl J Med 2011;364: 1878–9. [18] Ahle M, Drott P, Andersson RE. Epidemiology and trends of necrotizing enterocolitis in Sweden: 1987–2009. Pediatrics 2013 Aug;132(2):e443–51. [19] Talavera MM, Bixler G, Cozzi C, et al. Quality improvement initiative to reduce the necrotizing enterocolitis rate in premature infants. Pediatrics 2016 May;137(5) pii: e20151119.
Please cite this article as: S.M. Han, C.R. Hong, J. Knell, et al., Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: A multicenter cohort ana..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2020.02.046