Necrotizing enterocolitis in extremely low birth weight infants and associated risk factors: a retrospective analysis

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality in infants with extremely low birth weight (ELBW).

Objective: to determine the risk factors of NEC in ELBW infants.

Material and methods. A retrospective case-control study conducted at the neonatal intensive care unit of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation in the period from 2017 to 2019. 71 preterm infants were enrolled. The newborns were divided into 2 groups: group 1 (infants with NEC) – NEC group (n=26), and group 2 (infants without NEC) – no-NEC group (n=45). The clinical characteristics of both groups were evaluated. Logistic regression analyses were conducted to assess the risk factors of NEC in ELBW infants.

Results. There were statistically significant differences in abnormal antenatal umbilical artery flow (AAUF) frequency. It was defined as the absence or reversed end of the diastolic velocity obtained from the umbilical artery. In the 1st group – 6 (23.1%) cases, and in the 2nd group – 4 (8.9) (p=0.039). The frequency of birth of infants small for gestational age (OR 1.1, 95% CI 0.84–75.93) and patent ductus arteriosus (OR 3.3, 95% CI 0.73–15.31) did not differ significantly between NEC and no-NEC groups. The mortality (OR 23.3, 95% CI 2.74–198.08) and acute renal injury (AKI) (OR 9.5, 95% CI 1.85–49.47) were higher in the NEC group compared to the no-NEC group. There were statistically significant differences in the frequency of anemia and multiple red blood cells (RBC) transfusions between the 1st group and the 2nd group (p<0.05). Multiple RBC transfusions were more common in the NEC group. Colonization of the gut by the association of Malassezia furfur and Gram-negative bacteria was more common in the NEC group (OR 6.5, 95% CI 1.20–34.82). Meanwhile, breastfeeding was the protective factor for NEC in ELBW infants (OR 0.322, 95% CI 0.113–0.917).

Conclusion. The incidence of NEC in ELBW is high. It is affected by many antenatal and postnatal factors (AAUF, severe anemia, gut colonization with M. furfur, and Gram-negative bacteria). Breastfeeding significantly reduces the risk of NEC in ELBW infants.

Keywords:necrotizing enterocolitis; anemia; RBC transfusions; premature newborns; extremely low birth weight; acute kidney injury; Malassezia furfur

Funding. The study had no sponsor support.

Conflict of interest. The authors declare no conflict of interest.

For citation: Ionov O.V., Sharafutdinova D.R., Balashova E.N., Kirtbaya A.R., Kosterina E.E., Shakaya M.N., Bezlepkina M.B., Ryndin A.Yu., Priputnevich T.V., Bembeeva B.O., Dorofeeva E.I., Zubkov V.V., Degtyarev D.N. Necrotizing enterocolitis in extremely low birth weight infants and associated risk factors: a retrospective analysis. Neonatologiya: novosti, mneniya, obuchenie [Neonatology: News, Opinions, Training]. 2023; 11 (1): 28–41. DOI: https://doi.org/10.33029/2308-2402-2023-11-1-28-41 (in Russian)

Received 23.12.2022. Accepted 06.02.2023.

REFERENCES

1. Xiong T., Maheshwari A., Neu J., Ei-Saie A., Pammi M. An overview of systematic reviews of randomized-controlled trials for preventing necrotizing enterocolitis in preterm infants. Neonatology. 2020. 117 (1): 46–56. DOI: https://doi.org/10.1159/000504371

2.Meister A.L., Doheny K.K., Travagli R.A. Necrotizing enterocolitis: it’s not all in the gut. Exp Biol Med. 2020; 245 (2): 85–95. DOI: https://doi.org/10.1177/1535370219891971

3. Isayama T., Lee S.K., Mori R., Kusuda S., Fujimura M., Ye X.Y., et al. Comparison of mortality and morbidity of very low birth weight infants between Canada and Japan. Pediatrics. 2012. 130 (4): e957–65. DOI: https://doi.org/10.1542/peds.2012-0336

4.Ahle M., Drott P., Andersson R.E. Epidemiology and trends of necrotizing enterocolitis in Sweden: 1987–2009. Pediatrics. 2013; 132 (4): e443–51. DOI: https://doi.org/10.1542/peds.2012-3847

5.Patel R.M., Kandefer S., Walsh M.C., Bell E.F., Carlo W.A., Laptook A.R., et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med. 2015; 372: 331–40. DOI: https://doi.org/10.1056/NEJMoa1403489

6.Shulhan J., Dicken B., Hartling L., Larsen B.M. Current knowledge of necrotizing enterocolitis in preterm infants and the impact of different types of enteral nutrition products. Adv Nutr An Int Rev J. 2017. 8 (1): 80–91. DOI: https://doi.org/10.3945/an.116.013193

7.Jin Y.T., Duan Y., Deng X.K., Lin J. Prevention of necrotizing enterocolitis in premature infants - an updated review. World J Clin Pediatr. 2019. 8 (2): 23–32. DOI: https://doi.org/10.5409/wjcp.v8.i2.23

8.Jones I.H., Hall N.J. Contemporary outcomes for infants with necrotizing enterocolitis-a systematic review. J Pediatr. 2020. 220: 86–92.e3. DOI: 10.1016/j.jpeds.2019.11.011

9.Han S.M., Knell J., Henry O., Riley H., Hong C.R., Staffa S.J., et al. Long-term outcomes of severe surgical necrotizing enterocolitis. J Pediatr Surg. 2020; 55 (5): 848–51. DOI: https://doi.org/10.1016/j.jpedsurg.2020.01.019

10.Matei A., Montalva L., Goodbaum A., Lauriti G., Zani A. Neurodevelopmental impairment in necrotising enterocolitis survivors: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2020. 105 (4): 432–9.

11.Hau E.M., Meyer S.C., Berger S., Goutaki M., Kordasz M., Kessler U. Gastrointestinal sequelae after surgery for necrotising enterocolitis: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2019. 104 (3): 265–73.

12.Campos-Martinez A.M., Expósito-Herrera J., Gonzalez-Bolívar M., Fernández-Marin E., Uberos J. Evaluation of risk and preventive factors for necrotizing enterocolitis in premature newborns. A systematic review of the literature. Front Pediatr. 2022; 17; 10: 874976.

13.Wang F.S., Yu M.L., Li W.Z., Hong K., Bin X., Wang G.H. Intestinal tract and parenteral multi-organ sequential pathological injury caused by necrotizing enterocolitis. BMC Pediatr. 2020; 20 (1): 418.

14.Bell M.J., Ternberg J.L., Feigin R.D., Keating J.P., Marshall R., Barton L., et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg. 1978; 187: 1–7.

15.Intergrowth-21st translated resources – charts and tables. https://intergrowth21.tghn.org/translated-resources.

16.Patent: Selective nutrient medium for isolation of fungi of the Malassezia furfur species. Patent holders: Priputnevich T.V., Avners V.Y., Sukhikh G.T., Goldberg S.A. 2021. (in Russian)

17.Clinical recommendations. Invasive candidiasis in newborns. 2017. Electronic resource. https://neonatology.pro/wp-content/uploads/2018/02/klinrec_candidiasis_newborns_2017.pdf

18.Clinical recommendations. Congenital pneumonia. Moscow, 2017. Electronic resource. https://neonatology.pro/wp-content/uploads/2019/12/protokol_congenital_pneumonia_2017.pdf

19.Grosheva E.V., Degtyareva A.V., Ionov O.V., Lenyushkina A.A., Narogan M.V., Ryumina I.I. Clinical recommendations. Enteral feeding of premature infants. Moscow, 2015. (in Russian)

20.Moss R.L., Kalish L.A., Duggan C., et al. Clinical parameters do not adequately predict outcome in necrotizing enterocolitis: a multi-institutional study. J Perinatol. 2008; 28 (10): 665–74.

21.Been J.V., Lievense S., Zimmermann L.J., Kramer B.W., Wolfs T.G. Chorioamnionitis as a risk factor for necrotizing enterocolitis: a systematic review and meta-analysis. J Pediatr. 2013; 162 (2): 236–42.e2.

22.Duci M., Frigo A.C., Visentin S., Verlato G., Gamba P., Fascetti-Leon F. Maternal and placental risk factors associated with the development of necrotizing enterocolitis (NEC) and its severity. J Pediatr Surg. 2019; 54 (10): 2099–102.

23.Martini S., Annunziata M., Della Gatta A.N., Aceti A., Brunetti M., Pilu G., et al. Association between abnormal antenatal doppler characteristics and gastrointestinal outcomes in preterm infants. Nutrients. 2022; 14 (23), 5121.

24.Perger L., Mukhopadhyay D., Komidar L., et al. Maternal pre-eclampsia as a risk factor for necrotizing enterocolitis. J Matern Fetal Neonatal Med. 2016; 29 (13): 2098–103.

25.Huang Y., Zhang L., Sun H., Liu C., Yang Y., Lee S.K., et al. Neonatal outcome of small for gestational age infants born at 26–33 weeks’ gestation in Chinese neonatal intensive care units. Transl Pediatr. 2021; 10 (4): 754–64.

26.Nikitina I.V., Donnikov A.E., Krogh-Jensen O.A., Krasheninnikova R.V., Nepsha O.S., Lenyushkina A.A., Degtyarev D.N. Genetic predictors of necrotizing enterocolitis in neonates. Akusherstvo i ginekologiya [Obstetrics and Gynegology]. 2020; 12: 150–8. DOI: https://dx.doi.org/10.18565/aig.2020.12.150-158 (in Russian)

27.Tan X, Zhou Y, Xu L, Zhang L, Wang J, Yang W. The predictors of necrotizing enterocolitis in newborns with low birth weight: A retrospective analysis. Medicine (Baltimore). 2022;101(7):e28789. doi:10.1097/MD.0000000000028789

28.Garg P.M., Paschal J.L., Ansari M., Block D., Inagaki K., Weitkamp J.H. Clinical impact of NEC-associated sepsis on outcomes in preterm infants. Pediatr Res. 2022. Epub ahead of print. PMID: 35352003.

29.Bowker R.M., Yan X., De Plaen I.G. Intestinal microcirculation and necrotizing enterocolitis: the vascular endothelial growth factor system. Semin Fetal Neonatal Med. 2018; 23 (6): 411–5.

30.Pammi M, De Plaen IG, Maheshwari A. Recent Advances in Necrotizing Enterocolitis Research: Strategies for Implementation in Clinical Practice. Clin Perinatol. 2020; 47 (2): 383–97.

31.Sabnis A., Carrasco R., Liu S.X., et al. Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis. Neonatology. 2015; 107 (3): 191–8.

32.MohanKumar K., Namachivayam K., Song T., et al. A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions. Nat Commun. 2019; 10 (1): 3494.

33.Lee J.H. An update on necrotizing enterocolitis: pathogenesis and preventive strategies. Korean J Pediatr. 2011; 54: 368–72.

34.Nikitina I., Donnikov A., Krogh-Jensen O., Krasheninnikovа R., Lenyushkina A. Necrotizing enterocolitis in neonates: early genetic markers. 4th Congress of Joint European Neonatal Societies: Nutrition. Pediatr Res. 2021. 90: 29–30.

35.Whyte R., Kirpalani H. Low versus high haemoglobin concentration threshold for blood transfusion for preventing morbidity and mortality in very low birth weight infants. Cochrane Database Syst Rev. 2011; (11): CD000512.

36.Hay S., Zupancic J.A.F., Flannery D.D., Kirpalani H., Dukhovny D. Should we believe in transfusion-associated enterocolitis? Applying a GRADE to the literature. Semin Perinatol. 2017; 41 (1): 80–91.

37.Rai S.E., Sidhu A.K., Krishnan R.J. Transfusion-associated necrotizing enterocolitis re-evaluated: a systematic review and meta-analysis. J Perinat Med. 2018; 46 (6): 665–76. DOI: 10.1515/jpm-2017-0048

38.Patel R.M., Knezevic A., Shenvi N., et al. Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very low-birth-weight infants. JAMA. 2016; 315 (9): 889–97.

39.Neu J., Pammi M. Pathogenesis of NEC: Impact of an altered intestinal microbiome. Semin Perinatol. 2017; 41 (1): 2935. DOI: https://doi.org/10.1053/j.semperi.2016.09.015

40.Fu X., Li S., Jiang Y., Hu X., Wu H. Necrotizing enterocolitis and intestinal microbiota: The timing of disease and combined effects of multiple species. Front Pediatr. 2021; 9: 657349.

41.Li Y., Jia C., Lin X., Lin L., Li L., Fan X., et al. The diversity of the intestinal flora disturbed after feeding intolerance recovery in preterm twins. Front Pediatr. 2021; 9: 648979.

42.Carson R., Monaghan-Nichols A.P., DeFranco D.B., Rudine A.C. Effects of antenatal glucocorticoids on the developing brain. Steroids. 2016; 114: 25–32.

43.Battarbee A.N., Ros S.T., Esplin M.S., Biggio J., Bukowski R., Parry S., et al. Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes. Am J Obstet Gynecol MFM. 2020; 2 (1): 100077.

44.Wong D., Abdel-Latif M., Kent A., NICUS Network. Antenatal steroid exposure and outcomes of very premature infants: a regional cohort study. Arch Dis Child Fetal Neonatal Ed. 2014; 99 (1): F12–20.

45.Roberts D., Brown J., Medley N., Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (Review). Cochrane Database Syst Rev. 2017; 1 (3): 1–273.

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CHIEF EDITOR
CHIEF EDITOR
Degtyarev Dmitriy Nikolaevich
Doctor of Medical Sciences, Professor, Deputy Director for Scientific Research of the V.I. Kulakov Obstetrics, Gynecology and Perinatology National Medical Research Center of Ministry of Healthсаre of the Russian Federation, Head of the Chair of Neonatology at the Clinical Institute of Children's Health named after N.F. Filatov, I.M. Sechenov First Moscow State Medical University, Chairman of the Ethics Committee of the Russian Society of Neonatologists, Moscow, Russian Federation

ORCID iD 0000-0001-8975-2425

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