The protocol for this systematic review was registered in the International Prospective Register of systematic Reviews (PROSPERO) database. This systematic review was conduc-ted and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20].

All authors independently searched the databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Scholar, Scopus, and Web of Science, from inception to May, 2020. Details of search words and search results are given in Web Table I. The references of full text articles were checked for possible inclusion as additional articles.

Data extraction and quality assessment: After removing duplicates, individual study details were extracted in a pre-designed format by two authors (PS, MS) indepen-dently, including author, year of publication, geographic location, study period, research design, sample size (calculated and analysed total and in each group), inclusion and exclusion criteria, procedure details, characteristics of participants, including mean gestation, birth weight, gender, thick/thin meconium, definitions and incidences of outcomes. Any disagree-ment related to collated data was resolved by the third author (SB).

Quality of studies was assessed independently by all authors using Cochrane Collaborations Risk of Bias tool [22] based on the domains: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective outcome reporting; other bias. Any disagreement was resolved by mutual discussion.

Out of the initial database search of 374 articles and 3 additional articles through manual search, 12 articles were retrieved, after screening titles, abstracts and removing duplicates. Of these, 9 studies, including 3668 neonates [5-13], met our inclusion criteria and were subjected to meta-analysis (Fig.1). The characteristics of the studies included in this review are summarized in Web Table I. Seven trials were conducted in India [5,7-10,12,13], and two were conducted in Saudi Arabia [6] and Nepal [11]. Two studies were quasi-randomized [6,10], while the rest were RCTs. The study population was homogenous across the studies. All studies included vigorous late-preterm and term neonates born through MSAF, who did not develop respiratory distress at birth.

Fig. 1 PRISMA flow diagram.

The definition of feeding intolerance varied across the studies. While five studies [5,7,10-12] defined feeding intolerance as vomiting, abdominal distension, and increased gastric residuals, two studies [6,9] considered vomiting and retching and one study took vomiting and abdominal distension as a signs of feeding intolerance [13]. Singh, et al. did not mention the criteria of feeding intolerance in their trial [8]. Very slow feeding/poor suck was considered a component of feeding intolerance in the study of Narchi, et al. [6]. Period of observation for feeding intolerance ranged from 48-72 hours [5,7-12] or till discharge [7,9] whereas it was not specified by Narchi, et al. [6] and Yadav, et al. [13].

The procedure of gastric lavage varied across the studies, using feeding tubes of variable sizes, 6 Fr [10-12], 8 Fr [7,9,10,13] or 10 Fr [5] through oral [5,9] or nasal route [7,10-13] and lavage being conducted using 10 mL/kg [5,7,10-13] or 20 mL [9] of normal saline [5,7,9-13] in the aliquots of 5 mL [10] or 10 mL [7,11,12]. Feeding intolerance was the primary outcome in seven studies [6,7,9-13], while proportion of infants developing meconium aspiration syndrome within 72 hours of age [5] and the need for subsequent gastric lavage [8], respectively, were the primary outcomes in the other two studies. Only one study monitored the procedure of gastric lavage using a pulse oximeter [5]. Web Fig. 1A and Web Fig. 1B summarize the quality of the studies. There was no publication bias as per the Funnel plot (Web Fig.2).

The time of establishment of breastfeeding, exclusive breastfeeding rate at discharge, need and duration of respiratory support, as well as complications like feeding tube placement errors and gastric/esophageal perforation were not reported by any of the studies.

The quality of evidence assessed using the GRADE (Web Table III), shows that except for the incidence of feeding intolerance, the effect size of other outcomes was non-estimable due to the small number of occurrences.

In the present systematic review, low-quality evidence from nine RCTs showed that gastric lavage performed immediately after delivery room stabilization before initiation of feeding resulted in a significant reduction in the incidence of feeding intolerance in vigorous late preterm and term neonates born through meconium-stained amniotic fluid. None of the studies reported any adverse events related to gastric lavage and none of the studies looked for feeding tube placement errors and gastric/esophageal perforation.

The studies included in this review had high rates of bias, mainly attributable to lack of allocation conceal-ment, quasi-randomized design [6,10] and absence of blinding of the outcome assessors [5-13]. Seven studies evaluated the adverse effects of gastric lavage in the form of apnea, bradycardia, local trauma or cyanosis and no difference was found between the groups [5,7,9-13]. Narchi, et al. [6] assessed for apnea and local trauma, which was not documented in any study neonate. Though all the studies reported gastric lavage to be a safe procedure, desaturations were not evaluated with pulse oximeters, except in one study [5]. The route of feeding tube placement being non-uniform across studies, it could affect the incidence of adverse effects [25]. Gastric aspiration with feeding tube placement has been shown to increase the mean arterial blood pressure, retching, disruption of pre-feeding behavior [26], with the development of functional gastrointestinal disorders later in life [27].

None of the studies have mentioned the time of occurrence of vomiting/retching in relation to the procedure or the initiations of feeds. The definition of feeding intolerance was not uniform across the studies. Slow/poor sucking, taken as feeding intolerance, by a study is more suggestive of neurological problems or immaturity. None of the studies have evaluated the effect of the intervention on clinically more relevant outcomes such as time to establish breastfeeding, exclusive breastfeeding rate at discharge, or initiation of immediate skin-to-skin contact in the delivery room.

Gastric lavage can potentially affect the incidence of meconium aspiration syndrome. While on one hand, gastric lavage may prevent meconium aspiration syndrome by clearing meconium from the stomach, thereby preventing subsequent vomiting and aspiration [3]; on the other hand, it may predispose to meconium aspiration syndrome by inducing retching, vomiting and aspiration of gastric content while inserting the feeding tube [28]. The incidence of meconium aspiration syndrome, reported by four studies, was low [5,8,9,13], which could be attributed to the inclusion of only vigorous neonates with neonates at risk for meconium aspiration syndrome, like those with low Apgar scores, respiratory depression requiring resuscitation were excluded.

The limitation of the review was that data for out-comes like meconium aspiration syndrome and adverse events could not be pooled as the reported incidences were nil in most of the studies. Proposed subgroup ana-lyses could not be done due to the lack of data in the included trials. Non-vigorous neonates requiring delivery room resuscitation were excluded by all.

To conclude, low-quality evidence supported the role of gastric lavage for the prevention of feeding intolerance in vigorous late preterm and term neonates born through meconium-stained amniotic fluid. Though the procedure seems to be apparently safe, one should be cautious to recommend this practice as the adverse events related to gastric lavage were not evaluated critically and the effects of this procedure on the routine newborn care practices such as skin-to-skin contact, and breastfeeding rates were lacking. Evidence in non-vigorous neonates, who are more prone for the development of respiratory distress and feeding intolerance, were lacking. Well-designed RCTs with defined outcome variables under strict monitoring for procedure-related complications are needed.

Note: Additional material related to this study is available with the online version at www.indianpediatrics.net

Contributors: PS: conceptualized the review, literature search, data analysis and manuscript writing; MK: literature search, data analysis and manuscript writing; SB: conceptualized the review, literature search, data analysis and manuscript writing.

Funding: None; Competing interest: None stated.

1. Viraraghavan VR, Nangia S, Prathik BH, et al. Yield of meconium in non-vigorous neonates undergoing endotracheal suctioning and profile of all neonates born through meconium-stained amniotic fluid: A prospective observational study. Paediatr Int Child Health. 2018;38:266-70.

2. Chiruvolu A, Miklis KK, Chen E, Petrey B, Desai S. Delivery room management of meconium-stained newborns and respiratory support. Pediatrics. 2018;142:e20181485.

3. Narchi H, Kulaylat N. Feeding problems with the first feed in neonates with meconium-stained amniotic fluid.　Paediatr Child Health. 1999;4:327 30.

4. Deshmukh M, Balasubramanian H, Rao S, Patole S. Effect of gastric lavage on feeding in neonates born through meconium-stained liquor: A systematic review.　Arch Dis Child Fetal Neonatal Ed. 2015;100:F394-9.

5. Gidaganti S, Faridi MM, Narang M, Batra P. Effect of gastric lavage on meconium　aspiration syndrome and feed intolerance in vigorous　infants born with meconium stained amniotic fluid - A　randomized control trial.　Indian Pediatr. 2018;55:206-10.

6. Narchi H, Kulaylat N. Is gastric lavage needed in neonates with meconium-stained amniotic fluid?　Eur J Pediatr. 1999;158:315-7.

7. Ameta G, Upadhyay A, Gothwal S, Singh K, Dubey K, Gupta A. Role of gastric lavage in vigorous neonates born with meconium stained amniotic fluid.　Indian J Pediatr. 2013;80:195 8.

8. Singh KB, Jain R, Babu R, Jyoti J, Singh MK, Parasher I. Role of routine gastric lavage in term and late preterm neonates born through meconium stained amniotic: a randomised control trial. J Evol Med Dent Sci. 2013;2:9868-75.

9. Sharma P, Nangia S, Tiwari S, Goel A, Singla B, Saili A. Gastric lavage for prevention of feeding problems in neonates with meconium-stained amniotic fluid: A randomised controlled trial.　Paediatr Int Child Health. 2014;34:115 9.

10. Garg J, Masand R, Tomar BS. Utility of gastric lavage in vigorous neonates delivered with meconium stained liquor: a randomized controlled trial.　Int J Pediatr. 2014;2014:204807.

11. Shah L, Shah GS, Singh RR, Pokharel H, Mishra OP. Status of gastric lavage in neonates born with meconium stained amniotic fluid: A randomized controlled trial.　Ital J Pediatr. 2015;41:85.

12. Kumar A, Gupta RP, Singh A. Role of gastric lavage in newborn with meconium stained amniotic fluid: A randomized controlled trial. IOSR-JDMS. 2017;16:51-3.

13. Yadav SK, Venkatnarayan K, Adhikari KM, Sinha R, Mathai SS. Gastric lavage in babies born through meconium stained amniotic fluid in prevention of early feed intolerance: A randomized controlled trial.　J Neonatal Perinatal Med. 2018;11:393 7.

14. Hutton EK, Thorpe J. Consequences of meconium stained amniotic fluid: what does the evidence tell us?　Early Hum Dev. 2014;90:333 9.

15. Quandt D, Schraner T, Ulrich Bucher H, ArlettazMieth R. Malposition of feeding tubes in neonates: is it an issue?　J Pediatr Gastroenterol Nutr. 2009;48:608-11.

16. Shiao SY, Youngblut JM, Anderson GC, DiFiore JM, Martin RJ. Nasogastric tube placement: Effects on breathing and sucking in very-low-birth-weight infants.　Nurs Res. 1995;44:82 8.

17. Gasparella M, Schiavon G, Bordignon L, et al. Iatrogenic traumas by nasogastric tube in very premature infants: our cases and literature review.　Pediatr Med Chir. 2011;33:85 8.

18. Maruyama K, Shiojima T, Koizumi T. Sonographic detection of a malpositioned feeding tube causing esophageal perforation in a neonate.　J Clin Ultrasound. 2003;31:108 10.

19. Metheny NA, Meert KL, Clouse RE. Complications related to feeding tube placement.　Curr Op Gastroenterol. 2007;23:178 82.

20. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6:e1000097.

21. Fanaro S. Feeding intolerance in the preterm infant.　Early Hum Dev. 2013;89:S13-20.

22. Higgins JPT, Thomas J, Chandler J, et al, editors. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. Chichester (UK): John Wiley & Sons, 2019.

23. Review Manager (RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020.

24. Schünemann H, Broek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE working group, 2013.

25. Greenspan JS, Wolfson MR, Holt WJ, Shaffer TH. Neonatal gastric intubation: differential respiratory effects between naso-gastric and orogastric tubes. Pediatr Pulmonol. 1990;8:254-8.

26. Widström AM, Ransjö-Arvidson AB, Christensson K, Matthiesen AS, Winberg J, Uvnäs-Moberg K. Gastric suction in healthy newborn infants. Effects on circulation and developing feeding behaviour. Acta Paediatr Scand. 1987;76:566-72.

27. Anand KJ, Runeson B, Jacobson B. Gastric suction at birth associated with long-term risk for functional intestinal disorders in later life. J Pediatr. 2004;144:449-54.

28. Khazardoost S, Hantoushzadeh S, Khooshideh M, Borna S. Risk factors for meconium aspiration in meconium stained amniotic fluid. J Obstet Gynaecol. 2007;27:577-9.