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Three Part Question

[In preterm baby], does [gastric acidity inhibitor ]increases the risk of [necrotising enterocolitis]?

Clinical Scenario

You are a neonatal Registrar and called by the nurse to review a 10 days old preterm baby born at 27weeks gestation for vomiting. Baby is otherwise well in self with normal systemic examination. Baby is receiving expressed breast milk with thickener. You planned to commence the baby on Ranitidine for suspected gastro oesophageal reflux. You wonder whether ranitidine can increase the risk of necrotising enterocolitis (NEC) in this baby.

Search Strategy

The Cochrane Library, MEDLINE (1948 to April 2011) and EMBASE (1947 to 2011).
‘Ranitidine’, ‘cimetidine’, ‘famotidine’, ‘histamine H2 antagonist’, ‘proton pump inhibitor’, ‘omeprazole’, ‘anti ulcer agent’, ‘gastric acid inhibitor’ and ‘necroti#ing enterocolitis’ are the keywords used for the search.

Search Outcome

3 relevant papers identified

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Guillet R, Stoll BJ, Cotton M, et al. 2006 USA	11,072 infants of 401 to 1500gm in birth weight	Retrospective Case Control Study (Level 4)	Incidence of modified Bells stage II or above NEC	H2 Blocker use was associated with an increased incidence of NEC. Odds Ratio OR: 1.71; 95% CI: 1.34-2.19. p < 0.0001.	Information about the type of milk and enteral feeding regimes was not available. No matching done for gestation.
Douglas Drenckpohl, Lisa Knaub, Catherine Schneider etal 2010 USA	324 premature infants of 23 -36 weeks gestation	Retrospective Case Control Study (Level 4)	Incidence of NEC	Parenteral H2 Blocker use was associated with an increased incidence of NEC. Odds Ratio OR:4.46 CI: 1.5-13.29. p = 0.01. Oral H2 Blocker use did not show significant difference.	Retrospective Study. Duration of treatment with H2 Blocker varied.
Carrion V, Egan EA 1990 USA	68 infants of < 1,250gm in birth weight	Prospective double blinded study (Level 3)	Incidence of NEC	Incidence of NEC was significantly lower in the HCL supplemented group. Gram negative enteric bacterial count in gastric aspirates was significantly higher in group with gastric pH > /= 4.5 compared with the group where gastric pH ≤ 4.0.	Non randomised and small study

Comment(s)

There is one retrospective case control study addressing the association of H2 blocker therapy and development of NEC in very low birth weight babies. The controls were matched for birth weight, race and neonatal network centre. Conditional logistic regression method was used to determine the effect H2 blocker use on the incidence of NEC but controlled for gender, site of birth, Apgar score of <7 at 5minutes and post natal steroids. They found that H2 blocker use was associated with an increased incidence of NEC when data collection was truncated by postmenstrual age (Odds ratio: 1.71) or when data collection was truncated by chronological age (Odds ratio: 1.49). There was no information available regarding type of milk (breast milk or formula milk). Data was not analysed controlling for confounding factors like gestational age and intrauterine growth retardation. Douglas etal study was again a retrospective case control study which had 3 controls for each case. Infants were primarily matched by gestational age at birth, birth weight, and, when possible, ethnicity. Significantly more infants who had H2 blockers added to their TPN solution developed NEC than did infants who did not have an H2 blocker added to their TPN solution, 58% versus 21%. Multiple logistic regression method was used and found that parenteral H2 Blocker use increases the risk of developing NEC with p = 0.01. But oral H2 Blocker use did not show any significant difference. Carrion V etal study was a prospective double blinded study in which babies with birth weight < 1,250gm were either receiving HCL or water supplement with the milk. The gastric enteric bacterial count was strongly correlated with gastric pH over 4 (p < 0.001). Incidence of NEC was significantly lower in HCL supplemented group (p< 0.02). But this was a small study with a sample size of only 68 babies. Unfortunately there is no good quality randomised controlled study looking at whether gastric acidity inhibitors increase the risk of NEC in preterm babies.

Clinical Bottom Line

There is some evidence but not strong enough to suggest definite causal relation between the use of gastric acidity inhibitors and NEC in preterm babies. But gastric acid is present for a purpose and caution should be taken before commencing gastric acidity inhibitors in preterm babies. Avoid using them as routine prophylaxis and use only when there is clear clinical indication.

References

1. Guillet R, Stoll BJ, Cotton M, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants Pediatrics 2006;117:e137-e142.
2. Douglas Drenckpohl, Lisa Knaub, Catherine Schneider etal Risk Factors That May Predispose Premature Infants to Increased Incidence of Necrotizing Enterocolitis ICAN: Infant, Child, & Adolescent Nutrition 2010 2: 37
3. Carrion V, Egan EA Prevention of neonatal necrotizing enterocolitis Journal of Pediatric Gastroenterology and Nutrition 1990 Oct;11(3):317-23.