Researchers have published new evidence on the safety and efficacy of various pharmacological interventions for the prevention and treatment of upper gastrointestinal (GI) bleeding in infants. At present, there are no guidelines that specifically address upper GI bleeding in newborns. Findings were published in a recent issue of Cochrane Database of Systematic Reviews.

Background

Upper GI bleeding is typically a mild, self-limiting condition which affects approximately 20% of newborns admitted to neonatal intensive care units. Reported causes of GI bleeding in newborns include deficiency in vitamin K, allergy to cow’s milk proteins, coagulation disorders, sepsis, stress-related gastritis, and trauma from nasogastric tube placement. GI bleeding in newborns can be especially severe when associated with other underlying comorbidities. Yet, a bleeding associated mortality rate as an outcome of newborns with upper GI bleeding has not been reported.


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Upper GI bleeding in adults is typically treated using acid suppression agents. H2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), antacids, and mucosal protective agents are the pharmacological interventions commonly used to treat conditions associated with upper GI bleeding. However, current recommendations for the prevention and treatment of upper GI bleeding in newborns are based on those used for adults   because evidence-based recommendations supporting similar benefits for newborns are not readily available.

Objective

Researchers assessed how various pharmacological interventions currently used in adults to prevent and treat upper GI bleeding to reduce morbidity and mortality compared with placebo, no treatment, supportive therapy, or each other when used to prevent and treat this same condition in newborns.

Methods

Researchers studied randomized controlled trials (RCTs), quasi-RCTs and cluster-RCTs, and included all preterm and term infants with, or at risk of, upper GI bleeding. Criteria and standard methods of Cochrane and Cochrane Neonatal were used, and researchers searched for and reviewed full-text studies published on PubMed, as well as unpublished studies. A total of 388 records were screened, and 11 studies with 818 newborns met the criteria for inclusion in this review.

Types of Interventions Studied

Researchers analyzed the following comparisons.

A) Comparisons between drug classes:

1. PPIs vs H2RAs

2. PPIs vs antacids

3. PPIs vs bismuth

4. PPIs vs sucralfate

5. PPIs vs placebo, no treatment or supportive therapy

6. H2RAs vs antacids

7. H2RAs vs bismuth

8. H2RAs vs sucralfate

9. H2RAs vs placebo, no treatment, or supportive therapy

10. Antacids vs bismuth

11. Antacids vs sucralfate

12. Antacids vs placebo, no treatment, or supportive therapy

13. Bismuth vs sucralfate

14. Bismuth vs placebo, no treatment, or supportive therapy

15. Sucralfate vs placebo, no treatment, or supportive therapy

B) Comparisons between specific drugs of different classes:

1. Specific H2RAs vs specific PPIs

2. Specific antacids vs specific PPIs

3. Bismuth vs specific PPIs

4. Sucralfate vs specific PPIs

5. Specific antacid vs specific H2RAs

6. Bismuth vs specific H2RAs

7. Sucralfate vs specific H2RAs

8. Specific antacids vs bismuth

9. Specific antacids vs sucralfate

10. Bismuth vs sucralfate

C) Comparisons between specific drugs within a drug class:

1. Specific H2RAs vs specific H2RAs

2. Specific PPIs vs specific PPIs

3. Specific antacids vs specific antacids

D) Comparisons of combinations of specific drugs:

1. H2RAs plus 1 or more of the following: antacids, sucralfate, or bismuth salts vs PPIs

2. H2RAs plus 1 or more of the following: antacids, sucralfate, or bismuth salts vs placebo, no treatment, or supportive therapy

3. PPIs plus 1 or more of the following: antacids, sucralfate, or bismuth salts vs H2RAs

4. PPIs plus 1 or more of the following: antacids, sucralfate, or bismuth salts vs placebo, no treatment, or supportive therapy

Primary and Secondary Outcomes

There were 3 primary outcomes: all-cause mortality to near-term age or discharge, any upper GI bleeding in newborns at risk for upper GI bleeding, and number of days of upper GI bleeding in newborns with this condition.

There were 20 secondary outcomes, including detection of gastric lesions, all-cause infant mortality, anemia requiring blood transfusion, volume of blood transfused for treatment of upper GI bleeding, and number of blood transfusions for treatment of upper GI bleeding.

Interventions

There were 4 trials in which infants at high risk for GI bleeding were enrolled with the goal of prevention. All 4 studies compared an H2RA vs no treatment. The first study compared cimetidine 5 mg/kg/day for 5 days vs no treatment; the second study compared ranitidine 5 mg/kg/day intravenously divided into 3 doses for 4 days vs no treatment; the third study compared cimetidine 5 mg/kg/dose intravenously 2 per day for 3 to 5 days vs no treatment; the fourth study compared ranitidine 5 mg/kg/day intravenously, 3 divided doses for 4 days regardless of gastric pH vs no treatment.

There were 7 trials in which infants with active GI bleeding were enrolled to receive treatment. Four of these trials compared an H2RA vs no treatment. The first study compared cimetidine 3 mg/kg to 5 mg/kg intravenous 6 to 8 hourly until bleeding stopped, then continued for 3 to 5 days longer vs no treatment; the second study compared famotidine 0.3 mg/kg 12 hourly for 48 to 72 hours until bleeding stopped for 24 hours vs usual therapy; the third study compared ranitidine 0.6 mg/kg loading dose followed by 0.15 mg/kg/hour intravenous infusion until bleeding stopped for 24 hours vs no treatment; the fourth study compared ranitidine 3 mg/kg/day to 5 mg/kg/day intravenously for 3 to 5 days, and 1/3 Smecta packet then 1/4 packet 3 times per day vs usual therapy.

The remaining 3 trials compared a PPI vs no treatment. The first study compared omeprazole 1 mg/kg twice per day for 5 days plus usual therapy vs usual therapy on its own; the second study compared omeprazole 0.6 mg/kg intragastric once per day for 5 days plus usual therapy vs usual therapy; the third study compared omeprazole 0.7 mg/kg intragastric every day for 5 days vs usual therapy.

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Results

Prevention of Upper GI Bleeding in Newborns

In a single trial with 53 infants, no difference was reported in mortality from use of an H2RA compared with no treatment. Quality of evidence was graded very low. Meta-analysis of 4 trials with 329 infants found that upper GI bleeding was reduced from use of H2RA (typical risk ratio [RR] 0.36; 95% confidence interval [CI], 0.22-0.58; typical risk difference [RD] -0.20; 95% CI, -0.28 to −0.11; number needed to treat for an additional beneficial outcome [NNTB] 5; 95% CI, 4-9) compared with no treatment, and that there were no serious adverse reactions. Quality of evidence was graded moderate.

Treatment of Upper GI Bleeding in Newborns

There were 7 trials that treated 489 newborns for upper GI bleeding using an H2RA or PPI. Meta-analysis of 2 trials that included 131 infants revealed no significant difference in mortality from use of an H2RA compared with no treatment. Quality of evidence was graded low. Meta-analysis of 2 trials that included 104 infants found a reduction in duration of GI bleeding from use of any inhibitor of gastric acid compared with no treatment (mean difference -1.06 days; 95% CI, -1.28 to -0.84). Quality of evidence was graded low.

Meta-analysis of 6 trials that included 451 infants showed a reduction in continued upper GI bleeding from use of an inhibitor of gastric acid compared with no treatment (typical RR 0.36; 95% CI, 0.26-0.49; typical RD -0.26; 95% CI, -0.33 to -0.19; NNTB 4; 95% CI, 3-5). Quality of evidence was graded low. A single trial that included 38 infants reported no difference in anemia requiring blood transfusion from use of an H2RA compared with no treatment. There were no serious adverse reactions reported in any of the studies involving a PPI, nor in the 3 trials that included 226 infants in which an H2RA was used.

Researchers found no evidence that the use of higher doses of gastric acid inhibitors can further reduce GI bleeding in newborns. However, studies consistently reported that H2RA prevented GI bleeding in high-risk infants, and that both H2RAs and PPIs reduced duration of and continued GI bleeding in infants with this condition. One study reported no effect on anemia requiring blood transfusion.

Implications for Practice and Research

Researchers concluded that use of an H2RA may reduce the risk for GI bleeding in high-risk newborns, as there was moderate-quality evidence to support this treatment. Furthermore, use of an H2RA or PPI may reduce the duration of upper GI bleeding and incidence of continued bleeding in newborns with this condition, though this finding was backed by low-quality evidence.

There is no evidence that use of an H2RA or PPI in newborns affects mortality or the need for blood transfusion. The safety of these interventions remains unclear, since there were no studies that reported the incidence of necrotizing enterocolitis, sepsis, ventilator- or hospital-associated pneumonia, or long-term outcome. Lastly, there is no evidence that shows added benefits from using a higher dose of an H2RA or PPI for the prevention and treatment of GI bleeding in newborns.

Additional trials will be required to determine whether the clinical efficacy of H2RAs and PPIs in reducing GI bleeding and duration in newborns outweighs the potential harms. Trials will also be needed to compare the use of H2RAs vs PPIs and the use of intravenous vs intragastric administration of medication in newborns with GI bleeding.

Reference

Green DS, Abdel-Latif ME, Jones LJ, Lui K, Osborn DA. Pharmacological interventions for prevention and treatment of upper gastrointestinal bleeding in newborn infants [published online July 2, 2019]. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD011785.pub2.