A 5-week-old infant is admitted to a high dependency unit with paroxysmal cough associated with dusky episodes. The severity and frequency of cough paroxysm increases and 48 h later pernasal swab confirms the diagnosis of pertusis. You want to treat the infant with erythromycin. However, you have heard that erythromycin can cause hypertrophic pyloric stenosis in young infants. So you decide to find out more before starting the treatment.

Structured clinical question

Are the young infants (subject) exposed to erythromycin (intervention) at risk for developing hypertrophic pyloric stenosis (outcome)?

Search strategy and outcome

Primary sources

Medline (1951–2006) via Dialog DATA star:

Keywords: erythromycin or maciolides AND pyloric stenosis or infantile hypertrophic pyloric stenosis.

Limits: Human, English.

Outcome

A total of 30 articles were found. All the abstracts were read and six relevant articles were identified for the analysis (table 1).^1–6 One systematic review included in the analysis was primarily designed to look at the use of erythromycin as a prokinetic agent in preterm infants.⁶ Another systemic review⁷ looking at the use of erythromycin for the same was read but not included in the analysis. This review included only two studies. One of those was included in the other systemic review, analysed here, and the second study was published only in abstract form, and the possible association between erythromycin and pyloric stenosis was not discussed. Three other relevant case reports^8–10 were read but not included in the analysis because of small sample sizes in all of them.

Embase and Pubmed: Same search strategy used. No further relevant papers found.

Secondary sources

Cochrane Database and Bestbets website: No further papers found.

Comments

Infantile hypertrophic pyloric stenosis is a condition of early infancy in which hypertrophy of pylorus results in gastric outlet obstruction. The aetiology of this condition remains unclear. Genetic predisposition acting in conjunction with environmental factors is the most widely accepted explanation.

Erythromycin is a motilin receptor agonist. It has been hypothesised that erythromycin interacts with motilin receptors, inducing strong gastric and pyloric bulb contractions and resulting in pylorus hypertrophy.^11–12 Thus, it is plausible that young infants treated with erythromycin may be at increased risk for developing hypertrophic pyloric stenosis. Four cohort studies^1,4 were found that dealt with this possible causal association. All of them were retrospective and had methodological flaws, but unanimously suggested that young infants treated with a high, antimicrobial dose of erythromycin (about 40 mg/kg/day) are at risk for developing hypertrophic pyloric stenosis. The risk was reported to be substantially higher (8–10-fold) in the first 2 weeks of life in term or near-term infants and did not differ by erythromycin preparations (ethylsuccinate or estolate). Infants treated with erythromycin for longer durations (>14 days) were found to be at higher risk than those treated for shorter durations.

Erythromycin is excreted into breast milk, and the level of erythromycin in breast milk is 50–100% of the level in maternal plasma.¹³ So it would not be unreasonable to suspect that maternal use of macrolides during breast feeding may also increase the risk of infantile hypertrophic pyloric stenosis. A large population-based cohort study⁵ was found dealing with this question and suggested that the use of macrolides during breast feeding increases the risk of infantile hypertrophic pyloric stenosis.

Newer macrolides, such as azithromycin, have recently become popular among clinicians because of the shorter duration of treatment and fewer gastrointestinal side effects than erythromycin. Only a small number of infants treated with azithromycin after the first 6 weeks of life were included in the study by Mahon et al.³ None of them developed pyloric stenosis. In another study,¹⁴ primarily designed to look at efficacy of azithromycin as a post-pertusis exposure chemoprophylactic agent, 58 neonates were given azithromycin. None of them developed pyloric stenosis. Further evidence is required before a definite conclusion can be drawn regarding the use of newer macrolides and subsequent development of pyloric stenosis.

Erythromycin is used in preterm babies with feed intolerance in some centres. A systematic review⁶ looking at the use of erythromycin as a prokinetic agent failed to consider the issue of erythromycin-related side effects, including pyloric stenosis adequately, given the small sample size and insufficient data on long-term follow-up in the included studies.

At this stage, on the basis of published evidence, it can be concluded that young infants exposed to erythromycin in the first few weeks of life are at greater risk for developing hypertrophic pyloric stenosis. The highest risk seems to be in the first 2 weeks of life in term or near-term infants, and with courses of >14 days. Infants exposed to erythromycin through breast milk may be at risk for developing hypertrophic pyloric stenosis, although further evidence is required to confirm this causal association.

Erythromycin should only be used in young infants (<4 weeks) when the therapeutic benefits outweigh the risks and no alternative agent is available

Acknowledgements

I thank Dr Ros Jones, Consultant Paediatrician, Wexham Park Hospital, Slough, Berkshire, for her critical comments about the article.