The association of prenatal and postnatal macrolide exposure with subsequent development of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis

Infantile hypertrophic pyloric stenosis (IHPS) is a common cause of gastrointestinal obstruction in infancy, affecting up to three of 1000 live births [1, 2]. It is also the most acquired cause for surgical operation in the early days of life [3]. The underlying pathology is muscle hypertrophy at the pyloric region [4], which leads to obstruction of the gastric outlet. The infant commonly presents with projectile non-bilious vomiting and some degree of dehydration in the first 2–12 weeks of life. Initially, investigators thought that IHPS had a congenital origin, but it is now believed to be an acquired condition. The exact etiology remains unknown, but genetic and environmental factors have been implicated as risk factors for IHPS occurrence [5‐8]. For example, having a caesarean section, prematurity, primiparity, young maternal age, and smoking were reported as significant IHPS risk factors [9]. IHPS has also been shown to have strong familial aggregation, especially among twins [10].

One suspected environmental risk factor is the exposure to macrolides—mainly erythromycin—in early infancy; however, supporting evidence for this association remains elusive [11]. Both infants and mothers could need antibiotics during the perinatal period, including macrolides. For example, macrolides are the recommended medications for treatment and prophylaxis of pertussis in infants [12], and erythromycin is recommended for the treatment of chlamydia infection in pregnancy. The proposed explanation of the association with pyloric stenosis is that erythromycin, which is a motilin agonist, interacts with motilin receptors and this stimulates contraction of the gastrointestinal smooth muscles; these contractions could produce hypertrophy of the pylorus [13]. The aim of the present study was to conduct a systematic review and meta-analysis of the association between exposure to macrolides, including erythromycin, and the development of pyloric stenosis.

This meta-analysis study reviewed the association between macrolide exposure, focusing on erythromycin, and the development of pyloric stenosis in infants at different times of exposure: prenatal, direct postnatal infant use, and indirect postnatal through maternal use and feeding.

The main finding in this meta-analysis was the strong association between direct postnatal infant exposure to erythromycin and IHPS (RR = 3.17, 95% CI: 2.38–4.23). Individual studies reporting on the time of exposure have indicated a strong association for early exposure during the first two weeks of life. Conversely, indirect exposure through maternal use, either prenatally or postnatally, has a limited association with the risk of IHPS.

For prenatal exposure, our meta-analysis of cohort studies showed a modest increase in risk with marginal statistical significance for prenatal exposure to macrolides; however, the pooled results of the cohort and case-control studies could not achieve statistical significance. Prenatal erythromycin exposure was not associated with IHPS based on the pooled results of either the cohort studies or the case-control studies. Although the placental transfer of erythromycin is documented, the amount transferred is limited to around 2.6% of the maternal serum concentration [32]. Limited transplacental transfer has also been observed for roxithromycin and azithromycin [33]. In contrast, clarithromycin has shown a high transplacental transfer [34]. Different macrolides appear to have different transplacental transfer capacities, which may explain the mixed results among individual studies and the less prominent effect of erythromycin exposure during pregnancy compared to direct postnatal infant exposure.

For postnatal maternal exposure (breastfeeding), our pooled results did not show a statistically significant association with IHPS. Biologically, the macrolides are secreted in breast milk; however, the measurable levels in breast milk are much smaller than the standard therapeutic doses used in infants [26]. Noticeably, Lund et al. reported a higher rate ratio among infants exposed to macrolides through breastfeeding during the first two weeks of life (Rate Ratio = 3.49; 95% CI = 1.92–6.34) compared to infants exposed during the 14–120 days period (Rate Ratio = 0.7; 95% CI = 0.26–1.90) [26]. This finding agrees with those for direct infant exposure discussed above, where exposure during the first two weeks of life had a higher risk of IHPS.

A common theory for explaining how erythromycin can lead to IHPS is its interaction with motilin receptors [23]. Erythromycin is proposed to act as a motilin agonist that leads to increased activity of the migrating motor complexes and strong gastric and duodenal contractions. Frequent contractions, in turn, are believed to lead to pyloric hypertrophy and subsequent obstruction. This theory is supported by the delayed occurrence of IHPS among premature infants, since motilin receptors are not functional prior to 32 weeks of gestation [23]. In fact, Hussain and Herson [35] conducted a preliminary database analysis and concluded that premature infants maybe less susceptible to IHPS as a result of exposure to erythromycin compared to term infants.

The present study has also some limitations. First, most of the included studies are based on registry data. Although the use of registry data overcomes the problem of recall bias, the ascertainment of exposure and outcome is not always optimum. For example, registry data can confirm a medication prescription, but cannot guarantee adherence to the antibiotic protocol by the women or infants (except for hospitalized patients). Moreover, the completeness of the data within the registry databases was also questioned previously due to the delayed registration of infant data [36]. Second, the number of studies included in the analysis was small, especially when we studied the association with postnatal maternal use. Only two studies have been identified regarding the association between IHPS and postnatal maternal exposure (breastfeeding). Although we followed the recommended practice [37, 38] and opted to pool the results to get the best available estimate, the results need cautious interpretation due to the limited number of underlying studies. Finally, the accuracy of the risk estimate may be influenced by the quality of the included studies. We assessed the risk of bias in individual studies using a recommended tool (NOS); two studies scored six out of nine, while the remaining studies scored seven or higher.

This meta-analysis synthesizes the best available evidence to give a single estimate of the association between perinatal macrolide exposure and IHPS, providing valuable information for researchers, clinicians, and policy-makers. In summary, good evidence supports an increased risk of IHPS due to direct infant exposure to erythromycin. However, the evidence on the effects of prenatal or postnatal maternal exposure is not conclusive and the current research available does not support the presence of an association.