Safety of azithromycin in pediatrics: a systematic review and meta-analysis.

PURPOSE: To evaluate the toxicity of azithromycin in neonates, infants, and children. METHODS: A systematic review was performed for relevant studies using Medline (Ovid), PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, and International Pharmaceutical Abstracts. We calculated the pooled incidence of adverse drug reactions (ADRs) associated with azithromycin based on prospective studies (RCTs and prospective cohort studies) and analyzed the risk difference (RD) of ADRs between azithromycin and placebo or other antibiotics using meta-analysis of RCTs. RESULTS: We included 133 studies with 4243 ADRs reported in 197,675 neonates, infants, and children who received azithromycin. The safety of azithromycin as MDA in pediatrics was poorly monitored. The main ADRs were diarrhea and vomiting. In prospective non-MDA studies, the most common toxicity was gastrointestinal ADRs (938/1967; 47.7%). The most serious toxicities were cardiac (prolonged QT or irregular heart beat) and idiopathic hypertrophic pyloric stenosis (IHPS). Compared with placebo, azithromycin did not show increased risk ADRs based on RCTs (risk difference - 0.17 to 0.07). The incidence of QT prolonged was higher in the medium-dosage group (10-30 mg/kg/day) than that of low-dosage group (≤ 10 mg/kg/day) (82.0% vs 1.2%). CONCLUSION: The safety of azithromycin as MDA needs further evaluation. The most common ADRs are diarrhea and vomiting. The risk of the most serious uncommon ADRs (cardiac-prolonged QT and IHPS) is unknown.

Association between exposure to macrolides and the development of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis.

Macrolides are bacteriostatic antibiotics with a broad spectrum of activity against Gram-positive bacteria. The aim of this study was to systematically review and meta-analyze the association between infantile hypertrophic pyloric stenosis (IHPS) and macrolides. Nine databases were searched systematically for studies with information on the association between macrolides and IHPS. We combined findings using random effects models. Our study revealed 18 articles investigating the association between macrolides and IHPS. There was a significant association between the development of IHPS and erythromycin (2.38, 1.06-5.39). The association was strong when erythromycin was used during the first 2 weeks of life (8.14, 4.29-15.45). During breastfeeding, use of macrolides showed no significant association with IHPS in infants (0.96, 0.61-1.53). IHPS was not associated with erythromycin (1.11, 0.9-1.36) or macrolides use during pregnancy (1.15, 0.98-1.36).Conclusions: There is an association between erythromycin use during infancy and developing IHPS in infants. However, no significant association was found between macrolides use during pregnancy or breastfeeding. Additional large studies are needed to further evaluate potential association with macrolide use. What is known? • Erythromycin intake in the first 2 weeks of life is associated with an increased risk of pyloric stenosis. What is New? • There is currently no evidence of significant association between macrolides use during pregnancy or breastfeeding and pyloric stenosis.

Post-natal erythromycin exposure and risk of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis.

PURPOSE: Macrolide antibiotics, erythromycin, in particular, have been linked to the development of infantile hypertrophic pyloric stenosis (IHPS). Our aim was to conduct a systematic review of the evidence of whether post-natal erythromycin exposure is associated with subsequent development of IHPS. METHODS: A systematic review of postnatal erythromycin administration and IHPS was performed. Papers were included if data were available on development (yes/no) of IHPS in infants exposed/unexposed to erythromycin. Data were meta-analysed using Review Manager 5.3. A random effects model was decided on a priori due to heterogeneity of study design; data are odds ratio (OR) with 95 % CI. RESULTS: Nine papers reported data suitable for analysis; two randomised controlled trials and seven retrospective studies. Overall, erythromycin exposure was significantly associated with development of IHPS [OR 2.45 (1.12-5.35), p = 0.02]. However, significant heterogeneity existed between the studies (I 2 = 84 %, p < 0.0001). Data on erythromycin exposure in the first 14 days of life was extracted from 4/9 studies and identified a strong association between erythromycin exposure and subsequent development IHPS [OR 12.89 (7.67-2167), p < 0.00001]. CONCLUSION: This study demonstrates a significant association between post-natal erythromycin exposure and development of IHPS, which seems stronger when exposure occurs in the first 2 weeks of life.

Pharmacokinetics of Transfer of Azithromycin into the Breast Milk of African Mothers.

Azithromycin (AZI) is used for its antibiotic and antimalarial properties in pregnancy. Reported estimates of AZI breast milk transfer, based on concentrations in mostly single samples from small numbers of women, have suggested that infant intake is safe. To better characterize infant intake and the associated potential benefits and risks, AZI was measured by liquid chromatography-mass spectrometry in four breast milk samples taken over 28 days postpartum from each of 20 Gambian women given 2 g AZI during labor. A population pharmacokinetic model utilizing published parameters for AZI disposition in pregnancy, the present breast milk concentrations, and increasing/decreasing sigmoid maximum-effect (Emax) functions adequately described temporal changes in the milk/plasma ratio. The median estimated absolute and relative cumulative infant doses were 4.5 mg/kg of body weight (95% prediction interval, 0.6 to 7.0 mg/kg) and 15.7% (95% prediction interval, 2.0 to 27.8%) of the maternal dose, respectively; the latter exceeded the recommended 10% safety limit. Although some infants with bacterial infections may benefit from AZI in breast milk, there is a risk of hypertrophic pyloric stenosis with a worst-case number needed to harm of 60 based on the present and available epidemiologic data. (This study has been registered at ClinicalTrials.gov under registration no. NCT01800942.).

Use and Safety of Erythromycin and Metoclopramide in Hospitalized Infants.

OBJECTIVE: Prokinetic medications are used in premature infants to promote motility and decrease time to full enteral feeding. Erythromycin and metoclopramide are the most commonly used prokinetic medications in the neonatal intensive care unit (NICU), but their safety profile is not well defined. METHODS: We conducted a large retrospective cohort study using data from 348 NICUs managed by the Pediatrix Medical Group. All of the infants exposed to ≥1 dose of erythromycin, metoclopramide, or both, from a cohort of 8,87,910 infants discharged between 1997 and 2012 were included. We collected laboratory and clinical information while infants were exposed to erythromycin or metoclopramide and described the frequency of laboratory abnormalities and clinical adverse events (AEs). RESULTS: Metoclopramide use increased from 1997 to 2005 and decreased from 2005 to 2012, whereas erythromycin use remained stable. Erythromycin use was most often associated with a diagnosis of feeding problem (40%), whereas metoclopramide was most often associated with a diagnosis of gastroesophageal reflux (59%). The most common laboratory AE during exposure to erythromycin or metoclopramide was hyperkalemia (8.6/1000 infant days on erythromycin and 11.0/1000 infant days on metoclopramide). Incidence of pyloric stenosis was greater with erythromycin than with metoclopramide (10/1095, 0.9% vs 76/19,001, 0.4%; P = 0.01), but odds were not significantly increased after adjusting for covariates (odds ratio 0.52, 95% confidence interval [CI] 0.26-1.02, P = 0.06). More infants experienced an AE while treated with metoclopramide than with erythromycin (odds ratio 1.21, 95% CI 1.03-1.43). CONCLUSIONS: Metoclopramide was associated with increased risk of AEs compared with erythromycin. Studies are needed to confirm safety and effectiveness of both the drugs in infants.

Environmental pesticides increase the risk of developing hypertrophic pyloric stenosis.

BACKGROUND: Hypertrophic pyloric stenosis (HPS) is a condition noted within the first several weeks of life that results in hypertrophy of the pyloric muscle between the stomach and duodenum. The etiology has not been elucidated but genetic and environmental influences are suspected. We hypothesized that agricultural pesticides would be associated with an increased incidence of pyloric stenosis. STUDY DESIGN: Data from infants with HPS were obtained from the Indiana Birth Defects Registry (IBDR) for all counties in Indiana from 2005 to 2009. Data from all live births were obtained from the Indiana State Health Department (ISHD). Maternal demographics and clinical characteristics of infants were abstracted. The US Geological Survey (USGS) provided estimated use of agricultural pesticides (EPEST), and these values were correlated with HPS incidence. Univariate and multivariate logistical regression models were used to assess the association between HPS risk and pesticide use. RESULTS: A total of 442,329 newborns were studied with 1313 HPS cases recorded. The incidence of HPS was 30/10,000 live births. HPS incidence was correlated with total county pesticide use, as well as subcategories of pesticides (fungicides, fumigants, insecticides, herbicides). Indiana counties were then divided into low, moderate and high pesticide use (mean±standard deviation: 127,722±73,374, 308,401±36,915, and 482,008±97,260pounds of pesticides). Incidence of HPS was 26, 29, and 36 cases per 10,000 in low, moderate and high pesticide-use counties respectively. Subset analysis showed that the positive association between HPS and county pesticide use was more likely for male infants from mothers who were white, aged 20-35 years, had education at high school or lower, and smoked (p<0.05). CONCLUSION: Pesticide use correlated significantly with incidence of HPS. Positive correlations between HPS risk and pesticide use were found for most risk factors. Further studies will be needed to verify our findings and further delineate the nature of this correlation.

Azithromycin in early infancy and pyloric stenosis.

BACKGROUND AND OBJECTIVE: Use of oral erythromycin in infants is associated with infantile hypertrophic pyloric stenosis (IHPS). The risk with azithromycin remains unknown. We evaluated the association between exposure to oral azithromycin and erythromycin and subsequent development of IHPS. METHODS: A retrospective cohort study of children born between 2001 and 2012 was performed utilizing the military health system database. Infants prescribed either oral erythromycin or azithromycin as outpatients in the first 90 days of life were evaluated for development of IHPS. Specific diagnostic and procedural codes were used to identify cases of IHPS. RESULTS: A total of 2466 of 1 074 236 children in the study period developed IHPS. Azithromycin exposure in the first 14 days of life demonstrated an increased risk of IHPS (adjusted odds ratio [aOR], 8.26; 95% confidence interval [CI], 2.62-26.0); exposure between 15 and 42 days had an aOR of 2.98 (95% CI, 1.24-7.20). An association between erythromycin and IHPS was also confirmed. Exposure to erythromycin in the first 14 days of life had an aOR of 13.3 (95% CI, 6.80-25.9), and 15 to 42 days of life, aOR 4.10 (95% CI, 1.69-9.91). There was no association with either macrolide between 43 and 90 days of life. CONCLUSIONS: Ingestion of oral azithromycin and erythromycin places young infants at increased risk of developing IHPS. This association is strongest if the exposure occurred in the first 2 weeks of life, but persists although to a lesser degree in children between 2 and 6 weeks of age.

Transient hypertrophic pyloric stenosis due to prostoglandin infusion.

Prostaglandin E1 (PGE1) is widely used in ductus-dependant congenital heart disease to maintain the patency of ductus. Hypertrophic pyloric stenosis (HPS) due to gastric mucosal proliferation is a rare complication of prolonged PGE infusion. A male newborn who developed HPS during PGE1 infusion is presented to discuss the clinical features and treatment modalities of PGE-related transient HPS. The boy was 2500 g and born at 35 weeks of gestation from a 23-year-old mother. He was admitted to neonatal intensive care with breathing difficulty and cyanosis. His echocardiography revealed pulmonary atresia, ventricular septal defect and major aorta-pulmonary collateral (MAPCA). PGE infusion with a dose of 0.05 mcg kg⁻¹ was initiated. At the 8th day of infusion, he developed non-billous vomiting. Ultrasonographic evaluation revealed 1.9 cm length of pyloric channel and 0.5 cm of wall thickness on 11th day and diagnosed as HPS. On 42th postnatal day, he underwent MAPCA closure, right modified Blalock-Taussi shunt and repair of pulmonary artery bifurcation with bovine patch. PGE infusion was stopped and enteral nutrition was started on 8th postoperative day. Control ultrasonography on 12th postoperative day revealed normal pyloric channel length (0.9 cm) and wall thickness (0.3 cm). Prolonged use of PGE infusion in neonates with congenital heart disease may cause transient HPS. The clinical and radiological features of HPS relieves after stopping PGE infusion. It should be kept in mind that HPS due to PGE infusion can be transient and pyloromyotomy should be kept for patients with persistent findings.

Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: nationwide cohort study.

OBJECTIVE: To assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS). DESIGN: Nationwide register based cohort study. SETTING: Denmark, 1996-2011. PARTICIPANTS: 999,378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery for IHPS, and potential confounders. MAIN OUTCOME MEASURES: Surgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth. RESULTS: 880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11 (-0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02). CONCLUSIONS: Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.

Development of pyloric stenosis after a 4-day course of oral erythromycin.

Early exposure to oral erythromycin in young infants, particularly in the first 2 weeks of life, has previously been associated with the development of hypertrophic pyloric stenosis. We report a case of an infant who received an abbreviated 4-day course of oral erythromycin for suspected Chlamydia conjunctivitis at 5 days of life then underwent pyloromyotomy for pyloric stenosis less than 2 weeks later. Health care providers should use erythromycin judiciously in neonates because only a few days of exposure to this medication may lead to the development of a surgical condition of gastric outlet obstruction.

[A new possible phenotype of carbimazole embryopathy: A case report]. / Un nouveau phénotype possible d'embryopathie au carbimazole : à propos d'une observation.

Many disorders have been described in infants exposed to carbimazole during the first weeks of pregnancy. The most common of them are congenital aplasia cutis, choanal atresia and esophageal atresia. Rather unspecific dysmorphic features and developmental delay have also been reported. This set of congenital malformations suggests the existence of a phenotype of carbimazole embryopathy. To date, about 30 cases have been reported. We report on a new case of pregnancy accidentally conducted under carbimazole which gave birth to a newborn presenting with a hypertrophic pyloric stenosis associated with hiatus hernia and tracheomalacia. These anomalies have been associated with other malformations already identified in children exposed in utero to carbimazole such as scalp defects, retrognathia and gothic palate. As no relation between propylthiouracil and congenital malformations has yet been described, this drug seems highly preferable for pregnant women presenting with hyperthyroidism during the 1st trimester of their pregnancy.

Gastric outlet obstruction due to an iatrogenic cause in a neonatal period - report of two cases.

Gastric mucosa hyperplasia is a rare cause of upper gastrointestinal obstruction in the neonatal period. One of the etiologic factors of this disorder is prolonged prostaglandin E1 (PGE1) therapy of neonates with congenital cyanotic heart diseases. Continuous PGE1 administration ensures patency of the ductus arteriosus, which is essential for stabilizing the general condition until cardiac surgery can be performed. The clinical symptoms of gastric mucosa foveolar hyperplasia due to long-term PGE1 therapy simulate hypertrophic pyloric stenosis. However, the characteristic ultrasound appearance of both pathologies facilitates determination of the final diagnosis and further treatment. We present two cases of neonates with gastric mucosa and submucosa hyperplasia revealed during ultrasound examination. The results of the ultrasound examination combined with clinical anamnesis allowed diagnosis of gastric mucosa foveolar hyperplasia due to prolonged PGE1 therapy.

Infantile hypertrophic pyloric stenosis in infants treated with azithromycin.

Seven-week-old 32-week premature triplets were hospitalized because of rhinorrhea, cough with color change and posttussive emesis. One infant had a positive direct fluorescent antibody test for Bordetella pertussis, so all were treated with 5 days of azithromycin. Two of the infants were subsequently diagnosed with hypertrophic pyloric stenosis and underwent surgical pyloromyotomies 6 and 7 weeks, respectively, after the initial admission.