|Year : 2020 | Volume
| Issue : 2 | Page : 217-225
Effect of oral erythromycin in the treatment of preterm infants with feeding intolerance
Yasser Abdel Rahman Ahmed1, Yasser Tolba Kassem2, Eman Atia Abdel Rahman3
1 Professor of Pediatrics Faculty of Medicine, Department of Pediatrics, Al Azhar University, Assuit Branch, Egypt
2 Lecturer of Pediatrics Faculty of Medicine, Department of Pediatrics, Al Azhar University, Assuit Branch, Egypt
3 Resident of Pediatrics Department of Pediatrics, Kafr El-sheikh General Hospital, Egypt
|Date of Submission||27-Aug-2019|
|Date of Decision||25-Mar-2020|
|Date of Acceptance||04-May-2020|
|Date of Web Publication||24-Jul-2020|
Bachelor of Medicine Eman Atia Abdel Rahman
20, Syria Street, Sector 2, Kafr El-Sheikh
Source of Support: None, Conflict of Interest: None
Background It usually takes several days or even weeks to establish full enteral feeding (FEF) in preterm infants because of feeding intolerance (FI) related to gastrointestinal hypomotility. Clinical trials on prokinetic agents in preterm neonates, especially erythromycin, have reported conflicting results. There are limited data on prokinetic effect of erythromycin in preterm infants.
Objective The authors aimed to evaluate the effect of oral administration of erythromycin in the treatment of preterm infants born at 30 weeks of gestation or more.
Patients and methods A clinical trial was conducted on 60 preterm neonates born equal or more than 30 weeks of gestational age and admitted to the neonatal ICU at Kafr El-Shiekh General Hospital. Infants with FI were randomly divided into two groups: group A received oral erythromycin and group B did not receive treatment with erythromycin. Time to achieve FEF was considered as a primary outcome measure. Duration of parenteral nutrition (PN) expressed in number of days; number of days that feeds were withheld owing to FI; and duration of hospitalization were the other outcomes.
Results Erythromycin group attained FEF earlier than the group without treatment with erythromycin. Therefore, PN duration was shorter in erythromycin group than the group without treatment. Moreover, the duration of hospitalization was shorter in erythromycin group than the other group.
Conclusion This data suggest that oral erythromycin effectively reduces the time required to reach FEF, duration of PN, and length of hospital stay in stable preterm infants.
Keywords: erythromycin, feeding intolerance, preterm
|How to cite this article:|
Ahmed YR, Kassem YT, Abdel Rahman EA. Effect of oral erythromycin in the treatment of preterm infants with feeding intolerance. Al-Azhar Assiut Med J 2020;18:217-25
|How to cite this URL:|
Ahmed YR, Kassem YT, Abdel Rahman EA. Effect of oral erythromycin in the treatment of preterm infants with feeding intolerance. Al-Azhar Assiut Med J [serial online] 2020 [cited 2020 Aug 9];18:217-25. Available from: http://www.azmj.eg.net/text.asp?2020/18/2/217/290596
| Introduction|| |
Premature birth is now the biggest global killer of young children, with more than 1 million children dying each year owing to the complications of preterm birth, mostly in the developing world. Approximately 70% of neonatal deaths are owing to preterm births, as well as 25–50% of cases of long-term neurologic impairment in children .
Nonetheless, there are many complications that accompany being born prematurely, which are subdivided into short-term problems and long-term problems. Short-term problems include hypothermia, hypoglycemia, respiratory distress, neonatal jaundice and kernicterus, neonatal sepsis, intraventricular brain hemorrhage, and necrotizing enteritis . Long-term problems include bronchopulmonary dysplasia, neurodevelopment impairment, hearing impairment, retinopathy of prematurity, childhood hospital admissions, cognitive and neuromotor impairments, and behavioral and psychomotor problems .
Fasting or delayed introduction of feeding may possibly impair gastrointestinal (GI) functions. To minimize feeding intolerance (FI) in preterm infants, the practice of ‘minimal enteral nutrition’ is considered as an alternative to complete fasting in many units .
A cyclic group of caudally migrating contractions, known as the migrating motor complex (MMC), occur in the stomach and small intestine during fasting. The MMC is thought to sweep residual products of digestion toward the colon serving as a housekeeper. MMC is primarily controlled by local enteric nervous system and modulated by hormones including motilin and somatostatin .
Motor patterns of the GI tract differ in preterm infants as compared with adults. During fasting, few infants display MMC but demonstrate episodes of motor quiescence that alternate with episodes of nonmigrating phasic activity. When preterm infants ingest milk, duodenal motor activity may increase, as in adults (mature feed response), remain unchanged (intermediate feed response), or decrease (immature feed response). The occurrence of these responses also changes with gestational age .
Regarding preterm infants, gastric emptying is delayed when compared with term infants owing to immaturity of duodenal motor function and absence of coordination between the antrum and duodenum. Intestinal transit is also longer in preterm infants than their term counterparts. Total gut transit time varies between 1 and 5 days in preterm infants as compared with 4–12 h in adults .
FI is a common phenomenon in the newborn ICU, affecting 16–29% of preterm infants. FI is defined as the inability to digest enteral feedings presented by increased gastric residuals, abdominal distension, and/or emesis and is frequently encountered in the preterm infant and often leads to a disruption of the feeding plan .
Gastric residuals represent the principal sign of presentation of FI. Gastric residual volume (GRV) has different definitions in the literature, spanning from an absolute (ml/kg) to a relative quantity (% of the previous feeding volume). The GRV, as an absolute value, independently from the volume of milk ingested in the previous meal or in the entire day, which should be considered pathological, ranges from 2 to 5 ml/kg .
Vast heterogeneity emerges among authors about what percentage GRV should be considered pathological, from a minimum of 10% day volume to a maximum of 70% day volume. When considering only the previous meal, GRV was considered ‘excessive’ if 20–30% of feeding volume in more dated literature or 50% feeding volume by other authors .
Apnea, bradycardia, and temperature instability are also included as symptoms of FI but solely for the purposes of the nursing assessment to provide guidance on identification of potential progression to more serious complications such as pneumatosis intestinalis and necrotizing enterocolitis (NEC) .
Motilin is a 22-amino acid peptide found in GI M cells, some enterochromaffin cells, and proximal small intestine. It is synthesized by endocrine cells of the duodenojejunal mucosa, which plays a critical role in the regulation of the GI interdigestive motility. It is accepted that its binding and activation of motilin receptor induce the phase III contraction of MMC .
Erythromycin is a macrolide antibiotic that also acts as a motilin receptor agonist, thereby stimulating intestinal peristalsis. It is sometimes used to promote gut motility in infants with delayed gastric emptying, poor small bowel motility, or GER .
The difference in responses to a low or antimicrobial dose of erythromycin can be explained by the presence of two different types of motilin receptors. The ‘neural’ receptor is stimulated by a low dose that triggers the phase III MMCs. The ‘muscle’ receptor on the contrary is stimulated by higher doses of erythromycin triggering strong non-propagated antral contractions and inhibiting MMCs .
| Patients and methods|| |
The study was conducted from August 2018 to May 2019 at Kafr El-Sheikh General Hospital.
A clinical trial was conducted that included 60 preterm neonates born equal or more than 30 weeks of gestational age.
Infants were randomly divided into two groups: group A (erythromycin group) received oral erythromycin, and group B did not receive any treatment with erythromycin. No infant was excluded from the study in both groups.
Verbal consent from the mother or the caregiver to participate in the study was taken.
The following were the inclusion criteria:
- Newborns admitted to newborn ICU experiencing FI.
- Preterm newborns (30 weeks-36 6/7 weeks).
- Normal and low-birth-weight infants.
The following were the exclusion criteria:
- Major congenital abnormalities.
- Congenital GI abnormalities.
- Positive surgical history.
- Current or previous history of NEC within 7 days of the onset of FI.
- History of prokinetic drugs such as metoclopramide.
Infants who were enrolled in the study were categorized into two groups:
- Group A: erythromycin-treated infants who received therapeutic high dose (10 mg/kg/dose) divided every 6 h for 2 days, followed by 4 mg/kg/dose for another 5 days (erythromycin ethylsuccinate suspension 200 mg/5 ml produced by Pharco Pharmaceuticals, Alexandria, Egypt) through nasogastric/orogastric feeding tube. It was administered at the first day of occurrence of FI and continued up to 7 days after the start of treatment .
- Group B: group without treatment by erythromycin.
All the participants followed the same feeding protocol.
Feeds were started in both groups of infants as early as possible when they are clinically stable via orogastric or nasogastric tube. Content of feeding was either breast milk (preterm breast milk is 290 mOsm/l) or formula for preterm infants (260 mOsm/l). Initial volume is 2 ml/kg per feed, and then the feeding was advanced not faster than 10 ml/kg/day .
Every infant in the study was monitored and evaluated regarding the following:
Gestational age (detected by prenatal ultrasonography).
Obstetric history (circulage, obstructed labor, oligohydramnios, placenta previa, and placental separation).
Prenatal history (diabetes mellitus, hypertension, maternal urinary tract infection, etc.).
Natal history (PROM, type of delivery, and site of delivery).
Postnatal history (Apgar score at 1 and 5 min, aggressive resuscitation, respiratory distress, cyanosis, etc.).
Need for resuscitation (Apgar score).
- Clinical examination:
General examination General condition and activity.Vital signs (color, heart rate, respiratory rate, temperature, and capillary refill time).Estimation of gestational age (new Ballard Score).Anthropometric measurements (weight, length, and head and abdominal circumferences).
Chest: respiratory distress, air entry, grunting, retraction, and adventitious sound.
Abdomen: abdominal masses, distension, palpation of organs, auscultation of intestinal sounds, gastric ryle passage, and the potency of the anus.
Cardiovascular system (CVS): heart rate, perfusion, peripheral pulses, heart sounds, and murmur.
Central nervous system (CNS): level of consciousness, fontanels, tone, and reflexes.
Extremities and genitalia: congenital anomalies should be excluded.
- Routine laboratory investigation included the following: complete blood count, C-reactive protein, blood gases (if needed), blood culture, and stool analysis with occult blood in stool.
- Radiological investigation included abdominal radiography.
- Clinical criteria of FI included the following:
- Gastric residuals greater than 30% of previous feeding.
- Abdominal distension (increase in abdominal circumference >2 cm).
- Emesis (>two times in a 24-h period).
- Coffee ground or bile stained vomiting.
- Occult or gross blood in stool.
- Apnea and bradycardia.
- Outcome parameters included the following:
- Days to achieve full enteral feeds (as a primary outcome).
- Duration of parenteral nutrition (PN).
- Number of days that feeds were withheld owing to FI.
- Duration of hospitalization.
The aim of the study was explained to the parents of each patient before collection of data, verbal consent was taken from the parents of each patient in the study, and privacy of all data was assured.
| Results|| |
This is a clinical trial where 60 infants were included (30 weeks to <37 weeks of gestational age).
[Table 1] shows that the mean GA in erythromycin group was 32.17±1.54 weeks, in which there were 15 males and 15 females. The mean GA in the group without treatment by erythromycin was 32.00±1.58 weeks, in which there were 14 males and 16 females. The mean birth weight was 1547±256 g in the erythromycin group and 1531±317 g in the group without treatment by erythromycin. According to the birth percentile, 26 infants were appropriate for gestational age, whereas three infants were small for gestational age in erythromycin group and 23 infants were appropriate for gestational age and seven infants were small for gestational age in the group without treatment by erythromycin.
|Table 1 Comparison between erythromycin group and group without treatment by erythromycin regarding demographic data|
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[Table 2] shows that there was a statistically significant increase in the group without treatment by erythromycin in comparison with erythromycin group regarding the number of days needed to reach full enteral feeding (FEF), number of days feed withheld due to FI, age at FEF (days), duration of PN (days), and duration of hospitalization, as shown in [Table 2].
|Table 2 Comparison between erythromycin group and group without treatment by erythromycin regarding full enteral feeding, days feed withheld owing to feeding intolerance, duration of parenteral nutrition, and duration of hospitalization|
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[Table 3] shows there was no statistically significant difference regarding type of feeding among studied groups.
|Table 3 Comparison between erythromycin group and group without treatment by erythromycin regarding the type of feeding|
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[Table 4] shows that there was no statistically significant difference in risk factors for NEC among studied groups.
|Table 4 Comparison between erythromycin group and group without treatment by erythromycin regarding risk factor for necrotizing enterocolitis|
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[Table 5] shows that there was no statistically significant difference regarding vital signs at the time of enrollment among the studied groups.
|Table 5 Comparison between erythromycin group and group without treatment by erythromycin regarding vital signs at the time of enrollment|
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[Table 6] shows that there was no statistically significant difference regarding anthropometric measurements in both studied groups.
|Table 6 Comparison between erythromycin group and group without treatment by erythromycin regarding anthropometric measurements at the time of enrollment|
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[Table 7] shows that there was no statistically significant difference regarding signs of feeding intolerance among studied groups.
|Table 7 Comparison between erythromycin group and group without treatment by erythromycin regarding signs of feeding intolerance|
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[Table 8] shows that there was no statistically significant difference regarding age at starting enteral feeding and starting time of the enrollment among the studied groups.
|Table 8 Comparison between erythromycin group and group without treatment by erythromycin regarding age at starting enteral feeding and starting time of the enrollment|
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[Table 9] shows that there was a statistically significant decrease in the group without treatment by erythromycin in comparison with erythromycin group regarding hemoglobin and hematocrit.
|Table 9 Comparison between erythromycin group and group without treatment by erythromycin regarding complete blood count|
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[Table 10] shows that there was no statistically significant difference regarding occult blood in stool among studied groups.
|Table 10 Comparison between erythromycin group and group without treatment by erythromycin regarding occult blood in stool|
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| Discussion|| |
One of the major challenges facing the neonatologist is to help the preterm infant attain full enteral feeds without the complications of NEC and PN-related septicemia or cholestasis .
Erythromycin is a motilin receptor agonist which has been studied as a prokinetic agent for over 20 years. Erythromycin affects the gut and gallbladder, stimulates enteric nerve and smooth muscle, increases antral motility (resulting is strong, nonpropagating gastric contractions), and triggers MMCs in newborns .
The aim of the work was to evaluate the effect of administration of oral erythromycin in preterm infants with feeding intolerance born 30 weeks of gestation or more and aimed to determine whether their administration decreases time needed to reach FEF in preterm infants with feeding intolerance. A total of 60 newborns were enrolled in the study and categorized into two groups: group A included 30 preterm newborns with feeding intolerance, and this group was treated with high dose of oral erythromycin, and group B included 30 preterm newborn with feeding intolerance and did not receive oral erythromycin.
The present study showed no statistically significant differences between erythromycin-treated group and the group without treatment by erythromycin regarding gestational age. The mean gestational age of the group without treatment by erythromycin was 32.00±1.58 weeks and in erythromycin group was 32.17±1.54 weeks.
Our study showed no statistically significant difference between erythromycin-treated group and the group without treatment by erythromycin regarding clinical and demographic data including birth weight, birth percentiles, gestational age, and sex on admission, which comes in agreement with Nuntnarumit et al.  and Ng et al. .
In our study, we used therapeutic high dose of erythromycin (10 mg/kg every 6 h for 2 days, followed by 4 mg/kg every 6 h for another 5 days). This comes in agreement with Nuntnarumit et al. , in which oral erythromycin given at 10 mg/kg every 6 h for 2 days, followed by 4 mg/kg every 6 h for another 5 days in preterm infants who were 35 weeks, and there was a decrease in the time required to establish FEFs compared with placebo (P<0.001). However, in our study, the studied infants were less than 37 weeks of gestational age.
Erythromycin is generally used as a prokinetic agent for the treatment of feeding intolerance in preterm infants; however, results from previous studies significantly vary owing to different medication dosages, routes of administration, and therapy durations .
In our present study, we used an oral therapeutic high dose of erythromycin, and we also observed a decrease in time required to reach FEF in the studied infants when compared with the control group. In discordance to our study, Ng et al.  studied intermediate dose of oral erythromycin given at 5 mg/kg/dose of erythromycin every 6 h for 14 days in preterm infants and observed a decrease in time required to reach FEF in stable VLBW preterm.
Mohammadizadeh et al.  gave the erythromycin-treated group oral erythromycin at low dose (1.5 mg/kg every 6 h) and observed that there was improvement in enteral nutrition and significant difference in time required to reach FEF between the two studied groups.
In our study, there was no statistically significant difference between the two groups regarding the type of feeding, which comes in agreement with Nuntnarumit et al. and Ng et al. ,.
The present study showed no statistically significant difference between the two groups regarding signs of feeding intolerance, which comes in agreement with Nuntnarumit et al. . Clinical signs of feeding intolerance other than excessive GRV may better correlate with the risk of NEC, such as abdominal distention (increase >2 cm in abdominal girth) and/or other intestinal signs (absence of bowel sounds, emesis, abdominal wall discoloration, and bloody stool), especially if associated with systemic warning signs (apnea, bradycardia, temperature instability, and acidosis); however, even isolated abdominal distention may not correlate with poor feeding outcome .
In our study, it was found that there is a statistically significant difference between the two groups regarding the number of days feed withheld owing to FI, which comes in agreement with Nuntnarumit et al. .
The importance of adequate enteral nutrition, including achievement of FEFs during the first few weeks following delivery in preterm infants, is well known. A delay in attainment of FEFs is associated with adverse neurodevelopmental outcomes in premature infants, thereby emphasizing the critical need for strategies to optimize enteral nutrition in this population .
Moreover, prolonged PN in preterm infants increases the risk of developing cholestatic jaundice, sepsis, liver impairment, rickets of prematurity, and postnatal growth restriction .
The primary outcome in the study by Ng et al.  was the time to attain FEF (150 ml/kg/day), and they found that erythromycin administration resulted in earlier attainment of FEF in preterm infants with feeding intolerance compared with control, which comes in agreement with our present study where erythromycin group attained FEF earlier than the group without treatment by erythromycin, and as a result, PN was stopped earlier in the erythromycin group than the other group. This finding comes in contrast with Ng et al. , where they found that the time to achieve FEF after beginning the treatment was comparable between the studied groups.In our study, there was no statistically significant difference between the two studied groups regarding risk factors for NEC. NEC is the major cause of death from GI disease in premature infants. Despite the complex and multifactorial nature of the pathogenesis of NEC, three major risk factors have been implicated in its development: prematurity, bacterial colonization of the gut, and formula-feeding .
In our study, there was no statistically significant difference between the two studied groups regarding the age at start of enteral feeding and age of start of the enrollment. This comes in agreement with Ng et al. . Optimization of enteral nutrition in preterm neonates has become a priority, considering that postnatal growth restriction is a major and almost universal issue in this population. Most protein and energy deficit associated with postnatal growth restriction occurs within the first two weeks of life .
In discordance with Nuntnarumit et al. , our study showed significantly lower duration of hospitalization in erythromycin group in comparison with the group without treatment by erythromycin, which is considered a main target for those populations.
In our study, there was statistically significant difference between the two studied groups regarding hemoglobin and hematocrit, as it was lower in control group when compared with erythromycin group.
| Conclusion|| |
- Feeding intolerance is a common problem in preterm infants; however, there is no sharp line of demarcation between it and clinically suspected NEC.
- Enteral nutrition in preterm neonates has become a priority to the neonatologists for avoidance of postnatal growth restriction in this population.
- Therapeutic oral erythromycin may effectively reduce the time required to reach FEF, duration of PN, and length of hospital stay in stable preterm infants.
- Antenatal care should be improved aiming to decrease preterm delivery in order to prevent diseases associated with prematurity.
- Prevention and treatment of feeding intolerance is essential for appropriate growth and development of infants.
- This research study suggests that enteral erythromycin administration may be of benefit in treating feeding intolerance in preterm infants.
- Repeated studies should be implemented with lower doses of erythromycin to assess the lowest effective dose could be used.
- The use of standardized feeding guidelines and breast milk are the only feeding practices that showed consistent improvement in feeding tolerance especially in preterm infants.
- Delaying feedings in an attempt to eliminate NEC and feeding intolerance may result in more complications.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]