Effects of Melatonin on Excessive Crying in Neonates. A Randomized Controlled Clinical Trial.

Overview

the goal of this clinical trial is to learn if melatonin could reduce the duration of excessive crying and infantile colic in neonates and if this drug can be an option to be used in treating such problem- infantile colic and crying which creates anxiety to the parents, and to assess the safety of using melatonin in neonates. the author invited 165 mothers of 165 neonates having excessive crying more than 3 hours per day over 3 days per week, with ages ranged from 14-20 days with 4 categories of neonates according to the status of delivery: Cesarean section, Difficult labor, premature delivery, Small for gestational Age (IUGR) babies, as well as normal delivery neonates. these neonates will be randomly assigned into group Of melatonin 82 neonates, and 83 neonates will receive oral multivitamins as placebo that was made comparable to melatonin in taste and viscosity and color by the research pharmacy in Mosul, the dose of Melatonin will be 0.1mg/kg/12 hourly ,given daily up to 28 days of the start of administration of both melatonin and multivitamin. randomization is performed using opaque sealed envelopes which are sequentially numbered from 1-178 and allocation is concealed from mothers and the author. the clinic nurse will be the responsible for distribution of allocations. The mother will be instructed to record the daily duration of crying in minutes and report these values by telephone follow up throughout the study. The study design is a double-blinded randomized clinical trial. the whole study is to be conducted in a pediatric clinic prospectively. the group of neonates with melatonin will be compared with the group of neonates receiving multivitamins as placebo in the mean-crying times using t-tests

Introduction Excessive crying in early infancy is a common and distressing condition for parents and caregivers and represents a frequent cause of medical consultation during the neonatal period. Crying that persists for more than three hours per day, on more than three days per week, in an otherwise healthy infant is often described as excessive or inconsolable crying \[1\]. Although usually self limited, prolonged crying may negatively affect infant parent bonding, increase parental anxiety, and lead to inappropriate feeding practices or unnecessary medical investigations \[2\]. The etiology of excessive crying in infants is multifactorial and poorly understood, with proposed mechanisms including immaturity of the nervous system, gastrointestinal discomfort, and perinatal stresses \[3\]. Crying typically starts early in neonatal period, averaging two to three hours per day, and gradually declines by three to four months \[4\]. While most cases are benign, excessive crying has been associated with parental exhaustion, stress, and in rare cases, child abuse due to caregiver frustration \[5\]. Organic causes such as gastroesophageal reflux, cow's milk protein allergy, or urinary tract infection are identified in less than five percent of infants presenting with excessive crying \[6\]. The majority of cases are functional, often categorized under "infantile colic," which is defined by recurrent and prolonged episodes of crying without an identifiable medical cause \[7\]. Several hypotheses have been proposed to explain infantile colic and excessive crying, including gastrointestinal dysmotility, altered gut microbiota, food hypersensitivity, and psychosocial stressors \[8\]. Excessive crying in neonates can often be associated with perinatal stresses such as prematurity, difficult labor and intrauterine growth restriction IUGR \[9\]. Importantly, excessive crying is not only a medical issue but also a psychosocial one, as it can increase maternal depression risk, and strain family dynamics \[10\]. Management strategies for excessive crying range from parental reassurance and behavioral interventions to dietary modifications and pharmacological approaches. Probiotics such as Lactobacillus reuteri have shown promise in reducing crying duration by modulating gut microbiota \[8\]. Emerging evidence also suggests that melatonin may play a therapeutic role. Melatonin, a neurohormone secreted by the pineal gland, regulates circadian rhythms and has been implicated in gastrointestinal motility and antioxidant defense. Clinical trials have demonstrated that melatonin supplementation can improve sleep patterns and reduce infantile crying \[11\]. Its mechanisms include entrainment of circadian rhythms \[12\], modulation of gut motility \[13\], and stabilization of cortisol-melatonin balance \[14\]. Reviews emphasize melatonin's safety profile in neonates and its potential as a chronobiotic therapy \[15\]. Despite this interest in melatonin use in pediatric sleep disorders, evidence regarding its effect on excessive crying in early infancy still remains limited. This study aims to evaluate the effect of oral melatonin drops on crying duration in neonates with excessive crying by assessing the daily mean-times in crying over a defined follow up period. Methods Un-blinded randomized, controlled clinical study was conducted (according to CONSORT statement) in a private pediatric clinic in Mosul, Iraq, during the period from 15 January to June 2025, to evaluate the effect of melatonin on excessive crying in neonates. A total of 165 neonates aged 14-20 days (mean ±SD: 17 ±4 days) presenting with excessive crying were enrolled. Excessive crying in neonates was defined as crying lasting more than 3 hours per day on more than 3 days per week. Infants were categorized according to potential perinatal risk factors: cesarean section (n = 26), difficult delivery (n = 63), intrauterine growth restriction/small for gestational age (IUGR/SGA) (n = 33), premature vaginal delivery (n = 21), and normal vaginal delivery (n = 12). Cesarean section was either emergency or elective. A delivery was considered difficult if labor was prolonged, perinatal minimal hypoxia or if episiotomy or obstetric maneuvers were required. Infants were categorized as small for gestational age SGA (intrauterine growth restriction, IUGR) when their birth weight was below the 10th percentile for gestational age. Infants were recruited from neonates attending a private pediatric clinic in Mosul who presented with excessive crying, and detailed information was obtained through reports provided by their mothers. They were randomly assigned into two groups: Group A (melatonin, n = 83) and Group B (placebo, n = 82). Randomization was performed using opaque sealed envelopes, which were sequentially numbered from 1 to 178, and allocation was concealed from mothers, who were not informed whether their infant received melatonin or placebo. Group A received melatonin drops at a dose of 0.1 mg/kg twice daily at night for 28 consecutive days, beginning on the first clinic visit \[16\]. Group B received placebo drops consisting of a multivitamin preparation. Mothers documented the infants' crying duration in minutes on days 1,7,14, and 28, and reported these values via telephone. Throughout the study, mothers were instructed to report any unusual adverse effects potentially associated with melatonin use, including excessive sleepiness, vomiting, diarrhea, seizures, or skin rash. Independent sample t-tests were performed to compare mean crying times between the two groups at days 1,7,14, and 28. The melatonin preparation employed in this experiment was obtained from a reputable, pharmaceutical-grade brand, ensuring consistency, purity, and reliability of dosage. The primary outcome was the mean crying times at days 1,7,14, and 28 Statistical analysis was performed using independent sample t tests to compare mean crying times between groups at each time point. A p value \< 0.05 was considered statistically significant. SPSS statistics version 30(2024) was used to analyze the data.