Efficacy of expressed breast milk alone or in combination with paracetamol in reducing pain during retinopathy of prematurity screening: A randomized controlled trial

Background: The aim of this study was to determine the eﬃcacy of expressed breast milk (EBM) alone or in combina�on with oral paracetamol for pain reduc�on during re�nopathy of prematurity (ROP) screening. Methods: A randomized control trial was conducted in two departments of Bangabandhu Sheikh Mujib Medical University. A total of 60 pre-term neonates who underwent ROP screening were randomized into three equal groups. Group A got nes�ng and swaddling as per instu-onal protocol (control). Group B received 2 ml EBM two minutes prior to the ROP screening and Group C received 15 mg/kg syrup paracetamol 30 minutes prior to the ROP screening and EBM like Group B. Premature infant pain proﬁle (PIPP) scores was used prior, during and 2 minutes a�er ROP screening procedure. Results: The three groups were similar in terms of baseline characteris�cs. The mean (standard devia�on) PIPP scores during the procedure were 16.4 (1.1), 15.0 (1.8) and 13.4 (1.8) in control, EBM, and EBM with paracetamol groups respec�vely. The PIPP scores were signiﬁcantly lower in the EBM and EBM with paracetamol groups during the procedure compared to control group. The mean diﬀerence in PIPP scores (during minus before procedure) of the EBM (10.2; 95% CI 9.4  10.9) and EBM with paracetamol (8.9; 95


Retinopathy of prematurity (ROP) has been widely
acknowledged to be the primary cause of preventable childhood blindness in developing countries.It is recommended for preterm infants with gestational age <35 weeks or birth weight <2000 grams and infants of a gestational age greater than 35 weeks who are believed to be at high risk for ROP. 1 However, the procedure for ROP is painful and is known to cause stress and physical debilitation among preterm neonates, especially because of the use of eyelid speculum and scleral indentation.Globally, most newborns admitted to neonatal intensive care units (NICUs) are subjected to repeat these painful procedures which have shortand long-term sequelae.It may lead to permanent changes in brain processing and maladaptive behavior later. 2 As evident that most premature neonates are capable of feeling pain therefore, experiencing such pain in early stage of life may have long term neurological consequences. 3onates are unable to express their pain verbally.They rely on their caregivers to recognize, assess, and manage their pain. 4 pain during various procedures. 6Expressed breast milk (EBM) sweet solutions (oral sucrose or glucose solutions), and various drugs such as paracetamol have been studied in the various clinical trials to relieve procedural pain with equivocal results. 7,8ROP screening in newborns causes severe pain during the procedure, with residual pain lasting up to 30 minutes afterward.
Breast milk has higher levels of tryptophan.Tryptophan is a precursor to melatonin, which has been shown in animal studies to increase concentrations of beta endorphin, a naturally occurring endorphin that is thought to be one of the mechanisms responsible for breast milk's analgesic effect. 9 this study, we tried to compare two commonly used methods to relieve procedural pain, namely EBM and paracetamol.The purpose of this study was to determine the efficacy of EBM alone or in combination of EBM with oral paracetamol for pain reduction during retinopathy of prematurity (ROP) screening among preterm infants.The mean difference between before and during and, before and after were further analyzed between and within the groups.Comparison between groups were done by post hoc test.The difference was considered significant for P<0.05.

RESULTS
The baseline parameters among all the three groups were similar and no significant difference in the mean gestational age, birth weight, age at the time of screening among the three groups (TABLE 1).The mean  2).

DISCUSSION
We aimed to assess the efficacy of EBM alone or combination of EBM with paracetamol for relieving pain during ROP screening among premature neonates.
Although several nonpharmacological and pharmacological agents are being used to treat neonatal pain, none of them are well established.Among the analgesics studied for newborn pain, breastfeeding/breast milk is a natural, readily available, easy to use, and potentially risk-free option.[11] Our study observed that the PIPP scores were significantly lower in the EBM and EBM with paracetamol groups during the procedure compared to control group, which is consistent with previous findings. 10,13,14Despite the fact that topical anesthetic eye drops were administered prior to the ROP exams, as is standard clinical practice, preterm infants still required pain relief and assistance in recovering quickly afterward. 15sali et al investigated the effectiveness of expressed breast milk in reducing pain during ROP screening.
During the procedure, the expressed breast milk group had a significantly lower PIPP score than the control group.A significant difference between the two groups was observed 1 minute and 5 minutes after the procedure 10 .Moreover, Taplak et al investigated the pain-relieving effects of sucrose, breast milk, and distilled water and found that the breast milk group recovered from the procedure with less pain. 14 fact that venipuncture was used in these studies. 17,18 observed that in the EBM and EBM with paracetamol groups, the mean difference in PIPP scores (between before and during the procedure) was also substantially lower.No differences were found among three groups regarding mean difference of PIPP score between before and after procedure.But difference was found within group comparison.Naik A, et al reported that the control and study groups had equal PIPP scores during the ROP. 14,19ere were some limitations in this study.Last feeding time was not documented, which could have impact on pain scores.The study results cannot be generalized as neonate on ventilator, sick babies and those not on oral feeds who require eye examination for detection of ROP were not included in this study.

Conclusion
The breastmilk alone or in combination with paracetamol may alleviate pain during ROP screening among premature infants compared to standard practice like nested and swaddled.Future investigators may assess the efficacy and safety of higher doses of expressed breast milk or other more potent drugs to reduce the pain during ROP screening.
Surrogate markers have been studied and widely used to assess neonatal pain.These include motor responses, facial expressions, crying, and changes in physiologic parameters such as heart rate, blood pressure, oxygen saturation, and respiratory rate.Validated pain assessment scores include the Neonatal Facial Coding System, the Neonatal Infant Pain Scale, and the Premature Infant Pain Profile (PIPP). 5Efficacy of expressed breast milk alone or in combination with paracetamol in reducing pain during retinopathy of prematurity screening: A randomized controlled trial Many pharmacological and nonpharmacological interventions have been studied to alleviate neonates' examinations were video recorded by the resident physician.The video recording taken 20 seconds before procedure served as baseline (PIPP 1).The other two videos were taken during and 2 minutes post procedure and these were leveled as PIPP 2 and PIPP 3, respectively.Both Ophthalmologist and the researcher were blinded.Researcher who was blinded about the procedure observed the facial expression of the babies in video before, during and 2 minutes after the examination and timed the duration of brow bulge, eye squeeze and nasolabial furrow on the PIPP scale in all examinations.Video recordings that were found incomplete at this time, were discarded.Each video was replayed thrice, and the mean PIPP score was calculated and used for analysis.Data was analyzed using IBM Statistical Package for the Social Sciences (SPSS) version 25.0 (IBM Corp, Armonk, New York, USA).Variables were expressed in the percentages, mean, standard deviation and 95% confidence interval.Data were analyzed with the Chisquare test and one-way analysis of variance (ANOVA).

(
standard deviation) PIPP scores during the procedure were significantly lower in the EBM group [15.0 (1.8)] and EBM with paracetamol group [13.4 (1.8)] compared to control group [16.4 (1.1)].No significant differences were found before and after procedure of the PIPP scores among the three groups (TABLE Expressed breast milk alone or combination with paracetamol for pain reduction during ROP screening probability of detecting a three-point difference in PIPP score with 5% level of significance.Written informed consent was obtained from the parents.Newborns with multiple congenital anomalies, patient who is on mechanical ventilator during ROP examination, polyethylene Glycol drop (Tearon eye drop).One drop of this combined drop was instilled every 10 -15 minutes for four times starting 1 hour before the scheduled time for the examination.The procedure for screening involved the use of indirect ophthalmoscopy using a 20D lens and this was performed by an experienced ophthalmologist who was blind about the intervention.After instilling a topical anesthetic drop (Proparacaine), a wire speculum was inserted to keep the eyelids apart, and a scleral indenter was used whenever required.All the neonates were swaddled during the procedure.GroupA was served as the control group; babies in this group were nested and swaddled which is the standard practice in the unit.Group B received 2 ml of EBM (collected from mother in a sterile container) rate, minimum oxygen saturation, gestational age and three facial reactions, presence of nasolabial furrow, brow bulge and eye squeeze.It was graded as mild (<6), Chowdhury RM et al.Bangabandhu Sheikh Mujib Medical University Journal 2023; https://doi.org/10.3329/bsmmuj.v16i2.67208moderate (6  12) and severe (>12).The ROP screening

TABLE 1 Background status of the enrolled cases
Chowdhury RM et al.Bangabandhu Sheikh Mujib Medical University Journal 2023; https://doi.org/10.3329/bsmmuj.v16i2.67208Expressed breast milk alone or combination with paracetamol for pain reduction during ROP screening 108