The Effect of Oral Acetaminophen on Open Arterial Duct Closure in Premature Infants Less Than 32 Weeks

Background: In most term neonates, the ductus arteriosus closes functionally on the first day of life, and a permanently open ductus arteriosus is abnormal. Objectives: To evaluate the effect of oral acetaminophen on patent arterial duct (PDA) closure in premature infants less than 32 weeks. Methods: This randomized clinical trial was performed on 140 preterm neonates with gestational age less than 32 weeks and birth weight less than 1,500 g, admitted to the neonatal intensive care unit of Ali Enbe Abitalib Hospital in Zahedan between 2019 and 2021. The neonates were randomly divided into two groups, with and without acetaminophen administration. In the intervention group, acetaminophen drops were started during the first 24 hours after birth and were administered for five days. In both groups, echocardiography was performed five days after birth. Finally, the data were analyzed in SPSS software. Results: About 140 neonates with gestational age of ≤32 weeks and weight at birth ≤1,500 g were admitted for the study. The neonates were equally divided into two groups and acetaminophen medication assigned for one of the groups. Of the 70 neonates who did not receive acetaminophen administration, 75.7% had PDA closure spontaneously; this pattern was 94.3% in patients who had treatment with acetaminophen. This effect of treatment was significant (X 2 =9.468, p =0.002). Conclusion: The study showed significant improvement in PDA in neonates receiving paracetamol. This can have a significant impact on the treatment approach to preterm neonates.


Introduction
The arterial duct diverts blood away from the lungs during fetal life.It serves as the arterial connection between the aorta and the pulmonary artery.During normal cardiovascular embryological development, the arterial duct is formed by the sixth pair of embryonic arches. [1]After preterm birth, the ductus arteriosus frequently stays open, and in 34% of very low birth weight (LBW) infants (Gestational age [GA] <28 weeks as well as birth weight [BW] <1,000 g) the ductus suddenly closed on the third day of life.However, it usually functionally closes in no less than a day in full-term babies. [2]he causes of duct closure after birth are numerous, and it has been shown that the increase in arterial blood oxygen pressure that occurs with ventilation of the lungs after birth leads to duct closure. [3]The hemodynamic consequences of longer term PDA include excessive pulmonary circulation, which increases the risk of respiratory failure, pulmonary edema, and decreased alveolar growth associated with chronic lung disease; and systemic hypoperfusion, which may lead to renal failure and necrotizing enterocolitis. [4]The treatment of PDA in preterm neonates has been the subject of debate and controversy for many decades.Treatment options include fluid restriction, pharmacological intervention with nonsteroidal antiinflammatory drugs (NSAIDs) or paracetamol, or closing the duct by surgical ligation or heart catheterization. [5]DA closure, regardless of the type of method, also comes with risks.There is not always a consensus as to what gives the best prognosis for newborns, whether to wait or to close the PDA.Although pharmacological therapy appears to be less harmful, it is not without risks.As a result, efforts have been made to find a drug that, in addition to being effective, is safe. [6]tudies have shown that indomethacin was the drug of choice until 2010.Starting that year, and coinciding with the publication of the national consensus, ibuprofen replaced it.
Despite the similar efficacy between these two medications, indomethacin has been associated with a higher incidence of serious adverse reactions, such as acute and chronic renal failure, hyperkalemia, brain damage, and necrotizing enterocolitis. [7]n 2017, there was a need for analgesia in newborns with PDA closure, and as such, the first use of acetaminophen in this pathology appeared.It was considered to be beneficial to use only one drug for both purposes. [5]Several studies have shown that acetaminophen has an efficacy similar to that of ibuprofen [8] but with a lower incidence of acute renal failure, oliguria, [9] platelet dysfunction, gastrointestinal bleeding, hyperbilirubinemia, [10] and necrotizing enterocolitis. [11]herefore, the present study was conducted to evaluate the effect of oral acetaminophen in the closure of PDA in preterm neonates Noor Mohammad Noori 1 , Alireza Teimouri 1 , Abdollah Dehvari 1 , Somayeh Bagheie 1 , Hossein Ansari 1

Exclusion criteria
Preterm neonates suffering from congenital heart defects, for which the opening of the ductus arteriosus is vital, such as pulmonary atresia with intact ventricular septum, the presence of major congenital abnormalities or chromosomal abnormalities, a history of using nonsteroidal anti-inflammatory drugs during pregnancy by the mother, the presence of hydrops fetalis or primary pulmonary hypertension in newborns, Apgar >5 minutes, PDA with symptoms, the presence of vomiting or hematemesis in the first three days after birth, glucose-6-phosphate dehydrogenase deficiency in the blood based on pre-hospitalization tests, death during study for any reason, those discharged against medical advice, and those who needed ibuprofen treatment were excluded from the study.Presence of lifethreatening infections, grade 4-3 of intraventricular hemorrhage in the first 24 hours, urinary output less than mg/kg/h 1 in the past 8 hours, serum creatinine level higher than 1.8 mg/dl, platelet count <50,000 and hyperbilirubinemia that requires blood exchange, active necrotizing enterocolitis, intestinal perforation, liver dysfunction, gastrointestinal bleeding, retinopathy, bronchopulmonary dysplasia, parents' lack of consent to participate in the study were also causes for exclusion from the study.

Sample size and sampling method
All preterm neonates with a GA of <32 weeks and a BW <1,500 g, born in Ali Ibn Abi Talib (AS) hospital, Zahedan, who met the criteria for entering the study, were included in the study after obtaining parental consent and were randomly assigned.They were divided into two study groups using colored cards.It should be noted that the minimum sample size required for the study was determined by using the following formula; N={ p1(1-p1)+p2(1-p2)}/(p1-p2)2 *f(α,β); When; f(α,β)= 7.84, P1 = 0.67 (12) and P2 = 0.815(13) that resulted in 70 people in each group.

Method of conducting the study
Patients are placed in groups A and B using a table of random numbers.In group A, acetaminophen oral drops (acetaminophen Hakim Oral Drops, 100 mg/ml, Hakim Pharmaceutical Co., Tehran, Iran) at the rate of 15 mg/kg dose were administrated.They received each dose at six-hour intervals for five days.
Group B contained the newborns who were not administered acetaminophen.
Echocardiography was performed by a pediatric cardiologist using a GE Vivid 3 ultrasound machine (General Electric Healthcare) in the neonatal intensive care unit at the end of the fifth day after birth for both groups.PDA criteria in echocardiography included the ratio of left atrium diameter to aortic root being more than 1.3 mm and the diameter of the internal canal more than 1.5 mm.

Statistical analysis
Data were analyzed by SPSS 24.Quantitative and qualitative data were described by mean and standard deviation, respectively.Chi-square and Mann-Whitney U tests were used to compare qualitative and quantitative variables, respectively, and logistic regression was used to find the odds for PDA closure in neonates that underwent treatment.All statistical analysis applied considered significance to be 0.05.

Results
The purpose of this study was to determine the effect of oral acetaminophen in the closure of PDA in premature infants.First the PDA size was measured before grouping; the analysis revealed that the size of PDA was same in the two groups of premature neonates.PDA size before treatment was 2.80±0.042and 2.81±0.048 in groups of A and B, respectively (MWU=2172.00,p=0.245).The preterm neonates who were treated with acetaminophen were assigned to group A and the others (without treatment) to group B. Of preterm neonates who were treated by acetaminophen, about 94.3% experienced PDA closure.That was higher than those without treatment.
Table 1 reveals that all study variables had free distribution when analyzed with non-parametric testing.Table 2 shows nonparametric testing to compare the study variables between groups of premature neonates.These variables, such as weight (p=0.844),GA (p=0.714),Apgar in the first minute (p=0.86) and the fifth minute (p=0.991),left atrial to aortic root ratio (LA/Ao) (p=0.627) and PDA size (p=0.247)before treatment were similar in preterm neonates who were treated with acetaminophen compared with those who were not treated, but PDA size after treatment changed significantly, such that the mean PDA size after treatment was 0.6±1.2 and 0.16±0.67 in preterm neonates without and with treatment, respectively (p=0.004).
Figure 1 shows the association between groups of the preterm neonates and PDA status after treatment.Of the 70 neonates who were not referred for treatment, 75.7% had PDA closure spontaneously; this pattern was 94.3% in patients who were treated with acetaminophen.This effect of treatment was significant (X 2 =9.468, p=0.002).
Table 3 shows logistic regression odds ratio (OR) analysis to assess the effect of certain factors on PDA closure in preterm neonates.The results revealed that treatment exposure had a significant effect on closure of PDA.The preterm neonates who received acetaminophen treatment had regular odds of 5.292 times more often than preterm neonates who did not receive acetaminophen treatment (p=0.004).When the odds are adjusted by other factors, the resultant odds of PDA closure increased to 6.394 paracetamol induced early closure of the PDA without detectable side effects.
Aikio et al. [15] and Bagheri et al. [20] administered paracetamol to a group of newborns with PDA.They reported that the outcomes of echocardiography on day 4 showed PDA closure was higher in the treated compared to untreated groups.
Schindle et al. [21] aimed to investigate the safety profile of paracetamol used to close PDA during the early postnatal period.They concluded that early paracetamol treatment significantly reduced the number of neonates requiring intervention for PDA.
With a little reflection on the results of Dash et al., [18] this is a surprisingly different result for the effects of paracetamol, but it should be noted that this study evaluates only preterm infants with mean GA of 31.6 weeks.Dissimilar findings reported by Asbagh et al. [23] found that PDA closure was not affected by acetaminophen administration.In this study, 32 preterm neonates were entered into the study (thus, sample size was low in each group).That is the reason for having different results from many literatures and the present study results.(p=0.004).The regular OR of LA/Ao was less than 1.0 and indicates that as the LA/Ao increases, the PDA closure is less likely to occur.

Discussion
Paracetamol is an attractive option in cases in which COX inhibitors are contraindicated or ineffective. [14]he present study results show that from the preterm neonates who were not referred to treatment by acetaminophen, about threequarters had spontaneous PDA closure; this pattern was about 94.3% in those who underwent treatment by acetaminophen.Preterm neonates that underwent treatment had 5.3 times greater odds to experience PDA closure than those who were not affected by treatment.
Aikio et al. [15] has investigated the effect of early use of acetaminophen on reducing the incidence of residual patent arterial duct without side effects.From this study it is concluded that early administration of acetaminophen will increase the incidence of PDA closure.
Terrin et al. [16] in a review reported that paracetamol administration to treat PDA had a significant effect on PDA closure and reduced the number of interventions without severe side effects, similar to Höck et al. [17] The present study did not observe any side effects, which is dissimilar to Dash et al., [18] which demonstrated high intestinal bleeding after paracetamol medication.
To confirm the effectiveness of paracetamol treatment in PDA closure, similar outcomes were recorded by Harkin et al. [19] : that  spontaneous closure of PDA (66% before and 34% after hospital discharge) [24] compared with the present study that observed about 75% PDA closure in the neonates without treatment.Benitz et al. [25] found that among 63 treated neonates (7 primary ligation, 56 indomethacin), the ductus closed after primary treatment with indomethacin in 38 neonates; ligation was performed after indomethacin in 15, and 10 were discharged with PDA.
A left-to-right ductal shunt causes increased pulmonary blood flow and ductal steal from the systemic circulation and thus can have adverse effects on premature infants, although a causal relationship is not well defined. [25,26] [27] In preterm infants, spontaneous PDA closure occurs less frequently.PDA in preterm neonates is thought to be the result of generalized immaturity of the smooth muscle and biochemical oxygen sensing mechanisms.The time it takes to achieve closure is inversely proportional to GA at birth. [26,28] o be sure, the preterm ductus is transcriptionally different from vessels at term. [27]Failure A recent review compared oral paracetamol against intravenous ibuprofen in PDA closure and suggested that paracetamol was as effective as ibuprofen, with less gastrointestinal bleeding and lower serum creatinine levels. [14]Yang et al. [9] showed similar PDA closure rates between oral paracetamol and ibuprofen, but observed fewer side effects in neonates receiving paracetamol, with a lower prevalence of oliguria.As a result of this study, paracetamol showed less toxicity, and urinary plasma prostaglandin E2 levels were lower in this group.In the present study, it was observed that none of the variables, including gestational age, weight at birth, Apgar in minutes 1 and 5, birth order, and LA/Ao, were comparable between the groups of neonates.Additionally, none of the neonates treated with acetaminophen experienced any adverse side effects that affected their gastrointestinal or urinary systems.
Nemerofsky et al. [12] conducted a prospective observational study on 65 neonates with very low BW (<1,500 g) found that spontaneous ductal closure occurred at 7 days of age in 31% of neonates with BW <1000 g and 67% of neonates with BW >1,000 g.For neonates with BW <1,000 g, spontaneous closure occurred without intervention before discharge in 47% of cases.In another recent observational study, 100% of 32 very low BW neonates who were not treated had

Conclusion
The present study concluded that a significant gap existed between the rates of PDA closure of treated and untreated neonates by acetaminophen.It means that acetaminophen would be a significant accelerator of PDA closure, especially in preterm neonates in the early days of their lives.
Future studies with a larger sample size and with comparable treatment strategies for medical management of PDA closure are needed to identify the most effective and safest treatment with highest probability of successful closure.

Figure 1 -
Figure 1 -The distribution of PDA closure in groups of neonates with and without acetaminophen intervention

Table 1 -
Normality test for quantities variables

Table 2 -
Comparing some variables in preterm infants based on treatment

Table 3 -
Logistic regression analysis on affective variables on PDA status after treatment

Table 4 -
comparison between preterm neonates with PDA treatment with oral acetaminophen