Abstract
Introduction
Patent ductus arteriosus (PDA) is associated with increased morbidities and mortality in extremely preterm infants. The biological effect of acetaminophen on the closure of ductus has been shown; however, the effective and safe dosage for early treatment of the most preterm infants remains unknown.
Methods
In a single-centre, randomised, controlled, double-blind, phase II pilot trial, extremely low gestational age (ELGA, <28 wk) and/or birth weight (<1,000 g) infants were randomized to intravenous paracetamol or 0.45% saline-placebo. The treatment started before 96 h age, with loading dose of 20 mg/kg and maintenance of 7.5 mg/kg every 6 h for 9 days. Ductal patency was assessed prior to trial initiation and monitored daily, using cardiac ultrasound. Primary outcome was the duration of ductal closure. Secondary outcomes included ductal closure rates, treatment of symptomatic PDA, serum paracetamol levels, long-term morbidities, and mortality.
Results
After consent, 40 infants were randomly allocated soon after birth. The intention-to-treat analysis included 39 infants; 19 had paracetamol and 20 placebos. The median (IQR) ductal closure time was 3 (10) days in the paracetamol group, versus 14 (20) days in the placebo group (p = 0.031). Ductus was closed in 15 (75%) vs. 7 (35%) infants, respectively, p = 0.016 (number needed to treat = 3). Three infants in the placebo group received post-study treatment for PDA. The numbers of adverse events were similar in both study groups.
Conclusion
Early, 9-day paracetamol administration, compared to placebo, significantly shortened the ductal closure time without increase in adverse events in ELGA infants.
Keywords: Cardiac ultrasound, Extremely low birth weight, Acetaminophen, Patent ductus arteriosus, Premature infants
Introduction
In extremely low gestational age (ELGA, <28 weeks) infants, ductus arteriosus often fails to close, leading to patent ductus arteriosus (PDA) [1]. Hemodynamically significant PDA has been associated with increased morbidities and mortality [2]. Inhibition of cyclooxygenase (COX) often results in ductal constriction. Previously, early prophylactic paracetamol accelerated early ductal closure in very premature infants (<32 weeks), prior to its development to a persistent shunt, without safety issues [3, 4]. However, in the ELGA infants’ subgroup, no satisfactory effect on ductal closure was found. Increased efficacy of PDA closure, based on a murine model, using a higher dose of paracetamol was proposed, whereas others have stressed its potential toxicity [5, 6]. An ELGA infants’ pain therapy study revealed that the median paracetamol duration during intensive care was 9 days, without observed adverse effects [7].
Previous PDA treatments have included COX inhibitors, ibuprofen or indomethacin, or surgical operations [8]. However, they all proved to have notable risks. Paracetamol showed comparable effectiveness in ductal closure, with fewer acute adverse events [8]. A trend towards a less aggressive and selective PDA treatment strategy through expectant management has gained momentum due to the medications’ ineffectiveness regarding preterm infants’ long-term outcomes [9–11].
This pilot trial aimed to evaluate the efficacy and safety of early, low dose and long course of paracetamol for ELGA infants’ ductal closure. We hypothesized that a prolonged treatment period may benefit ELGA infants’ ductal closure, without increase in adverse effects.
Methods
Study Design
We conducted a randomized, double-blind, phase 2 clinical trial, in the Neonatal Intensive Care Unit (NICU) of Oulu University Hospital, Oulu, Finland, between September 2018 and March 2024. The study hospital offers tertiary neonatal care for the whole Northern Finland geographical area, for approximately 500,000 inhabitants. NICU had twelve beds with full intensive care readiness for acute care of premature infants. The trial adhered to Good Clinical Practice guidelines and was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT; online suppl. 1; for all online suppl. material, see https://doi.org/10.1159/000552204). The study protocol was approved by the Local Ethics Committee and the Finnish Medicines Agency. Written informed consent was obtained from parents within 96 h postnatally.
Participants
ELGA infants and/or infants with birth weight <1,000 g admitted to the NICU were eligible and screened within 96 h after birth (Fig. 1). Gestational age was defined by ultrasound during the early second trimester. Cardiac ultrasound was performed shortly after birth, prior to randomization, to confirm ductus arteriosus patency and to screen for congenital heart defects. In this early-phase trial, a patent ductus was the sole inclusion criterion; neither ductal size nor hemodynamic significance was required. An adaptation period up to 96 h was allowed before trial initiation. Exclusion criteria included spontaneous ductal closure on initial cardiac ultrasound, major congenital anomalies, chromosomal abnormalities, and severe or potentially life-threatening conditions, e.g., pulmonary hypertension, hydrops fetalis, and severe respiratory distress.
Fig. 1.
Consolidated standards of reporting trials diagram. ELGA, extremely low gestational age; NICU, neonatal intensive care unit; RD, respiratory distress; PPHN, persistent pulmonary hypertension of the newborn.
Randomization and Intervention
A designated delegate performed computer-generated randomization using a 4-block design. After written informed consent, eligible infants were randomly assigned to receive either intravenous paracetamol (Paracetamol Fresenius Kabi®, 10 mg/mL) – a loading dose 20 mg/kg followed by a maintenance dose of 7.5 mg/kg every 6 h, in accordance with the manufacturer’s guideline – or an equivalent volume of placebo (0.45% saline). The study drug was administered over 9-day period, totalling 36 doses. Upon trial designing, no pharmacologic rationale existed for paracetamol treatment in ELGA infants. The 9-day regimen was the manufacturer’s recommendation and selected based on an ELGA infant study that found it the median treatment duration with good tolerance [7]. Blinding was ensured by visual similarity of paracetamol and placebo solutions, both transparent in the syringe. Study drug preparation was performed by a dedicated nursing team not involved in patient care, in a separate research pharmacy. Per protocol, prior paracetamol exposure for pain management before enrolment was permitted; a few doses were considered acceptable given the extended recruitment and treatment periods. In such cases, the loading dose was omitted. Paracetamol was also used for analgesia, and since some infants received placebo, pain, and discomfort were monitored using a validated pain scale [12].
Assessments
Daily cardiac ultrasounds were performed by paediatric cardiologists or neonatologists trained in cardiology, all blinded to group allocation. Imaging was continued daily until 1 day after ductal closure or the final study drug dose. Ultrasound recordings were obtained using Vivid S70N (GE Healthcare, Helsinki, Finland) ultrasound devices equipped with appropriate transducers (12S or 6S). Given the fragility of ELGA infants and their susceptibility to clinical deterioration from handling, research procedures were minimized. Comprehensive ultrasound protocols were not pursued. Instead, daily targeted neonatal echocardiographic assessments focused on ductal calibre (measured in mm and mm/kg), specifically at the narrowest internal diameter on the pulmonary side of the ductus. In the most clinically unstable infants, a binary assessment of ductal flow (patent vs. closed) was deemed sufficient. The study protocol did not define prespecified criteria for the post-intervention PDA treatment. Infants requiring further management for ductal patency after the study drug period were treated at the discretion of the attending clinicians.
Residual volumes from routine blood samples were collected and stored at −70°C. Quantitative analysis of plasma or serum paracetamol concentrations was performed by Nordlab (Oulu, Finland), using the Syva® Emit®tox™ Acetaminophen Assay (Siemens Healthcare Diagnostics Inc, Erlangen, Germany). For further serum levels analyses, paracetamol half-time, approximately 6 h in preterm infants, was taken into consideration [13]. As the exact time points of both drug administration and sample obtainment were available to us, the samples were divided into early and late measurements to find out whether the serum levels increased in the later samples, potentially leading to drug accumulation (Fig. 3).
Fig. 3.
Paracetamol serum concentrations in the study infants. a Box plots showing daily paracetamol levels (mg/L, median, interquartile range) during the study drug period. Samples collected 0–4.0 h post-dose are represented by shaded bars (n = 114); samples collected 4.1–6.0 h post-dose are shown as open bars (n = 42). b Scatter plot of all measured paracetamol concentrations (n = 165) plotted against postmenstrual age on the day of sampling.
Outcomes and Collected Data
To evaluate the impact of long dosage on ELGA infants’ ductal closure, the primary outcome of the trial was the time to ductal closure, measured in days. Prespecified secondary outcomes included ductal closure rates and calibre (mm, mm/kg), PDA incidence and treatments, surfactant administration, modes and duration of respiratory support, duration of supplemental oxygen, inhaled nitric oxide, inotrope administration, fluid intake, diuresis, serum electrolyte and bilirubin levels, duration of phototherapy, confirmed and suspected infections, paracetamol serum concentrations, paracetamol use during the NICU stay, adverse events, long-term morbidities (bronchopulmonary dysplasia [BPD], retinopathy of prematurity [ROP], intracerebral haemorrhage [ICH], periventricular leukomalacia), their respective treatments, and mortality. Serious adverse events were defined as ICH grade 3–4, necrotizing enterocolitis (NEC), severe hyperbilirubinemia requiring exchange transfusion, neonatal pulmonary hypertension requiring inhaled nitric oxide, pulmonary haemorrhage, blood culture-positive sepsis, and death. Morbidities, including BPD, ICH, NEC, and ROP, were defined as previously [14–17].
Statistical Analysis
All analyses were conducted on an intention-to-treat basis using IBM® SPSS® Statistics 2023, version 29.0.1.0 (SPSS Finland Oy, Espoo, Finland). Statistical methods included non-parametric tests (Mann-Whitney U test, Pearson Chi-square test, and ANOVA), independent samples t test, and Pearson correlation, as appropriate. The ductal closure rates during the intervention period were analysed using the Cox proportional hazards modelling. A two-sided p < 0.05 was considered statistically significant.
To preserve blinding, the writing committee reviewed the primary outcome data, comparing treatments A versus B, and developed and recorded two interpretations: one assuming treatment A was paracetamol, and the other assuming it was placebo. The randomization code was only revealed after consensus was reached that no further changes would be made to the interpretation, at which point the correct version was selected.
Sample Size
In our previous 4-day trial, the mean (SD) postnatal age at ductal closure was 7.4 (14.1) days in the paracetamol group and 14.0 (21.5) days in the placebo group. Among the ELGA infant subgroup, closure occurred at 20.5 (21.0) and 35.8 (30.0) days, respectively [3]. We hypothesized that extending the duration of paracetamol treatment from 4 to 9 days would reduce ductal closure time from 35.8 to 7.4 days (effect size = 28.4 days) [7]. Based on this assumption, a sample size of 36 infants (18 per group) was calculated to achieve 80% power with a 5% alpha error. A total of 40 infants were recruited, including both ELGA and extremely low birth weight (<1,000 g) infants.
Results
Between September 1, 2018, and October 24, 2023, a total of 76 ELGA infants were either born at or transferred to Oulu University Hospital (Fig. 1). Following screening and exclusions, written informed consent was obtained for 40 eligible infants, and 75% enrolment rate was achieved. Twenty infants were randomized to receive paracetamol and 20 to placebo. Baseline clinical characteristics were comparable between the two groups (Table 1). One infant died early during the study period and, due to missing data, was excluded from all outcome analyses except the count of deaths.
Table 1.
Characteristics of the study patientsa
| | Paracetamol, n = 20 | Placebo, n = 20 |
|---|---|---|
| Prenatal | ||
| Maternal history of placental insufficiencyb, n (%) | 4 (20) | 4 (20) |
| Maternal history of hypertensive disorders of pregnancy, n (%) | 4 (20) | 7 (35) |
| Maternal diabetes, any type, n (%) | 4 (20) | 2 (10) |
| Chorioamnionitis, n (%) | 0 | 1 (5) |
| Other than Caucasian parent(s)c, n (%) | 0 | 4 (20) |
| Maternal use of antenatal paracetamol, n (%) | 9 (45) | 7 (35) |
| Maternal antenatal steroids, n (%) | 19 (95) | 20 (100) |
| Antenatal steroid doses, mean (SD) | 1.6 (0.8) | 1.7 (0.6) |
| Maternal antenatal magnesium infusion, n (%) | 15 (75) | 17 (85) |
| Caesarean delivery, n (%) | 16 (80) | 16 (80) |
| Prolonged premature rupture of membranes, n (%) | 2 (10) | 1 (5) |
| Durations of the prolonged premature rupture of membranes, h | 173; 432 | 675 |
| Neonatal | ||
| Gestational age at birth, weeks, mean (SD) | 25.9 (1.7) | 25.8 (1.9) |
| Gestational age >27+6 weeks, n (%) | 3 (15) | 4 (20) |
| Gestational age ≤24+0 weeks, n (%) | 5 (25) | 6 (30) |
| Birth weight, g, mean (SD) | 786 (209) | 764 (197) |
| Birth weight SD, mean (SD) | −1.04 (1.81) | −0.61 (1.26) |
| Small for gestational age, n (%) | 5 (25) | 4 (20) |
| Female, n (%) | 9 (45) | 8 (40) |
| Male, n (%) | 11 (55) | 12 (60) |
| Multiple birth, n (%) | 1 (5) | 2 (10) |
| Outborn, n (%) | 1 (5) | 0 |
| Umbilical blood pH, mean (SD) | 7.30 (0.11) | 7.27 (0.12) |
| Apgar scores at 1 min, median (IQR) | 4.5 (4) | 5.0 (4) |
| Apgar scores at 5 min, median (IQR) | 6 (4) | 6 (2) |
| Surfactant doses, mean (SD) | 1.35 (0.49) | 1.80 (0.83) |
| Postnatal age of the onset of the study drug, h, mean (SD) | 21.9 (17.3) | 20.6 (12.8) |
| Paracetamol intake prior to the study period, n (%) | 2 (10) | 2 (10) |
| Paracetamol doses, n, patient 1/patient 2 | 4/4 | 4/1 |
| Paracetamol mg/kg, patient 1/patient 2 | 41.6/40.8 | 42.5/20.2 |
| Age at 1st dose, h, patient 1/patient 2 | 4.1/7.4 | 4.3/15.8 |
aNo significant differences were found between the two groups in the listed categories, if not separately listed.
bPlacental insufficiency was defined as abnormalities of foetal haemodynamics and intrauterine growth restriction.
c p = 0.035, Pearson chi-square test.
Prior paracetamol administration for pain relief was permitted before enrolment. Four study participants, two in each group, had received paracetamol prior to randomization and therefore did not receive the study drug loading dose (Table 1). The number of pre-randomization paracetamol doses was four in both paracetamol group infants, and one and four in the placebo group infants.
Primary Outcome
Outcome data from daily cardiac examinations were available for 39 enrolled infants. None of the infants had a closed ductus arteriosus prior to randomization. The primary outcome – median (IQR) time to ductal closure – was significantly shorter in the paracetamol group compared to placebo: 3.0 (10) versus 14.0 (20) days (p = 0.031; Table 2).
Table 2.
Primary and secondary outcomes by treatment group
| Paracetamol, n = 20 | Placebo, n = 19a | p value | |
|---|---|---|---|
| Primary outcome | |||
| Ductal closure time, days, median (IQR) | 3 (10) | 14 (20) | 0.031b |
| Secondary outcomes | |||
| Ductal closure during the study period, n (%) | 15 (75) | 7 (37) | 0.016c |
| Patent ductus arteriosus; diagnosed after the study period, n (%) | 4 (20) | 9 (47) | 0.087c |
| Hemodynamically significant, treated, n (%) | 0 | 3 (16) | 0.072c |
| Ibuprofen, n (%) | 0 | 0 | N/A |
| Ligation, n (%) | 0 | 3 (16) | 0.072c |
| Pulmonary outcomes | |||
| Surfactant doses, median (IQR) | 1.0 (1) | 2.0 (1) | 0.102b |
| Mechanical ventilation, days, median (IQR) | 4.5 (11) | 6.0 (9) | 0.411b |
| Any respiratory support, days, median (IQR) | 45.0 (37) | 55.0 (46) | 0.531b |
| Supplemental oxygen, days, median (IQR) | 40.0 (29) | 56.0 (44) | 0.212b |
| Inhaled nitric oxide treatment, n (%) | 0 | 2 (11) | 0.136c |
| Adverse events during the study drug period | |||
| Number of patients receiving 0, 1, 2, or 3 inotropic drugsd | 14/3/3/0 | 12/4/4/0 | 0.803c |
| Oliguria (<1 mL/kg/h), n (%) | 2 (10) | 1 (5) | 0.579c |
| Polyuria (>5 mL/kg/h), n (%) | 4 (20) | 3 (16) | 0.732c |
| Intravenous + intra-arterial fluid intake (mL/kg/day), median (IQR)e | 68.3 (41.2) | 73.9 (29.7) | 0.141b |
| Hypernatremia (≥150 mmol/L), n (%) | 13 (65) | 13 (68) | 1.000c |
| Adverse events during NICU stay | |||
| Highest serum bilirubin, µmol/L, mean (SD) | 134 (20) | 135 (20) | 0.850f |
| Phototherapy periods/patient, n, mean (SD) | 3.4 (2.3) | 3.7 (2.2) | 0.647f |
| Clinical infection, n (%)g | 8 (40) | 11 (58) | 0.264c |
| Septicaemia: positive blood culture, n (%)h | 5 (25) | 5 (26) | 0.925c |
| Neonatal long-term outcomes | |||
| BPD grade 1: supplemental oxygen at 28 days, n (%) | 7 (35) | 8 (42) | 0.648c |
| BPD grade 2/3: supplemental oxygen </>30% at 36 wk PMA, n (%) | 1 (5) | 3 (16) | 0.267c |
| Retinopathy, grade 1–3, n (%) | 9 (50)i | 8 (42) | 0.630c |
| Retinopathy, treated, n (%) | 2 (11)i | 3 (16) | 0.677c |
| ICH, grades 1–2, n (%) | 8 (40) | 7 (37) | 0.839c |
| ICH, grades 3–4, n (%) | 3 (15) | 4 (21) | 0.622c |
| Cystic periventricular leukomalacia, n (%) | 1 (5) | 1 (5) | 1.000c |
| NEC, n (%)j | 1 (5) | 1 (11) | 0.970c |
| Death during the 1st hospitalization, n (%)k | 1 (5) | 3 (15) | 0.292c |
PMA, postmenstrual age.
aOne patient died after the 1st study drug dose and did not complete the trial.
bMann-Whitney U test.
cPearson Chi-square test.
dOptions for the inotropes: dopamine, dobutamine, and norepinephrine.
eIntravenous and intra-arterial fluid intake/day during the study drug.
fIndependent samples’ t test.
gClinical infection was defined as symptoms of septicaemia with negative blood culture.
hEarly onset (age ≤7 d), n = 4; late onset (age >7 d), n = 6.
iRetinopathy follow-up data were available for 18 patients.
jBoth had severe NEC, i.e., grade 3.
kAll deaths included.
Secondary Outcomes
At the initiation of the study drug, median (IQR) postnatal age was 22.1 (19.6) h in the paracetamol group and 21.6 (20.9) hours in the placebo group (p = 0.947). Ductal closure frequency was analysed using Cox proportional hazards modelling, revealing a faster closure rate in the paracetamol group (hazard ratio 2.69; 95% CI, 1.09–6.68; p = 0.033; Fig. 2). Following the final study drug dose, ductal closure was observed in 15 infants (75%) in the paracetamol group and 7 (35%) in the placebo group (p = 0.016; number needed to treat (NNT), NNT [95% CI] = 3 [2–11]). Among placebo group infants, no significant difference in ductal closure time (range) was found between those with prior paracetamol exposure (n = 2) and those without (n = 16): 16.5 (1) versus 11.5 (58) days, respectively (p = 0.732).
Fig. 2.
Cox proportional hazards analysis of ductal patency over the 10-day study period in paracetamol and placebo groups. HR, hazard ratio; CI, confidence interval.
Ductal calibre measurements were performed in infants who were clinically stable enough (online suppl. 2). Paracetamol-treated infants had smaller ductal calibres throughout the treatment period (p = 0.028; online suppl. 2A). However, when adjusted for birth weight, the difference was no longer statistically significant (p = 0.106; online suppl. 2B). During the outcome recording period, extending to hospital discharge, no significant differences in adverse events, morbidities, or mortality were observed between the groups (Table 2).
Paracetamol serum concentrations were analysed from the residual volumes of routine blood samples collected from 22 study infants (paracetamol group, n = 20; placebo group, n = 2), totalling 165 samples and stored at −70°C (Fig. 3). Concentrations remained within safe limits throughout the study period, ranging from 1.7 to 35.7 mg/L, without evidence of drug accumulation. Among paracetamol-treated infants, those with a persistently patent ductus (n = 5) had significantly higher mean (SD) paracetamol concentrations than those with closed ductus (n = 15): 18.2 (6.4) vs. 14.9 (6.7) mg/L, respectively (p = 0.008). However, prior to the median ductal closure time (i.e., within the first 3 days of treatment), no significant difference was observed between infants with open versus closed ductus: 18.8 (4.1) vs. 15.4 (5.3) mg/L (p = 0.059). Paracetamol concentrations were further analysed by study drug day, time elapsed since the previous dose, and postmenstrual age at sample collection (Fig. 3). Mean (SD) concentrations on study days 1 and 9 were 13.6 (3.9) and 16.0 (5.9) mg/L, respectively (p = 0.271). A significant inverse correlation in linear regression analysis between paracetamol concentration and postmenstrual age was detected (β = −0.375, p < 0.001; Fig. 3b). In the two placebo group infants who had received paracetamol prior to enrolment, serum concentrations declined progressively and became undetectable by study day 3.
Discussion
In this phase 2 pilot trial, a 9-day course of paracetamol was effective and safe for early ductal closure in ELGA infants: it significantly reduced ductal closure time [3]. The closure rate was significantly higher in the paracetamol group compared to placebo, with a low NNT (NNT = 3). PDA-associated morbidity was modest, and adverse events, commonly linked to COX inhibitors, were not observed [18].
A persistent clinical challenge remains in the treatment of the most immature infants, who may benefit from early ductal closure but in whom PDA closure often fails. Early administration of COX inhibitors, such as ibuprofen or indomethacin, can induce ductal closure, yet meta-analyses of randomized trials suggest these agents may pose greater risks than expectant management [11]. Although both COX inhibitors and paracetamol inhibit prostaglandin synthesis, their mechanisms of action differ, which may have therapeutic implications [19]. In studies dealing with pharmacological closure of haemodynamically significant PDA, various doses and courses have been used [4, 20, 21]. Emerging evidence suggests that ELGA infants may require higher doses due to tissue immaturity and reduced responsiveness to low-dose prostaglandin inhibitors [5, 22]. Previously, paracetamol pain treatment studies in ELGA infants demonstrated that prolonged treatment courses were feasible and well-tolerated [7, 23]. More recently, a phase 2 study, using Bayesian method, assessed various paracetamol dosing regimens in ELGA infants and found minimum effective dose for ductal closure a loading dose 25 mg/kg, followed by 10 mg/kg every 6 h for 5 days, with good tolerance [22]. The present study found paracetamol concentrations within the therapeutic range throughout the extended treatment period, supporting the safety in this population [24].
Several studies evaluated early interventions for ductal closure [11]. The efficacy of paracetamol in promoting PDA closure, combined with its favourable safety profile, has prompted randomized trials investigating its prophylactic use [4, 25]. Prophylactic paracetamol has been shown to reduce the incidence of hemodynamically significant PDA [3, 25, 26]. In a recent multicentre trial, the duration of the study drug was administered for 5 days, beginning before 12 h of age [25]. For infants born at the lowest gestational strata (23–26 weeks), phase 2 dosing was applied [22, 25]. Originally, it was assumed that due to severe morbidities, early inhibition of prostaglandin synthesis may be beneficial. However, although non-significant favourable trends were observed, no improvement in clinical outcomes could be demonstrated [25]. In the current study, early ductal closure was more frequent in the paracetamol group. These findings add evidence supporting prophylactic intervention for ductal closure in the ELGA population, while no significant evidence was found to challenge the superiority of expectant management for hemodynamically significant PDA.
The recruitment window extended up to 96 h postnatally, and the median (IQR) postnatal age at study drug initiation was 22.1 (19.6) hours in the paracetamol group and 21.6 (20.9) hours in the placebo group. These initiation times indicate successful early enrolment and a prophylactic treatment setting (Table 1). A 75% parental acceptance rate and absence of withdrawals during the 9-day intervention period further support the robustness of the data.
Present serum paracetamol concentrations remained stable and within therapeutic levels between study days 1 and 9 (Fig. 3), suggesting no drug accumulation or induction of metabolism [24]. During the study drug period and NICU stay, fewer adverse events or neonatal adverse outcomes were recorded in the paracetamol treatment group compared to placebo, without statistical significance (Table 2). Concerns have been raised regarding potential long-term neurodevelopmental or pulmonary adverse effects of paracetamol [6]. However, previous follow-up studies and retrospective cohort analyses have not demonstrated associations between early paracetamol exposure and common adverse effects [27–29]. In this study, respiratory morbidity rates were similar between groups (Table 2). Further research is needed to assess the long-term safety of paracetamol exposure across the lifespan. Acute paracetamol hepatotoxicity is mediated via its oxygenation pathway, producing the toxic intermediate N-acetyl-p-benzoquinone imine. This pathway is not active in preterm infants, and hepatotoxicity has been rare in unintentional overdose cases among them [13, 30].
The principal strength of this study lies in its double-blind, randomized trial design. Although the sample size was modest, statistical power was sufficient to detect differences in the primary outcome. Serial cardiac ultrasound assessments enabled accurate determination of ductal status, with closure confirmed the following day. However, comprehensive daily echocardiographic evaluations were not performed; instead, targeted ductal flow assessments were used to determine closure timing and rates. The study aimed to evaluate the timing of ductal closure and to characterize common adverse effects of paracetamol compared to placebo in this vulnerable population. The single-centre design limits generalizability, as treatment practices for preterm infants vary across institutions. The sample size was powered for the primary outcome, but insufficient to robustly assess secondary outcomes such as PDA-associated morbidities. Trial enrolment was prolonged due to the COVID-19 pandemic. Nevertheless, the data generated are encouraging and contribute meaningfully to future meta-analyses and trial design.
Conclusion
Early administration of paracetamol for 9 days was well-tolerated and significantly reduced ductal closure time in extremely premature infants. Larger trials are warranted to determine whether early prolonged paracetamol therapy, compared to expectant management, is safe and can reduce serious morbidities in this high-risk population.
Acknowledgments
The authors gratefully thank all participating infants and their families for their invaluable contribution to this study. We extend our sincere thanks to research nurse Riitta Vikeväinen for overseeing trial logistics, and to Clinisoft analysers Paula Kemppainen and Mervi Väisänen for their assistance in data retrieval. We are deeply grateful to the nursing staff of the NICU at Oulu University Hospital for their outstanding collaboration throughout the study period. The successful execution of this trial would not have been possible without the continued support of the clinical team. We especially acknowledge the following colleagues for performing study-patient ultrasound assessments over the course of the trial: Pia Härkin, Antti Härmä, Kati Kallio, Merja Kallio, Hanne-Kaisa Kaski, Tuula Kaukola, Saara Lehtiranta, Markku Leskinen, Riitta Marttila, Hanna-Leena Taskila, Marita Valkama, and Annu Varila. During the preparation of this work the authors used Microsoft Copilot to check English grammar. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.
Statement of Ethics
This study involves human participants and was approved by the Regional Ethics Board of the Ostrobothnia Hospital District, on May 5, 2018; reference No. 23/2018. Written informed consent was obtained from the participants’ parents before taking part.
Conflict of Interest Statement
Mikko Hallman was a member of the journal’s Editorial Board at the time of submission. None of the other authors have any conflict of interest to declare.
Funding Sources
This study was funded by the Alma and K.A. Snellman Foundation, Oulu, Finland (O.A., T.U.); Finnish Foundation for Pediatric Research (O.A., T.U.); Finnish Medical Foundation (O.A., T.U.), Sigrid Jusélius Foundation (M.H.). These foundations had no roles in the study design, execution and analysis, and manuscript conception, planning, writing, and decision to publish.
Author Contributions
Dr. Tiina Ukkonen conceptualized and designed the study, took part in the investigation, acquired funding, collected data, conducted the initial analyses and visualization, drafted the initial manuscript, and critically reviewed and revised the manuscript. Drs. Eveliina Ronkainen and Aliisa Laitala took part in the investigation, collected data, and critically reviewed and revised the manuscript. Dr. Timo Saarela confirmed the resources, supervised the study, and critically reviewed and revised the manuscript. Dr. Mikko Hallman conceptualized and designed the study and methodology, acquired funding and resources, administered the project, and critically reviewed and revised the manuscript for important intellectual content. Dr. Outi Aikio conceptualized and designed the study and methodology, took part in the investigation, acquired funding and resources, administered the project, coordinated and supervised data collection, conducted the initial analyses and visualization, and critically reviewed and revised the manuscript for important intellectual content.
Funding Statement
This study was funded by the Alma and K.A. Snellman Foundation, Oulu, Finland (O.A., T.U.); Finnish Foundation for Pediatric Research (O.A., T.U.); Finnish Medical Foundation (O.A., T.U.), Sigrid Jusélius Foundation (M.H.). These foundations had no roles in the study design, execution and analysis, and manuscript conception, planning, writing, and decision to publish.
Data Availability Statement
Deidentified individual participant data will not be made available because we did not obtain permission to share individual data. Further enquiries can be directed to the corresponding author.
Supplementary Material.
Supplementary Material.
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Data Availability Statement
Deidentified individual participant data will not be made available because we did not obtain permission to share individual data. Further enquiries can be directed to the corresponding author.
