Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial.

OBJECTIVE: To study the biologic effect of paracetamol, an inhibitor of prostaglandin synthase, on early closure of ductus arteriosus, and to evaluate possible adverse effects associated with the drug. STUDY DESIGN: In a controlled, double-blind, phase I-II trial, very low gestational age (<32 weeks) infants requiring intensive care were randomly assigned to intravenous paracetamol or placebo (0.45% NaCl). A loading dose of 20 mg/kg was given within 24 hours of birth, followed by 7.5 mg/kg every 6 hours for 4 days. Daily cardiac ultrasound examinations of ductal calibers were performed before the first dose, and until 1 day after the last dose. The main outcome was a decrease in the ductal caliber without side effects. RESULTS: Of 63 screened infants, 48 were randomized: 23 were assigned to paracetamol and 25 to placebo. Before the intervention, their ductal calibers were similar. During the intervention, the ductus closed faster in the paracetamol group (hazard ratio 0.49, 95% CI 0.25-0.97, P = .016). The mean (95% CI) postnatal ages for ductal closure were 177 hours (31.1-324) for the paracetamol-treated vs 338 hours (118-557) for controls (P = .045). Paracetamol serum levels were within the therapeutic range, and no adverse effects were evident. CONCLUSIONS: Prophylactic paracetamol induced early closure of the ductus arteriosus without detectable side effects. Further trials are required to determine whether intravenous paracetamol may safely prevent symptomatic patent ductus arteriosus. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938261; European Clinical Trials Database: EudraCT 2013-008142-33.

Survival analysis of a cohort of extremely preterm infants born in Finland during 2005-2013.

OBJECTIVE: This study aimed to analyze the mortality of extremely preterm infants (ELGA born alive before 28 weeks) until the postconceptional age of 42 weeks, death, or home discharge, whichever came first. It was focused especially on studying the relationship between antenatal risk factors, the time of death, and the postnatal morbidities associated with mortality. STUDY DESIGN: The original data obtained from the nationwide Finnish medical birth register of extremely preterm and low birthweight infants born during 2005-2013 were analyzed. The total population consisted of 1353 ELGA infants after the exclusion of 18 infants born with lethal congenital anomalies or genetic defects. Mortality risks were adjusted according to the length of gestation, the administration of antenatal steroids, and the delivery hospital. RESULTS: During the first 48 hours, extreme immaturity was seen to be the prominent cause of death, and intrauterine growth did not influence mortality. The ELGA population surviving for at least 48 hours (N = 1135) was submitted for mortality risk analysis. After the adjustments, small-for-gestational-age (SGA) (birth weight below -2 SD) was found to be the factor with the highest risk for demise [OR 6.2; 95% CI (3.9-10.0) p < .001]. Multiple deliveries were associated with increased risk for death [OR 1.5; 95% CI (1.0-2.1), p = .048] to a lesser extent. The main neonatal morbidities associated with the risk of mortality after 48 postnatal hours of life were severe intraventricular hemorrhage (IVH) [OR 4.4; 95% CI (3.0-6.7), p < .001], respiratory distress syndrome (RDS) [OR 2.6; 95% CI (1.3-5.0), p = .006], and necrotizing enterocolitis (NEC) [OR 2.3; 95% CI (1.5-3.4), p < .001]. The major morbidities associated with deaths among non-SGA infants were severe IVH (32.1% of all deaths), NEC (19.1%), and sepsis (8.4%). In SGA infants, severe respiratory disease (RDS, severe bronchopulmonary dysplasia, pulmonary hemorrhage, or pulmonary hypertension) was the main cause of death (60.9% of all deaths). Medical or surgical PDA treatment was not found to be associated with increased risk of death [OR 0.4; 95% CI (0.2-0.5), p < .001] compared to infants who had survived for more than 2 days. Severe preeclampsia was found to be associated with 42% of all ELGA-SGA births. After the adjustments, ELGA infants from pregnancies complicated by preeclampsia of the mother exhibited a significantly lower risk of severe IVH [OR 0.3; 95% CI (0.2-0.5), p < .001] compared to the non-preeclamptic mothers' infants. The low incidence of severe IVH was evident regardless of fetal growth in this patient group. CONCLUSIONS: SGA infants with less than 28 gestational weeks, who had survived for at least 2 days, had excessively high mortality due to severe pulmonary disease. Intrauterine growth had no influence on the risk of death, other than pulmonary causes. The infants of preeclamptic mothers exhibited an increased risk of intrauterine growth retardation; however, despite this serious complication, these infants exhibited a significant decrease in the risk for severe IVH.

Inflammatory biomarkers in very preterm infants during early intravenous paracetamol administration.

BACKGROUND: Paracetamol promotes early closure of patent ductus arteriosus (PDA), and it may affect inflammation after preterm birth. OBJECTIVE: The aim of this study was to evaluate the association between paracetamol treatment and serum inflammatory biomarkers in very preterm infants with respiratory distress. STUDY DESIGN: The infants were randomly assigned to intravenous paracetamol or placebo during the first 4 days of life, and others received a lower dose of paracetamol unblinded. Serum samples were used for the analysis of 10 cytokines, C-reactive protein (CRP) and malondialdehyde (MDA). The impact of paracetamol on the biomarkers was evaluated, based on the levels during the early (<60 h) and the later (60-120 h) postnatal age. RESULTS: Altogether, 296 serum samples from 31 paracetamol and 25 placebo group infants were analysed. Paracetamol had no effect on cytokine levels during the first 60 h when most induced PDA contractions took place. Later paracetamol treatment was associated with lower serum levels of several cytokines, including interleukin (IL-) 10, interferon gamma-induced protein (IP-) 10, and monocyte chemoattractant protein-1. CRP levels were lower in the paracetamol group during the early treatment. Amongst the infants who had severe morbidities, MDA was higher (p = .045), regardless of paracetamol treatment. CONCLUSION: No significant differences in the cytokine levels were evident between the treatment and placebo groups. However, during early treatment, CRP levels were lower in the paracetamol group. To clarify whether this was due to a decrease in cardiopulmonary distress, or a distinct anti-inflammatory effect, requires further studies.

Subgroup analysis of the early paracetamol trial to preterm infants found haemodynamic changes and improved oxygenation.

BACKGROUND: We previously reported in a randomised trial that early intravenous paracetamol accelerated contraction of ductus arteriosus in very preterm infants (<32 gestation weeks). AIMS: To monitor sequentially paracetamol effects on the blood pressure and brain tissue oxygenation in the infants participating the trial. METHODS: In a double-blind trial, intravenous paracetamol or placebo was infused to 48 very premature infants starting within 24 h of birth for four days. Besides the ductus arteriosus, we systematically measured blood pressure, peripheral (spO2) and regional cerebral oxygen saturation (rcSO2), and cerebral fractional tissue oxygen extraction (cFTOE) during the study period. RESULTS: Compared to the placebo, the paracetamol loading dose transiently decreased the arterial blood pressure. During treatment, the paracetamol-treated infants had higher spO2 (p = .042) and rcSO2 (p = .036) values than the placebo group infants. Additionally, the cFTOE values were lower in the paracetamol group during the study without statistical significance. All infants with closed ductus had higher tissue oxygenation and a lower cFTOE than infants with open ductus. CONCLUSIONS: Paracetamol caused modest haemodynamic effects and increased cerebral oxygenation. They were mostly due to early contraction of ductus. Additional direct drug-effects in brain are not ruled-out.

Morbidities associated with patent ductus arteriosus in preterm infants. Nationwide cohort study.

PURPOSE: To evaluate the predictive factors for the development of haemodynamically significant patent ductus arteriosus (PDA) in preterm infants and to study the morbidities associated with the treatment of PDA during the first hospitalization. MATERIALS AND METHODS: Data were collected from the Finnish national register of preterm infants (<32 gestational weeks) born in 2005-2013. In total, 3668 infants were included. Morbidities during the first hospitalization were analysed and compared between infants who received treatments for the closure of PDA (n = 1132) and infants who received no treatment for PDA (n = 2536). The results were adjusted for the duration of pregnancy, intrauterine growth pattern, antenatal steroids, delivery hospital and respiratory distress syndrome (RDS). RESULTS: RDS and mechanical ventilation were independently associated with an increased risk of PDA requiring treatment. Medical and surgical treatments were associated with the risk of severe bronchopulmonary dysplasia (BPD). Primary surgical ligation was associated with an increased risk of severe intraventricular haemorrhage (IVH) and necrotizing enterocolitis (NEC). Medical treatment itself and also followed by surgical ligation was associated with lower mortality. CONCLUSION: The severity of lung disease rather than prematurity per se was associated with the development of PDA requiring therapy. Both medical and surgical therapies for PDA were associated with severe BPD, and primary surgical ligation was associated with NEC and severe IVH.

Early paracetamol treatment associated with lowered risk of persistent ductus arteriosus in very preterm infants.

OBJECTIVES: Persistent ductus arteriosus (PDA) delays the recovery of very preterm infants (VLGA, gestation <32 weeks). Indomethacin/ibuprofen treatment and ligation of PDA have complications. As a prostaglandin synthase inhibitor paracetamol may also promote the closure of ductus arteriosus. We studied retrospectively whether early paracetamol therapy was associated with decreased incidence of PDA without adverse events. METHODS: On June 2009, we introduced intravenous paracetamol during early respiratory therapy. We included 105 VLGA infants who received paracetamol before the age of 72 h. The loading dose was 20 mg/kg followed by 7.5 mg/kg every 6 hours. The 96 VLGA infants admitted from January 2008 to May 2009 without lethal congenital disease were controls. Infants dying very early were excluded, leaving 102 paracetamol-exposed and 88 controls for analysis. RESULTS: After the introduction of paracetamol, the incidence of PDA decreased from 30.7% to 14.7% (p = 0.008). Ibuprofen treatment was given to 15 paracetamol-treated and to 26 control infants (p = 0.013). Three paracetamol-exposed and seven control infants required surgery. There was no detectable increase in adverse events. CONCLUSIONS: Annual incidence of PDA decreased after introduction of paracetamol. Efficacy and safety in promoting the early closure of ductus arteriosus remains to be established.