Paracetamol preceding very preterm birth: Is it safe?

INTRODUCTION: The use of paracetamol for pain relief in pregnancy is common. However, the influence of paracetamol on the perinatal adaptation of high-risk infants has not been studied. These data are important for safety, since another inhibitor of prostaglandin synthesis is harmful to infants born very preterm and increases serious morbidity. We studied whether the use of paracetamol had an adverse influence on neonatal adaptation and the outcomes of infants during the first hospitalization. MATERIAL AND METHODS: We studied the patient records of high-risk mothers and their infants born before 32 weeks of gestation for multiple variables over a period of 84 months in Oulu University Hospital, a regional tertiary care hospital caring for high-risk deliveries and providing neonatal intensive care. In a matched cohort setting, the exposition was defined as paracetamol use <24 h before childbirth. The controls had consumed no paracetamol up to 1 week before delivery. Infants with major anomalies were excluded. The primary outcome was defined as the need for early interventional treatments for the preterm infants. Outcomes during the first hospitalization were also studied. RESULTS: Altogether, 170 fetuses from 149 mothers were exposed to paracetamol during the study period. The control population, delivering during the same period, consisted of 118 non-exposed fetuses from 104 mothers. Among them, the mothers were pairwise matched according to their medications, amniotic fluid leakage time, clinical infections, and delivery mode. After matching, 72 mothers/group remained, resulting in 88 paracetamol-exposed infants and 85 controls. No perinatal adverse reactions were detected. There were no differences in either circulatory support during the first postnatal day or in the risk for major diseases during the first hospitalization. Paracetamol-exposed infants needed fewer acute delivery room therapies (51.1% vs 65.9%, mean difference -14.89; 95% confidence interval -0.29 to -0.003). Maternal total paracetamol dose in the 1 week before delivery correlated positively with Apgar scores. CONCLUSIONS: Antenatal paracetamol given within 24 h before birth had no adverse effects on extremely or very preterm infants. The long-term safety of paracetamol and the potential acute benefits for preterm infants during perinatal transition remain to be proven in larger, prospective settings.

Early closure mechanisms of the ductus arteriosus in immature infants.

AIM: According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects. METHODS: Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus. RESULTS: Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose-dependently constrict the ductus. Ibuprofen and indomethacin cause non-specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low-dose corticosteroid supplementation. CONCLUSION: The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops.

Intravenous Paracetamol Decreases Requirements of Morphine in Very Preterm Infants.

OBJECTIVE: To determine whether intravenous paracetamol therapy is effective in pain therapy in premature infants. STUDY DESIGN: From June 2009 to December 2011, 108 infants born very low gestational age (<32 weeks) (VLGA) were given intravenous paracetamol before the age of 72 hours. The loading dose was 20 mg/kg followed by 7.5 mg/kg every 6 hours. One hundred ten VLGA infants admitted from October 2007 to May 2009 formed the comparison group who received no paracetamol. Intravenous morphine was exclusively used as the opiate. Morphine dosage was calculated as the cumulative dose administered during the neonatal intensive care unit period. Pain symptoms were screened using pain scale scoring Neonatal Infant Acute Pain Assessment Scale. The number of apneas during the neonatal intensive care unit stay, and ventilation days per patient, were calculated. RESULTS: The mean (SD) total number of paracetamol doses per patient was 16.9 (11.7), and the postnatal age for the first dose was 13.3 (13.8) hours. Infants in the paracetamol group needed significantly fewer morphine doses per patient than the comparisons, 1.78 (4.56) doses vs 4.35 (11.53), P = .044. The exposed had lower cumulative morphine dosage 0.17 (0.45) mg/kg vs 0.37 (0.96) mg/kg, P = .047. There were no differences in the Neonatal Infant Acute Pain Assessment Scale scores, or the numbers of apneas, or ventilation days. There was no evidence of adverse events including hepatic toxicity. CONCLUSION: The need for morphine decreased significantly after the introduction of paracetamol for the VLGA infants.

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.

Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach.

BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. OBJECTIVE: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation. METHODS: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. RESULTS: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. CONCLUSIONS: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04459117.

Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure.

OBJECTIVE: To study antenatal risk factors and inflammatory responses during hypoxic respiratory failure (HRF) in infants of very low gestational age (VLGA, ≤32.0 weeks). STUDY DESIGN: Of a cohort of 765 VLGA infants, 144 required mechanical ventilation. Airway specimens from these patients were prospectively studied. Infants who developed HRF (oxygenation index >25) with echocardiographic diagnosis of pulmonary hypertension were treated with inhaled nitric oxide (iNO). Three gestation comparison groups were formed on the basis of specific antenatal complications: prolonged preterm rupture of membranes (PPROM), spontaneous preterm birth, and preeclampsia. Chest radiographs were studied and airway specimens were analyzed for concentrations of tumor necrosis factor-α, interleukin (IL)-6, IL-8, IL-10, IL-12p70, IL-1ß, and nitrite + nitrate over 4 days. RESULTS: Seventeen (2.2% of all VLGA infants) developed HRF. In all 17 cases, PPROM complicated the antenatal course; these infants responded to iNO, regardless of infection or PPROM. The chest radiographs of HRF and non-HRF PPROM infants were similar. Airway proinflammatory cytokines and nitrite + nitrate levels were low in infants with HRF, but they increased during iNO treatment and remained elevated after discontinuation of iNO. Each of the 3 comparison groups had different and characteristic patterns of airway cytokines and nitrite + nitrate levels. CONCLUSIONS: Seven percent of VLGA infants with preterm rupture of membranes and 15% of those with PPROM developed HRF, characterized by pulmonary hypertension that acutely responds to iNO. These infants may have a transient deficiency in the inflammatory response, including a defect in nitric oxide generation in airspaces.

Trial of paracetamol for premature newborns: five-year follow-up.

INTRODUCTION: Paracetamol is a commonly used pain medication for the very-high risk neonates and it is increasingly being used for patent ductus arteriosus treatment in preterm infants. However, randomized trial data on long-term consequences are not yet available, but there is some evidence of serious adverse effects on children exposed to paracetamol during pregnancy. PATIENTS AND METHODS: A five-year follow-up study of a placebo-controlled paracetamol trial on very preterm infants (PreParaS) was conducted (n = 48). Using a web-based parental questionnaire, parents answered questions about their children's cardiac and respiratory symptoms, allergies, neurodevelopment, infections, medications and hospitalizations. RESULTS: Most parents reported that their child had normal development (paracetamol 79% vs. placebo 65%). Physician-diagnosed asthma or allergy (paracetamol 10.5% vs. placebo 25.0%), or hospitalization due to respiratory symptoms (0 vs. 15%) were uncommon and neurological or neuro-psychiatric symptoms were rare. CONCLUSIONS: Current follow-up results on paracetamol-exposed very preterm infants may not be alarming suggesting that paracetamol administration shortly after birth is not associated with common adverse consequences.

Intravenous paracetamol for neonates: long-term diseases not escalated during 5 years of follow-up.

OBJECTIVE: To evaluate the long-term adverse reactions of paracetamol in children who required intensive care shortly after birth. Paracetamol is a widely used analgesic in neonates, but the long-term studies are lacking. Previous epidemiological studies have reported associations between early paracetamol intake and diseases in childhood. DESIGN: Five-year follow-up cohort of children who required intensive care shortly after birth. SETTING: Single tertiary care hospital; neonatal and paediatric intensive care units. INTERVENTIONS: Intravenous paracetamol was administered for pain and discomfort to the neonates during their intensive care, while for the control infants, it was not available. MAIN OUTCOME MEASURES: The primary outcome was the incidence of asthma; secondary outcomes were neonatal diseases and long-term morbidities (atopic dermatitis, inflammatory bowel disease, autism, speech disorders, cerebral palsy). Long-term morbidities were adjusted based on antenatal and neonatal risk factors. RESULTS: We screened all neonates admitted to the intensive care units soon after birth in Oulu University Hospital, Oulu, Finland, during 1 October 2007 to 31 December 2013. Altogether, 1552 infants needed intensive care. Of them, 735 (47%) were treated with intravenous paracetamol. We obtained their long-term data from the Finnish National Institute for Health and Welfare, including all physician-made diagnoses from all primary healthcare units and hospitals in Finland. We found no difference in the asthma incidence or in other long-term morbidities between paracetamol-treated and non-exposed infants. CONCLUSIONS: Intravenous paracetamol given to neonates did not associate with childhood disorders compared with the non-exposed infants during the 5-year follow-up. The previous hypothesis that early paracetamol use causes childhood morbidities was not confirmed.

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.

Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) and Ductus Arteriosus Closure After Premature Birth.

In preterm infants, a high risk of hemodynamically significant patent ductus arteriosus (PDA) exists and its persistence is associated with an increased risk of severe morbidity. Current pharmacological options include ibuprofen or indomethacin. However, treatment by indomethacin or ibuprofen of a large PDA was shown to reduce early pulmonary hemorrhage and later medical treatment but had no effect on neonatal death or morbidity. Early prophylactic treatment of ductus arteriosus by paracetamol seems to be an attractive opportunity to reduce life-threatening morbidity. However, there are currently no data regarding the pharmacokinetics (PK) and pharmacodynamics of paracetamol in preterm neonates in this potential new indication. In this study, we aimed to develop a population PK model for paracetamol and investigate the relationship between paracetamol exposure levels and time to contraction of the ductus. Data were modeled using Monolix software. A one-compartment model adequately described the paracetamol concentration-time course. A Weibull model adequately described the time to contraction of the ductus. Our results suggest that the dosage used in this study (i.e., first day 42.5 mg/kg, then 30 mg/kg/day) allows for reaching the maximum inhibition response from paracetamol regarding the time to close the ductus. However, this study pointed out a lower effect of paracetamol on extremely preterm neonates (below 27 weeks). Therefore, a dose-finding study focusing specifically on extremely preterm neonates with treatment efficacy and toxicity is strongly needed.

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.

NIV NAVA versus Nasal CPAP in Premature Infants: A Randomized Clinical Trial.

BACKGROUND: Noninvasive ventilation is recommended for neonatal respiratory distress to avoid adverse effects of invasive ventilation. OBJECTIVE: The aim of this study was to compare the feasibility of noninvasive neurally adjusted ventilatory assist (NIV NAVA) and continuous positive airway pressure (CPAP) in preterm newborn infants. METHODS: Forty preterm infants (gestational age 28+0 to 36+6 weeks) requiring CPAP and supplemental oxygen (FiO2 >0.23) for respiratory distress at <48 h of postnatal age were randomized to NIV NAVA or CPAP. The primary endpoint was the inspired oxygen concentration 12 h after study inclusion. Secondary endpoints were the duration of oxygen treatment, total duration of respiratory support, parenteral nutrition, blood gas values, patient comfort, need for invasive ventilation, and treatment complications. RESULTS: The mean FiO2 at the time of study inclusion was 0.29 in both groups. After 12 h of treatment, FiO2 was 0.26 ± 0.07 and 0.26 ± 0.04 in the NIV NAVA and CPAP groups, respectively (difference 0.006, 95% CI -0.4 to 0.5), with no difference between the groups during the course of noninvasive ventilation (p = 0.80). Seven patients (35%) in the NIV NAVA group and 10 (50%) in the control group required intubation (difference 15%, 95% CI -15.5 to 4.3, p = 0.36). Time to intubation, gas exchange, vital parameters, pain scale, treatment complications, and neonatal outcome did not differ between the groups. CONCLUSIONS: In the present trial, NIV NAVA had no statistically significant effect on oxygen requirements or the need for invasive ventilation in preterm newborn infants.

Nitrotyrosine and NO synthases in infants with respiratory failure: influence of inhaled NO.

Inhaled nitric oxide (NO) is a selective vasodilator in pulmonary hypertension. However, the safety of inhaled NO (iNO) has not been established. Using an immunohistochemical technique, we studied the expression of NO synthase (NOS) isoforms NOS1, NOS2, NOS3, and nitrotyrosine, the marker of toxic NO-superoxide pathway, in lung specimens from autopsies. Twelve infants dying with respiratory failure had iNO up to 60 parts per million for 0.1-15 days. Twelve control infants were matched in pairs on the basis of the diagnosis, number of gestational days at birth, age at death, and whether extracorporeal perfusion was required. In addition, 5 infants who died of SIDS or nonpulmonary trauma (healthy lungs) were compared to 8 age-matched cases with respiratory failure. Immunostaining was graded by the intensity of the color deposit and the frequency in specific cells stained. Inhaled NO tended to increase NOS2 expression in bronchiolar epithelium and adjacent tissue. There were no other differences in the distribution of nitrotyrosine or NOS isoforms between iNO-treated infants and the control group with respiratory failure. All NOS isoforms were evident in the lungs studied. In severe respiratory failure, nitrotyrosine was mostly detectable in the bronchiolar epithelium and alveolar exudates, whereas in healthy lungs those sites did not contain nitrotyrosine. The alveolar tissue of infants with progressive respiratory may be affected by the NO-superoxide pathway. However, inhalation of NO was not associated with a detectable increase in oxidant stress.

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.

Nitric oxide in critical respiratory failure of very low birth weight infants.

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator. In randomised trials, iNO increased gas exchange modestly and had no effect on the outcome (survival, chronic lung disease, CLD) in very low birth-weight (VLBW) infants. NO is an important component of the innate immune system and a lipid- soluble free radical scavenger that interacts with the surfactant system. VLBW infants with pneumonia and therapy-resistant, severe respiratory failure soon after birth were studied. Despite their infection, there was no detectable alveolar inducible NO synthase or nitrotyrosine, which is a toxic oxidation product of NO. These infants do not respond to exogenous surfactant and demonstrate severe pulmonary hypertension. However, they require exogenous surfactant prior to iNO. In most cases the disease is complicated by pneumonia and prolonged rupture of fetal membranes. We have shown evidence that iNO given within a few hours after birth reverses the progressive course of respiratory failure and pulmonary hypertension in VLBW infants.