Pharmacokinetics and safety of prolonged paracetamol treatment in neonates: An interventional cohort study.

AIMS: To investigate the pharmacokinetics and safety of prolonged paracetamol use (>72 h) for neonatal pain. METHODS: Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. RESULTS: Forty-eight neonates were enrolled (38 received paracetamol for >72 h). Median gestational age was 38 weeks (range 25-42), and bodyweight at inclusion was 2954 g (range 713-4750). Neonates received 16 doses (range 4-55) over 4.1 days (range 1-13.8). The median (range) dose was 10.1 mg/kg (2.9-20.3). The median oxidative metabolite concentration was 14.6 µmol/L (range 0.12-113.5) and measurable >30 h after dose. There was no significant difference (P > .05) between alanine aminotransferase and bilirubin measures at <72 h or >72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44-3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425-0.570), respectively. Median steady-state concentration from the parent model was 50.3 µmol/L (range 30.6-92.5), and the half-life was 3.55 h (range 2.41-5.65). CONCLUSION: Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates.

Preterm birth rates were slightly lower in Denmark during the first year of the COVID-19 pandemic compared with the previous 4 years.

AIM: Our aim was to investigate the rates of preterm births, live births and stillbirths in Denmark during the first year of the COVID-19 pandemic. METHODS: This was a national, cross-sectional registry-based study that used the Danish Newborn Quality database, which covers all births in Denmark. The proportions of preterm births were compared between the COVID-19 pandemic period of 1 March 2020 to 28 February 2021 and the preceding 4-year pre-pandemic period. RESULTS: We studied 60 323 and 244 481 newborn infants from the pandemic and pre-pandemic periods, respectively. The proportion of preterm live births and stillbirths declined slightly, from 6.29% during the pre-pandemic period to 6.02% during the pandemic period. This corresponded to a relative risk (RR) of 0.96, with a 95% confidence interval (CI) of 0.93-0.99 during the pandemic. The RRs for extremely preterm, very preterm and moderately preterm infants were 0.88 (95% CI 0.76-1.02), 0.91 (95% CI 0.82-1.02) and 0.97 (95% CI 0.93-1.01), respectively. CONCLUSION: This comparative study showed a small reduction in just over 4%, from 6.29 to 6.02% in the proportion of all preterm births during the pandemic period, compared with the previous four pandemic-free years. There were no differences between subcategories of preterm births.

Seasonal variation in the hypertensive disorders of pregnancy in Denmark.

INTRODUCTION: Hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, are leading causes of morbidity and mortality for both mother and fetus. It has been proposed that vitamin D affects a number of biological processes involved in the pathogenesis of hypertensive disorders of pregnancy. Therefore, a seasonal variation in the risk of these disorders might be expected in areas such as Denmark with marked seasonal variation in sunlight exposure. In this study, we aimed to evaluate the existence of this association. MATERIAL AND METHODS: We used information from a cohort of 50 665 previously healthy, nulliparous women with singleton pregnancies. All women gave birth between 1989 and 2010 at Aarhus University Hospital, Denmark. Logistic regression analyses combined with the cubic spline method were used to estimate the seasonal variation for each outcome: gestational hypertension and preeclampsia, after adjusting for calendar time. RESULTS: Of the 50 665 women included, 8.5% were diagnosed with a hypertensive disorder of pregnancy. The overall tendency was towards increasing risk when conceiving during spring and early summer, peaking midsummer, and subsequently decreasing steadily during late summer and fall to reach the nadir by winter. Seasonal variation was found for; gestational hypertension (P = .01); preeclampsia (P = .001) and early-onset preeclampsia (P = .014). CONCLUSIONS: We found a seasonal variation in the risk of the hypertensive disorders of pregnancy in a large cohort of Danish nulliparous women. The highest risk was seen in women with the estimated date of conception in June and August, that is, during summer. Seasonal variation in vitamin D status may explain this association.

Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study.

INTRODUCTION: Anticipated or actual pain in neonates results in use of paracetamol for prolonged pain relief in many neonatal intensive care units. Clinical trials examining safety of paracetamol exposure in neonates have been of short duration (1-3 days) and hepatic biomarkers and paracetamol metabolism are rarely reported in the same studies.We aim to investigate the safety (hepatic tolerance) and effectiveness of prolonged paracetamol exposure in neonates by measuring hepatic biomarkers, plasma concentrations of paracetamol and its metabolites and pain scores. In addition, we study a possible interaction between ethanol and paracetamol. METHODS AND ANALYSIS: A multicentre interventional cohort study.Neonates of any gestational age and up to 44 weeks postmenstrual age, treated with oral or intravenous paracetamol can be included.Alanine aminotransferase (ALT) and bilirubin are measured at baseline or within 24 hours after treatment initiation. P-paracetamol and metabolites are measured at steady state and every 2 days (opportunistically) together with ALT and bilirubin and lastly after discontinuation of treatment. COMFORT neo pain scores are collected longitudinally. COMFORT neo pain scores and population pharmacokinetic analysis of paracetamol samples will be analysed simultaneously using non-linear mixed effects models. One and two compartment models with first-order elimination will be tested for disposition. In addition, plasma ethanol is measured if the patient receives concomitant treatment with intravenous or oral phenobarbital containing ethanol as an excipient. ETHICS AND DISSEMINATION: Inclusion of patients can be postponed 24 hours after the first paracetamol dose. This is intended to make the inclusion process less stressful for parents. This study uses standard dosing strategies. The potential risks are additional blood samples, which are collected opportunistically to reduce additional heel pricks. TRIAL REGISTRATIONNUMBER: Ethics Comittee: H-17027244, EudraCT no: 2017-002724-25, BFH-2017-106, 05952.

Does physical activity during pregnancy adversely influence markers of the metabolic syndrome in adult offspring? A prospective study over two decades.

BACKGROUND: It is unknown whether physical activity during pregnancy (PA) has long-term impact on the metabolic profile of the offspring. We investigated associations of PA with markers of the metabolic syndrome (MS) in 20y old offspring. METHODS: Longitudinal study where 965 pregnant women during 1988-1989 had four dimensions of PA assessed by questionnaires in gestation week 30: PA at work; leisure time PA, daily amount of walking-biking and sport participation. The following MS markers were assessed in the offspring (n=439): body mass index (BMI), waist circumference, blood pressure, homeostasis model assessment insulin resistance as well as fasting plasma glucose, triglycerides, cholesterol (high-density lipoprotein (HDL), low-density lipoprotein and total cholesterol), insulin and leptin levels. RESULTS: Walking-biking PA in pregnancy is associated with unchanged or subtle, adverse changes of distinct MS markers among offspring including lower levels of HDL cholesterol (ratio 0.95 (95% CI 0.92 to 0.98) per 1 h increment in walking-biking), a higher diastolic blood pressure (difference 1.12 (95% CI 0.03 to 2.20) mm Hg/1 h increment) and a higher BMI (ratio 1.03 (95% CI 1.01 to 1.05) per 1 h increment). In separate analyses in males, these associations persisted and additional adverse associations were found for triglycerides, systolic blood pressure, waist circumference and leptin. No associations were detected with other measures of PA. CONCLUSIONS: The study did not substantiate any protective effects of PA in pregnancy. In contrast, data suggested that high amounts of daily walking-biking in pregnancy may have adverse effects on levels of HDL cholesterol, diastolic blood pressure and BMI in young adult offspring.

Cigarette smoking during pregnancy and hyperactive-distractible preschooler's: a follow-up study.

AIM: To study the association between intrauterine exposure to tobacco smoke and behavioural disorders in preschool children, primarily symptoms of inattention, hyperactivity and impulsivity but also hostile-aggressive and anxious-fearful symptoms. METHODS: We conducted a follow-up study in 1355 singletons born to Danish-speaking mothers. Information on smoking habits during pregnancy and other lifestyle factors was obtained from self-administered questionnaires filled in during second and third trimester. Approximately 3.5 years later, the parents provided information on their child's behaviour using the self-administered Preschool Behaviour Questionnaire. The children were categorized into three not mutually exclusive behaviour groups: hyperactive - distractible (13.6%), hostile-aggressive (4.6%), and anxious-fearful (6.4%) children. RESULTS: Compared with children of non-smokers, children born to women who smoked 10 or more cigarettes per day had a 60% increased risk of hyperactivity and distractibility perceived by the parents (OR 1.6; 95% CI 1.0-2.3; P < 0.05). The results were adjusted for maternal lifestyle factors and socioeconomic characteristics. Additional adjustment for perinatal factors and parental psychiatric hospitalization did not change the results substantially (OR 1.7; 95% CI 1.1-2.6). We found no statistically significant association between maternal smoking in pregnancy and hostile-aggressive and anxious-fearful behaviour in the offspring. CONCLUSION: Exposure to tobacco smoke in utero was associated with hyperactive-distractible behaviour in preschool children.