Extreme prematurity: Factors associated with perinatal management and morbi-mortality in western Normandy, France.

BACKGROUND: Extreme prematurity (birth before 26 weeks of gestation), presents complex challenges and can lead to various complications. Survival rates of extremely preterm infants are lower in France than in other countries. The choice between active and palliative care is decisive in managing these births. OBJECTIVE: To conduct an observational study focused on factors associated with perinatal management, mortality, and morbidity outcomes among extremely preterm births in a regional perinatal network. METHODS: We undertook a retrospective, multicenter study within the western Normandy perinatal network, encompassing live births between 230/6 and 256/6 weeks from 2015 to 2019. Data were extracted from the perinatal network database and medical records. RESULTS: One hundred and seven infants born from 94 women were included. In the antenatal period, 79 were exposed to corticosteroids, 66 to magnesium sulfate, and 67 to antibiotics. Active care at birth was provided to 84 neonates of whom 42 survived. In total, 65 infants died. Among the 42 surviving neonates, 9 experienced no severe morbidity, 29 displayed one and 4 exhibited two criteria of severe morbidity. Active care was associated with gestational age. Neonatal survival was correlated with antenatal exposure to antibiotics and magnesium sulfate as well as with postnatal corticosteroids. We found no significant association between mortality and gestational age at birth. CONCLUSION: Prognostic factors must be weighed to discuss active antenatal care which is crucial for survival of extremely preterm neonates. Cooperation between obstetricians and neonatal caregivers is a cornerstone on a regional perinatal network scale.

Evaluation of quality of care in neonatal anesthesia using a bundle of intraoperative parameters.

BACKGROUND: Maintenance of physiological homeostasis is key in the safe conduct of pediatric anesthesia. Achieving this goal is especially difficult in neonatal surgery. AIMS: The first aim was to document the absolute number of seven intraoperative parameters monitored during anesthesia in neonates undergoing gastroschisis surgery. The second aims were to determine the frequency of monitoring of each of these intraoperative parameters as well as the proportion of cases in which each parameter was both monitored and maintained within a pre-defined range. METHODS: This retrospective observational analysis includes data from 53 gastroschisis surgeries performed at Caen University Hospital (2009-2020). Seven intraoperative parameters were analyzed. First, we assessed if the intraoperative parameters were monitored or not. Second, when monitored, we assessed if these parameters were maintained within a pre-defined range, based on the current literature and on local agreement. RESULTS: The median [first-third Q], range (min-max) number of intraoperative parameters monitored during the 53 gastroschisis surgeries was 6 [5-6], range (4-7). There were no missing data for the automatically recorded ones such as arterial blood pressure, heart rate, end-tidal CO2, and oxygen saturation. Temperature was monitored in 38% of the patients, glycemia in 66%, and natremia in 68% of the cases. Oxygen saturation and heart rate were maintained within the pre-defined range in 96% and 81% of the cases respectively. The blood pressure (28%) and temperature (30%) were instead the least often maintained within the pre-defined range. CONCLUSION: Although a median of six out of the seven selected intraoperative parameters were monitored during gastroschisis repair, only two of them (oxygen saturation and heart rate) were maintained within the pre-defined range more than 80% of the time. It might be of interest to extend physiologic age- and procedure-based approach to the development of specific preoperative anesthetic planning.

Benefits and Risks of Antidepressant Drugs During Pregnancy: A Systematic Review of Meta-analyses.

BACKGROUND: The prescription of antidepressant drugs during pregnancy has been steadily increasing for several decades. Meta-analyses (MAs), which increase the statistical power and precision of results, have gained interest for assessing the safety of antidepressant drugs during pregnancy. OBJECTIVE: We aimed to provide a meta-review of MAs assessing the benefits and risks of antidepressant drug use during pregnancy. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search on PubMed and Web of Science databases was conducted on 25 October, 2021, on MAs assessing the association between antidepressant drug use during pregnancy and health outcomes for the pregnant women, embryo, fetus, newborn, and developing child. Study selection and data extraction were carried out independently and in duplicate by two authors. The methodological quality of included studies was evaluated with the AMSTAR-2 tool. Overlap among MAs was assessed by calculating the corrected covered area. Data were presented in a narrative synthesis, using four levels of evidence. RESULTS: Fifty-one MAs were included, all but one assessing risks. These provided evidence for a significant increase in the risks for major congenital malformations (selective serotonin reuptake inhibitors, paroxetine, fluoxetine, no evidence for sertraline; eight MAs), congenital heart defects (paroxetine, fluoxetine, sertraline; 11 MAs), preterm birth (eight MAs), neonatal adaptation symptoms (eight MAs), and persistent pulmonary hypertension of the newborn (three MAs). There was limited evidence (only one MA for each outcome) for a significant increase in the risks for postpartum hemorrhage, and with a high risk of bias, for stillbirth, impaired motor development, and intellectual disability. There was inconclusive evidence, i.e., discrepant results, for an increase in the risks for spontaneous abortion, small for gestational age and low birthweight, respiratory distress, convulsions, feeding problems, and for a subsequent risk for autism with an early antidepressant drug exposure. Finally, MAs provided no evidence for an increase in the risks for gestational hypertension, preeclampsia, and for a subsequent risk for attention-deficit/hyperactivity disorder. Only one MA assessed benefits, providing limited evidence for preventing relapse in severe or recurrent depression. Effect sizes were small, except for neonatal symptoms (small to large). Results were based on MAs in which overall methodological quality was low (AMSTAR-2 score = 54.8% ± 12.9%, [19-81%]), with a high risk of bias, notably indication bias. The corrected covered area was 3.27%, which corresponds to a slight overlap. CONCLUSIONS: This meta-review has implications for clinical practice and future research. First, these results suggest that antidepressant drugs should be used as a second-line treatment during pregnancy (after first-line psychotherapy, according to the guidelines). The risk of major congenital malformations could be prevented by observing guidelines that discourage the use of paroxetine and fluoxetine. Second, to decrease heterogeneity and bias, future MAs should adjust for maternal psychiatric disorders and antidepressant drug dosage, and perform analyses by timing of exposure.

Neonatal Hypotonia Following in Utero Exposure to Antidepressant Drugs.

Associations between fetal exposure to antidepressants and neonatal hypotonia were studied using VigiBase and the French PharmacoVigilance Database. We identified significant associations between neonatal hypotonia and clomipramine, venlafaxine, and imipramine. Reports from the French database implicated prolonged fetal exposure. Neonatal hypotonia may be associated with in utero exposure to antidepressants.

Prescription of Aminoglycosides in 23 French Neonatal Intensive Care Units.

Background: Aminoglycosides are the most prescribed antibiotics in neonatal intensive care units (NICU). Reducing exposure to antibiotics in the NICU is highly desirable, particularly through benchmarking methods. Methods: Description of aminoglycosides prescriptions in 23 French NICU using the same computerized system over a 4-year period (2017-2020). A benchmarking program of antibiotics prescription was associated. Results: The population included 53,818 patients. Exposition rates to gentamicin and amikacin were 31.7% (n = 17,049) and 9.1% (n = 4894), respectively. Among neonates exposed to gentamicin, 90.4% of gentamicin and 77.6% of amikacin treatments were started within the 1st week of life. Among neonates exposed to amikacin, 77.6% started amikacin within the 1st week. The average daily dose of gentamicin at first prescription increased over the study period from 3.9 in 2017 to 4.4 mg/kg/d in 2020 (p < 0.0001). Conversely, the corresponding amikacin daily doses decreased from 13.0 in 2017 to 12.3 mg/kg/d in 2020 (p = 0.001). The time interval between the first 2 doses of gentamicin was mainly distributed in 3 values during the first week of life: 49.4% at 24 h, 26.4% at 36 h, and 22.9% at 48 h. At first amikacin prescription, the time interval was distributed in 4 categories: 48% at 24 h, 4.1% at 30 h, 8.5% at 36 h, and 37.1% at 48 h. As compared to literature guidelines, the rates of overdose and underdose in gentamicin (1.5% and 2.7%) and amikacin (0.3% and 1.0%). They significantly decreased for gentamicin over the study period. In multivariate analysis, the factors significantly associated with GENT overdose were the year of admission, prematurity, length of stay, and duration of the treatment. Conclusion: This prescription strategy ensured a low rate of overdose and underdose, and some benefits of the benchmarking program is suggested.

Neurodevelopmental Outcomes after Premedication with Atropine/Propofol vs Atropine/Atracurium/Sufentanil for Neonatal Intubation: 2-Year Follow-Up of a Randomized Clinical Trial.

This study followed 173 newborn infants in the PREmedication Trial for Tracheal Intubation of the NEOnate multicenter, double-blind, randomized controlled trial of atropine-propofol vs atropine-atracurium-sufentanil for premedication before nonemergency intubation. At 2 years of corrected age, there was no significant difference between the groups in death or risk of neurodevelopmental delay assessed with the Ages and Stages Questionnaire. Trial registration Clinicaltrials.gov: NCT01490580.

Characteristics of prescription in 29 Level 3 Neonatal Wards over a 2-year period (2017-2018). An inventory for future research.

OBJECTIVES: The primary objective of this study is to determine the current level of patient medication exposure in Level 3 Neonatal Wards (L3NW). The secondary objective is to evaluate in the first month of life the rate of medication prescription not cited in the Summary of Product Characteristics (SmPC). A database containing all the medication prescriptions is collected as part of a prescription benchmarking program in the L3NW. MATERIAL AND METHODS: The research is a two-year observational cohort study (2017-2018) with retrospective analysis of medications prescribed in 29 French L3NW. Seventeen L3NW are present since the beginning of the study and 12 have been progressively included. All neonatal units used the same computerized system of prescription, and all prescription data were completely de-identified within each hospital before being stored in a common data warehouse. RESULTS: The study population includes 27,382 newborns. Two hundred and sixty-one different medications (International Nonproprietary Names, INN) were prescribed. Twelve INN (including paracetamol) were prescribed for at least 10% of patients, 55 for less than 10% but at least 1% and 194 to less than 1%. The lowest gestational ages (GA) were exposed to the greatest number of medications (18.0 below 28 weeks of gestation (WG) to 4.1 above 36 WG) (p<0.0001). In addition, 69.2% of the 351 different combinations of an medication INN and a route of administration have no indication for the first month of life according to the French SmPC. Ninety-five percent of premature infants with GA less than 32 weeks received at least one medication not cited in SmPC. CONCLUSION: Neonates remain therapeutic orphans. The consequences of polypharmacy in L3NW should be quickly assessed, especially in the most immature infants.

Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency Intubation: A Randomized Clinical Trial.

Importance: Propofol or a combination of a synthetic opioid and muscle relaxant are both recommended for premedication before neonatal intubation but have yet to be compared. Objective: To compare prolonged desaturation during neonatal nasotracheal intubation after premedication with atropine-propofol vs atropine-atracurium-sufentanil treatment. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial (2012-2016) in 6 NICUs in France that included 173 neonates requiring nonemergency intubation. The study was interrupted due to expired study kits and lack of funding. Interventions: Eighty-nine participants were randomly assigned to the atropine-propofol group and 82 to the atropine-atracurium-sufentanil group before nasotracheal intubation. Main Outcomes and Measures: The primary outcome was prolonged desaturation (Spo2 <80% lasting > 60 seconds), using intention-to-treat analysis using mixed models. Secondary outcomes assessed the characteristics of the procedure and its tolerance. Results: Of 173 neonates randomized (mean gestational age, 30.6 weeks; mean birth weight, 1502 g; 71 girls), 171 (99%) completed the trial. Of 89 infants, 53 (59.6%) in the atropine-propofol group vs 54 of 82 (65.9%) in the atropine-atracurium-sufentanil group achieved the primary outcome (adjusted RD, -6.4; 95% CI, -21.0 to 8.1; P = .38). The atropine-propofol group had a longer mean procedure duration than did the atropine-atracurium-sufentanil group (adjusted RD, 1.7 minutes; 95% CI, 0.1-3.3 minutes; P = .04); a less frequent excellent quality of sedation rate, 51.7% (45 of 87) vs 92.6% (75 of 81; P < .001); a shorter median time to respiratory recovery, 14 minutes (IQR, 8-34 minutes) vs 33 minutes (IQR, 15-56 minutes; P = .002), and shorter median time to limb movement recovery, 18 minutes (IQR, 10-43 minutes) vs 36 minutes (IQR, 19-65 minutes; P = .003). In the 60 minutes after inclusion, Spo2 was preserved significantly better in the atropine-propofol group (time × treatment interaction P = .02). Of the atropine-propofol group 20.6% had head ultrasound scans that showed worsening intracranial hemorrhaging (any or increased intraventricular hemorrhage) in the 7 days after randomization vs 17.6% in the atropine-atracurium-sufentanil group (adjusted RD, 1.2; 95% CI, -13.1 to 15.5, P = .87). Severe adverse events occurred in 11% of the atropine-propofol group and in 20% of the atropine-atracurium-sufentanil group. Conclusions and Relevance: Among neonates undergoing nonemergency nasotracheal intubation, the frequency of prolonged desaturation did not differ significantly between atropine used with propofol or atropine used with atracurium and sufentanil. However, the study may have been underpowered to detect a clinically important difference, and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01490580, EudraCT number: 2009-014885-25.

Late Surfactant Administration in Very Preterm Neonates With Prolonged Respiratory Distress and Pulmonary Outcome at 1 Year of Age: A Randomized Clinical Trial.

IMPORTANCE: Although immature neonate survival has improved, there is an increased risk of developing bronchopulmonary dysplasia, leading to significant respiratory morbidity. Measures to reduce bronchopulmonary dysplasia are not always effective or have important adverse effects. OBJECTIVE: To evaluate the effect of late surfactant administration in infants with prolonged respiratory distress on ventilation duration, respiratory outcome at 36 weeks' postmenstrual age, and at 1 year postnatal age. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial at 13 level III French perinatal centers. Participants included 118 neonates at less than 33 weeks' gestation who still required mechanical ventilation on day 14 (SD, 2) with fraction of inspired oxygen of more than 0.30. All survivors were eligible for follow-up. We performed an intent-to-treat analysis. INTERVENTIONS: Infants received 200 mg/kg of poractant alfa (surfactant) or air after randomization. At 1 year, after parents' interview, infants underwent physical examination by pediatricians not aware of the randomization. MAIN OUTCOMES AND MEASURES: The duration of ventilation was the primary outcome. The combined outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age and respiratory morbidity at 1 year of age were the main secondary outcome measures. RESULTS: Of the 118 infants who participated in the study, 65 (55%) were male. Fraction of inspired oxygen requirements dropped after surfactant, but not air, for up to 24 hours after instillation (0.36 [0.11] vs 0.43 [0.18]; P < .005). Severe bronchopulmonary dysplasia/death rates at 36 weeks' postmenstrual age were similar (27.1% vs 35.6%; P = .32). Less surfactant-treated infants needed rehospitalization for respiratory problems after discharge (28.3% vs 51.1%; P = .03); 39.5% vs 50% needed respiratory physical therapy (P = .35). No difference was observed for weight (7.8 [1.2] kg vs 7.6 [1.1] kg), height (69 [5] cm vs 69 [3] cm), and head circumference (44.4 [1.7] cm vs 44.2 [1.7] cm) measured at follow-up, nor for neurodevelopment outcome. CONCLUSIONS AND RELEVANCE: Late surfactant administration did not alter the early course of bronchopulmonary dysplasia. However, surfactant-treated infants had reduced respiratory morbidity prior to 1 year of age. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01039285.

Impaired lung function after intubation and mechanical ventilation for surgical ligation of the ductus arteriosus in preterm infants.

OBJECTIVE: Significant patent ductus arteriosus (PDA) in the preterm infant has been associated with pulmonary edema and impaired gas exchange. Therefore, surgical ligature of the DA may be required. However, the effects of intubation and mechanical ventilation on the PDA-induced lung dysfunction presently are unknown. The aim of the study was to investigate whether intubation and mechanical ventilation alter pulmonary function in the preterm infant with significant PDA. DESIGN: A prospective study. SETTING: The neonatal intensive care unit and department of anesthesiology in a university hospital. PARTICIPANTS: Preterm infants <32 weeks' gestational age treated with nasal continuous positive airway pressure (NCPAP) and requiring mechanical ventilation for undergoing surgical DA ligature. INTERVENTIONS: Respiratory, Doppler echocardiographic parameters, and chest x-ray transparencies of the lungs were measured during NCPAP and 2 hours after intubation and starting mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Twenty preterm infants (gestational age = 27 ± 1 wk, birth weight = 950 ± 140 g) were included. Heart rate, O(2) need, PaCO(2), and plasma lactate concentrations were significantly higher after intubation. The mean oxygenation index increased from 1.5 ± 0.6 to 7.2 ± 3 (p < 0.05). The overall transparencies of the lungs decreased after intubation. DA diameter, shortening fraction of the left ventricle, left pulmonary artery blood flow velocities, and left atrium/aorta did not change. CONCLUSION: In preterm infants with significant PDA, intubation and mechanical ventilation before surgical DA ligation may increase the O(2) need and PaCO(2) and may promote lung edema formation. Mechanical ventilation-induced impairment in lung function is not associated with a change in pulmonary or systemic circulation or DA flow. Special care should be taken to prevent respiratory failure when intubation and mechanical ventilation are required for undergoing surgical DA ligation in the preterm infant.

Effects of environmental tobacco smoke on the pulmonary circulation in the ovine fetus.

OBJECTIVE: Epidemiologic studies have highlighted an association between maternal smoking and persistent pulmonary hypertension of the newborn infant. However, the impact of exposure to tobacco smoke on the perinatal pulmonary circulation is currently unknown. The purpose of this study was to assess the pulmonary vascular effects of environmental tobacco smoke in the fetus. STUDY DESIGN: We performed surgery on 16 fetal lambs and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic blood flow transducer was placed around the left pulmonary artery to measure blood flow. The ewes were exposed to tobacco smoke for 2 hours. In another set of experiments, the pulmonary vascular response to increased fetal O(2) tension has been assessed after 2 hours of tobacco smoke inhalation or not (control group). RESULTS: Exposure to tobacco smoke decreased pulmonary blood flow by 30% and elevated pulmonary vascular resistance by 40%. The vasodilator response to increased O(2) tension was blunted after smoke inhalation compared with control animals. Smoke inhalation was associated with a decrease in fetal PaO(2) and SaO(2). CONCLUSION: Exposure to environmental tobacco smoke in pregnant ewes impairs both basal tone and vascular reactivity of the fetal lung.