Marie-Amélie De Tristan

MD, MSc Laetitia Martin-Marchand

MSc Jean-Michel Roué

PhD ; Kanwaljeet

J S Anand

MBBS D Phil

Véronique Pierrat

PhD ; Pierre Tourneux

PhD Pierre Kuhn

MD, PhD Christophe Milesi

MD Valérie Benhammou

PhD ; Pierre-Yves Ancel

PhD Ricardo Carbajal

PhD ; Xavier Durrmeyer
email: xavier.durrmeyer@chicreteil.fr

Association of Continuous Opioids and/or Midazolam during Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort Authors

The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database. Consultation by the editorial board or interested researchers may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

Objective: To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2 years in ventilated very premature infants.

Study design:

This national observational study included premature infants born before 32 weeks of gestation intubated within 1 hour after birth and still intubated at 24 hours from the French EPIPAGE 2 cohort. Bolus only-treated infants were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7 days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n=450) vs naive (n=472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age 2.

Results: Survival at age 2 was significantly higher in the treated group (92.5% vs 87.9%, risk difference [RD] 4.7%; 95%CI, 0.3 to 9.1; P=.037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%, RD 5.3%; 95%CI -0.3 to 11.0; P=.063). These results were confirmed by sensitivity analyses using 5 alternative models.

Conclusion:

Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24 hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2 years.

"No sedation" strategies in adults receiving mechanical ventilation usually include intermittent analgesia because mechanical ventilation causes discomfort. [START_REF] Strom | A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial[END_REF] Because of widespread concerns about developmental neurotoxicity, 2 however, many neonates receive mechanical ventilation without any sedation or analgesia. A European cohort study in 2012-2013 of 2142 neonates undergoing invasive ventilation reported that 18% received no analgesic, sedativehypnotic, or anesthetic treatment. [START_REF] Carbajal | Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study[END_REF] Current evidence does not support routine use of opioids [START_REF] Bellu | Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis[END_REF] or midazolam [START_REF] Ng | Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit[END_REF] in neonates undergoing mechanical ventilation. In 2019, however, clinical guidelines recommended continuous opioids for premature infants undergoing prolonged mechanical ventilation, based on a moderate level of evidence. [START_REF] Ancora | Evidencebased clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation[END_REF] The limited evidence of the risk/benefit ratio for opioid and sedative use indicates that current practices are heterogeneous. [START_REF] Carbajal | Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study[END_REF] analgesia/sedation is justified for ethical reasons and by the poorer longterm neurodevelopmental outcomes associated with repeated or prolonged painful experiences in the neonatal period. [START_REF] Valeri | Neonatal pain and developmental outcomes in children born preterm: a systematic review[END_REF] On the other hand, follow-up studies of randomized controlled trials comparing opioids with placebo in ventilated neonates [START_REF] De Graaf | Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial[END_REF][START_REF] Ferguson | A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood[END_REF][START_REF] Ancora | Follow-up at the corrected age of 24 months of preterm newborns receiving continuous infusion of fentanyl for pain control during mechanical ventilation[END_REF][START_REF] De Graaf | Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?[END_REF] and observational studies of neonatal opioid or sedative exposure [START_REF] Rozé | Prolonged Sedation and/or Analgesia and 5-Year Neurodevelopment Outcome in Very Preterm Infants[END_REF][START_REF] Zwicker | Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine[END_REF][START_REF] Steinhorn | Neonatal morphine exposure in very preterm infants-cerebral development and outcomes[END_REF][START_REF] Kocek | Evaluation of the relationship between opioid exposure in extremely low birth weight infants in the neonatal intensive care unit and neurodevelopmental outcome at 2 years[END_REF][START_REF] Lammers | Association of fentanyl with neurodevelopmental outcomes in very-low-birth-weight infants[END_REF][START_REF] Duerden | Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants[END_REF] provide conflicting results about their effects on neurodevelopment.

This study was conducted to assess the risk of long term neurotoxicity associated with start analgesia and/or sedation with continuous opioids/midazolam in the early course of a ventilated infant. Therefore, we analyzed the association between treatment with continuous opioids and/or midazolam during early mechanical ventilation and survival and sensorimotor outcomes at age 2 years among very premature infants still intubated after 24 hours of life.

We hypothesized that infants treated with opioids and/or midazolam would have survival rates and sensorimotor outcomes similar to those of infants who were not treated, after adjustment for probability of treatment.

METHODS

The EPIPAGE 2 (Etude éPIdémiologique sur les Petits Ages GEstationnels 2) study is a nationwide, prospective, observational, longitudinal birth-cohort study that recruited premature infants from March through December 2011. [START_REF] Ancel | EPIPAGE 2: a preterm birth cohort in France in 2011[END_REF][START_REF] Ancel | Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study[END_REF] Infants born at 22-26 weeks' gestation were recruited over eight months, those born at 27-31 weeks' gestation over six months, and those born at 32-34 weeks' gestation during a five-week period. [START_REF] Ancel | EPIPAGE 2: a preterm birth cohort in France in 2011[END_REF] All survivors were enrolled for longitudinal follow-up and included in the study at 2 years' corrected age if parents consented. [START_REF] Pierrat | Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks' gestation in France in 2011: EPIPAGE-2 cohort study[END_REF] Infants eligible for this study were born between 23 and 31 +6 weeks of gestation, were intubated in the delivery room or within the first hour of life, and remained intubated more than 24 hours after birth. They were excluded if born with major congenital abnormalities [START_REF] Delorme | Cause of Preterm Birth as a Prognostic Factor for Mortality[END_REF] or if the start date for opioid and/or midazolam treatment was missing.

Acknowledging that continuous analgesia and/or sedation were the preferred modalities in France [START_REF] Carbajal | Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study[END_REF] and that boluses of opioids or midazolam were at risk of adverse events [START_REF] Hall | Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial[END_REF][START_REF] Van Alfen-Van Der Velden | Effects of midazolam and morphine on cerebral oxygenation and hemodynamics in ventilated premature infants[END_REF][START_REF] Van Straaten | Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn[END_REF] , we excluded infants treated with boluses only. However, add on boluses during continuous opioids and/or midazolam administration were possible. Infants with a decision to limit or withhold care in the first week of life were also excluded because midazolam and/or opioids use in these infants was possibly part of palliative care, which was outside the scope of the present study.

Treated infants were those who received a continuous infusion of opioids and/or midazolam at some point during this first intubation period, before the age of 7 days. The naive group comprised those infants who did not receive a continuous infusion of opioids and/or midazolam during this first intubation; or who received these treatments only after the age of 7 days or after their first extubation (whichever came first); or never received these treatments. The treated and naive populations were defined using these criterions in order to mimic an interventional trial, i.e. without knowing possible later exposure to the studied drugs during the patient's clinical course.

This study focused on the first episode of invasive ventilation after birth because although guidelines recommend [START_REF] Sweet | European Consensus Guidelines on the Management of Respiratory Distress Syndrome -2019 Update[END_REF] and current practices corroborate [START_REF] Ferguson | Interventions to Improve Rates of Successful Extubation in Preterm Infants: A Systematic Review and Meta-analysis[END_REF] early extubation of intubated infants rapidly after birth, a common clinical question is whether to start analgesic and/or sedative treatment when extubation has not occurred soon after birth. [START_REF] Ancora | Evidencebased clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation[END_REF] In addition, we deemed this approach necessary for our data to be comparable with those from randomized controlled trials on this topic, which included intubated neonates in their first hours or days after birth. [START_REF] Simons | Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial[END_REF][START_REF] Anand | Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial[END_REF]

Outcomes

The 2 primary outcomes were death before corrected age 2 years and survival at this age without moderate or severe neuromotor or sensory disabilities, as previously defined. [START_REF] Pierrat | Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks' gestation in France in 2011: EPIPAGE-2 cohort study[END_REF] Data for cerebral palsy, vision, and hearing were obtained from medical reports available at the age-2 examination. Cerebral palsy was defined according to the diagnostic criteria of the Surveillance of Cerebral Palsy in Europe (SCPE) network, [START_REF]Surveillance of Cerebral Palsy in Europe. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Surveillance of Cerebral Palsy in Europe (SCPE)[END_REF] and motor ability was graded with the five-level Gross Motor Function Classification System (GMFCS). [START_REF] Ghassabian | Gross Motor Milestones and Subsequent Development[END_REF] Sensory disability was defined by deafness or blindness, and was considered to be moderate (unilateral) or severe (bilateral). Severe neuromotor or sensory disabilities included any of GMFCS level 3-5 cerebral palsy or severe visual or auditory impairment; moderate disability included GMFCS level 2 cerebral palsy and/or moderate visual or auditory impairment. Children without severe or moderate neuromotor or sensory disabilities had either no or minor neuromotor or sensory disabilities.

Secondary outcomes included outcomes at hospital discharge: survival without severe morbidities, [START_REF] Ancel | Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study[END_REF] severe brain abnormalities on brain ultrasound before discharge (defined as grade III or IV IVH and/or periventricular leukomalacia), cumulative mechanical ventilation duration, and length of hospitalization for infants surviving to discharge. They also included 2 outcomes at 2 years' corrected age: cerebral palsy and an Ages and Stages Questionnaire (ASQ) score below threshold defined as a score lower than two standard deviations below the mean on any of the 5 domains (communication abilities, gross and fine motor skills, problem solving abilities, and personal-social skills) [START_REF] Flamant | Parent-completed developmental screening in premature children: a valid tool for follow-up programs[END_REF] .

Statistical analyses

A propensity score approach was used to control for the nonrandom assignment of patients to the treated or naive groups. The propensity score was defined as the infant's probability of exposure to continuous opioids and/or midazolam based on his/her individual observed covariates and estimated with a logistic regression model. In this model, opioid and/or midazolam treatment was the dependent variable and was studied in relation to the baseline characteristics clinically or statistically associated with the exposure and/or the outcome. The propensity score included the following covariates: gestational age; sex; intrauterine growth restriction (birth weight < 10th centile for gestational age and sex, based on the French "EPOPé" intrauterine growth curves 32 ); cause of prematurity in 4 classes: preterm premature rupture of membranes, preterm labor, hypertensive disorders, and other causes (e.g., placental abruption, triplet or quadruplet births); antenatal steroid use; prenatal magnesium sulfate use; delayed cord clamping; inborn status; mode of delivery (cesarean or vaginal); maternal anesthesia (general, epidural, or no anesthesia); birth asphyxia defined as a 5minute Apgar score <7 or base deficit <-7 in the first 12 hours of life; number of doses of surfactant received (0, 1, or 2 or more); caffeine treatment in the first 2 days of life; maternal age (<25, 25-35 or > 35 years); mother's country of birth (France or elsewhere); parity; number of children (singleton or multiple); and family socioeconomic status, defined as the highest occupational status of the mother and father, or the mother only if she was a single parent, divided into 4 categories: management jobs, public and administrative jobs, workers or no job declared. We also included in the model the volume of activity of the unit where the infant was born, defined by the number of infants included in the EPIPAGE 2 study in the unit, divided into terciles.

The main analysis used inverse probability of treatment weighting (IPTW) to attribute different weights to children according to their propensity score, that is, their probability of assignment to receive opioid and/or midazolam treatment. By this weighting, we created a synthetic sample (IPTW sample) in which treatment assignment was independent of measured baseline covariates. [START_REF] Austin | The performance of inverse probability of treatment weighting and full matching on the propensity score in the presence of model misspecification when estimating the effect of treatment on survival outcomes[END_REF][START_REF] Thomas | Using Propensity Score Methods to Create Target Populations in Observational Clinical Research[END_REF] Balance in the observed baseline covariates between treated and naive patients in the initial and IPTW samples was assessed by examining standardized differences. A standardized difference below 10% is considered an acceptable imbalance between groups. [START_REF] Austin | Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples[END_REF] In the initial sample all percentages were weighted to take differences in the recruitment periods into account for infants born at 24-26 weeks and 27-31 weeks. Comparisons between groups for treatment exposure through hospital discharge used the Rao-Scott Fadjusted chi-square.

Differences in outcomes between groups were expressed as risk differences calculated with a generalized estimating equation (GEE) regression analysis to take the center effect into account. Survival in both groups was estimated by Kaplan-Meier survival curves and compared with Cox models in the IPTW sample. All tests were 2-sided and P values less than .05 were considered significant.

Missing data were handled with multiple imputations using chained equations with the R package 'mice'. Imputation model variables included exposure to continuous opioids and/or midazolam, propensity score variables, and outcomes. Categorical variables were imputed by using logistic or multinomial regression and continuous variables by a linear regression model. We generated 50 independent imputed datasets with 30 iterations each, pooled according to the Rubin rule. [START_REF] Rubin | Multiple imputation in health-care databases: an overview and some applications[END_REF] All analyses were performed with R (version 3.6.1) and SAS (version 9.4) software packages.

Six sensitivity analyses, primarily intended to reduce the effect of extreme weights within the propensity score, were conducted by: a) symmetric trimming of weights; 37 b) asymmetric trimming of weights; 38 c) overlap weighting; 39 d) stabilized weights; 40 e) propensity score matching; and f) negative control [START_REF] Lipsitch | Negative controls: a tool for detecting confounding and bias in observational studies[END_REF] , i.e. an outcome that is not expected to be different between groups such as the proportion of children with a weight inferior to the 10 th percentile of the World Health Organization (WHO) 42 curve at the 2-year visit.

We performed exploratory analyses similar to the main analysis in these subgroups defined a priori: 1) infants born before 29 weeks' gestation; 2) infants treated only with opioids in the treated group; 3) infants treated with midazolam in the treated group; 4) only infants who never received continuous opioids and/or midazolam at any time in the naive group. A new propensity score was calculated in each of these specific populations.

Ethics

RESULTS

Population

The study included 922 of the 981 eligible infants born before 32 weeks of gestation and still intubated at 24 hours after birth (Figure 1). Baseline characteristics of the treated (n=450) and naive (n=472) groups before imputation are summarized in Table I (available at www.jpeds.com). Table II andFigure 2 (available at www.jpeds.com) show the standardized differences between treated and naive groups in the initial and IPTW samples. Standardized differences ranged from 0.6 to 35.5 in the initial sample and were below 0.10 for all covariates after IPTW. Distributions of propensity scores and of weights are illustrated in Figure 3, A and B (available at www.jpeds.com), respectively and show a substantial overlap.

Throughout their hospitalization, infants in the treated group were significantly more frequently exposed to the studied drugs than infants from the naive group (Table III) because 290 infants (63.7%) in the naive group never received continuous opioids or midazolam. In the first week after birth and before their first extubation, infants in the treated group received the following drugs, alone or in combination, by continuous infusion: sufentanil (n=241), midazolam (n=161), which was the only sedative used, morphine (n=125), and fentanyl (n=69). Among the 161 infants treated with midazolam, 34 received it alone and 127 received an association of midazolam and opioids. Some infants in the treated group also received continuous opioids and/or midazolam after day 7 or their first extubation but less frequently than those in the naive group (Table III). After their first extubation or after the age of 7 days 182 infants in the naive group received the following drugs alone or in combination: midazolam (n=113), sufentanil (n=97), morphine (n=77), and fentanyl (n=24) (Table III).

Neuromotor and/or sensory status were imputed for 94 infants in the treated and 107 in the naive group.

Primary outcomes

At 2 years' corrected age, survival was significantly higher in the treated group: 92.5% vs 87.9% in the naive group (adjusted risk difference 4.7, 95% CI 0.3 to 9.1, P=.037) (Table IV).

Survival without moderate or severe neuromotor or sensory disabilities at that age was 86.6% in the treated group vs 81.3% in the naive group (adjusted risk difference 5.3%, 95% CI -0.3 to 11.0, P=.063) (Table IV).

Secondary outcomes

At hospital discharge, survival without severe morbidity, severe brain abnormalities on brain ultrasound, duration of mechanical ventilation, and length of hospitalization did not differ significantly between the treated and naive groups (Table IV). Similarly, rates of cerebral palsy and ASQ below threshold were not significantly different between the groups at age 2 years (Table IV).

Figure 4 (available at www.jpeds.com) presents the Kaplan-Meier mortality curves over the first 150 days in both groups. Over time, cumulative mortality was lower in the treated group (log rank test P=.035). In-hospital causes of death for the initial cohort are reported in Table V (available at www.jpeds.com).

Sensitivity and subgroup analyses

The survival rate at 2 years' corrected age was significantly higher in the treated group when symmetric or asymmetric trimming of weights and stabilized weights were used, but the difference between the groups did not reach statistical significance with overlap weighting or a propensity score-matched cohort (Table VI; available at www.jpeds.com). Survival without moderate or severe neuromotor or sensory disabilities at this age did not differ significantly between the groups in any sensitivity analyses (Table VI). The result with negative control showed that the proportion of infants with a weight below the 10 th percentile of the WHO curve 42 was not significantly different between groups (32.5% in the treated vs 30.0% in the naive group, P=.49).

The results of the exploratory subgroup analyses were consistent with the main analysis among infants born before 29 weeks' gestation (Table VII; available at www.jpeds.com), in the analysis including infants who received only continuous opioids in the treated group (Table VIII; available at www.jpeds.com), in the analysis including infants who received continuous midazolam in the treated group (Table IX; available at www.jpeds.com), and that including infants who never received continuous opioids and/or midazolam in the naive group (Table X; available at www.jpeds.com).

DISCUSSION

In this nationwide comparative effectiveness study, continuous opioid and/or midazolam infusions during a first episode of invasive ventilation that started on day 1 were significantly associated with higher survival rates. Furthermore, no harmful effect on survival without moderate or severe sensorimotor impairment was observed at 2 years' corrected age.

Previous randomized trials in intubated premature infants reported that death rates did not differ significantly between morphine-and placebo-treated infants. [START_REF] Simons | Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial[END_REF][START_REF] Anand | Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial[END_REF][START_REF] Anand | Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates[END_REF] Hypotheses potentially explaining the better survival include the use of continuous infusion as opposed to boluses, the type of opioids used, or chance. In the NEOPAIN trial, morphine boluses were suspected of having adverse effects in hypotensive extremely immature infants, [START_REF] Hall | Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial[END_REF] but continuous infusion of morphine was not an independent risk factor for high-grade intraventricular hemorrhage in logistic regression models. [START_REF] Anand | Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial[END_REF] Despite the limited literature about sufentanil in neonates, it was the opioid most frequently used in the present study. [START_REF] Nguyen The Tich | Effects of sufentanil on electroencephalogram in very and extremely preterm neonates[END_REF][START_REF] Schmidt | Comparison of sufentanil versus fentanyl in ventilated term neonates[END_REF][START_REF] Seguin | Safety and efficacy of sufentanil therapy in the ventilated infant[END_REF][START_REF] Soreze | Reduced Sufentanil Doses are Effective for Postoperative Analgesia After Ductal Closure in Extremely Premature Infants: A 10 Years Retrospective Cohort Study[END_REF] Whether all opioids have similar effects on human neurodevelopment is unknown, although an animal study suggested that sufentanil, but not fentanyl, might protect the developing brain from injury. [START_REF] Laudenbach | Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain[END_REF] However, considering the potential deleterious effects of continuous fentanyl, a molecule close to sufentanil, on long-term outcomes in preterm neonates [START_REF] Ancora | Follow-up at the corrected age of 24 months of preterm newborns receiving continuous infusion of fentanyl for pain control during mechanical ventilation[END_REF] , cautious use of sufentanil should be recommended.

Follow-up studies of randomized controlled trials comparing sensorimotor outcomes in ventilated infants who received morphine or placebo in the first week of life have yielded conflicting results. Neonates from a multicenter trial from 2000 to 2002 who were randomized to morphine vs placebo had significantly lower scores on the ''visual analysis'' IQ subtest at age 5 years. [START_REF] De Graaf | Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial[END_REF] However, the next follow-up study from the same trial found no deleterious effect and possible positive effects of morphine on executive function [START_REF] De Graaf | Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?[END_REF] and pain sensitivity [START_REF] Valkenburg | Long-Term Effects of Neonatal Morphine Infusion on Pain Sensitivity: Follow-Up of a Randomized Controlled Trial[END_REF] at age 8-9 years. Currently, the largest randomized controlled trial comparing morphine with placebo recruited 898 neonates, [START_REF] Anand | Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial[END_REF] but the assessment of only 19 of them at the age 5-year follow-up precludes any conclusions. [START_REF] Ferguson | A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood[END_REF] Prospective cohort studies have reported neonatal morphine exposure is associated with impaired cerebellar growth, [START_REF] Zwicker | Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine[END_REF] regional diminution of cortical volumes, and short-term behavioral impairments [START_REF] Steinhorn | Neonatal morphine exposure in very preterm infants-cerebral development and outcomes[END_REF] in very preterm neonates. However, these studies neither adjusted for such potential confounders as obstetric or parental factors [START_REF] Zwicker | Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine[END_REF][START_REF] Steinhorn | Neonatal morphine exposure in very preterm infants-cerebral development and outcomes[END_REF] nor attempted to reduce bias by a propensity score approach, as here. Nevertheless, considering the potential deleterious dose-dependent effect of opioids [START_REF] Zwicker | Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine[END_REF] , assumptions on administered doses in the present study can be made. In the 2 randomized controlled trials conducted at the beginning of the 21 st century, morphine was used with an initial bolus of 100 µg/kg followed by infusions of at least 10 µg/kg/h [START_REF] Simons | Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial[END_REF][START_REF] Anand | Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial[END_REF] . Since the second decade of the 21 st century, lower doses have been recommended for morphine starting at 5 µg/kg/h [START_REF] Ancora | Evidencebased clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation[END_REF][START_REF] Durrmeyer | Use of analgesic and sedative drugs in the NICU: integrating clinical trials and laboratory data[END_REF] with even lower doses (2.5 µg/kg 1.5 /h for infants aged less than 10 days) in a clinical trial assessing the efficacy of paracetamol for postoperative analgesia in neonates [START_REF] Ceelie | Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial[END_REF] . Although large cohort studies do not report data on analgesic' or sedatives ' doses used [START_REF] Carbajal | Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study[END_REF][START_REF] Mehler | Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003-2010[END_REF] , we can speculate, based on the previous comments and personal practices [START_REF] Soreze | Reduced Sufentanil Doses are Effective for Postoperative Analgesia After Ductal Closure in Extremely Premature Infants: A 10 Years Retrospective Cohort Study[END_REF] , that opioids and midazolam were administered in the present study with the goal of using the minimal effective dose. We can also speculate that these treatments were used based on clinical indications, not as a routine procedure as in an interventional trial. However, we had no information on unit's protocols to support this assumption. The differences in outcomes observed between the present study and the previously published randomized controlled trials [START_REF] Simons | Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial[END_REF][START_REF] Anand | Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial[END_REF] could thus be attributable to a "doseeffect" and/or to a more appropriate selection of treated infants.

A Cochrane review of midazolam included only 3 studies published between 1994 and 2001 and concluded that further research is needed about its effectiveness and safety in ventilated neonates. [START_REF] Ng | Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit[END_REF] An observational study reported an association between midazolam and impaired development at 18 months. [START_REF] Duerden | Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants[END_REF] Although reported data have not supported the use of midazolam in the neonate [START_REF] Ng | Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit[END_REF] this drug it is still commonly used in the NICU worldwide as illustrated by several large cohort studies: 18% of VLBW infants received midazolam in Germany in 2010 [START_REF] Mehler | Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003-2010[END_REF] , 25% of ventilated neonates received midazolam in European NICUs in 2012-2013 [START_REF] Carbajal | Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study[END_REF] , 17% of preterm infants born< 33 weeks GA received midazolam or other sedatives in Canadian NICUs between 2010 and 2014 [START_REF] Borenstein-Levin | Narcotics and Sedative Use in Preterm Neonates[END_REF] , and in 2012 in the US, 24% of ventilated very preterm infants participating in the Pediatrix Medical Group Data Warehouse received benzodiazepines [START_REF] Zimmerman | Sedation, Analgesia, and Paralysis during Mechanical Ventilation of Premature Infants[END_REF] . The present results do not support any sensorimotor toxicity of midazolam, keeping in mind the unknown doses used and the difficulty in identifying midazolam's specific toxicity due to its frequent use in combination with other drugs such as opioids.

Nevertheless, reducing the use of opioids and benzodiazepines in premature neonates seems desirable and future studies should more carefully assess the risk/benefit ratio of other drugs such as paracetamol or dexmedetomidine. [START_REF] Tauzin | Managing neonatal pain in the era of non-invasive respiratory support[END_REF] The strengths of this study include its population-based cohort design and the prospective enrollment of very preterm infants in France in 2011. The data collected reflect daily bedside practices and enabled the inclusion of a broad non-selected sample, as opposed to a randomized trial requiring perinatal consent and perhaps with a risk of selection bias affecting outcomes regardless of the allocated arm. [START_REF] Rich | Enrollment of extremely low birth weight infants in a clinical research study may not be representative[END_REF] This study also has a much larger population than any previous analgesia/sedation study with a 2-year follow-up. Standardized definitions of outcomes following international recommendations and systematic and prospective data collection increase its external validity and comparability with previous studies. Because French practices in this area do not differ greatly from those in many other European countries, [START_REF] Carbajal | Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study[END_REF][START_REF] Mehler | Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003-2010[END_REF] these results may be applicable elsewhere. The numerous sensitivity analyses, generally consistent with the main analysis, support the robustness of the results.

Limitations

First, infants who had been intubated between 1 and 24 hours after birth or extubated before 24 hours were not included in this study; we sought to exclude infants intubated for surfactant administration and rapid extubation and those with very short-term ventilation. The current findings, therefore, apply to the majority of preterm infants with prolonged (> 24 hours) primary respiratory failure due to lung immaturity. It might not apply in settings where invasive ventilation is delayed in favor of non-invasive ventilation. Second, the naive group as defined in the study's design included infants who received midazolam and/or opioids after their first episode of mechanical ventilation, which could be considered as a confounding factor. In addition, no information was available on the indication for these later treatments. We can not rule out that these infants received these late treatments because of prolonged mechanical ventilation or complications such as necrotizing enterocolitis or sepsis.

However, survival without neonatal morbidity and cumulated durations of invasive ventilation were not statistically different between the treated and naive groups, which does not support this hypothesis. As stated in the methods, we aimed to assess an early sedation/analgesia strategy for ventilated infants, regardless of future sedation or analgesia drugs use, as would be the case in an interventional trial. Moreover, the subgroup analysis among infants who never received the studied drugs showed no difference with the treated group for the main outcomes. Third, no information was available about the opioid or midazolam doses used or the existence of local protocols or policies within each unit. Enormous variability has been observed in clinical practices, with up to 100-fold differences in opioid doses in ventilated children. [START_REF] Anand | Opioid analgesia in mechanically ventilated children: results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl study[END_REF] This point is critical, as cumulative neurotoxic effects have been suggested for both morphine [START_REF] Zwicker | Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine[END_REF] and midazolam [START_REF] Duerden | Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants[END_REF] in very premature infants. Fourth, sensorimotor outcomes were assessed at 2 years of age; these are not always consistent with later school-age outcomes. Nonetheless, assessment at age 2 years is usually considered a good safety indicator. [START_REF] Marlow | Is survival and neurodevelopmental impairment at 2 years of age the gold standard outcome for neonatal studies?[END_REF] An analysis of neurodevelopmental outcomes at age 5 within the EPIPAGE 2 cohort is planned. Fifth pain was not assessed in this study; this information together with the opioid and/or midazolam doses would have been useful for assessing their association with our predefined outcomes. Sixth, all analyses were based on a propensity score which can only control for the known confounders it includes [START_REF] Thomas | Using Propensity Score Methods to Create Target Populations in Observational Clinical Research[END_REF] . As in any propensity-score based study, we cannot rule out potential confounders that were not taken into account. Seventh, the analyses were performed post-hoc.

The clinical practice of continuous opioid and/or midazolam infusions in very premature infants during an initial episode of mechanical ventilation continued after 24 hours of age was associated with improved survival without any increase in the likelihood of moderate or severe neuromotor or sensory impairments at a corrected age of 2 years. These results suggest that the current use of continuous opioids and/or midazolam, not including bolus only use, does not appear to have a major sensorimotor neurotoxic effect in this population. This finding might help reduce barriers to the use of such treatments in mechanically ventilated preterm neonates and thus contribute to their more humane care.

Major congenital abnormalities n=295

Decision to limit or withhold care in the first week after birth n=94

Premature infants born at 22 to 31 +6 For each variable, percentages might not sum up to 100%, due to rounding. a Data are presented as numbers (percentages) of patients unless otherwise indicated. Percentages and risk difference are weighted to take into account the differences in recruitment periods between gestational age groups. b Data are presented as percentages only unless otherwise indicated since numerators are not relevant for the IPTW sample. c Small-for-gestational age was defined as birth weight less than the 10th percentile for gestational age and sex based on French intrauterine growth curves (Ego 2016). d Defined as a 5-minute Apgar score < 7 or base deficit <-7 in the first 12 hours of life a Data are presented as number (percentages) of patients unless otherwise indicated. Percentages and risk difference are weighted to take into account the differences in recruitment periods between gestational age groups. b Data are presented as percentages only unless otherwise indicated since numerators are not relevant for the IPTW sample. c Risk differences and mean differences were calculated with a generalized estimation equation regression analysis (GEE) to take into account a potential center effect. d Severe neuromotor or sensory disabilities included any of GMFCS level 3-5 cerebral palsy or severe visual or auditory impairment; moderate disability included GMFCS level 2 cerebral palsy and/or moderate visual or auditory impairment. e Severe morbidity was defined as severe bronchopulmonary dysplasia, severe necrotizing enterocolitis, or severe retinopathy (stage 3 or treatment needed) or any of the following severe cerebral abnormalities on cranial ultrasonography: intraventricular hemorrhage with ventricular dilatation (Grade III IVH) or intraparenchymal hemorrhage (IPH), or cystic periventricular leukomalacia f According to the criteria of the Surveillance of Cerebral Palsy in Europe (SCPE). g An ASQ score below threshold was defined as a score lower than 2 standard deviations below the mean on any of the 5 domains. a Data are presented as number (percentages) of patients unless otherwise indicated. Percentages and risk difference are weighted to take the differences in recruitment periods between gestational age groups into account. b Data are presented as percentages only unless otherwise indicated since numerators are not relevant for the IPTW sample. c Risk differences and mean difference were calculated with a generalized estimation equation regression analysis (GEE) to take a potential center effect into account. d Severe neuromotor or sensory disabilities included any of GMFCS level 3-5 cerebral palsy or severe visual or auditory impairment; moderate disability included GMFCS level 2 cerebral palsy and/or moderate visual or auditory impairment. e Severe morbidity was defined as severe bronchopulmonary dysplasia, severe necrotizing enterocolitis, or severe retinopathy (stage 3 or treatment needed) or any of the following severe cerebral abnormalities on cranial ultrasonography: intraventricular hemorrhage with ventricular dilatation (Grade III IVH) or intraparenchymal hemorrhage (IPH), or cystic periventricular leukomalacia (see detailed definitions in the Supplement). f According to the criteria of the Surveillance of Cerebral Palsy in Europe (SCPE). g An ASQ score below threshold was defined as a score lower than two standard deviations below the mean on any of the 5 domains a Data are presented as number (percentages) of patients unless otherwise indicated. Percentages and risk difference are weighted to take the differences in recruitment periods between gestational age groups into account. b Data are presented as percentages only unless otherwise indicated since numerators are not relevant for the IPTW sample. c Risk differences and mean difference were calculated with a generalized estimation equation regression analysis (GEE) to take a potential center effect into account. d Severe neuromotor or sensory disabilities included any of GMFCS level 3-5 cerebral palsy or severe visual or auditory impairment; moderate disability included GMFCS level 2 cerebral palsy and/or moderate visual or auditory impairment. e Severe morbidity was defined as severe bronchopulmonary dysplasia, severe necrotizing enterocolitis, or severe retinopathy (stage 3 or treatment needed) or any of the following severe cerebral abnormalities on cranial ultrasonography: intraventricular hemorrhage with ventricular dilatation (Grade III IVH) or intraparenchymal hemorrhage (IPH), or cystic periventricular leukomalacia (see detailed definitions in the Supplement). f According to the criteria of the Surveillance of Cerebral Palsy in Europe (SCPE). g An ASQ score below threshold was defined as a score lower than 2 standard deviations below the mean on any of the 5 domains. a Data are presented as number (percentages) of patients unless otherwise indicated. Percentages and risk difference are weighted to take the differences in recruitment periods between gestational age groups into account. b Data are presented as percentages only unless otherwise indicated since numerators are not relevant for the IPTW sample. c Risk differences and mean difference were calculated with a generalized estimation equation regression analysis (GEE) to take a potential center effect into account. d Severe neuromotor or sensory disabilities included any of GMFCS level 3-5 cerebral palsy or severe visual or auditory impairment; moderate disability included GMFCS level 2 cerebral palsy and/or moderate visual or auditory impairment. e Severe morbidity was defined as severe bronchopulmonary dysplasia, severe necrotizing enterocolitis, or severe retinopathy (stage 3 or treatment needed) or any of the following severe cerebral abnormalities on cranial ultrasonography: intraventricular hemorrhage with ventricular dilatation (Grade III IVH) or intraparenchymal hemorrhage (IPH), or cystic periventricular leukomalacia (see detailed definitions in the Supplement). f According to the criteria of the Surveillance of Cerebral Palsy in Europe (SCPE). g An ASQ score below threshold was defined as a score lower than 2 standard deviations below the mean on any of the 5 domains.

EPIPAGE 2

 2 received approval from the National Data Protection Authority (Commission Nationale de l'Informatique et des Libertés (CNIL) n°911009) and from 2 ethics committees: the consultative committee on the treatment of information on personal health data for research purposes (approval granted November 18, 2010, reference 10.626) and the committee for the protection of people participating in biomedical research (approval granted March 18, 2011, reference Comité de Protection des Personnes (CPP) SC-2873).

Figure 1 .Figure 2 .

 12 Figure 1. Population flow chart

Figure 3 .

 3 Figure 3. Distributions of propensity scores (A) and weights (B) in the IPTW sample

Figure 4 .

 4 Figure 4. Cumulative probability of death in the first 150 days after birth in the IPTW

Figure 1

 1 Figure 1

Table I .

 I weeks of gestation in the Epipage 2 study, admitted to the NICU n=3678 Baseline characteristics of the population before imputation

	Figure 3
	A				No. (%)	B
				Treated n=450	Naive n=472
	Gestational age (weeks)
		No. with data available		450 (100)	472 (100)
		23		1 (0.2)	2 (0.3)
		24		24 (4.4)	26 (4.5)
		25		68 (12.5)	69 (12.1)
		26		90 (16.6)	86 (15.0)
		27		68 (16.9)	84 (19.8)
		28		67 (16.6)	75 (17.6)
		29 30 31		59 (14.6) No invasive ventilation 24 hours after birth 59 (13.9) 42 (10.4) 39 (9.2) n=2189 31 (7.7) 32 (7.5)
	Small-for-gestational age b
		No. with data available		450 (100)	472 (100)
	Yes Gender No. with data available		124 (28.3) Type of ventilation 24 hours after birth missing 144 (31) n=119 450 (100) 472 (100)
		Boy		236 (52.7)	241 (51.6)
	Birth asphyxia c
		Eligible infants Intubated in the delivery room or before 1 hour of life, No. with data available 446 (99.1) 464 (98.3)
		Yes	still intubated at 24 hours of life 207 (53.2)	199 (47.1)
	Delivery route		n=981
		No. with data available		446 (99.1)	464 (98.3)
		Vaginal		163 (34.7)	161 (33.1)
	Inborn status No. with data available Yes		Bolus only opioid and/or midazolam treatments 450 (100) 472 (100) n=33 361 (80.0) 399 (84.0)
	Multiple birth		135/450 (29.2)	163/472 (34.6)
	No. with data available Yes Antenatal steroids No. with data available		450 (100) Start date of opioid and/or midazolam treatments 472 (100) 135 (29.2) 163 (34.6) missing n=26 437 (97.1) 455 (96.4)
		Yes		264 (60.9)	291 (63.7)
	Antenatal Mg sulfate
		No. with data available		444 (98.7)	465 (98.5)
	Treated infants n= 450 Delayed cord clamping Yes No. with data available		26 (5.8) 434 (96.4)	35 (7.8) Untreated infants n= 472 443 (93.9)
		Yes		5 (1.2)	28 (6.4)
	Survivors at age 2 n= 413 Number of doses of surfactant No. with data available None	435 (96.7) 12 (3.1)	Survivors at age 2 459 (97.2) n= 419 24 (5.6)
		One		234 (53.9)	297 (65.0)
		Two or more		189 (43.0)	138 (29.3)
	Refused follow up Caffeine treatment in the first two days of life		Refused follow up
	n= 23	No. with data available		446 (99.5)	n= 22 467 (98.9)
		Yes		202 (46.6)	293 (64.1)
	Cause of prematurity
		No. with data available		450 (100)	472 (100)
	Missing or incomplete medical Preterm labor		201 (43.7)	Missing or incomplete medical 192 (40.6)
	assessment	PROM		108 (23.5)	assessment 111 (22.4)
	n= 71	Hypertensive disorders		111 (26.1)	n= 85 117 (26.2)
		Other		30 (6.7)	52 (10.7)
		Evaluation for neuromotor and/or	Evaluation for neuromotor and/or
		sensory outcomes at age 2	sensory outcomes at age 2
		n= 319			n= 312

Table 1 (

 1 continued): Baseline characteristics of the population before imputation

	No. (%) a
	Treated n=450	Naive n=472

Abbreviations: PROM, premature rupture of membranes. a Except for No. of patients with data available, all percentages are weighted to take into account the differences in recruitment periods between gestational age groups. For each variable, percentages might not sum up to 100%, due to rounding. b Small-for-gestational age was defined as birth weight less than the 10th percentile for gestational age and sex based on French intrauterine growth curves

(Ego 2016)

. c Defined as a 5-minute Apgar score < 7 or base deficit <-7 in the first 12 hours of life

Table II .

 II Baseline characteristics of initial and IPTW samples and standardized differences between groups after imputation

			Samples after imputation and weighting
		Initial sample, No. (%) a		IPTW sample, % b
	Clinical characteristics	Treated (n=450)	Naive (n=472)	SD, %	Treated (n=450)	Naive (n=472)	SD, %
	Gestational age (weeks)
	23	1 (0.2)	2 (0.3)		0.6	0.4
	24	24 (4.4)	26 (4.5)		5.9	5.6
	25	68 (12.5)	69 (12.1)		14.2	15.1
	26	90 (16.6)	86 (15)		18.3	18.3
	27	68 (16.9)	84 (19.8)	10.0	16.5	16.4	6.4
	28	67 (16.6)	75 (17.6)		15.9	15.5
	29	59 (14.6)	59 (13.9)		12.1	12.8
	30	42 (10.4)	39 (9.2)		8.9	9.3
	31	31 (7.7)	32 (7.5)		7.7	6.6
	Small-for-gestational age c	124 (28.3)	144 (31.0)	6.0	28.7	29.0	0.6
	Boy	236 (52.7)	241 (51.6)	2.3	51.7	51.7	0.1
	Birth asphyxia d	241 (53.3)	229 (47.4)	12.1	50.8	50.9	0.1
	Vaginal delivery	165 (35.0)	166 (33.5)	2.9	35.5	36.2	1.4
	Inborn status	361 (80.0)	399 (84.0)	10.3	81.3	82.0	1.9
	Multiple birth	135 (29.2)	163 (34.6)	11.7	32.3	31.5	1.7
	Antenatal steroids	269 (60.4)	301 (63.6)	6.8	60.9	59.9	2.0
	Antenatal Mg sulfate	26 (5.9)	35 (7.7)	7.4	6.8	6.8	0.1
	Delayed cord clamping	6 (1.5)	33 (7.0)	27.6	4.6	4.2	1.6
	Number of doses of surfactant
	None	12 (3.0)	24 (5.6)		4.1	4.0
	One	242 (53.9)	304 (64.9)	29.6	57.8	57.3	1.4
	2 or more	195 (43.0)	142 (29.5)		38.1	38.7
	Caffeine treatment in the first 2 days of life	204 (46.8)	296 (64.2)	35.5	53.5	53.8	0.6
	Cause of prematurity
	Preterm labor	201 (43.7)	192 (40.6)		42.5	42.8
	PROM Hypertensive disorders	108 (23.5) 111 (26.1)	111 (22.4) 117 (26.2)	14.5	23.5 24.4	22.9 25.2	2.3
	Other	30 (6.7)	52 (10.7)		9.5	9.1
	Maternal age
	< 25 years	111 (24.9)	116 (24.1)		25.4	24.3
	25 to 35 years	266 (58.6)	277 (59)	2.1	59.2	60.0	2.4
	> 35 years	73 (16.5)	79 (16.9)		15.5	15.6
	Primiparous	223 (48.8)	243 (51.6)	5.4	50.8	51.7	1.8
	Maternal general anesthesia	79 (18.1)	86 (18.3)	0.6	17.8	18.2	1.0
	Family socio-economic status
	Executive jobs	103 (22.5)	75 (16)		19.5	20.1
	Public and administrative jobs 189 (42.7) Workers 139 (31.2)	238 (50.6) 141 (29.8)	19.4	46.5 30.1	46.2 29.8	1.6
	No job declared	17 (3.6)	17 (3.6)		4.0	3.9
	Mother born in France	332 (73.5)	371 (79.0)	13.0	75.1	75.6	1.3
	Volume of activity of the unit
	< 55 infants	126 (28.6)	170 (36.0)		31.4	30.9
	[55-75[ infants	146 (32.0)	146 (31.2)	17.1	31.5	31.6	1.2
	> 75 infants	178 (39.5)	156 (32.9)		37.0	37.5
	Abbreviations: IPTW, inverse probability of treatment weighting; SD, standardized difference; PROM,
	premature rupture of membranes.

Table III .

 III Treatments with continuous opioids and/or midazolam through hospital discharge in the treated and naive groups Except for No. of patients with data available, all percentages are weighted to take into account the differences in recruitment periods between gestational age groups. For each variable, percentages might not sum up to 100%, due to rounding. b Rao-Scott F-adjusted chi-square

		No. (%) a
	Drugs	Treated group n=450	Naive group n=472	P value b
	No opioids or midazolam	0 (0)	290 (63.7)	-
	Sufentanil
	Total No. of treated patients	269 (59.4)	97 (19.0)	< .001
	No. treated before first extubation or day 7	241 (55.2)	0	-
	No. treated after first extubation or day 7	28 (5.5)	97 (19.0)	< .001
	Median [IQR] age at treatment initiation, day	0 [0; 1]	14 [8; 24]	-
	Cumulative duration of treatment
	No. with data available	264 (98.1)	96 (99.0)	-
	Median [IQR], day	4 [2; 10]	6 [2; 13]	-
	Morphine
	Total No. of treated patients	171 (37.3)	77 (14.9)	< .001
	No. treated before first extubation or day 7	125 (27.7)	0	-
	No. treated after first extubation or day 7	46 (9.6)	77 (14.9)	0.013
	Median [IQR] age at treatment initiation, day	0 [0; 5]	19 [13; 30]	-
	Cumulative duration of treatment
	No. with data available	169 (98.8)	75 (97.4)	-
	Median [IQR], day	8 [3; 25]	9 [5; 17]	-
	Fentanyl
	Total No. of treated patients	74 (16.1)	24 (4.7)	< .001
	No. treated before first extubation or day 7	69 (15.0)	0	-
	No. treated after first extubation or day 7	5 (1.1)	24 (4.7)	0.001
	Median [IQR] age at treatment initiation, day	1 [0; 2]	16 [8; 28]	-
	Cumulative duration of treatment
	No. with data available	73 (98.6)	24 (100)	-
	Median [IQR], day	3 [1; 10]	3 [2; 9]	-
	Midazolam
	Total No. of treated patients	239 (51.9)	113 (22.4)	< .001
	No. treated before first extubation or day 7	161 (36.4)	0	-
	No. treated after first extubation or day 7	78 (15.5)	113 (22.4)	0.006
	Median [IQR] age at treatment initiation, day	1 [0; 11]	15 [12; 25]	-
	Cumulative duration of treatment
	No. with data available	234 (97.9)	113 (100)	-
	Median [IQR], day	4 [2; 10]	4 [2; 11]	-
	Abbreviations: IQR, interquartile range
	a

Table IV .

 IV Results for primary and secondary exploratory outcomes in the initial and IPTW samples after imputation IPTW, inverse probability of treatment weighting; ASQ, Ages and Stages Questionnaires; IQR, Interquartile range; SD, standard deviation.

				Frequency or duration of Events
		Initial sample, No (%) a		IPTW sample, % b
	Outcomes	Treated group (n=450)	Naive group (n=472)	Risk or mean differences: treated group minus naive group (95% CI) c	Treated group (n=450)	Naive group (n=472)	Risk or mean differences: treated group minus naive group (95% CI) c
	Primary outcomes
	Survival at 2 years,	413 (92.3)	419 (89.7)	2.6 [-1.2; 6.5]	92.5	87.9	4.7 [0.3; 9.1]
	Survival at 2 years without moderate or severe neuromotor or sensory disabilities d	385 (86.2)	390 (83.7)	2.6 [-2.3; 7.4]	86.6	81.3	5.3 [-0.3; 11.0]
	Secondary exploratory outcomes
	Survival at discharge without severe neonatal morbidity e	292 (66.7)	295 (64.8)	1.9 [-5.5; 9.3]	66.2	59.9	6.4 [-1.9; 14.6]
	Outcomes at discharge
	Cumulative duration of mechanical ventilation (day)
	Median [IQR]	8 [3; 21]	5 [2; 16]	-	8 [3; 22]	6 [2; 21]	-
	Mean (SD)	13.7 (13.9)	11.5 (14.3)	2.2 [-0.7; 5.1]	14.4 (14.5)	13.0 (14.9)	1.3 [-2.1; 4.8]
	Duration of hospital stay (day)
	Median [IQR]	80 [61; 98]	76 [61; 99]	-	81 [62; 101] 79 [62; 101]	-
	Mean (SD)	83.0 (30.7)	81.4 (29.9)	1.6 [-3.4; 6.6]	84.1 (31.0)	85.1 (31.4)	1.0 [-4.7; 6.8]
	Outcomes at age 2 among survivors
	Cerebral palsy f	26 (6.7)	35 (8.3)	-1.6 [-5.7; 2.5]	6.6	8.8	-2.3 [-7.1; 2.5]
	ASQ below threshold g	207 (49.3)	214 (50.7)	-1.4 [-9.8; 6.9]	51.1	51.4	-0.3 [-9.1; 8.6]
	Abbreviations:

Table VIII .

 VIII Exploratory subgroup analyses among infants exclusively treated with opioids in the treated groups: primary and secondary outcomes in the initial and IPTW samples after multiple imputation IPTW, inverse probability of treatment weighting; ASQ, Ages and Stages Questionnaires; IQR, Interquartile range; SD, standard deviation.

				Frequency or duration of Events
		Initial sample, No (%) a		IPTW sample, % b
	Outcomes	Treated group (n=289)	Naive group (n=472)	Risk or mean differences: treated group minus naive group (95% CI) c	Treated group (n=289)	Naive group (n=472)	Risk or mean differences: treated group minus naive group (95% CI) c
	Primary outcomes
	Survival at 2 years,	270 (94.1)	419 (89.7)	4.4 [0.6; 8.1]	94.2	88.2	6.0 [1.8; 10.2]
	Survival at 2 years without moderate or severe neuromotor or sensory disabilities d	253 (88.1)	390 (83.7)	4.4 [-0.6; 9.5]	88.7	81.6	7.1 [1.3; 12.8]
	Secondary exploratory outcomes
	Survival at discharge without severe neonatal morbidity e	193 (68.7)	295 (64.8)	3.8 [-4.8; 12.5]	68.8	60.2	8.6 [-1.1; 18.2]
	Severe cerebral abnormalities at discharge e	32 (10.6)	55 (11.4)	-0.8 [-5.1; 3.5]	9.8	12.3	-2.5 [-7.2; 2.2]
	Outcomes at discharge
	Cumulative duration of mechanical ventilation (day)
	Median [IQR]	8 [3; 21]	5 [2; 16]	-	8 [3; 22]	6 [2; 21]	-
	Mean (SD)	14.7 (14.7)	11.5 (14.3)	3.2 [0.0; 6.3]	14.8 (14.9)	13.1 (15.0)	1.7 [-2.0; 5.4]
	Duration of hospital stay (day)
	Median [IQR]	80 [61; 99]	76 [61; 99]	-	81 [62; 101] 79 [63; 101]	-
	Mean (SD)	85.8 (32.3)	81.4 (29.9)	4.5 [-1.5; 10.4]	86.8 (32.8)	84.4 (30.9)	2.3 [-4.5; 9.2]
	Outcomes at age 2 among survivors
	Cerebral palsy f	18 (7.4)	35 (8.3)	-0.9 [-5.5; 3.7]	6.9	8.9	-2.1 [-7.2; 3.1]
	ASQ below threshold g	135 (48.9)	214 (50.7)	-1.8 [-11.1; 7.4]	50.6	51.6	-1.0 [-11.1; 9.0]
	Abbreviations:

Table IX .

 IX Exploratory subgroup analyses among infants treated with midazolam in the treated groups: primary and secondary outcomes in the initial and IPTW samples after multiple imputation IPTW, inverse probability of treatment weighting; ASQ, Ages and Stages Questionnaires; IQR, Interquartile range; SD, standard deviation.

				Frequency or duration of Events
		Initial sample, No (%) a		IPTW sample, % b
		Treated	Naive	Risk or mean	Treated	Naive	Risk or mean
	Outcomes	group (n=161)	group (n=472)	differences: treated group minus naive group (95% CI) c	group (n=161)	group (n=472)	differences: treated group minus naive group (95% CI) c
	Primary outcomes
	Survival at 2 years,	143 (89.3)	419 (89.7)	-0.4 [-5.8; 5.0]	89.6	88.2	1.4 [-4.4; 7.2]
	Survival at 2 years without moderate or severe neuromotor or sensory disabilities d	132 (83.0)	390 (83.7)	-0.7 [-7.4; 5.9]	83.2	82.1	1.1 [-8.1; 10.6]
	Secondary exploratory outcomes
	Survival at discharge without severe neonatal morbidity e	99 (63.3)	295 (64.8)	-1.6 [-11.3; 8.1]	63.9	61.9	1.7 [-9.8; 13.2]
	Severe cerebral abnormalities at discharge e	32 (19.9)	55 (11.4)	8.5 [1.8; 15.2]	18.1	12.0	6.1 [-1.2; 13.4]
	Outcomes at discharge
	Cumulative duration of mechanical ventilation (day)
	Median [IQR]	8 [4; 15]	5 [2; 16]	-	8 [2; 20]	6 [2; 17]	-
	Mean (SD)	12.0 (12.2)	11.5 (14.3)	0.4 [-2.7; 3.6]	13.0 (13.4) 12.5 (14.7)	0.6 [-3.1; 4.3]
	Duration of hospital stay (day)
	Median [IQR]	75 [59; 92]	76 [61; 99]	-	81 [60; 95] 78 [62; 101]	-
	Mean (SD)	77.8 (26.8)	81.4 (29.9)	-3.6 [-9.3; 2.1]	81.3 (27.6) 83.2 (30.6)	-1.9 [-8.5; 4.6]
	Outcomes at age 2 among survivors
	Cerebral palsy f	8 (5.5)	35 (8.3)	-2.8 [-8.0;2.3]	5.5	8.4	-2.9 [-11.2; 5.4]
	ASQ below threshold g	72 (50.0)	214 (50.7)	-0.7 [-11.9; 10.4]	48.1	50.8	-2.7 [-16.1; 10.6]
	Abbreviations:

Table X .

 X Exploratory subgroup analyses among infants who never received continuous opioids or midazolam in the naive group: primary and secondary outcomes in the initial and IPTW samples after multiple imputation IPTW, inverse probability of treatment weighting; ASQ, Ages and Stages Questionnaires; IQR, Interquartile range; SD, standard deviation.

				Frequency or duration of Events
		Initial sample, No (%) a		IPTW sample, % b
	Outcomes	Treated group (n=450)	Naive group (n=290)	Risk or mean differences: treated group minus naive group (95% CI) c	Treated group (n=450)	Naive group (n=290)	Risk or mean differences: treated group minus naive group (95% CI) c
	Primary outcomes
	Survival at 2 years,	413 (92.3)	277 (95.9)	-3.5 [-7.2; 0.2]	93.0	92.8	0.2 [-6.8; 7.2]
	Survival at 2 years without moderate or severe neuromotor or sensory disabilities d	385 (86.2)	259 (89.8)	-3.5 [-8.6; 1.6]	87.3	87.2	0.1 [-7.5; 7.7]
	Secondary exploratory outcomes
	Survival at discharge without severe neonatal morbidity e	292 (66.7)	222 (77.6)	-10.9 [-22.2; 0.4]	68.5	70.3	-1.8 [-17.0; 13.4]
	Severe cerebral abnormalities at discharge e	64 (14.0)	21 (7.5)	6.5 [2.2; 10.7]	13.0	8.5	4.5 [-0.9; 9.9]
	Outcomes at discharge
	Cumulative duration of mechanical ventilation (day)
	Median [IQR]	8 [3; 21]	3[2; 7]	-	8 [3; 19]	5 [2; 12]	-
	Mean (SD)	13.7 (13.9)	7.2 (10.2)	6.5 [2.6; 10.4]	13.2 (13.7)	10.2 (12.9)	3.0 [-3.2; 9.2]
	Duration of hospital stay (day)
	Median [IQR]	80 [61; 98]	69 [55; 82]	-	79 [60; 97]	76 [76; 92]	-
	Mean (SD)	83.0 (30.7)	71.5 (22.1)	11.5 [5.3; 17.6]	81.8 (30.5)	76.7 (23.6)	5.1 [-2.7; 12.8]
	Outcomes at age 2 among survivors
	Cerebral palsy f	26 (6.7)	22 (7.7)	-1.0 [-5.4; 3.4]	6.4	6.7	-0.3 [-5.0; 4.5]
	ASQ below threshold g	207 (49.3)	129 (46.6)	2.6 [-6.3; 11.6]	49.7	49.1	0.5 [-9.6; 10.7]
	Abbreviations:

ACKNOWLEDGMENTS

We thank the physicians, nurses, and other healthcare providers at the participating institutions for their contributions and the parents who allowed us to gather data related to their infants. We also thank Mrs Jo-Ann Cahn for editing the manuscript and reviewing for English language.

Funded by the French Institute of Public Health Research /Institute of Public Health and its partners the French Health Ministry, the National Institute of Health and Medical Research, the National Institute of Cancer, and the National Solidarity Fund for Autonomy (ANR-11-EQPX-0038) from the National Research Agency through the French Equipex Program of Investments in the Future, the PremUp Foundation, the Fondation de France, and the Fondation Apicil. The funders/sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. X.D. reports grants from Ministry of Health, outside the submitted work; personal fees and nonfinancial support from Chiesi Pharmaceuticals, outside the submitted work. The other authors declare no conflicts of interest. Portions of this study

a Data are presented as number (percentages) of patients unless otherwise indicated. Percentages and risk difference are weighted to take the differences in recruitment periods between gestational age groups into account. b Data are presented as percentages only unless otherwise indicated since numerators are not relevant for the IPTW sample. c Risk differences and mean difference were calculated with a generalized estimation equation regression analysis (GEE) to take a potential center effect into account. d Severe neuromotor or sensory disabilities included any of GMFCS level 3-5 cerebral palsy or severe visual or auditory impairment; moderate disability included GMFCS level 2 cerebral palsy and/or moderate visual or auditory impairment. e Severe morbidity was defined as severe bronchopulmonary dysplasia, severe necrotizing enterocolitis, or severe retinopathy (stage 3 or treatment needed) or any of the following severe cerebral abnormalities on cranial ultrasonography: intraventricular hemorrhage with ventricular dilatation (Grade III IVH) or intraparenchymal hemorrhage (IPH), or cystic periventricular leukomalacia (see detailed definitions in the Supplement). f According to the criteria of the Surveillance of Cerebral Palsy in Europe (SCPE). g An ASQ score below threshold was defined as a score lower than 2 standard deviations below the mean on any of the 5 domains.