Gestational age at diagnosis of early-onset fetal growth restriction and impact on management and survival: a population-based cohort study.

OBJECTIVE: To investigate the impact of gestational age (GA) at diagnosis of fetal growth restriction (FGR) on obstetric management and rates of live birth and survival for very preterm infants with early-onset FGR. DESIGN: Population-based cohort study. SETTING: All maternity units in 25 French regions in 2011. POPULATION: Fetuses diagnosed with FGR before 28 weeks of gestation among singleton births between 22 and 31 weeks of gestation without severe congenital anomalies. METHODS: We studied the effects of GA at diagnosis on perinatal management and outcomes. We used multivariable regression to identify antenatal factors (maternal characteristics, ultrasound measurements and sex) associated with the probability of live birth. MAIN OUTCOMES MEASURES: Live birth and survival to discharge from neonatal care. RESULTS: A total of 436 of 3698 fetuses were diagnosed with FGR before 28 weeks (11.8%); 66.9% were live born and 54.4% survived to discharge. 50% were live born when diagnosis occurred before 25 weeks, 66% at 25 weeks and >90% at 26 and 27 weeks of gestation. In all, 94.1% of live births were by prelabour caesarean, principally for maternal indications before 26 weeks. Low GA at diagnosis, an estimated fetal weight or abdominal circumference below the third centile and male sex were adversely associated with live birth in adjusted models. CONCLUSION: Gestational age at FGR diagnosis had an impact on the probability of live birth and survival, after consideration of other perinatal characteristics. Investigations of the outcomes of births with early-onset FGR need to include stillbirths and information on the GA at which FGR is diagnosed. TWEETABLE ABSTRACT: Evaluations of active management of pregnancies with early onset growth restriction should include stillbirths.

Changes in management policies for extremely preterm births and neonatal outcomes from 2003 to 2012: two population-based studies in ten European regions.

OBJECTIVE: To investigate changes in maternity and neonatal unit policies towards extremely preterm infants (EPTIs) between 2003 and 2012, and concurrent trends in their mortality and morbidity in ten European regions. DESIGN: Population-based cohort studies in 2003 (MOSAIC study) and 2011/2012 (EPICE study) and questionnaires from hospitals. SETTING: 70 hospitals in ten European regions. POPULATION: Infants born at <27 weeks of gestational age (GA) in hospitals participating in both the MOSAIC and EPICE studies (1240 in 2003, 1293 in 2011/2012). METHODS: We used McNemar's Chi2 test, paired t-tests and conditional logistic regression for comparisons over time. MAIN OUTCOMES MEASURES: Reported policies, mortality and morbidity of EPTIs. RESULTS: The lowest GA at which maternity units reported performing a caesarean section for acute distress of a singleton non-malformed fetus decreased from an average of 24.7 to 24.1 weeks (P < 0.01) when parents were in favour of active management, and 26.1 to 25.2 weeks (P = 0.01) when parents were against. Units reported that neonatologists were called more often for spontaneous deliveries starting at 22 weeks GA in 2012 and more often made decisions about active resuscitation alone, rather than in multidisciplinary teams. In-hospital mortality after live birth for EPTIs decreased from 50% to 42% (P < 0.01). Units reporting more active management in 2012 than 2003 had higher mortality in 2003 (55% versus 43%; P < 0.01) and experienced larger declines (55 to 44%; P < 0.001) than units where policies stayed the same (43 to 37%; P = 0.1). CONCLUSIONS: European hospitals reporting changes in management policies experienced larger survival gains for EPTIs. TWEETABLE ABSTRACT: Changes in reported policies for management of extremely preterm births were related to mortality declines.

Impaired alveolarization and intra-uterine growth restriction in rats: a postnatal genome-wide analysis.

Intra-uterine growth restriction (IUGR) dramatically increases the risk of bronchopulmonary dysplasia in preterm babies, a disease characterized by arrested alveolarization and abnormal microvascular angiogenesis. We have previously described a rodent low protein diet (LPD) model of IUGR inducing impaired alveolarization, but failed to demonstrate any modification of the classical factors involved in lung development. We performed a genome-wide microarray analysis in 120 rat pups with LPD-induced IUGR and their controls, at three key time points of the alveolarization process: postnatal day 4 (P4): start of alveolarization; P10: peak of the alveolarization process and P21: end of the alveolarization process. Results were analysed using Arraymining, DAVID and KEGG software and validated by qRT-PCR and western blots. Considering a cut-off of 2:1 as significant, 67 transcripts at P4, 102 transcripts at P10 and 451 transcripts at P21 were up-regulated, and 89 transcripts at P4, 25 transcripts at P10 and 585 transcripts at P21 were down-regulated. Automatic functional classification identified three main modified pathways, 'cell adhesion molecules', 'cardiac muscle contraction' and 'peroxisome proliferator-activated receptor' (PPAR). Protein analysis confirmed involvement of the PPAR pathway, with an increase of FABP4, an activator of this pathway, at P4 and an increase of adiponectin at P21. Other data also suggest involvement of the PPAR pathway in impaired alveolarization. Our results show that deregulation of the PPAR pathway may be an important component of the mechanism inducing impaired alveolarization observed in IUGR. The complete dataset is available as GEO profiles on the Gene Expression Omnibus (GEO) database ( www.ncbi.nih.gov/geo/, GEO Accession No. GSE56956).

Antenatal phosphodiesterase 4 inhibition restores postnatal growth and pulmonary development in a model of chorioamnionitis in rabbits.

Chorioamnionitis is implicated in the pathophysiology of bronchopulmonary disease, and the associated inflammatory response is responsible for adverse effects on alveolar development. The aim of this work was to analyze the effects of a phosphodiesterase 4 (PDE4)-selective inhibitor, rolipram (a modulator of the inflammatory response), in an experimental model of chorioamnionitis on pulmonary development and on the processes of infection and inflammation. Rabbit mothers were assigned to four groups: 1) saline serum inoculation (controls); 2) Escherichia coli intrauterine inoculation (C+); 3) rolipram infusion (R+); and 4) E. coli inoculation + rolipram infusion (C+R+). High rates of morbility and mortality were noticed in mothers and pups (5 of 13 pregnant rabbits in groups with rolipram). Alveolar development, inflammation, and infection were analyzed in pups at day 0 and day 5. At day 0, in the context of chorioamnionitis, rolipram significantly decreased birth weight (p < 0.01) relative to that of controls (p < 0.05). At day 5, weight normalized in group C+R+ but not in group C+ relative to controls (p < 0.001); moreover, alveolar airspace volume was preserved in group C+R+ but not in group C+ (p < 0.05). Interstitial volume decreased in group C+ versus controls (p < 0.05) but was preserved in group C+R+. Specific alveolar area was not significantly modified by rolipram. No significant difference was found concerning bronchoalveolar lavage cellularity, and all blood cultures remained sterile. In this model of impaired alveologenesis, rolipram significantly preserved specific alveolar density. However, PDE4 inhibition induced antenatal fetal demise and growth retardation.

Respiratory distress management in moderate and late preterm infants: The NEOBS Study.

OBJECTIVE: To investigate the characteristics and management of respiratory failure (RF) in moderate-to-late preterm infants. METHODS: NEOBS was a prospective, multicenter, observational study conducted in 46 neonatal intensive care units caring for preterm infants (30+0/7 to 36+6/7 weeks of gestation [WG]) in France in 2018. The cohort was stratified into two groups: 30-33 WG (group 1) and 34-36 WG (group 2). Infants with early neonatal RF were included and the outcomes assessed were maternal, pregnancy, and delivery characteristics and how RF was managed. RESULTS: Of the 560 infants analyzed, 279 were in group 1 and 281 were in group 2. Most pregnancies were singleton (64.1%), and 67.4% of women received prenatal corticosteroids (mostly two doses). Infants were delivered by cesarean section in 59.6% of cases; 91.7% of the infants had an Apgar score ≥7 at 5min. More than 90% of infants were hospitalized post-birth (median duration, 36 and 15 days for groups 1 and 2, respectively). Medical intervention was required for 95.7% and 90.4% of the infants in group 1 and group 2, respectively, and included noninvasive ventilation (continuous positive airway pressure [CPAP]: 88.5% and 82.9%; high-flow nasal cannula: 55.0% and 44.7%, or other) and invasive ventilation (19.7% and 13.2%). The two main diagnoses of RF were respiratory distress syndrome (39.8%) and transient tachypnea of the newborn (57.3%). Surfactant was administered to 22.5% of the infants, using the less invasive surfactant administration (LISA) method for 34.4% of the patients. In the overall population, 8.6% of the infants had respiratory and/or hemodynamic complications. CONCLUSIONS: The NEOBS study demonstrated that CPAP was widely used in the delivery room and the LISA method was chosen for 34.4% of the surfactant administrations for the management of RF in moderate-to-late preterm infants. The incidence of RF-related complications was low.

Mortality and morbidity of preterm neonates weighing less than 750g: A 2-year retrospective cohort study.

BACKGROUND: The rate of premature births in France is 6% and is increasing, as is the rate of extremely premature births. Morbidity and mortality rates in this population remain high despite significant medical progress. We aimed to evaluate the morbidity and mortality rate in preterm neonates weighing<750g and to evaluate their outcome at 2 years' corrected age (CA). METHODS: This was a retrospective monocentric study including babies born between May 2011 and April 2013 who were preterm and weighed<750g. We evaluated mortality and morbidity in the neonatal period. At 2 years' CA, we focused on developmental quotient (DQ) with the Brunet-Lézine test, on neurosensory assessment (sleeping/behavior), and growth evaluation. RESULTS: Among the 107 infants included, 29 (27%) died in the neonatal period. Mean gestational age was 25.6 weeks' gestation. Female sex and higher birth weight were independent predictors of survival. A total of 61 (78.2%) infants showed extra-uterine growth retardation at 36 weeks' postmenstrual age. At 2 years' CA, 57 children were followed up; 38 were evaluated using the Brunet-Lézine test, 20 (52.6%) had a DQc<85, and none had a severe developmental delay (DQc<50). Six (10%) children had cerebral palsy and 22 of 56 (39.2%) showed language delay. Growth retardation persisted in 15 of 52 (28.8%) children. CONCLUSION: Our results confirm the acute fragility of extremely low-birth-weight babies with a high rate of morbidity and mortality. At 2 years' CA, this population still shows a considerable rate of mild difficulties, whose long-term evolution needs to be followed.

[Propositions for perinatal care at extremely low gestational ages - Working group on "Extremely low gestational ages" for SFMP, CNGOF, and SFN]. / Propositions sur la prise en charge en cas d'extrême prématurité ­ Le groupe de travail « Extrême Prématurité ¼ pour la SFMP, le CNGOF et la SFN.

OBJECTIVES: International literature suggests that active perinatal management at extremely low gestational ages improves survival without increasing the risk of impairment in survivors, compared to less active management. Although these results are limited to a small number of countries, they question current practices in France. New propositions on perinatal management of extremely preterm infants have carried out by the French Society of Perinatal Medicine, the French Society of Neonatology and the National College of French Obstetricians and Gynecologists. METHODS: This group was set up in 2015 on the initiative of the professional societies and in collaboration with parents' and users' associations. The work was based on a review of the literature on the prognosis of extremely preterm children, as well as on recommendations by European societies. Based on this information, a text was produced, submitted to all members of the working group and definitively validated in April 2019. RESULTS: This text offers a decision-making guideline for the management at extremely low gestational ages. Its principles are: the administration of steroids independently of management (resuscitation or comfort care); a prognostic evaluation and a collegial decision, outside the context of the emergency; a consensus on the information to be given to parents before going to inform them and gather their opinion. CONCLUSIONS: These new propositions will contribute to modifying perinatal care at extremely low gestational ages in France.

Antenatal infection in the rabbit impairs post-natal growth and lung alveolarisation.

Clinical and experimental studies indicate an association between chorioamnionitis and bronchopulmonary dysplasia in preterm infants. The present authors hypothesised that, in the rabbit, antenatal infection may impair lung development after birth, despite effective maternal antibiotic therapy. Pregnant rabbits received an intra-uterine inoculation of 10(3) Escherichia coli colony forming units or vehicle at the end of gestation (day 29). Intravenous ceftriaxone therapy was initiated 8 h after inoculation for a period of 8 days. Pups born between 60 and 84 h after inoculation were kept with their mother until sacrifice on days 0, 1, 5, 8 and 15. Blood cultures from antenatally infected animals were sterile at birth. Postnatal growth was significantly impaired by day 8. Lung morphometry showed a significant decrease of alveolar surface density and interstitial density, with a significant increase of alveolar airspace volume, indicating impaired alveolarisation for the first 2 weeks of postnatal life. Inflammatory and apoptotic processes were not detected in the lung at birth or subsequently. Intra-uterine infection in rabbits is, therefore, responsible for concomitant postnatal growth retardation and abnormal pulmonary development despite early and effective antenatal antibiotic therapy. This may constitute an alternative model to study the consequences of antenatal infection on postnatal growth and lung development.

[Organization of intensive care in situation of avian flu pandemic]. / Organisation de la réanimation en situation de pandémie de grippe aviaire.

The influenza pandemic will create a major increase in demand for hospital admissions, particularly for critical care services. The recommendations detailed herein have been elaborated by experts from medical societies potentially involved in this situation and focus on general hospital organization. Intensive care units will initially face high demand for admission; the Healthcare Authorities must therefore study how ICU capacity can be expanded. Pediatric intensive care units will be particularly affected by this situation of relative bed shortage, since young children, particularly infants, are expected to be affected by severe clinical forms of avian flu. Therefore, the weight threshold for admission to the adult ICU was lowered to 20 kg. Neonatal intensive care units (NICU) should remain, if possible, low viral density areas. Mixed (neonatal and pediatric) intensive care units could be dedicated to infants and children only. NICU admission of extreme premature babies should be limited in this difficult situation. Pediatric intensive care units (PICU) admission capacity could be doubled by using intermediate care and postoperative care units. The staff could be increased by doctors and nurses involved in canceled programmed activities. Healthcare workers transferred to PICU should be given special training.

[The organisation of intensive care in a situation of pandemic avian influenza]. / Organisation de la réanimation en situation de pandémie de grippe aviaire.

The development of an epidemic of avian influenza will have a major impact on the organisation and structure of the facilities for treatment. This paper, the product of collaboration between the six learned societies concerned, analyses the impact of a possible pandemic on the various aspects of management of patients requiring intensive care. It describes the organisation of hospital pathways for flu and non-flu patients with, in particular, the necessary actions in terms of separation of care facilities, the triage of patients and the cancellation of non-urgent activities. It analyses the preconditions necessary for the efficient functioning of intensive care and the predictable limiting factors. It underlines the importance of training of medical and paramedical personnel. Finally, it tackles the specific problems of paediatric intensive care: organisation, capacity for admissions and training.

Palivizumab administration in preterm infants in France: EPIPAGE-2 cohort study.

BACKGROUND: Several countries, including France, have restricted the indications for monoclonal antibodies directed against respiratory syncytial virus (RSV) compared to the marketing authorization (MA). No new data concerning use of palivizumab on a national scale have been published since the 2007 update of the national guidelines. OBJECTIVES: To describe palivizumab administration for RSV prophylaxis during the first RSV season in infants born prematurely in France in 2011. METHODS: Infants from the national population-based cohort EPIPAGE-2 born at≤34 weeks' gestation, discharged home before 31 March 2012 and followed-up at 1year were included. The RSV season ran from 1 October 2011 to 31 March 2012. Prophylaxis was deemed "initiated" if the infant had received at least one dose of palivizumab during this period and "complete" if it had received at least five doses or as many doses as the number of exposed months. The reference documents were the MA and French Transparency Committee guidelines (TC). RESULTS: Prophylaxis was indicated in 3586 of 3608 infants (99.7%) according to the MA and 1315 of 3608 (16.7%) according to the TC. A total of 1906 infants (26.6%) received at least one dose of palivizumab. The overall rate of conformity with TC indications was 85%, but was lower for infants born at 27-32 weeks' gestation. The rate of complete prophylaxis was 77.2%. The factors associated with prophylaxis initiation were low gestational age, low birthweight, high maternal educational level, type of neonatal unit, and date at discharge. Factors associated with complete prophylaxis were respiratory impairment, high educational level, and characteristics related to living conditions (absence of siblings at home, type of childcare). CONCLUSIONS: Palivizumab administration in France generally conformed with TC guidelines, but could be further improved for infants born at 27-32 weeks' gestation without bronchopulmonary dysplasia.

[End of life in neonatal medicine under the direction of French law]. / Fin de vie en médecine néonatale à la lumière de la loi.

Two recent laws have significantly reformed the French Public Health Code: the law of March 4th 2002, related to the patient's rights and the quality of the health care system and the law of April 22nd 2005, related to the patient's rights and the end of life. These changes have prompted health care professionals involved in perinatal and neonatal medicine to update their considerations on the ethical aspects of the end of life in neonatal medicine. Therefore, the authors examined the clauses of the law related to the patient's rights and to the end of life, confronting them with the distinctive features of neonatal medicine. In this paper, the medical practices, which are either prohibited or authorized in the course of end of life are considered: prohibition of euthanasia, authorization for alleviating pain at the risk of shortening life, authorization for restricting, withholding or withdrawing treatments. Next, the justifications provided by the legislation to authorize these practices are analysed: prohibition of unreasonable obstinacy and respect for individual wishes. Then, the conditions required by the law to determine and to implement these acts are discussed: consultation with the healthcare staff and justified advice from a consulting physician, consideration of parental opinion, registration of the decision and its justifications into the patient's medical file, protection of the dying patient's dignity and preservation of his life quality by providing palliative care. Lastly, we report the terms of the ethical dilemma which may occur in the area of neonatal medicine in spite of genuine and persevering efforts in order to conciliate legal requirement and ethical responsibility.

[Perinatal care for extremely preterm infants. Considerations of the "risks in pregnancy" department]. / Prise en charge de la prématurité extrême. Réflexions du département hospitalo-universitaire (DHU) « risques et grossesse ¼.

Decisions regarding whether to initiate or forgo intensive care for extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients and must be taken into account. After a short review of these factors, we present the thoughts and proposals of the Risks and Pregnancy department. The proposals are to limit emergency decisions, to better take into account other factors than gestational age and prenatal predicted fetal weight in assessing the prognosis, to introduce multidisciplinary consultation in the evaluation and proposals that will be discussed with the parents, and to separate prenatal steroid therapy from decision-making regarding whether or not to administer intensive care.

[Single-donor protocol: Transfusion practices and multiple transfusion risk factors in neonatal intensive care unit]. / Protocole donneur unique : pratiques transfusionnelles et facteurs de risque des transfusions multiples en réanimation néonatale.

In France since 2002, the single-donor transfusion protocol, using four pediatric units from the same adult donor's packed red blood cells (PRBCs) in multiply transfused newborns, is recommended in preterm neonates to reduce the risks of infection and alloimmunization. This protocol is controversial, however, because it causes the transfusion of stored blood, which could have adverse consequences. Before the new recommendations of the French Haute Autorité de santé (National authority for health) in 2015, we conducted a national practice survey in 63 neonatal intensive care units (NICU) and a retrospective study of the characteristics of 103 children transfused within our unit, to better target beneficiaries. The practice survey showed that 30 % of French NICUs no longer used the protocol in 2014, due to logistical or financial problems, or concerns about the transfusion of stored blood. The practices were heterogeneous. Few NICUs used a written protocol. In our NICU, the use of single-donor protocol involved the use of units stored for more than 20 days in half of the cases beginning with the third unit used. Six-term newborns were mainly transfused once, which does not seem to warrant the single-donor transfusion protocol. The use of this protocol caused the loss of 50 % of the manufactured units, which go unused. In multivariate analysis, two factors were predictive of multiple transfusion within our population of 95 premature neonates undergoing transfusion: low-term and a high Clinical Risk Index for Babies (CRIB) score. The risk of multiple transfusions would be reduced by about 15 % for each additional week of gestation and approximately 16 % per point within the CRIB score. These variables integrated into a statistical model predict the risk of multiplying transfusions. According to the ROC curve, a calculated risk higher than 50 % is the appropriate cut-off value to transfuse with the single-donor transfusion protocol. This would limit its indications, saving more than 130 pediatric units of blood for 100 transfused children. A prospective study in our department will allow internal validation of this test.

[Lung protective strategies for premature infants]. / Stratégies de protection pulmonaire chez les prématurés.

Despite many advances in perinatal medicine, bronchopulmonary dysplasia still frequently occurs in very premature infants. The very fragile lungs of these infants therefore have to be protected from birth. The protective strategies consist in applying positive expiratory pressure immediately, and using exogenous surfactant in a prophylactic or early use approach. The recent, variable flow, continuous positive airway pressure (CPAP) systems are very efficient and may allow to avoid tracheal intubation, or to facilitate weaning. When mechanical ventilation has to be used, high peak pressure and/or high tidal volume have to be avoided in order to prevent volutrauma. Accepting not to normalize PCO(2) contributes to it. High frequency oscillatory ventilation, which actually does not prevent bronchopulmonary dysplasia, is an extremely efficient ventilatory support technique for severe respiratory failure. Postnatal gluco-corticoid use reduces the rate of bronchopulmonary dysplasia at 36 weeks, but also results in an increased incidence of long-term neurological handicaps. In our experience, using these treatments can be avoided. Maternal transfer to a level three perinatal center, associated with the adequate use of theses lung protective strategies following very premature birth enable the less unfavorable results to be obtained.

[Oxygen weaning]. / Sevrage de l'oxygène.

Oxygen weaning is a controversial problem which can be summarized in three questions: what do we expect from oxygen supplementation? what are the optimal targets? with what sort of monitoring? We shall try to evaluate these different questions assuming the uncertainty of the proposed answers and the short-lived character of them.

[Skin care and transcutaneous monitoring in neonatal intensive care unit]. / Peau: soins d'hygiène et techniques de surveillance par voie cutanée en réanimation néonatale.

Newborn skin, particularly in preterm infants, is exposed to iatrogenic complications resulting from lesions provoked by diagnosis and therapeutic devices. This paper reviews some principles of skin care in neonatal intensive care units and focuses on iatrogenic lesions and the proposed methods to prevent them.

[Epidemiology of preterm birth: Prevalence, recent trends, short- and long-term outcomes]. / Épidémiologie de la prématurité: prévalence, évolution, devenir des enfants.

Every year, approximately 15 million babies are born preterm worldwide (before 37 completed weeks of gestation), putting the global preterm birth rate at 11%; they are about 60,000 in France. About 85% of these births are moderate (32-33 weeks) to late preterm babies (34-36 weeks), 10% are very preterm babies (28-31 weeks) and 5% are extremely preterm babies (< 28 weeks). Though neonatal mortality rates are dropping, they remain high and are largely determined by gestational age at birth (over 10% mortality for infants born before 28 weeks, 5-10% at 28-31 weeks and 1-2% at 32-34 weeks). Severe neonatal morbidity and disabilities during childhood are also frequent and vary with gestational age. For example, the risk of motor or cognitive impairment is 2 to 3 times higher among children born between 34 and 36 weeks than among children born full-term. Therefore, every preterm baby must be carefully monitored. Recent cohort studies have focused on extremely preterm births; however, awareness of potential outcome and prognosis of all preterm babies is a crucial step for health professionals caring for these children. Huge disparities exist between high- and low-income countries, but also among high-income countries themselves.

[Recombinant human erythropoietin in neonates: guidelines for clinical practice from the French Society of Neonatology]. / L'érythropoïétine humaine recombinante chez le nouveau-né : recommandations pour la pratique clinique de la Société française de néonatologie.

OBJECTIVE: 1/To assess the effectiveness and safety of EPO in reducing red blood cell (RBC) transfusions in preterm infants. 2/To provide guidelines for clinical practice in France. METHODS: 1/This systematic evidence review is based on PubMed search, Cochrane library. 2/Using French National Authority for Health methods concerning guidelines for clinical practice. RESULTS: Early EPO reduced the risk of RBC transfusions, donor exposure, and the number of transfusions in very preterm infants (LE2). Late EPO reduced the risk of RBC transfusions and the number of transfusions in very preterm infants (LE2). There is no difference between the effectiveness of early and late EPO (LE2). There is no difference between high-dose and low-dose EPO (LE2). The level of evidence is too low to recommend the intravenous route. EPO has no impact on the rate of bronchopulmonary dysplasia, necrotizing enterocolitis (LE3), and retinopathy of prematurity (LE2). The level of evidence is too low to recommend EPO for neuroprotection in very preterm or term infants. CONCLUSIONS: EPO to reduce RBC transfusion in very preterm infants is recommended (Level A). The optimal time to start therapy is unknown (Level B). The recommended dose is 750IU/kg/week via three subcutaneous injections for 6weeks (Level B).