Neonatal end-of-life decision-making almost 20 years after the EURONIC study: A French survey.

Nearly 20 years ago the EURONIC study reported that French neonatologists sometimes deemed it legitimate to terminate the lives of newborn infants when the prognosis appeared extremely poor. Parents were not always informed of these decisions. Major change has occurred since then and is described herein. MATERIAL AND METHODS: A survey was conducted in the Île-de-France region, from 1 January to 31 January 2016. Professionals from 15 neonatal intensive care units (NICUs) were invited to complete a questionnaire. RESULTS: A total of 702 questionnaires were collected and 670 responses were analyzed. Knowledge of the law differed according to professional status, with 71% of MDs (medical staff, MS), compared with 28% of nonmedical staff (NMS) declaring that they had good knowledge of the law. Most MDs and NMS believed that withholding or withdrawing life-sustaining treatments (WWLST) could be decided and implemented after a delay. Half of them thought that WWLST would always result in death. Although required by law, a consulting MD attended the collegial meeting required before deciding on WWLST in only half of the cases. Parents were almost always informed of the decision thereafter by the physician in charge of their infant. The most frequent disagreement with parents was observed when WWLST was the option selected. In this case, most professionals suggested postponing WWLST, continuing intensive care and dialogue with parents, aiming at a final shared decision. Major differences were observed between NICUs with regard to the withdrawal of artificial nutrition and hydration. Finally, 14% of MDs declared that infant active terminations of life still occurred in their NICU. Major differences concern WWLST and active termination of life, whose meaning has been partly modified since 2001. CONCLUSION: Several major changes were observed in this survey: (1) treatment withdrawal decisions are made today in agreement with the law; (2) parents' information and involvement in the decision process have profoundly changed; (3) active termination of life (euthanasia) very rarely occurs; only at the end of a process in accordance with ethical principles and within the law is this decision made.

[Palliative care for newborn infants with congenital malformations or genetic abnormalities]. / Démarche palliative chez le nouveau-né atteint de malformations ou d'anomalies génétiques sévères.

The choice of palliative care can be made today in the perinatal period, as it can be made in children and adults. Palliative care, rather than curative treatment, may be considered in three clinical situations: babies born at the limits of viability, withholding/withdrawing treatments in the NICU, and babies with severe malformations of genetic abnormalities identified during pregnancy. Only the last situation is addressed hereafter. In newborn infants as in older patients, palliative care aims at taking care of the baby and at providing comfort and well-being. The presence of human beings by the newborn infant, most importantly the parents and family, is of utmost importance. The available time should not be used only for care and medical treatments. Sufficient time should be kept for the parents to interact with the baby and for human presence and warmth. The best interests of the newborn infant are the main element for guiding appropriate care. Before birth, the choice of palliative care for newborn infants requires successive steps: (1) establishing a diagnosis of malformation(s) or genetic abnormalities; (2) making a prognosis and ruling out intensive treatments at birth and thereafter; (3) giving the parents appropriate information; (4) assisting the pregnant woman in deciding to continue pregnancy while excluding intensive treatment of the newborn baby; (5) dialoguing with parents about the expected duration of the baby's life and the related uncertainty; (6) planning of palliative care to be implemented at birth; (7) preparing a plan with the parents for discharging the infant from the hospital and for taking care of him over a long time, when it is deemed possible that the baby may live for more than a few days.

[Very premature births: Dilemmas and management. Part 1. Outcome of infants born before 28 weeks of postmenstrual age, and definition of a gray zone]. / Naissances très prématurées : dilemmes et propositions de prise en charge. Première partie : pronostic des naissances avant 28 semaines, identification d'une zone grise.

With very preterm deliveries, the decision to institute intensive care, or, alternatively, to start palliative care and let the baby die, is extremely difficult, and involves complex ethical issues. The introduction of intensive care may result in long-term survival of many infants without severe disabilities, but it may also result in the survival of severely disabled infants. Conversely, the decision to withhold resuscitation and/or intensive care at birth, which is an option at the margin of viability, implies allowing babies to die, although some of them would have developed normally if they had received resuscitation and/or intensive care. Withholding intensive care at birth does not mean withholding care but rather providing palliative care to prevent pain and suffering during the time period preceding death. The likelihood of survival without significant disabilities decreases as gestational age at birth decreases. In addition to gestational age, other factors greatly influence the prognosis. Indeed, for a given gestational age, higher birth weight, singleton birth, female sex, exposure to prenatal corticosteroids, and birth in a tertiary center are favorable factors. Considering gestational age, there is a gray zone that corresponds to major prognostic uncertainty and therefore to a major problem in making a "good" decision. In France today, the gray zone corresponds to deliveries at 24 and 25 weeks of postmenstrual age. In general, babies born above the gray zone (26 weeks of postmenstrual age and later) should receive resuscitation and/or full intensive care. Below 24 weeks, palliative care is the only option offered in France at the present time. Decisions within the gray zone will be addressed in the 2nd part of this work.

[Very premature births: Dilemmas and management. Second part: Ethical aspects and recommendations]. / Naissances très prématurées : dilemmes et propositions de prise en charge. Seconde partie : enjeux éthiques, principes de prise en charge et recommandations.

In the first part of this work, the outcome following very premature birth was assessed. This enabled a gray zone to be defined, with inherent major prognostic uncertainty. In France today, the gray zone corresponds to deliveries occurring at 24 and 25 weeks of postmenstrual age. The management of births occurring below and above the gray zone was described. Withholding intensive care at birth for babies born below or within the gray zone does not mean withholding care but rather providing palliative care to prevent pain and suffering during the time period preceding death. Given the high level of uncertainty, making good decisions within the gray zone is problematic. Decisions should be based on the infant's best interests. Decisions should be reached with the parents, who are entitled to receive clear and comprehensive information. Possible decisions to withhold intensive care should be made following the procedures described in the French law of April 2005. Guidelines, based on gestational age and the other prognostic elements, are proposed to the parents before birth. They are applied in an individualized fashion, in order to take into account the individual features of each case. At 25 weeks, resuscitation and/or full intensive care are usually proposed, unless unfavorable factors, such as severe growth restriction, are associated. A senior neonatologist will attend the delivery and will make decisions based on both the baby's condition at birth and the parents' wishes. At 24 weeks, in the absence of unfavorable associated factors, the parents' wishes should be followed in deciding between initiating full intensive care or palliative care. Below 24 weeks, palliative care is the only option to be offered in France at the present time.

Capnocytophaga species and preterm birth: case series and review of the literature.

Capnocytophaga, a genus of Gram-negative anaerobes that inhabit the oral cavity, has been reported to be an unusual cause of chorioamnionitis and neonatal infection. We report five cases of Capnocytophaga spp. infections in preterm infants (one proven infection and four probable infections) and review 14 previously reported cases. We suggest that Capnocytophaga sp. may be responsible for some occult causes of chorioamnionitis or preterm birth, and that the prevalence of this infection may be higher than previously reported.

[Apnea of prematurity: what's new?]. / Apnées du prématuré : données récentes.

Prematurity apnea remains a major clinical problem that requires treatment choices which are sometimes difficult. Prematurity apnea occurs in most infants of gestational age at birth less than 33 weeks. It is a developmental disorder which usually reflects a "physiological" immaturity of respiratory control. However, neonatal diseases may be associated and play an additive role, resulting in an increased incidence of apnea. Careful screening should therefore be performed in order to make sure that no other factor than immaturity is involved in the occurrence of apnea. Short apnea (less than 10s, without hypoxemia and bradycardia), due to immaturity, are not clinically relevant. More prolonged apnea, that last for more than 15 or 20s, and / or apnea associated with bradycardia or oxygen desaturation, results in short-term disturbances of cerebral haemodynamics and oxygenation, which may negatively impact on neurodevelopmental outcome. Evaluating the immediate severity of apnea and the risks that apnea may affect long-term outcome remains a challenge. The choice of treatments is based on a few evidences. Caffeine citrate, which reduces the incidence of apnea, has been used for decades. However, a thorough evaluation of risks and benefits of this medication has been performed only recently. Caffeine citrate was found to be safe and resulted in unexpected benefits. In treated infants, compared with controls, indeed, a decreased incidence of the following complications was recorded: bronchopulmonary dysplasia at 36 weeks of conceptional age, patent ductus arteriosus, cerebral palsy at 18 months of age. Nasal CPAP can be used in association with caffeine citrate, when the latter is not effective enough.

[Abnormal ocular findings in the nursery and in the first few weeks of life: a mandatory, yet difficult and neglected screening]. / Anomalies oculaires en maternité et dans les premières semaines de vie: un dépistage obligatoire, difficile et négligé

Recommendations issued by the French Health Ministry include ocular screening in the first days of life and at 2 and 4 months. The aim is to detect ocular abnormalities requiring early treatment, in order to improve the prognosis. Paediatricians working in the nursery should therefore be trained in order to perform ocular screening, which requires using an ophthalmoscope. This is not yet common practice in all nurseries. Red-reflex is one of the most important elements of testing. Possible diagnoses suggested by abnormal red-reflex include retinoblastoma, or abnormalities of eye transparency, such as cataract. Any detected ocular abnormality requires specialised consultation. At the present time, paediatricians remain insufficiently aware and trained about ocular screening.

[How to decide with precision, justice, and equity? Reflections on decision-making in the context of extreme prematurity. Part two: moving toward making the best possible decision: defining conditions for putting decisions into practice]. / Comment décider avec justesse, justice et équité? Réflexion sur la décision en situation d'extrême prématurité. Deuxième partie: comment tendre vers une décision optimale? Définition des conditions d'exercice de la décision.

Extreme premature child's long-term prognostic is getting better and better known, and if a resuscitation procedure is possible at birth, it won't guarantee survival or a survival free of disability. Incertitude toward individual prognosis and outcome for those children remains considerable. In this field, we are at the frontier of medical knowledge and the answer to the question, "how to decide the ante and postnatal care" is crucial. This work is focused on this problematic of decision-making in the context of extreme prematurity. It attempts to deconstruct this concept and to explicit its stakes. Thus, with the support of the medical sources and of philosophical debates, we tried to build a decision-making procedure that complies with the ethical requirements of medical care, accuracy, justice and equity. This decision-making procedure is primarily concerned with the singularity of each decision situation and it intends to link it closely to the notions of rationality and responsibility.

[How to decide with precision, justice, and equity? Reflections on decision-making in the context of extreme prematurity. Part one: the problematics of decision-making in the context of extreme prematurity]. / Comment décider avec justesse, justice et équité? Réflexion sur la décision en situation d'extrême prématurité. Première partie: problématique de la décision dans le contexte de la prématurité extrême.

Extreme premature child's long-term prognostic is getting better and better known, and if a resuscitation procedure is possible at birth, it won't guarantee survival or a survival free of disability. Incertitude toward individual prognosis and outcome for those childs remains considerable. In this field, we are at the frontier of medical knowledge and the answer to the question, "how to decide the ante and postnatal care?" is crucial. This work is focused on this problematic of decision making in the context of extreme prematurity. It attempts to deconstruct this concept and to explicit its stakes. Thus, with the support of the medical sources and of philosophical debates, we tried to build a decision-making procedure that complies with the ethical requirements of medical care, accuracy, justice and equity. This decision-making procedure is primarily concerned with the singularity of each decision situation and it intends to link it closely to the notions of rationality and responsibility.

[Cleft of the lower lip, mandible and sternum. A case report and review of the literature]. / Fente labiomandibulaire et sternale. A propos d'un cas et revue de la littérature.

The Authors report a case of cleft interesting the lower lip and mandible with a sternal cleft. This association is exceptional, it was described in three world cases to this day. At this occasion, a review of the literature is realized, in particular concerning the associated malformatives anomalies and the therapeutic behaviour. It seems to us indispensable to realize an early reconstruction, specially bone correction, and to collaborate with a multidisciplinary team to obtain a good result and a better social incorporation of the child.

[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.

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method.

OBJECTIVE: Intravenous ibuprofen (IBU) has been found to be as effective as indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants and has been associated with fewer adverse effects in comparative phase III studies. The dose regimen used (10-5-5 mg/kg/day) was based on limited pharmacokinetic data and no phase II study was available to determine the optimal dose of IBU for this indication. The present study was designed to determine the minimum effective dose regimen (MEDR) of IBU (one course) required to close ductus arteriosus in preterm infants. METHOD: A double-blind dose-finding study was conducted using the continual reassessment method, a Bayesian sequential design. Two distinct target closure rates were initially chosen according to postmenstrual age (PMA) at birth: 80% in infants with a PMA of 27-29 weeks, and 50% in infants with a PMA < 27 weeks. Forty neonates (20 in each PMA group) with PDA were treated between days 3 and 5 of life. Four different dose regimens were tested: loading doses of 5, 10, 15 or 20 mg/kg, followed by two doses (1/2 loading dose) at 24-h intervals. Efficacy was evaluated by echocardiography 24 h after the third infusion. RESULTS: In infants with a PMA of 27-29 weeks, the estimated MEDR was 10-5-5 mg/kg with a final estimated probability of success of 77% (95% credibility interval: 56-92%). The 15-7.5-7.5 mg/kg dose regimen had a better estimated probability of success (88%, 95% credibility interval: 68-97%), but resulted in more minor renal adverse effects. In contrast, in infants with a PMA < 27 weeks, the estimated MEDR was 20-10-10 mg/kg with an estimated probability of success of 54.8% (95% credibility interval: 22-84%), whereas the conventional dose regimen resulted in a low estimated probability of success (30.6%, 95% credibility interval: 13-56%). In these infants, compared with those with a PMA of 27-29 weeks, minor renal adverse effects were more frequent from the 10-5-5 mg/kg/day dose regimen and did not appear to be clearly dose related. CONCLUSION: This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.

[Erythropoietin and anemia in premature infants]. / Erythropoïétine et anémie du prématuré.

Anemia of prematurity is characterized by low reticulocyte counts and inadequate erythropoietin response, for which many premature infants receive multiple blood transfusions. To reduce the number of those transfusions, treatment with EPO and iron supplementation is routinely used in premature infants. Even if the efficacy of this treatment is demonstrated, the results are not so good in the very low birth weight infants or very small gestational age infants and the need of transfusion is still important. This is due for a large part to blood loss in these very small infants. But there are also other explanations. Thus the pharmacokinetics of EPO is different in premature infants and newborn than in adults. Best dose, best way of administration (i.v. or subcutaneous), best number of injections per week are not already known. Further study has to be done to achieve a better use and efficacy of this treatment.

[Prenatal risk evaluation, parent information and mode of delivery]. / Evaluation des risques en anténatal, information des parents et prise en charge de l'accouchement.

Perinatal networks, antenatal administration of glucosteroids, postnatal administration of surfactant, and new techniques for mechanical ventilation, have considerably improved the prognosis of extremely preterm infants. Such recent progress in perinatology had enabled neonatologists to provide intensive care for infants born after 24 and 28 weeks of gestation. This practice raises serious medical and ethical issues. The optimal mode of delivery of such newborns is not well established mainly because available studies are retrospective and subjected to biases. Moreover, perinatologists are implicated in the continuing discussion on ethical issues that modify clinical practices.

[Extremely preterm infants: resuscitation criteria in the delivery room and dialogue with parents before birth]. / Critères de réanimation des prématurissimes en salle de naissance: quel discours en anténatal?

The resuscitation of extremely preterm infants presents complex medical, social and ethical issues for the families and the health professionals. The principle of a systematic resuscitation "temporary intensive care" does not prohibit the question of a limit in terms of gestational age and birth weight. In France, a do not resuscitate order (comfort care alone) is appropriate for newborns weighing less than 500g and/or with a gestational age of less than 24 weeks' since the mortality is nearly 100%. The survival of infants born at 24 weeks' gestational age remains low with significant risks of chronic medical problems and neurodevelopmental disabilities. The decisions regarding the extent of resuscitative efforts depend on antenatal factors, condition of the neonate at birth and the parental opinion. Before the delivery, parents should receive appropriate information about survival and risks of adverse long-term outcome. The physician should follow the parents' desires whenever the parents' decision would not obviously violate the infants' best interests. However, they must be informed that decisions about neonatal management made before the delivery can have to be changed in the delivery room, depending on the condition of the neonate at birth. At 25 weeks of gestational age, the prognosis is better and the resuscitation should be more intensive.

Stability and biological activity of epoietin beta in parenteral nutrition solutions.

The aim of this in vitro study was to determine stability and biological activity of epoietin (Epo) beta in a parenteral nutrition solution over 24 h. Epo beta was added to the parenteral nutrition solution which was administered through intravenous tubing and a Posidyne Neo filter. Samples were collected after 0, 4, 12, and 24 h. The Epo concentrations were measured before and after filter passage by an ELISA assay. The Epo biological activity was determined in the UT7/Epo cell line. The Epo concentration in the parenteral nutrition solution remained stable for 24 h. However, 35% of the Epo was adsorbed by the filter. The samples collected induced proliferation of UT7/Epo cells. These results suggest that Epo can be administered in parenteral nutrition solutions, but the dosage would need to be increased when a filter is used.

Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome.

BACKGROUND: Early use of high-frequency ventilation and exogenous surfactant is proposed as the optimal mode of ventilatory support in infants with respiratory distress syndrome. In very premature infants, we tested the hypothesis that high-frequency versus conventional ventilation could decrease exogenous surfactant requirements and improve pulmonary outcome, without altering the complication rate, including that of severe intraventricular hemorrhage. METHODS: Preterm infants with a postmenstrual age of 24 to 29 weeks, presenting with respiratory distress syndrome were randomly assigned to high-frequency oscillatory ventilation (lung volume recruitment strategy) or conventional ventilation. RESULTS: Two hundred seventy-three infants were enrolled. One hundred fifty-three had a postmenstrual age of 24 to 27 weeks, and 143 had a birth weight /=2 instillations of exogenous surfactant (30% vs 62%; odds ratio:.27; 95% confidence interval:.16-.44) and no difference in pulmonary outcome. The incidence of severe intraventricular hemorrhage was 24% in the high-frequency group and 14% in the conventional ventilation group (adjusted odds ratio: 1.50; 95% confidence interval:.68-3.30). CONCLUSION: Early use of high-frequency oscillatory ventilation in very premature infants decreases exogenous surfactant requirements, does not improve the pulmonary outcome, and may be associated with an increased incidence of severe intraventricular hemorrhage.