Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.

Successful liver transplantation using a whole liver graft with gallbladder agenesis: First report in pediatric liver transplantation.

INTRODUCTION: Gallbladder agenesis (GA) is a rare congenital condition, occurring in approximately 40/100.000. It is likely due to an embryologic mishap in the development of the gallbladder bud and can be associated with other congenital variations in biliary anatomy. However, the liver likely suffers no functional impairment and can be safely used for transplantation. To the best of our knowledge, this is the first case report describing a pediatric liver transplantation (PLT) using a graft with GA. CASE REPORT: A 10-year-old boy with methylmalonic aciduria underwent isolated liver transplant with a deceased graft from a donor with no relevant medical or surgical history and normal laboratory tests. During the back-table liver preparation procedure, no evidence of gallbladder was found, raising the possibility of a GA, confirmed by intraoperative cholangiography. The liver transplantation procedure was uneventful despite the particularly rare combination of biliary tree anatomic distribution found in the cholangiography. At 1 year of follow-up, there were no clinical, laboratory, or imagological signs of bile leaks or anastomotic site stricture. DISCUSSION: The present report highlights the importance of the accurate knowledge of the vasculobiliary anatomic variation, particularly in extremely rare cases, such as GA, and in complex hepatobiliary procedures, such as PLT. In our opinion, grafts with GA should not be discarded for transplantation.

Outcomes of choledochal cysts with or without intrahepatic involvement in children after extrahepatic cyst excision and Roux-en-Y hepaticojejunostomy.

BACKGROUND: Type I and type IV-A choledochal cysts (CC) in Todani's classification are the most frequent types of CC. Unlike type I cyst, in which the dilatation is confined to the extrahepatic bile duct, type IV-A affects both extra and intrahepatic ducts. AIM: To review our experience of complete cyst excision with Roux-en-Y hepaticojejunostomy for the treatment of type I and type IV-A CC in childhood, in order to better characterize these entities. MATERIAL AND METHODS: Data was collected retrospectively from a cohort of children who underwent cyst resection for CC from 1989 to 2011 in our institution. RESULTS: Twelve patients were submitted to surgical excision of extrahepatic cyst and hepaticojejunostomy for treatment of type I (n = 6) and type IV-A (n = 6) cysts, with a complication rate of 25% (n = 3) and no mortality. Long term follow-up was available in 92% of patients, with a median of 10 years (2-22 years). Morbidities consisted of bile leak (2 patients) and late-onset cholestasis (1 patient); two of these required anastomotic revision. The results did not reveal any significant differences between the groups regarding postoperative outcomes (P > 0.05). Preoperative intrahepatic dilatation was found to permanently vanish in 83% of patients diagnosed with type IV-A cyst after operative repair. CONCLUSIONS: Intrahepatic dilatation of type IV-A cyst in children did not adversely affect the postoperative outcome after conventional surgical repair. This operative approach was effective in the management of type I and type IV-A cysts.

Auxiliary liver transplantation for management of acute liver failure in children - Systematic review.

INTRODUCTION: Liver transplantation (LT) remains the standard of care in the treatment of acute pediatric liver failure (PALF) for the replacement of a severely damaged native liver in patients who are unlikely to recover. However, this is burdened by the consequences of long-term immunosuppression. Auxiliary partial liver orthotopic transplantation (APOLT) has emerged as a possible improved approach, by providing a graft that assures liver function until the regeneration of the native liver occurs, and then allows for possible progression to immunosuppression withdrawal. No previous systematic review has assessed APOLT for PALF. The aim of this work is to provide information on survival, postoperative complications, and withdrawal of immunosuppression after APOLT for PALF. METHODS: The study was carried out according to the recommendations of the preferred report items for systematic reviews and meta-analyzes (PRISMA). We searched several electronic databases until October 31st, 2020, using the search terms "acute liver failure", "auxiliary liver transplant" and the MESH term "liver failure, acute". All types of clinical publications that presented results on APOLT for PALF, in English or Portuguese, and restricted to humans and for children under 18 years old were included. The following exclusion criteria were applied: "follow-up time <6 months", "does not report complications" and "does not report immunosuppression regimen (double vs triple)". Demographic data, clinical characteristics at the time of surgery and postoperative results were analyzed. RESULTS: A total of 14 references (including 45 patients) were selected, including 3 case series (6-20 patients) and 11 case reports. Of the 45 subjects, 33 (73.3%) were male and 12 (26.7%) female. In most cases (n = 30; 66.7%), the cause of PALF was undetermined. All patients underwent APOLT. Their median age was 9 (range 0.6-17) years. In the postoperative period, the immunosuppression regimen was double in 34 (75.6%) and triple in 11 (24.4%) individuals. The main postoperative complications were rejection and infection. Over a follow-up period of 6 months to 14 years, 10 (22.2%) patients died. The main cause of death was sepsis (70%). Six (13.3%) patients were retransplanted. Of the survivors (n = 35), 68.6% achieved complete withdrawal from the immunosuppression regimen. CONCLUSION: Based on current published evidence, APOLT for the treatment of PALF is a safe option, with an acceptable rate of complications and mortality. It has the great advantage of providing an immunosuppression-free life in the majority (68.6%) of survivors.

Donor Surgical Morbidity in Pediatric Living-Donor Liver Transplant: A Portuguese Experience.

PURPOSE: Living-donor liver transplant emerged as an alternative treatment for end stage liver disease due to the lack of cadaveric organs availability that met the demand. In Portugal, pediatric living-donor liver transplant (P-LDLT) was initiated in 2001 in Portugal in order to compensate for the scarcity of cadaveric organs for such cases. The aim of this study was to retrospectively analyze the morbi-mortality of the 28 donors included in P-LDLT program performed at Coimbra's Pediatric Hospital (CHUC), a Portuguese reference center. METHODS: We retrospectively collected pertinent donor data and stratified complications according to Clavien's scoring system. RESULTS: In total, 28.6% (n=8) of the donors had surgical complications. According to Clavien-Dindo's classification, two donors had major complications (Clavien grade ≥3), four donors had grade 2 complications, and two donors had grade 1 complications. There were no P-LDLT-related mortalities in the present case series. The most common verified complications were biliary tract injuries and superficial incisional infections, which are consistent with the complications reported in worldwide series. CONCLUSION: These patients from CHUC shows that donor hepatectomy in P-LDLT is a safe procedure, with low morbidity and without mortality.

ABO Incompatible Liver Transplantation in Children: A 20 Year Experience from Centres in the TransplantChild European Reference Network.

An increasing number of AB0-incompatible (AB0i) liver transplantations (LT) are being undertaken internationally in recent years due to organ shortages and the need for urgent transplantation. The aim of our study was establish the value of ABOi LT from available retrospective results of AB0i pediatric liver transplantations performed in European reference centers now belonging to the TransplantChild, European Reference Network (ERN). Data from medical records were analyzed, including demographic data, diagnosis, urgency of transplantation, time on the waiting list, PELD/MELD score, desensitization procedures, immunosuppression, selected post-transplant complications, and patient and graft survival. A total of 142 patients (pts) with transplants between 1986 and 2018 in 8 European transplant centers were included in the study. The indications for liver transplantation were: cholestatic diseases in 62 pts, acute liver failure in 42 pts, and other conditions in the remaining 38 pts. Sixty-six patients received grafts from living donors, and seventy-six received grafts from deceased donors. Both patient and graft survival were significantly affected by deceased donor type, urgent transplantation, and the development of vascular complications. In the multivariate analysis, vascular complications had a negative impact on patient and graft survival, while a longer time from the first AB0i LT in the study showed better results, suggesting an international learning experience. In conclusion, we believe that AB0i LT in children is now a safe procedure that may be adopted more readily in children.

Current Practices on Diagnosis, Prevention and Treatment of Post-Transplant Lymphoproliferative Disorder in Pediatric Patients after Solid Organ Transplantation: Results of ERN TransplantChild Healthcare Working Group Survey.

(1) Background: Post-transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation (SOT). However, there is lack of consensus in PTLD management. Our aim was to establish a present benchmark for comparison between international centers and between various organ transplant systems and modalities; (2) Methods: A cross-sectional questionnaire of relevant PTLD practices in pediatric transplantation was sent to multidisciplinary teams from 17 European center members of ERN TransplantChild to evaluate the centers' approach strategies for diagnosis and treatment and how current practices impact a cross-sectional series of PTLD cases; (3) Results: A total of 34 SOT programs from 13 European centers participated. The decision to start preemptive treatment and its guidance was based on both EBV viremia monitoring plus additional laboratory methods and clinical assessment (61%). Among treatment modalities the most common initial practice at diagnosis was to reduce the immunosuppression (61%). A total of 126 PTLD cases were reported during the period 2012-2016. According to their histopathological classification, monomorphic lesions were the most frequent (46%). Graft rejection after PTLD remission was 33%. Of the total cases diagnosed with PTLD, 88% survived; (4) Conclusions: There is still no consensus on prevention and treatment of PTLD, which implies the need to generate evidence. This might successively allow the development of clinical guidelines.

Oesophageal atresia with tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease: outcome of a rare phenotype.

Oesophageal atresia with or without tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease are surgical malformations of the gastrointestinal tract typically diagnosed early in the neonatal period and varying in severity and prognosis. This report describes a full-term male newborn presenting simultaneous oesophageal atresia with distal tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease. In addition to the complex types of gastrointestinal malformations involved, the combination of ileal atresia and Hirschsprung's disease, as well as ganglion cells distal to intestinal atresia, resulted in a challenging diagnosis. Despite a successful outcome, the patient presented increased morbidity and prolonged hospitalisation. We highlight some important findings that may aid the early diagnosis of Hirschsprung's disease in this clinical setting. To our knowledge, the association of oesophageal atresia/tracheo-oesophageal fistula, ileal atresia and Hirschsprung's disease has not been previously reported.

Grafts of porcine intestinal submucosa for repair of cervical and abdominal esophageal defects in the rat.

Porcine small intestinal submucosa (SIS) is a cell-free collagen matrix that has demonstrated its ability as scaffold material for constructive remodeling of damaged or missing tissue. The purpose of this study was to evaluate the morphology and function of esophagoplasty in rat using a porcine SIS scaffold for the repair of a semi-circumferential defect in the cervical or in the abdominal esophagus. Sixty-seven rats underwent surgical excision of the anterior wall either of the cervical or of the abdominal esophagus and subsequent repair of the defect with an SIS patch graft. Outcomes of weight gain, signs of dysphagia, hematological and serum chemistry parameters, and barium swallow studies were used to assess the progress of healing and function over a 150-day time period. The grafts were studied for gross changes and histology at predetermined time points. Ninety-four percent of the SIS-treated rats survived, showing no significant differences in survival rate between groups. The grafted animals did well, without signs of dysphagia, and gaining weight. Barium swallow studies showed no evidence of fistula, significant stenosis, or diverticula. No hematological or serum biochemistry abnormalities were found. By 150 days, the SIS graft was replaced with esophageal-derived tissues. Specimens were completely lined by keratinized stratified squamous epithelium and showed complete regeneration of muscle fibers and scarce immunoreactivity for nerve. In the rat model, a patch graft technique using porcine SIS appears to induce esophageal regrowth either in cervical and abdominal esophagus. The repair mechanism occurred through a regenerative healing process.

[Perioperative morbidity and mortality in the first year of life: a systematic review (1997-2012)]. / Morbimortalidade perioperatória no primeiro ano de idade: revisão sistemática (1997-2012).

BACKGROUND AND OBJECTIVES: Although many recognize that the first year of life and specifically the neonatal period are associated with increased risk of anesthetic morbidity and mortality, there are no studies directed to these pediatric subpopulations. This systematic review of the scientific literature including the last 15 years aimed to analyze the epidemiology of morbidity and mortality associated with general anesthesia and surgery in the first year of life and particularly in the neonatal (first month) period. CONTENT: The review was conducted by searching publications in Medline/PubMed databases, and the following outcomes were evaluated: early mortality in the first year of life (<1 Yr) and in subgroups of different vulnerability in this age group (0-30 days and 1-12 months) and the prevalence of cardiac arrest and perioperative critical/adverse events of various types in the same subgroups. CONCLUSIONS: The current literature indicates great variability in mortality and morbidity in the age group under consideration and in its subgroups. However, despite the obvious methodological heterogeneity and absence of specific studies, epidemiological profiles of morbidity and mortality related to anesthesia in children in the first year of life show higher frequency of morbidity and mortality in this age group, with the highest peaks of incidence in the neonates' anesthesia.

Perioperative morbidity and mortality in the first year of life: a systematic review (1997-2012).

BACKGROUND AND OBJECTIVES: Although many recognize that the first year of life and specifically the neonatal period are associated with increased risk of anesthetic morbidity and mortality, there are no studies directed to these pediatric subpopulations. This systematic review of the scientific literature including the last 15 years aimed to analyze the epidemiology of morbidity and mortality associated with general anesthesia and surgery in the first year of life and particularly in the neonatal (first month) period. CONTENT: The review was conducted by searching publications in Medline/PubMed databases, and the following outcomes were evaluated: early mortality in the first year of life (<1 year) and in subgroups of different vulnerability in this age group (0-30 days and 1-12 months) and the prevalence of cardiac arrest and perioperative critical/adverse events of various types in the same subgroups. CONCLUSIONS: The current literature indicates great variability in mortality and morbidity in the age group under consideration and in its subgroups. However, despite the obvious methodological heterogeneity and absence of specific studies, epidemiological profiles of morbidity and mortality related to anesthesia in children in the first year of life show higher frequency of morbidity and mortality in this age group, with the highest peaks of incidence in the neonates' anesthesia.

A rat model for the study of intestinal heterotopic gastropathy.

This study analyzes an experimental model for the study of reactions from gastric tissue exposed to enteric environment. Morphological studies were performed by histological, histochemical and immunohistochemical methods, using formalin-fixed biopsies of full-wall-thickness gastric implants in a whole-wall jejunal defect. These grafts suffered severe lesions, characterized by chronic atrophic gastritis, foveolar hyperplasia, glandular cystic transformation, and intestinal metaplasia. Increase in acidic mucins was also observed. There was no proliferating cell nuclear antigen (PCNA) overexpression. The results suggest that this model can be useful to investigate the heterotopic grastropathy and can be applied in further research studies.

[Pediatric anesthetic during brain immaturity and neurodevelopment disorders]. / Anestesia pediátrica em período de imaturidade cerebral e perturbações do neurodesenvolvimento.

INTRODUCTION: Several experimental and clinical studies suggest that drugs used in pediatric anesthesia may exert undesirable effects on the developing central nervous system. The objective of this review was to assess the results and conclusions of published studies on long lasting neurodevelopment disorders following exposure to anesthetics in children in a phase of brain immaturity. MATERIAL AND METHODS: We performed a literature search in several sources (PubMed, SciELO and Cochrane Library) using the terms 'Pediatric anesthesia OR Pediatric anesthetic OR Developing brain anesthetic OR Developing brain anesthesia AND behavior disorders'. We selected human studies, referring to long lasting neurodevelopment effects after exposure to anesthetics in the first four years of life. RESULTS: Ten retrospective studies met the inclusion criteria. Of these, seven suggest risk of neurobehavioral disorders after exposure of small children to anesthetics, as opposed to the results obtained by the other three. DISCUSSION: Although mostly using large databases, the studies found are retrospective, vary in test groups, include sometimes avoidable confounders and some present inaccuracies in the choice of the test and control populations that can compromise the reliability of the results. CONCLUSION: Because of the numerous limitations of the few studies available, the reported results are still deemed insufficient to change current clinical practice. However, although it is undisputable that anesthesia should be provided when needed, regardless of age, the warnings found in literature are worrisome, therefore whenever surgery is unavoidable in small children, alternatives that may help reduce the risks of anesthetic exposure should be sought.

Introdução: Diversos estudos experimentais e clínicos sugerem que fármacos usados em anestesia pediátrica podem exercer efeitos indesejáveis sobre o sistema nervoso central imaturo. O objetivo desta revisão consistiu em avaliar os resultados e conclusões de estudos publicados na literatura sobre perturbações persistentes do neurodesenvolvimento após exposição a anestésicos de crianças em fase de imaturidade cerebral. Material e Métodos: Realizámos uma pesquisa bibliográfica em diversas bases de dados (PubMed, SciELO e Cochrane Library), utilizando os termos 'Pediatric anesthesia OR Pediatric anesthetic OR Developing brain anesthetic OR Developing brain anesthesia AND behavior disorders' e foram incluídos os estudos em humanos, referentes a efeitos persistentes no neurodesenvolvimento após exposição a anestésicos nos primeiros quatro anos de idade. Resultados: Dez estudos retrospetivos cumpriram os critérios de inclusão. Destes, sete sugerem alteração do neurodesenvolvimento por exposição de criança pequena à anestesia, por oposição aos resultados obtidos pelos restantes três. Discussão: Embora maioritariamente utilizem bases de dados amplas, os estudos encontrados são retrospetivos, variam nos grupos teste, incluem variáveis de confusão por vezes contornáveis e alguns apresentam incorreções na escolha da população teste e controlo que podem comprometer a fiabilidade dos resultados. Conclusão: As numerosas limitações dos poucos estudos clínicos disponíveis fazem com que a informação reportada ainda se considere insuficiente para mudar a prática clínica atual. No entanto, sendo indiscutível que se mantêm as recomendações para providenciar anestesia quando necessária, independentemente da idade, os alertas encontrados na literatura são preocupantes, existindo indicação para que sempre que possível sejam ponderadas alternativas que possam contribuir para diminuir os riscos da exposição anestésica.

In vivo biocompatibility of Resilon compared with gutta-percha in a pre-clinical model.

BACKGROUND: The aim of this study was to investigate in vivo biocompatibility of Resilon, compared with gutta-percha, at short and long-term following implantation in a rat subcutaneous implantation model. MATERIALS AND METHODS: Male Wistar rats were implanted subcutaneously with either Resilon or gutta-percha or were sham controls. Tissues were harvested at 8 days or 60 days after implantation and were evaluated histologically for inflammation and fibrous encapsulation. The severity of histologic injury, scored on a scale of 0-4 and quantitative analysis of the capsule wall thickness were determined for statistical analysis. Data were analyzed by Student t-test, one-way analysis of variance, Kruskal-Wallis or Mann-Whitney's tests as appropriate. A value of P ≤ 0.05 was considered statistically significant. RESULTS: No behavioral changes or visible signs of physical impairment were observed at 8 days or 60 days post-implantation. Histopathologic observation of the implanted sites at each time-point showed that both Resilon and gutta-percha implants induced foreign body reaction, showing minimal to mild inflammatory reactions in most cases, which diminished significantly with time. Compared with gutta-percha, the capsule wall was thinner (P < 0.05) after Resilon implantation at day 8 and significantly (P = 0.01) thicker at day 60. In addition, capsule wall thickness showed a trend to increase with time after implantation in the Resilon groups (P < 0.05), opposed to the significant decrease (P = 0.016) observed after implantation in the gutta-percha groups, suggesting lesser long-term biocompatibility of Resilon. CONCLUSION: Our findings validate Resilon as an in vivo biocompatible material. However, our data suggest that long-term biocompatibility of Resilon, despite validated, is inferior to that of gutta-percha control.

Early mortality after neonatal surgery: analysis of risk factors in an optimized health care system for the surgical newborn.

OBJECTIVE: Anesthetic and operative interventions in neonates remain hazardous procedures, given the vulnerability of the patients in this pediatric population. The aim was to determine the preoperative and intraoperative factors associated with 30-day post-operative mortality and describe mortality outcomes following neonatal surgery under general anesthesia in our center. METHODS: Infants less than 28 days of age who underwent general anesthesia for surgery during an 11-year period (2000 - 2010) in our tertiary care pediatric center were retrospectively identified using the pediatric intensive care unit database. Multiple logistic regression was used to identify independent preoperative and intraoperative factors associated with 30-day post-operative mortality. RESULTS: Of the 437 infants in the study (median gestational age at birth 37 weeks, median birth weight 2,760 grams), 28 (6.4%) patients died before hospital discharge. Of these, 22 patients died within the first post-operative month. Logistic regression analysis showed increased odds of 30-day post-operative mortality among patients who presented American Society of Anesthesiologists physical status (ASA) score 3 or above (odds ratio 19.268; 95%CI 2.523 - 147.132) and surgery for necrotizing enterocolitis/gastrointestinal perforation (OR 5.291; 95%CI 1.962 - 14.266), compared to those who did not. CONCLUSION: The overall in-hospital mortality of 6.4% is within the prevalence reported for developed countries. Establishing ASA score 3 or above and necrotizing enterocolitis/gastrointestinal perforation as independent risk factors for early mortality in neonatal surgery may help clinicians to more adequately manage this high risk population.

Juvenile polyposis of infancy in a child with deletion of BMPR1A and PTEN genes: surgical approach.

Juvenile polyposis of infancy is the most severe and life-threatening form of juvenile polyposis. This disease typically presents in the first two years of life with gastrointestinal bleeding, diarrhea, inanition, and exudative enteropathy. In very few reports concerning this entity, a large deletion in the long arm of chromosome 10 (10q23), encompassing the PTEN and BMPR1A genes, was found. The authors report a case of delayed diagnosis of juvenile polyposis of infancy at 6 years of age. A 3.34 Mb long de novo deletion was identified at 10q23.1q23.31, encompassing the PTEN and BMPR1A genes. The disease course was severe with diarrhea, abdominal pain, inanition, refractory anemia, rectal bleeding, hypoalbuminemia, and exudative enteropathy. A sub-total colectomy, combined with intraoperative endoscopic removal of ileal and rectal stump polyps, was required for palliative disease control.

Predictors of major postoperative complications in neonatal surgery.

OBJECTIVE: To investigate the incidence and severity of early postoperative complications and to identify their risk factors in newborns undergoing surgery under general anesthesia. METHODS: We conducted a retrospective analysis of data from 437 critically ill newborns undergoing surgery in a tertiary pediatric surgical center, between January 2000 and December 2010. Complications that occurred within the first 30 days after surgery were classified using the Clavien-Dindo system, for which grades III to V were considered severe. We used univariate and multivariate analysis to evaluate pre- and intraoperative variables potentially predictive of severe postoperative complications. RESULTS: The incidence of at least one serious complication was 23%, with a median of one complication per patient 1:3. Altogether, there were 121 serious complications. Of these, 86 required surgical, endoscopic or radiological interventions (grade III), 25 endangered life, with uni or multi-organ failure (grade IV) and ten resulted in death (grade V). The most common complications were technical (25%), gastrointestinal (22%) and respiratory (21%). We identified four independent risk factors for severe postoperative complications: reoperation, operation for congenital diaphragmatic hernia, preterm birth less than 32 weeks of gestational age and abdominal surgery. CONCLUSION: The incidence of severe postoperative complications after neonatal surgeries under general anesthesia remains high. The conditions considered independent risk factors for those can guide interventions to improve results.

Lasting developmental effects of neonatal fentanyl exposure in preweanling rats.

The present study aimed to determine whether neonatal treatment with fentanyl has lasting effects on stressed developing brain. Six-day-old rats were assigned to one of three groups (10 males/group): (1) fentanyl (incision+fentanyl), (2) saline (incision+0.9% saline), and (3) unoperated (unoperated sham). Pups with a plantar paw incision received repetitive subcutaneous injections of fentanyl or vehicle through postnatal days (PNDs) 6 to 8. A nonoperated sham group served as nonstressed control. Studies included assessment of development from PND 6 to PND 21 (growth indices and behavioral testing). Fentanyl administered twice daily for three days after surgical incision had no impact on early growth and development, as measured on PND 9, but showed a lasting impact on later growth, enhanced behavioral development, and lower anxiety, as measured through PNDs 10-21. While this does not completely support a benefit from such treatment, our findings may contribute to support the neonatal use of fentanyl, when indicated, even in premature newborns.