Enhanced in utero allogeneic engraftment in mice after mobilizing fetal HSCs by α4ß1/7 inhibition.

In utero hematopoietic cell transplantation (IUHCT) is a novel nonmyeloablative approach that results in donor-specific tolerance and mixed allogeneic chimerism. Clinical application is limited by low levels of donor cell engraftment. Competition from endogenous hematopoietic stem cells (HSCs) for limited "space" in fetal hematopoietic organs remains a significant barrier to successful IUHCT. AMD3100, a CXCR4 inhibitor, and firategrast, an α4ß1 and α4ß7 integrin inhibitor (α4ß1/7), have been shown to disrupt HSC retention in the postnatal hematopoietic niche. We hypothesized that maternal administration of AMD3100 and/or firategrast prior to IUHCT would mobilize endogenous HSCs from the fetal liver (FL) and result in preferential FL homing of donor HSCs and enhanced long-term engraftment following IUHCT in an allogeneic mouse model. We demonstrate that (1) both agents cross the placenta with rapidly detectable fetal serum concentrations following maternal administration; (2) firategrast treatment alone or with AMD3100 mobilizes endogenous HSCs from the FL and results in increased FL homing of donor HSCs following IUHCT; and (3) enhanced donor HSC homing following firategrast treatment translates into increased long-term multilineage donor cell engraftment. This approach highlights the potential of mobilization strategies to overcome barriers to successful engraftment and increase the clinical promise of IUHCT.

The Intravenous Route of Injection Optimizes Engraftment and Survival in the Murine Model of In Utero Hematopoietic Cell Transplantation.

In utero hematopoietic cell transplantation (IUHCT) has the potential to treat a number of congenital hematologic disorders. Clinical application is limited by low levels of donor engraftment. Techniques that optimize donor cell delivery to the fetal liver (FL), the hematopoietic organ at the time of IUHCT, have the potential to enhance engraftment and the clinical success of IUHCT. We compared the 3 clinically applicable routes of injection (intravenous [i.v.], intraperitoneal [i.p.], and intrahepatic [i.h.]) and assessed short- and long-term donor cell engraftment and fetal survival in the murine model of IUHCT. We hypothesized that the i.v. route would promote direct donor cell homing to the FL, resulting in increased engraftment and allowing for larger injectate volumes without increased fetal mortality. We demonstrate that the i.v. route results in (1) rapid diffuse donor cell population of the FL compared with delayed diffuse engraftment after the i.p. and i.h. routes; (2) higher FL and spleen engraftment at early prenatal time points; (3) enhanced stable long-term peripheral blood donor cell engraftment; and (4) improved survival at higher injectate volumes, allowing for higher donor cell doses and increased long-term engraftment. These findings support the use of an i.v. route for clinical protocols of IUHCT.

Association of Age at Duodenal Atresia Repair With Outcomes: A Pediatric NSQIP Analysis.

PURPOSE: Neonates with duodenal atresia (DA) are often born prematurely and undergo repair soon after birth, while others are delayed to allow for growth until closer to term corrected gestational age (cGA). Premature infants have been demonstrated to experience worse outcomes, but it is unclear whether delaying surgery mitigates the increased morbidity. This study evaluates the association of timing of DA repair with postoperative morbidity. METHODS: We retrospectively evaluated neonates undergoing DA repair from the National Surgical Quality Improvement Program-Pediatric database (2015-2020). A multivariable regression analyzed factors associated with composite morbidity, including cGA and age in days of life (DOL) at surgery. A propensity score matched analysis was completed in premature neonates born at ≤35 weeks gestation to compare outcomes at similar birth gestational ages (bGA) and birth weight who underwent early (<7 DOL) versus delayed (≥7 DOL) repair. RESULTS: 809 neonates were included with a median bGA of 36 weeks (IQR 34-38), birth weight of 2.46 kg (IQR 1.96-2.95), and DOL at surgery of 2 (IQR 1-5). Infants born ≤35 weeks represented 35.23% of the cohort. On multivariable analysis, increasing cGA at surgery was associated with decreased morbidity (OR: 0.91, CI [0.84, 0.99]), and increasing DOL at surgery was associated with increased morbidity (OR: 1.02, CI [1.00, 1.04]). On propensity score matched analysis, delayed repairs were associated with increased postoperative ventilation (6 days vs. 2 days, p < 0.05); however, there were no differences in composite or surgical morbidity between early and delayed repairs. CONCLUSIONS: Morbidity after DA repair in neonates ≤35 weeks cGA is primarily driven by non-surgical causes, but delaying surgery does not appear to mitigate the risks associated with prematurity. It seems reasonable to consider repair in neonates around 33-34 weeks gestation without prohibitive risk factors. Optimal timing of DA repair requires a delicate balance between these factors. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective Cohort Study.

Concurrent Cholecystectomy Does Not Increase Splenectomy Morbidity in Patients With Hemolytic Anemia: A Pediatric NSQIP Analysis.

PURPOSE: Children undergoing splenectomy for hemolytic anemia often have cholelithiasis, which may or may not be symptomatic. It is unclear whether concurrent cholecystectomy increases length of stay or morbidity after splenectomy. The purpose of this study was to compare morbidity among children undergoing laparoscopic splenectomy alone versus splenectomy with concurrent cholecystectomy in patients with hemolytic anemia. METHODS: We retrospectively evaluated children with hemolytic anemia undergoing non-traumatic laparoscopic splenectomy in the National Surgical Quality Improvement Program-Pediatric database (2012-2020). Outcomes were compared for patients undergoing splenectomy alone (n = 1010) versus splenectomy with cholecystectomy (n = 371). Pearson's Chi-square and Student's t-tests were utilized as appropriate. Propensity score-matching was completed, controlling for eight demographic and clinical variables. RESULTS: 1381 patients were identified, 73.1% undergoing splenectomy alone and 26.9% splenectomy with cholecystectomy. Splenectomy with cholecystectomy patients were older (10.9 years vs. 8.4 years, p < 0.01), more likely to have hereditary spherocytosis (56.1% vs. 40.8%, p < 0.01), less likely to have sickle cell disease (12.1% vs. 33.5%, p < 0.01), more likely ASA class 1 or 2 (49.3% vs. 42.1%, p < 0.01), and had similar preoperative hematocrit levels (29.6 vs. 29.3, p = 0.33). The splenectomy with cholecystectomy group was less likely to receive preoperative blood transfusions (13.5% vs. 25.4%, p < 0.01). There were 360 pairs selected on propensity score-matching, and splenectomy with cholecystectomy was associated with increased operative time (182 min vs. 145 min, p < 0.01) and decreased occurrences of a postoperative transfusion (4.2% vs. 8.9%, p = 0.01). Length of stay after surgery (2.5 days vs. 2.3 days, p = 0.13), composite morbidity (3.9% vs. 3.4%, p = 0.69), and 30-day readmission rates (3.3% vs. 7.4%, p = 0.08) were all similar. CONCLUSIONS: Splenectomy with cholecystectomy is associated with similar postoperative morbidity, length of stay and readmission rates compared to splenectomy alone. These data support the safety of concurrent cholecystectomy with splenectomy for children with cholelithiasis in the setting of hemolytic anemia. TYPE OF STUDY: Retrospective Cohort Study. LEVEL OF EVIDENCE: Level III.

Short-Term Neurodevelopmental Outcome in Children Born With High-Risk Congenital Lung Lesions.

BACKGROUND: This study sought to evaluate neurodevelopmental outcome in survivors of high-risk congenital lung lesions (CLLs) who underwent prenatal intervention or postnatal surgery within the first month of life. METHODS: Forty-five high-risk CLL survivors underwent assessment using the Bayley Scales of Infant Development, 3rd Edition between July 2004 and December 2016. Scores were grouped as average, at-risk, and delayed based on SD intervals. Correlations between outcome and risk factors were analyzed by Fisher's exact test or two-sided t test as appropriate, with significant p values <0.05. RESULTS: Open prenatal intervention was required in 13 (28.9%) children (fetal surgical resection, n = 4 , ex utero intrapartum treatment, n = 9), whereas 32 (71.1%) children had respiratory distress postnatally and required resection within the first month of life. Mean age at follow-up was 19.3 ± 10.3 months. Mean composite scores were within the expected average range. A total of 62.2% scored within the average range for all domains. At-risk scores were found in 26.7% of children in at least one domain, and 11.1% had delays in at least one domain. Neurodevelopmental outcome was similar between treatment groups. Prolonged ventilator support and neonatal intensive care unit stay, need for supplemental oxygen at day of life 30, gastroesophageal reflux disease, and delayed enteral feeding were associated with neurologic delays (all p < 0.05). CONCLUSIONS: Neurodevelopmental scores for high-risk CLL survivors in infancy and toddlerhood are age appropriate. Neither fetal intervention nor the need for postnatal resection within the first month of life increases the risk of delays. Surrogate markers of a complicated neonatal course are predictive of adverse outcome.

Prenatal growth characteristics of lymphatic malformations.

PURPOSE: The natural history of prenatally diagnosed lymphatic malformations (LM) remains unknown. The ability to predict growth of a lesion is important to prenatal counseling and any future prenatal intervention. We describe the prenatal growth patterns of LMs as they relate to gestational age, anatomical location, and postnatal management. METHODS: A retrospective review of fetuses prenatally diagnosed with an LM who were followed with serial ultrasounds from 2003 to 2014 was performed with attention to the growth of the lesion as indicated by the lesion volume ratio (LVR). RESULTS: Thirty patients with LM had serial ultrasound measurements between 19 and 39weeks gestation. The LVR increased in 53%, decreased in 23%, and remained stable in 23% of fetuses from the initial to the final ultrasound. Unlike other locations that demonstrated both positive and negative growth profiles, axillary lesions only demonstrated increased growth. Lesions with positive growth increased throughout gestation (peak LVR at 35±3weeks). Twenty-four patients had postnatal interventions, including surgical resection, sclerotherapy, and surgery + sclerotherapy. CONCLUSION: LMs have variable prenatal growth profiles. The majority of lesions, especially axillary LMs, will continue to grow throughout gestation and will not reach a growth plateau until the end of gestation. LEVEL OF EVIDENCE: Level III (Retrospective cohort study).

Effect of single and multiple courses of maternal betamethasone on prenatal congenital lung lesion growth and fetal survival.

PURPOSE: Administration of maternal betamethasone (BMZ) is a therapeutic option for fetuses with large microcystic congenital lung lesions at risk for, or causing, hydrops. Not all fetuses respond to a single course of BMZ. We review our experience with the use of single and multiple courses of maternal BMZ for the management of these patients. METHODS: A retrospective review of fetuses with congenital lung lesions managed with maternal BMZ from 2003 to 2014 was performed. RESULTS: Forty-three patients were managed with prenatal steroids (28 single course, 15 multiple courses). Single course recipients demonstrated a reduction in lesion size and resolution of hydrops in 82% and 88% of patients respectively compared to 47% and 56% in recipients of multiple steroid courses. Survival of multiple course patients (86%) was comparable to that of single course patients (93%) and improved compared to non-treated historical controls. Multiple course recipients demonstrated an increased need for open fetal surgery and postnatal surgery at a younger age. CONCLUSION: Fetuses who fail to respond to a single course of BMZ may benefit, as indicated by hydrops resolution and improved survival, from additional courses. However, failure to respond is indicative of a lesion which may require fetal or immediate neonatal resection.

Thoracoamniotic shunts for the management of fetal lung lesions and pleural effusions: a single-institution review and predictors of survival in 75 cases.

PURPOSE: Hydrops and pulmonary hypoplasia are associated with significant morbidity and mortality in the setting of a congenital lung lesion or pleural effusion (PE). We reviewed our experience using in utero thoracoamniotic shunts (TA) to manage fetuses with these diagnoses. METHODS: A retrospective review of fetuses diagnosed with a congenital lung lesion or pleural effusion who underwent TA shunt placement from 1998-2013 was performed. RESULTS: Ninety-seven shunts were placed in 75 fetuses. Average gestational age (±SD) at shunt placement and birth was 25±3 and 34±5 weeks. Shunt placement resulted in a 55±21% decrease in macrocystic lung lesion volume and complete or partial drainage of the PE in 29% and 71% of fetuses. 69% of fetuses presented with hydrops, which resolved following shunt placement in 83%. Survival was 68%, which correlated with GA at birth, % reduction in lesion size, unilateral pleural effusions, and hydrops resolution. Surviving infants had prolonged NICU courses and often required either surgical resection or tube thoracostomy in the perinatal period. CONCLUSION: TA shunts provide a therapeutic option for select fetuses with large macrocystic lung lesions or PEs at risk for hydrops and/or pulmonary hypoplasia. Survival following shunting depends on GA at birth, reduction in mass size, and hydrops resolution.

Are sequential compression devices commonly associated with in-hospital falls? A myth-busters review using the patient safety net database.

OBJECTIVES: Sequential compression devices (SCDs) help prevent deep venous thrombosis and pulmonary embolism in hospitalized patients; however, clinicians often decline to use this therapy because of a perceived increased risk for patient falls. There is limited information regarding the association between the use of SCDs and patient falls. In this study, we analyze if SCD use is a common risk factor for in-hospital falls. METHODS: We used the Patient Safety Net event reporting system at our university-affiliated hospital to retrospectively quantify reports of SCD-related falls over a nearly 5-year period (July 1, 2004, through May 25, 2009). The primary outcome was to determine how often SCD-related falls occurred in relation to SCD patient days. Secondary aims of this study included an assessment of the severity of SCD-related falls, as well as potential risk factors for such falls. RESULTS: Three thousand five hundred sixty-two total falls were reported during our study period, 16 of which (0.45%) were SCD-related falls. There were 0.063 SCD-related falls per 1000 SCD patient days or 1 fall for every 15,774 SCD patient days. The mean age of patients was 57.8 ± 14.4 years, 69% were male subjects, 81% were on a surgical ward, and 69% occurred while attempting to toilet. Only 2 of the SCD-related falls caused temporary harm that required intervention. CONCLUSIONS: Sequential compression device use is rarely associated with in-hospital patient falls, and SCD-related falls are not more harmful than other types of falls.