A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease.

The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.

Perinatal risk factors associated with acute kidney injury severity and duration among infants born extremely preterm.

BACKGROUND: We evaluated time-varying perinatal risk factors associated with early (≤7 post-natal days) and late (>7 post-natal days) severe acute kidney injury (AKI) occurrence and duration. METHODS: A secondary analysis of Preterm Erythropoietin Neuroprotection Trial data. We defined severe AKI (stage 2 or 3) per neonatal modified Kidney Disease: Improving Global Outcomes criteria. Adjusted Cox proportional hazards models were conducted with exposures occurring at least 72 h before severe AKI. Adjusted negative binomial regression models were completed to evaluate risk factors for severe AKI duration. RESULTS: Of 923 participants, 2% had early severe AKI. In the adjusted model, gestational diabetes (adjusted HR (aHR) 5.4, 95% CI 1.1-25.8), non-steroidal anti-inflammatory drugs (NSAIDs) (aHR 3.2, 95% CI 1.0-9.8), and vancomycin (aHR 13.9, 95% CI 2.3-45.1) were associated with early severe AKI. Late severe AKI occurred in 22% of participants. Early severe AKI (aHR 2.5, 95% CI 1.1-5.4), sepsis (aHR 2.5, 95% CI 1.4-4.4), vasopressors (aHR 2.9, 95% CI 1.8-4.6), and diuretics (aHR 2.6, 95% CI 1.9-3.6) were associated with late severe AKI. Participants who had necrotizing enterocolitis or received NSAIDs had longer severe AKI duration. CONCLUSION: We identified major risk factors for severe AKI that can be the focus of future research. IMPACT STATEMENT: Time-dependent risk factors for severe acute kidney injury (AKI) and its duration are not well defined among infants born <28 weeks' gestation. Over 1 in 5 infants born <28 weeks' gestation experienced severe AKI, and this study identified several major time-dependent perinatal risk factors occurring within 72 h prior to severe AKI. This study can support efforts to develop risk stratification and clinical decision support to help mitigate modifiable risk factors to reduce severe AKI occurrence and duration.

Implementing an exclusive human milk diet for preterm infants: real-world experience in diverse NICUs.

BACKGROUND: Human milk-based human milk fortifier (HMB-HMF) makes it possible to provide an exclusive human milk diet (EHMD) to very low birth weight (VLBW) infants in neonatal intensive care units (NICUs). Before the introduction of HMB-HMF in 2006, NICUs relied on bovine milk-based human milk fortifiers (BMB-HMFs) when mother's own milk (MOM) or pasteurized donor human milk (PDHM) could not provide adequate nutrition. Despite evidence supporting the clinical benefits of an EHMD (such as reducing the frequency of morbidities), barriers prevent its widespread adoption, including limited health economics and outcomes data, cost concerns, and lack of standardized feeding guidelines. METHODS: Nine experts from seven institutions gathered for a virtual roundtable discussion in October 2020 to discuss the benefits and challenges to implementing an EHMD program in the NICU environment. Each center provided a review of the process of starting their program and also presented data on various neonatal and financial metrics associated with the program. Data gathered were either from their own Vermont Oxford Network outcomes or an institutional clinical database. As each center utilizes their EHMD program in slightly different populations and over different time periods, data presented was center-specific. After all presentations, the experts discussed issues within the field of neonatology that need to be addressed with regards to the utilization of an EHMD in the NICU population. RESULTS: Implementation of an EHMD program faces many barriers, no matter the NICU size, patient population or geographic location. Successful implementation requires a team approach (including finance and IT support) with a NICU champion. Having pre-specified target populations as well as data tracking is also helpful. Real-world experiences of NICUs with established EHMD programs show reductions in comorbidities, regardless of the institution's size or level of care. EHMD programs also proved to be cost effective. For the NICUs that had necrotizing enterocolitis (NEC) data available, EHMD programs resulted in either a decrease or change in total (medical + surgical) NEC rate and reductions in surgical NEC. Institutions that provided cost and complications data all reported a substantial cost avoidance after EHMD implementation, ranging between $515,113 and $3,369,515 annually per institution. CONCLUSIONS: The data provided support the initiation of EHMD programs in NICUs for very preterm infants, but there are still methodologic issues to be addressed so that guidelines can be created and all NICUs, regardless of size, can provide standardized care that benefits VLBW infants.

Standardizing Prostaglandin Initiation in Prenatally Diagnosed Ductal-Dependent Neonates; A Quality Initiative.

Prostaglandin E1 (PGE) is used in patients with ductal-dependent congenital heart disease (CHD). Side effects of apnea and fever are often dose dependent and occur within 48 h after initiation. We initiated a standardized approach to PGE initiation after our institution recognized a high incidence of side effects and a wide variety of starting doses of PGE. Neonates with prenatally diagnosed ductal-dependent CHD were identified, started on a standardized protocol that started PGE at 0.01 mcg/kg/min, and evaluated for PGE related side effects. Compliance, outcomes and dose adjustments during the first 48 h post-PGE initiation were evaluated. Fifty patients were identified (25 pre-intervention; 25 post-intervention). After intervention, compliance with the protocol was 96%, and apnea or fever occurred in 28% (compared to 63% pre-intervention, p = 0.015). Dose adjustments (either increase or decrease) prior to cardiac surgery were similar in both cohorts (60%, 52%, p = 0.569). There were no mortalities or emergent procedures performed due to ductus arteriosus closure. Standardizing a protocol for initiating PGE in prenatally diagnosed ductal-dependent CHD was successful and reduced the incidence of apnea, fever, and sepsis evaluations. A starting dose of 0.01 mcg/kg/min did not cause increased adverse effects.

Standing Intravenous Acetaminophen Is Associated With a Reduction of Post-operative Opioid Use in Infants Aged Less Than 1 Year Treated on the Acute Care Floor.

INTRODUCTION: Given the negative clinical effects opiates can have, the search for alternative forms of analgesia to treat post-operative pain continues. We implemented an opiate reduction strategy using standing intravenous (IV) acetaminophen for infants aged less than 1 y who underwent abdominal or anorectal surgery and recovered on the acute care floor. MATERIALS AND METHODS: Infants were administered standing IV acetaminophen every 6 h for a minimum of 48 h as the main form of post-operative analgesia. Pain severity was objectively scored using the Face, Legs, Activity, Cry, and Consolability (FLACC) scale. A before-and-after retrospective cohort analysis was performed and process control charts were used to examine trends in post-operative opiate use in our pre-intervention (January 2012 to January 2016), roll-out (January 2016 to December 2016), and post-intervention (December 2016 to December 2020) cohorts. RESULTS: A total of 131 infants were included: 56 in the pre-intervention, 17 in the roll-out, and 58 in the post-intervention group. Patient demographics were equivalent. The intervention was associated with a 36-fold reduction in post-operative morphine equivalents (median 0.36 mg/kg in the pre-intervention group versus 0.0 mg/kg in the post-intervention group, P < 0.0001). The median and maximum FLACC pain scores along with clinical safety profiles were statistically equivalent between the groups. The intervention was associated with a 2-d reduction in post-operative length of stay (P < 0.0001). CONCLUSIONS: Standing IV acetaminophen is associated with a reduction of post-operative opioid use in infants being treated on the acute care floor while maintaining equivalent FLACC pain scores. Similar opiate reduction strategies may be of value at other institutions.

Oligohydramnios: a prospective study of fetal, neonatal and maternal outcomes in low-middle income countries.

BACKGROUND: Oligohydramnios is a condition of abnormally low amniotic fluid volume that has been associated with poor pregnancy outcomes. To date, the prevalence of this condition and its outcomes has not been well described in low and low-middle income countries (LMIC) where ultrasound use to diagnose this condition in pregnancy is limited. As part of a prospective trial of ultrasound at antenatal care in LMICs, we sought to evaluate the incidence of and the adverse maternal, fetal and neonatal outcomes associated with oligohydramnios. METHODS: We included data in this report from all pregnant women in community settings in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo (DRC) who received a third trimester ultrasound as part of the First Look Study, a randomized trial to assess the value of ultrasound at antenatal care. Using these data, we conducted a planned secondary analysis to compare pregnancy outcomes of women with to those without oligohydramnios. Oligohydramnios was defined as measurement of an Amniotic Fluid Index less than 5 cm in at least one ultrasound in the third trimester. The outcomes assessed included maternal morbidity and fetal and neonatal mortality, preterm birth and low-birthweight. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models using general estimating equations to account for the correlation of outcomes within cluster. RESULTS: Of 12,940 women enrolled in the clusters in Guatemala, Pakistan, Zambia and the DRC in the First Look Study who had a third trimester ultrasound examination, 87 women were diagnosed with oligohydramnios, equivalent to 0.7% of those studied. Prevalence of detected oligohydramnios varied among study sites; from the lowest of 0.2% in Zambia and the DRC to the highest of 1.5% in Pakistan. Women diagnosed with oligohydramnios had higher rates of hemorrhage, fetal malposition, and cesarean delivery than women without oligohydramnios. We also found unfavorable fetal and neonatal outcomes associated with oligohydramnios including stillbirths (OR 5.16, 95%CI 2.07, 12.85), neonatal deaths < 28 days (OR 3.18, 95% CI 1.18, 8.57), low birth weight (OR 2.10, 95% CI 1.44, 3.07) and preterm births (OR 2.73, 95%CI 1.76, 4.23). The mean birth weight was 162 g less (95% CI -288.6, - 35.9) with oligohydramnios. CONCLUSIONS: Oligohydramnos was associated with worse neonatal, fetal and maternal outcomes in LMIC. Further research is needed to assess effective interventions to diagnose and ultimately to reduce poor outcomes in these settings. TRIAL REGISTRATION: NCT01990625.

Polyhydramnios among women in a cluster-randomized trial of ultrasound during prenatal care within five low and low-middle income countries: a secondary analysis of the first look study.

BACKGROUND: In many low and low-middle income countries, the incidence of polyhydramnios is unknown, in part because ultrasound technology is not routinely used. Our objective was to report the incidence of polyhydramnios in five low and low-middle income countries, to determine maternal characteristics associated with polyhydramnios, and report pregnancy and neonatal outcomes. METHODS: We performed a secondary analysis of the First Look Study, a multi-national, cluster-randomized trial of ultrasound during prenatal care. We evaluated all women enrolled from Guatemala, Pakistan, Zambia, Kenya and the Democratic Republic of Congo (DRC) who received an examination by prenatal ultrasound. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models with general estimating equations to control for cluster-level effects. The diagnosis of polyhydramnios was confrimed by an U.S. based radiologist in a majority of cases (62%). RESULTS: We identified 305/18,640 (1.6%) cases of polyhydramnios. 229 (75%) cases were from the DRC, with an incidence of 10%. A higher percentage of women with polyhydramnios experienced obstructed labor (7% vs 4%) and fetal malposition (4% vs 2%). Neonatal death was more common when polyhydramnios was present (OR 2.43; CI 1.15, 5.13). CONCLUSIONS: Polyhydramnios occured in these low and low-middle income countries at a rate similar to high-income contries except in the DRC where the incidence was 10%. Polyhydramnios was associated with obstructed labor, fetal malposition, and neonatal death. TRIAL REGISTRATION: NCT01990625 , November 21, 2013.

Team-Based Implementation of an Exclusive Human Milk Diet.

BACKGROUND: The University of Virginia neonatal intensive care unit is a 51-bed unit with approximately 600 to 700 admissions per year. Despite evidenced-based clinical care, necrotizing enterocolitis (NEC) and feeding intolerance remained problematic. PURPOSE: In September 2016, the neonatal intensive care unit implemented an exclusive human milk diet (EHMD) for infants born 1250 g or less with the goal of reducing NEC, feeding intolerance, parenteral nutrition use, and late-onset sepsis. Length of stay, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity were also evaluated. METHODS: A work group developed systems for charging and documenting products used in an EHMD. Outcomes were compared with a control group of similar infants born prior to the availability of the EHMD. RESULTS: Infants who received an EHMD had significantly fewer late-onset sepsis evaluations (P = .0027) and less BPD (P = .018). While not statistically significant, less surgical NEC was also demonstrated (4 cases vs 1 case, which was 57% of total NEC cases vs 14.3%) while maintaining desirable weight gain and meeting financial goals. IMPLICATIONS FOR PRACTICE: A multidisciplinary team that implements financial and documentation systems can provide a sustainable clinical practice that improves patient outcomes. Ongoing evaluations of clinical and financial data provide valuable information to guide future clinical practices related to the EHMD. IMPLICATIONS FOR RESEARCH: Future research on the anti-inflammatory effect of an EHMD is needed to provide direction regarding a potential dose-dependent response for reduced BPD rates and severity. The role of human milk and prevention or mitigation of sepsis is not fully understood, but the reduction of the number of late-onset sepsis evaluations may support the relationship between an EHMD and infection protection. Exploring clinical and financial outcomes for implementing the EHMD in infants born more than 1250 g remains a key area for research.

Neonatal Intensive Care Unit Length of Stay Reduction by Heart Rate Characteristics Monitoring.

OBJECTIVE: To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT). STUDY DESIGN: We performed a retrospective analysis of length of stay metrics among 3 subpopulations (all patients, all survivors, and survivors with positive blood or urine cultures) enrolled in a multicenter, RCT of HRC monitoring. RESULTS: Among all patients in the RCT, infants randomized to receive HRC monitoring were more likely than controls to be discharged alive and prior to day 120 (83.6% vs 80.1%, P = .014). The postmenstrual age at discharge for survivors with positive blood or urine cultures was 3.2 days lower among infants randomized to receive HRC monitoring when compared with controls (P = .026). Although there were trends in other metrics toward reduced length of stay in HRC-monitored patients, none reached statistical significance. CONCLUSIONS: HRC monitoring is associated with reduced mortality in VLBW patients and a reduction in length of stay among infected surviving VLBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00307333.

Factors influencing referrals for ultrasound-diagnosed complications during prenatal care in five low and middle income countries.

BACKGROUND: Ultrasound during antenatal care (ANC) is proposed as a strategy for increasing hospital deliveries for complicated pregnancies and improving maternal, fetal, and neonatal outcomes. The First Look study was a cluster-randomized trial conducted in the Democratic Republic of Congo, Guatemala, Kenya, Pakistan and Zambia to evaluate the impact of ANC-ultrasound on these outcomes. An additional survey was conducted to identify factors influencing women with complicated pregnancies to attend referrals for additional care. METHODS: Women who received referral due to ANC ultrasound findings participated in structured interviews to characterize their experiences. Cochran-Mantel-Haenszel statistics were used to examine differences between women who attended the referral and women who did not. Sonographers' exam findings were compared to referred women's recall. RESULTS: Among 700 referred women, 510 (71%) attended the referral. Among referred women, 97% received a referral card to present at the hospital, 91% were told where to go in the hospital, and 64% were told that the hospital was expecting them. The referred women who were told who to see at the hospital (88% vs 66%), where to go (94% vs 82%), or what should happen, were more likely to attend their referral (68% vs 56%). Barriers to attending referrals were cost, transportation, and distance. Barriers after reaching the hospital were substantial. These included not connecting with an appropriate provider, not knowing where to go, and being told to return later. These barriers at the hospital often led to an unsuccessful referral. CONCLUSIONS: Our study found that ultrasound screening at ANC alone does not adequately address barriers to referrals. Better communication between the sonographer and the patient increases the likelihood of a completed referral. These types of communication include describing the ultrasound findings, including the reason for the referral, to the mother and staff; providing a referral card; describing where to go in the hospital; and explaining the procedures at the hospital. Thus, there are three levels of communication that need to be addressed to increase completion of appropriate referrals-communication between the sonographer and the woman, the sonographer and the clinic staff, and the sonographer and the hospital. TRIAL REGISTRATION: NCT01990625 .

Evidence of Early Pulmonary Hypertension Is Associated with Increased Mortality in Very Low Birth Weight Infants.

Objective The objective of this study was to describe the inhospital outcomes of a high-risk cohort of very low birth weight infants with evidence of pulmonary hypertension (PHT) within the first 2 weeks after delivery. Design A retrospective cohort study of consecutively admitted neonates with birth weight < 1,500 g admitted to a Level IV neonatal intensive care unit who were evaluated by echocardiogram between 72 hours and 14 days. Results A total of 343 eligible infants were included in the cohort with a median gestational age of 25.5 weeks and birth weight of 790 g. Evidence of early PHT was associated with birth weight Z-score (odds ratio [OR]: 0.65, confidence interval [CI]: 0.48-0.87) and maternal African American race (OR: 1.9, CI: 1.03-3.69). Early PHT was associated with decreased in-hospital survival compared with those with no evidence of PHT (OR: 2.0, CI: 1.02-3.90), and was associated with an increased rate of moderate-to-severe bronchopulmonary dysplasia at 36 weeks postmenstrual age (OR: 2.92, CI: 1.24-6.89). Conclusion The presence of early PHT on echocardiogram between 72 hours and 14 days of age was associated with decreased in-hospital survival and worse pulmonary outcomes. This population represents a group of infants who warrant further investigation to improve outcomes.

Caffeine Exposure and Risk of Acute Kidney Injury in a Retrospective Cohort of Very Low Birth Weight Neonates.

OBJECTIVE: To evaluate the association between caffeine exposure and acute kidney injury (AKI) in very low birth weight (VLBW; ≤1500 g) neonates. STUDY DESIGN: We retrospectively reviewed a cohort of 140 VLBW neonates consecutively admitted to the University of Virginia's neonatal intensive care unit from March 2011 to June 2012, excluding only those admitted >2 days of age or who died at <2 days after birth. We separately analyzed a subgroup of 44 neonates who received prolonged invasive respiratory support (mechanical ventilation for first 7 days after birth). The exposure of interest was caffeine exposure in the first week after birth. The primary outcome was AKI within the first 10 days after birth according to the Kidney Disease: Improving Global Outcomes system, modified to include only serum creatinine. RESULTS: Caffeine exposure occurred in 72.1% of all patients and 54.5% of those who received prolonged invasive respiratory support. AKI occurred less frequently in neonates who received caffeine (all patients: 17.8% vs 43.6%; P = .002; prolonged invasive respiratory support: 29.2% vs 75.0%; P = .002). Caffeine exposure was associated with decreased odds for AKI in logistic regression models adjusted for sex, birth weight, gestational age, small for gestational age status, illness severity on admission, and receipt of indomethacin, invasive ventilation, dopamine, aminoglycosides, and vancomycin (all patients: OR 0.22; 95% CI 0.07-0.75, P = .02; prolonged invasive respiratory support subgroup: OR 0.06; 95% CI 0.01-0.57, P = .02). CONCLUSIONS: In a cohort of VLBW neonates, those exposed to caffeine were less likely to experience AKI.

Histiocytic disorders of the chest: imaging findings.

Histiocytic disorders of the chest comprise a broad spectrum of diseases. The lungs may be involved in isolation or as part of systemic disease. Some of these disorders are primary and have unknown etiology, and others result from a histiocytic response to a known cause. Among primary histiocytic disorders, pulmonary Langerhans cell histiocytosis (PLCH) is the most common; others include Erdheim-Chester disease and Rosai-Dorfman disease. Adult PLCH occurs almost exclusively in adults aged 20-40 years who smoke. Pediatric PLCH is extremely rare and typically occurs as part of multisystemic disease. Erdheim-Chester disease affects middle-aged and older adults; thoracic involvement usually occurs as part of systemic disease. Rosai-Dorfman disease affects children and young adults and manifests as painless cervical lymphadenopathy. Examples of secondary histiocytic disorders are storage diseases such as Gaucher disease, Niemann-Pick disease, and Fabry disease; pneumoconiosis such as silicosis and coal workers' pneumoconiosis; and infections such as Whipple disease and malakoplakia. These disorders are characterized at histopathologic examination on the basis of infiltration of alveoli or the pulmonary interstitium by histiocytes, which are a group of cells that includes macrophages and dendritic cells. Dendritic cells are a heterogeneous group of nonphagocytic antigen-presenting immune cells. Immunohistochemical markers help to distinguish among various primary histiocytic disorders. Characteristic radiologic findings in the appropriate clinical context may obviate biopsy to establish a correct diagnosis. However, in the absence of these findings, integration of clinical, pathologic, and radiologic features is required to establish a diagnosis.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones.

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 µg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [µg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production.

First look: a cluster-randomized trial of ultrasound to improve pregnancy outcomes in low income country settings.

BACKGROUND: In high-resource settings, obstetric ultrasound is a standard component of prenatal care used to identify pregnancy complications and to establish an accurate gestational age in order to improve obstetric care. Whether or not ultrasound use will improve care and ultimately pregnancy outcomes in low-resource settings is unknown. METHODS/DESIGN: This multi-country cluster randomized trial will assess the impact of antenatal ultrasound screening performed by health care staff on a composite outcome consisting of maternal mortality and maternal near-miss, stillbirth and neonatal mortality in low-resource community settings. The trial will utilize an existing research infrastructure, the Global Network for Women's and Children's Health Research with sites in Pakistan, Kenya, Zambia, Democratic Republic of Congo and Guatemala. A maternal and newborn health registry in defined geographic areas which documents all pregnancies and their outcomes to 6 weeks post-delivery will provide population-based rates of maternal mortality and morbidity, stillbirth, neonatal mortality and morbidity, and health care utilization for study clusters. A total of 58 study clusters each with a health center and about 500 births per year will be randomized (29 intervention and 29 control). The intervention includes training of health workers (e.g., nurses, midwives, clinical officers) to perform ultrasound examinations during antenatal care, generally at 18-22 and at 32-36 weeks for each subject. Women who are identified as having a complication of pregnancy will be referred to a hospital for appropriate care. Finally, the intervention includes community sensitization activities to inform women and their families of the availability of ultrasound at the antenatal care clinic and training in emergency obstetric and neonatal care at referral facilities. DISCUSSION: In summary, our trial will evaluate whether introduction of ultrasound during antenatal care improves pregnancy outcomes in rural, low-resource settings. The intervention includes training for ultrasound-naïve providers in basic obstetric ultrasonography and then enabling these trainees to use ultrasound to screen for pregnancy complications in primary antenatal care clinics and to refer appropriately. TRIAL REGISTRATION: Clinicaltrials.gov (NCT # 01990625).

Necrotizing enterocolitis is one disease with many origins and potential means of prevention.

BACKGROUND: The field of necrotizing enterocolitis (NEC) research has been in existence for over 60 years. During the first five decades little progress in NEC prevention and no definitive progress in treatment was achieved. One of the major determinants of this ineffectiveness may have been a global propensity to lump NEC into a single disease entity rather than a spectrum of diseases with a common outcome. The driver of this philosophy was most likely statistical, in that researchers desired large cohorts to optimize statistical power. Additionally, in the past quarter century, our preterm NEC cohorts were (and in some cases still are) contaminated with spontaneous intestinal perforations (SIP). This completely different acquired neonatal intestinal disease (ANID) markedly alters clinical characteristics and outcomes in NEC cohorts and subsets if not addressed. Unfortunately, cohort size has been proven to be less important than data quality when it comes to NEC over this last decade of research. Emerging progress in NEC prevention has been greatly enhanced as a result of dividing well-defined NEC into subsets of disease origin and investigating these entities individually. REVIEW OBJECTIVES: The purpose of this review is to offer the bedside clinician a concise, up-to-date review of recent advances in NEC reductionism. The reader should understand the history and basic theory behind NEC subsets, their application to NEC prevention, and comprehend that prevention of NEC requires a comprehensive quality improvement strategy that is likely best realized with a zero tolerance approach. CONCLUSIONS: We are entering a new era of NEC prevention. NICUs that embrace and achieve effective NEC prevention strategies will rapidly outpace their contemporaries. Because NEC is still the major driver of morbidity and mortality in most NICUs today, those who reject or fail in this pursuit will likely face increasingly severe consequences due to growing requirements for outcomes transparency.

Post-operative Opioid Reduction Protocol Reduces Racial Disparity in Clinical Outcomes in Children.

INTRODUCTION: Racial disparities in health outcomes continue to exist for children requiring surgery. Previous investigations suggest that clinical protocols may reduce racial disparities. A post-operative opioid reduction protocol was implemented in children undergoing abdominal surgery who were less than 1 years old at a tertiary level hospital. The purpose of this investigation was to determine if the clinical protocol was associated with a reduction in racial disparity in post-operative opioid prescribing patterns and associated clinical outcomes. METHODS: A post-operative opioid reduction protocol based on standing intravenous acetaminophen, educational sessions with nursing staff, and standardized post-operative sign-out between the surgical and NICU teams was implemented in children under 1 year old in 2016. A time series and before and after analysis was conducted using a historical pre-intervention cohort (Jan 2011-Dec 2015) and prospectively collected post-intervention cohort (Jan 2016-Jan 2021). Primary outcomes included post-operative opioid use and post-operative pain scores stratified by race. Secondary outcomes included associated clinical outcomes also stratified by race. RESULTS: A total of 249 children were included in the investigation, 117 in the pre-intervention group and 132 in the post intervention group. The majority of patients in both cohorts were either White or Black. The two cohorts were equally matched in terms of pre-operative clinical variables. In the pre-intervention cohort, the median post-operative morphine equivalents in White children was 2.1 mg/kg (IQR 0.2, 11.1) while in Black children it was 13.1 mg/kg (IQR 2.4, 65.3), p-value = 0.0352. In the post-intervention cohort, the median value for White children and Black children was statistically identical (0.05 mg/kg (IQR 0, 0.5) and 0.0 mg/kg (IQR 0, 0.3), respectively, p-value = 0.237). This pattern was also demonstrated in clinical variables including length of stay, intubation length and total parenteral nutrition use. In the pre-intervention cohort, the total length of stay for white children was 16 days while for black children it was 45 days (p = 0.007). In the postintervention cohort the length of stay for both White and Black children were identical at 8 days (p = 0.748). CONCLUSION: The use of a clinical opioid reduction protocol implemented at a tertiary medical center was associated with a reduction in racial disparity in opioid prescribing habits in children. Prior to the protocol, there was a racial disparity in clinical variables associated with prolonged opioid use including length of stay, TPN use, and intubation length. The clinical protocol reduced variability in opioid prescribing patterns in all racial groups which was associated with a reduction in variability in associated clinical variables. LEVEL OF EVIDENCE: Level III.

Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis.

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease.

Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus.

OBJECTIVE: To test the hypothesis that infants who are just being introduced to enteral feedings will advance to full enteral nutrition at a faster rate if they receive "trophic" (15 mL/kg/d) enteral feedings while receiving indomethacin or ibuprofen treatment for patent ductus arteriosus. STUDY DESIGN: Infants were eligible for the study if they were 23(1/7)-30(6/7) weeks' gestation, weighed 401-1250 g at birth, received maximum enteral volumes ≤60 mL/kg/d, and were about to be treated with indomethacin or ibuprofen. A standardized "feeding advance regimen" and guidelines for managing feeding intolerance were followed at each site (N = 13). RESULTS: Infants (N = 177, 26.3 ± 1.9 weeks' mean ± SD gestation) were randomized at 6.5 ± 3.9 days to receive "trophic" feeds ("feeding" group, n = 81: indomethacin 80%, ibuprofen 20%) or no feeds ("fasting [nil per os]" group, n = 96: indomethacin 75%, ibuprofen 25%) during the drug administration period. Maximum daily enteral volumes before study entry were 14 ± 15 mL/kg/d. After drug treatment, infants randomized to the "feeding" arm required fewer days to reach the study's feeding volume end point (120 mL/kg/d). Although the enteral feeding end point was reached at an earlier postnatal age, the age at which central venous lines were removed did not differ between the 2 groups. There were no differences between the 2 groups in the incidence of infection, necrotizing enterocolitis, spontaneous intestinal perforation, or other neonatal morbidities. CONCLUSION: Infants required less time to reach the feeding volume end point if they were given "trophic" enteral feedings when they received indomethacin or ibuprofen treatments.

Peer review comments augment diagnostic error characterization and departmental quality assurance: 1-year experience from a children's hospital.

OBJECTIVE: The objective of our study was to categorize radiologist peer review comments and evaluate their functions within the context of a comprehensive quality assurance (QA) program. MATERIALS AND METHODS: All randomly entered radiology peer review comments at our institution were compiled over a 1-year period (January 1, 2011, through December 31, 2011). A Web-based commercially available software package was used to query the comments, which were then exported into a spreadsheet. Each comment was then placed into a single most appropriate category based on consensus decision of two board-certified pediatric radiologists. QA scores associated with each comment were recorded. RESULTS: A total of 427 peer review comments were evaluated. The majority of comments (85.9%) were entered voluntarily with QA scores of 1. A classification system was devised that augments traditional error classification. Seven broad comment categories were identified: errors of observation (25.5%), errors of interpretation (5.6%), inadequate patient data gathering (3.7%), errors of communication (9.6%), interobserver variability (21.3%), informational and educational feedback (23.0%), and complimentary (11.2%). CONCLUSION: Comment-enhanced peer review expands traditional diagnostic error classification, may identify errors that were underscored, provides continuous educational feedback for participants, and promotes a collegial environment.