Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia.

Rationale: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.Objectives: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.Methods: Newborn mice were exposed to 75% O2 for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with Foxm1 or Foxf1 cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.Measurements and Main Results: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.Conclusions: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.

Respiratory Medications in Infants <29 Weeks during the First Year Postdischarge: The Prematurity and Respiratory Outcomes Program (PROP) Consortium.

OBJECTIVE: To determine patterns of respiratory medications used in neonatal intensive care unit graduates. STUDY DESIGN: The Prematurity Respiratory Outcomes Program enrolled 835 babies <29 weeks of gestation in the first week. Of 751 survivors, 738 (98%) completed at least 1, and 85% completed all 4, postdischarge medication usage in-person/telephone parental questionnaires requested at 3, 6, 9, and 12 months of corrected age. Respiratory drug usage over the first year of life after in neonatal intensive care unit discharge was analyzed. RESULTS: During any given quarter, 66%-75% of the babies received no respiratory medication and 45% of the infants received no respiratory drug over the first year. The most common postdischarge medication was the inhaled bronchodilator albuterol; its use increased significantly from 13% to 31%. Diuretic usage decreased significantly from 11% to 2% over the first year. Systemic steroids (prednisone, most commonly) were used in approximately 5% of subjects in any one quarter. Inhaled steroids significantly increased over the first year from 9% to 14% at 12 months. Drug exposure changed significantly based on gestational age with 72% of babies born at 23-24 weeks receiving at least 1 respiratory medication but only 40% of babies born at 28 weeks. Overall, at some time in the first year, 55% of infants received at least 1 drug including an inhaled bronchodilator (45%), an inhaled steroid (22%), a systemic steroid (15%), or diuretic (12%). CONCLUSION: Many babies born at <29 weeks have no respiratory medication exposure postdischarge during the first year of life. Inhaled medications, including bronchodilators and steroids, increase over the first year.

Implementation of a Regional Perinatal Data Repository from Clinical and Billing Records.

Objectives To describe the implementation of the first phase of a regional perinatal data repository and to provide a roadmap for others to navigate technical, privacy, and data governance concerns in implementing similar resources. Methods Our implementation integrated regional physician billing records with maternal and infant electronic health records from an academic delivery hospital. These records, representing births during 2013-2015, constituted a data core supporting linkage to additional ancillary data sets. Measures obtained from pediatric follow-up, urgent care, emergency, and inpatient encounters were linked at the individual level as were measures obtained by home visitors during pre- and postnatal encounters. Residential addresses were geocoded supporting linkage to area-level measures. Results Integrated data contained regional billing records for 69,290 newborns representing approximately 81% of all regional live births and nearly 95% of live births in the region's most populous county. Billing records linked to 7293 infant delivery hospital records and 7107 corresponding maternal hospital records. Manual review demonstrated 100% validity of matches among audited records. Additionally, 2430 home visiting records were linked to the data core as were pediatric primary care, urgent care, emergency department, and inpatient visits representing 42,541 children. More than 99% of the newborn billing records were geocoded and assigned a census tract identifier. Conclusions for Practice Our approach to methodological and regulatory challenges affords opportunities for expansion of systems to integrate electronic health records originating from additional medical centers as well as individual- and area-level linkage to additional data sets relevant to perinatal health.

Racial Differences in the Influence of Interpregnancy Interval on Fetal Growth.

Objectives Assess the influence of maternal race on the association between interpregnancy interval (IPI) and risk of small for gestational age (SGA) and large for gestational age (LGA) births. Methods Statewide population-based cohort study of 380,520 singleton births. We calculated risk of SGA and LGA births following IPIs of 0 to <6, 6 to <12, 12 to <24 (referent), 24 to <60 months, and ≥60 months, by maternal race after adjustment for confounding influences. Results The highest risk for SGA among white women followed short IPI of 0 to <6 months [adjRR 1.14 (95 % CI 1.08-1.21)], and long IPI ≥ 60 months [adjRR 1.37 (95 % CI 1.31-1.43)]. Only long IPI ≥ 60 months increased SGA risk in black women [adjRR 1.22 (95 % CI 1.13-1.32)]. LGA risk in white women was lowest with shortest and longest IPIs, 0 to <6 [adjRR 0.80 (95 % CI 0.76-0.84)] and ≥60 months [adjRR 0.68 (95 % CI 0.66-0.70)]. The crude risk of LGA was directly proportional to longer IPIs in black women. However, after adjusting for confounding effects of age, obesity, excessive gestational weight gain, and gestational diabetes, the effect was reversed to reduced risk following long IPI ≥ 60 months [adjRR 0.82 (95 % CI 0.74-0.91)], similar to that of white women. Conclusions In black and white women, an interpregnancy interval of 1-2 years is associated with optimal fetal growth. In addition to birth spacing, addressing modifiable factors such as pre-pregnancy BMI, monitoring gestational weight gain, and control of gestational diabetes in black women may help optimize fetal growth.

Infant Mortality, Cause of Death, and Vital Records Reporting in Ohio, United States.

Introduction Infant mortality rate is a sensitive metric for population health and well-being. Challenges in achieving accurate reporting of these data can lead to inaccurate targeting of public health interventions. We analyzed a cohort from a pediatric tertiary care referral medical center to evaluate concordance between autopsy cause of death (COD) and death certificate documentation for infants <1 year of age. We predicted that infant COD as documented through vital records would not correspond to that as determined by autopsy. Methods We conducted a retrospective review comparing causes of infant death reported through Ohio Department of Health documents to those on Cincinnati Children's Hospital Medical Center autopsy reports over an 8-year period from January 1, 2006 through December 31, 2013. Results We analyzed 276 total cases of which 167 (61.5 %) represented infants born preterm. Autopsy reports identified 55 % of cases had a congenital anomaly. Additionally, 34 % of all cases had primary or contributing COD related to infection and 14.5 % of all cases indicated chorioamnionitis. We identified 156 (56.5 %) death certificates discordant with autopsy COD of which 52 (33.3 %) involved infection and 24 (15.4 %) involved congenital anomalies. Discussion There are opportunities to improve COD reporting through training for providers, and improvement of established state certification systems. Future strategies to reduce infant mortality will be better informed through enhancements in vital records COD reporting.

Care Coordination Associated with Improved Timing of Newborn Primary Care Visits.

Objective Despite practice recommendations that all newborns be examined within 3-5 days after discharge, many are not seen within this timeframe. Our objective was to determine the association between care coordination and timing of newborn follow-up. Methods This retrospective study evaluated 6251 newborns from eight maternity hospitals who scheduled a primary care appointment at one of two academic pediatric practices over 3.5 years. Two programs were sequentially implemented: (1) newborn discharge coordination, and (2) primary care intake coordination. Primary outcome was days between discharge and follow-up, dichotomized as ≤ or >5 days. Number of rescheduled appointments and loss to follow-up were also assessed. Adjusted relative risks (RR) and odds ratios (OR) were determined by piecewise generalized linear and logistic regression. Results Among 5943 newborns with a completed visit, 52.9 % were seen within 5 days of discharge (mean 6.7 days). After multivariable adjustment, the pre-exposure period (8 months) demonstrated a downward monthly trend in completing early follow-up (RR 0.93, p < 0.001). After initial program implementation, we observed a 3 % monthly increase (RR 1.03, p < 0.001 for test of slope change from pre-exposure to post-exposure), such that likelihood of recommended follow-up increased by roughly 72 % after discharge coordinator implementation and roughly 33 % after primary care coordinator implementation. The latter was also associated with a 13 % monthly decrease in odds of loss to follow-up (OR 0.87, p < 0.001). Conclusions for Practice Care coordination increases adherence among low income families to recommended newborn follow-up after birth hospitalization.

Universal maternal drug testing in a high-prevalence region of prescription opiate abuse.

OBJECTIVE: To evaluate the efficacy of a universal maternal drug testing protocol for all mothers in a community hospital setting that experienced a 3-fold increase in neonatal abstinence syndrome (NAS) over the previous 5 years. STUDY DESIGN: We conducted a retrospective cohort study between May 2012 and November 2013 after the implementation of universal maternal urine drug testing. All subjects with positive urine tests were reviewed to identify a history or suspicion of drug use, insufficient prenatal care, placental abruption, sexually transmitted disease, or admission from a justice center, which would have prompted urine testing using our previous risk-based screening guidelines. We also reviewed the records of infants born to mothers with a positive toxicology for opioids to determine whether admission to the special care nursery was required. RESULTS: Out of the 2956 maternal specimens, 159 (5.4%) positive results were recorded. Of these, 96 were positive for opioids, representing 3.2% of all maternity admissions. Nineteen of the 96 (20%) opioid-positive urine tests were recorded in mothers without screening risk factors. Seven of these 19 infants (37%) required admission to the special care nursery for worsening signs of NAS, and 1 of these 7 required pharmacologic treatment. CONCLUSION: Universal maternal drug testing improves the identification of infants at risk for the development of NAS. Traditional screening methods underestimate in utero opioid exposure.

Influence of interpregnancy interval on neonatal morbidity.

OBJECTIVE: We sought to assess the influence of birth spacing on neonatal morbidity, stratified by gestational age at birth. STUDY DESIGN: This was a population-based retrospective cohort study using Ohio birth records, 2006 through 2011. We compared various interpregnancy interval (IPI) lengths in multiparous mothers with the rate and risk of adverse newborn outcomes. The frequency of neonatal intensive care unit admission or neonatal transport to a tertiary care facility was calculated for births occurring after IPI lengths: <6, 6 to <12, 12 to <24, 24 to <60, and ≥60 months, and stratified by week of gestational age. Neonatal morbidity risk was calculated for each IPI compared to 12 to <24 months (referent), and adjusted for the concomitant influences gestational age at birth, maternal race, age, and prior preterm birth. RESULTS: We analyzed 395,146 birth outcomes of singleton nonanomalous neonates born to multiparous mothers. The frequency and adjusted odds of neonatal morbidity were lowest following IPI of 12 to <24 months (4.1%) compared to short IPIs of <6 months (5.7%; adjusted odds ratio [adjOR], 1.40; 95% confidence interval [CI], 1.32-1.49) and 6 to <12 months (4.7%; adjOR, 1.19; 95% CI, 1.13-1.25), and long IPIs 24 to <60 months (4.6%; adjOR, 1.12; 95% CI, 1.08-1.17) and ≥60 months (5.8%; adjOR, 1.34; 95% CI, 1.28-1.40), despite adjustment for important confounding factors including gestational age at birth. The lowest frequency of adverse neonatal outcomes occurred at 40-41 weeks for all IPI groups. The frequency of other individual immediate newborn morbidities were also increased following short and long IPIs compared to birth following a 12- to <24-month IPI. CONCLUSION: IPI length is a significant contributor to neonatal morbidity, independent of gestational age at birth. Counseling women to plan an optimal amount of time between pregnancies is important for newborn health.

Prematurity and respiratory outcomes program (PROP): study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States.

BACKGROUND: With improved survival rates, short- and long-term respiratory complications of premature birth are increasing, adding significantly to financial and health burdens in the United States. In response, in May 2010, the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) funded a 5-year $18.5 million research initiative to ultimately improve strategies for managing the respiratory complications of preterm and low birth weight infants. Using a collaborative, multi-disciplinary structure, the resulting Prematurity and Respiratory Outcomes Program (PROP) seeks to understand factors that correlate with future risk for respiratory morbidity. METHODS/DESIGN: The PROP is an observational prospective cohort study performed by a consortium of six clinical centers (incorporating tertiary neonatal intensive care units [NICU] at 13 sites) and a data-coordinating center working in collaboration with the NHLBI. Each clinical center contributes subjects to the study, enrolling infants with gestational ages 23 0/7 to 28 6/7 weeks with an anticipated target of 750 survivors at 36 weeks post-menstrual age. In addition, each center brings specific areas of scientific focus to the Program. The primary study hypothesis is that in survivors of extreme prematurity specific biologic, physiologic and clinical data predicts respiratory morbidity between discharge and 1 year corrected age. Analytic statistical methodology includes model-based and non-model-based analyses, descriptive analyses and generalized linear mixed models. DISCUSSION: PROP incorporates aspects of NICU care to develop objective biomarkers and outcome measures of respiratory morbidity in the <29 week gestation population beyond just the NICU hospitalization, thereby leading to novel understanding of the nature and natural history of neonatal lung disease and of potential mechanistic and therapeutic targets in at-risk subjects. TRIAL REGISTRATION: Clinical Trials.gov NCT01435187.

Biologically aware lighting for newborn intensive care.

OBJECTIVE: We designed and implemented a novel neonatal intensive care (NICU) lighting system to support the current understanding of daylight-coupled physiology. METHODS: We created a system that generates wavelengths corresponding to the known blue and violet activation spectra of non-visual opsins. These are known to mediate energy management and related physiologic activity. RESULTS: Light produced by the system spans the visible spectrum, including violet wavelengths that are blocked by modern glazing and not emitted by standard LED fixtures. System features include automated light and dark phases that mimic dawn/dusk. The system also matches length of day seasonality. Spectral composition can be varied to support translational research protocols. Implementation required a comprehensive strategy to inform bedside providers about the value and use of the lighting system. CONCLUSION: Full-spectrum lighting for the NICU is feasible and will inform the optimization of the NICU environment of care to support optimal neonatal growth and development.

Spatial analysis of preterm birth demonstrates opportunities for targeted intervention.

To develop a specific, targeted intervention strategy for reducing preterm birth through use of geographic analysis. We utilized Hamilton County, Ohio vital records and Census data from 2003 to 2006. Spatial scanning statistics allowed determination of the prevalence of preterm birth for any geographical point. Attributable risk calculations demonstrated heterogeneity of risk factors within areas of high or low preterm birth prevalence. Three geographically separate areas with high preterm birth proportions (>16%) had differing primary risk factors for preterm birth, including short interpregnancy interval, previous preterm birth, and low prepregnancy weight, despite similarities in demographics and physical location. Primary risk factors also differed when comparing areas with high and low preterm birth proportions, with diabetes and smoking having primary associations in the lower risk areas. Each local region of high preterm birth proportion as well as those with average or low proportion displayed distinct hierarchies of attributable risk. The heterogeneous distribution of preterm birth proportion within an urban county is complex and requires location specific analysis to develop targeted interventions.

Regional comparison of self-reported late pregnancy cigarette smoking to mass spectrometry analysis.

OBJECTIVE: To report a more accurate prevalence estimate of late pregnancy nicotine exposures. STUDY DESIGN: A cross-sectional study during a 2-month period in 2019. Participants were women delivering in any of the six county maternity hospitals who consented to universal drug testing at the time of delivery as part of routine hospital admission. RESULTS: Of 2531 tested samples, 18.7% tested positive for high levels of cotinine indicating primary smoking or other primary use of tobacco products. Together, 33.0% of the study population tested positive for nicotine exposure during late pregnancy compared to vital records which reported 8.2% cigarette smoking during the third trimester of pregnancy and 10.5% cigarette smoking at any time during pregnancy through maternal self-report. CONCLUSION: Captured vital birth smoking measures vastly underreport actual primary exposures to nicotine products. Vital birth data also fail to capture secondhand exposures which constitute a significant proportion of the population.

Respiratory medication use in extremely premature (<29 weeks) infants during initial NICU hospitalization: Results from the prematurity and respiratory outcomes program.

BACKGROUND: The use of medications to treat respiratory conditions of extreme prematurity is often based upon studies of adults or children over 2 years of age. Little is known about the spectrum of medications used or dosing ranges. To inform the design of future studies, we conducted a prospective analysis of respiratory medication exposure among 832 extremely low gestational age neonates. METHODS: The prematurity and respiratory outcomes program (PROP) enrolled neonates less than 29-week gestation from 6 centers incorporating 13 clinical sites. We collected recorded daily "respiratory" medications given along with dosing information through 40-week postmenstrual age or neonatal intensive care unit discharge if earlier. RESULTS: PROP participants were exposed to a wide range of respiratory medications, often at doses beyond published recommendations. Nearly 50% received caffeine and furosemide beyond published recommendations for cumulative dose. Those who developed bronchopulmonary dysplasia were more likely to receive treatment with respiratory medications. However, more than 30% of PROP subjects that did not develop bronchopulmonary dysplasia also were treated with diuretics, systemic steroids, and other respiratory medications. CONCLUSION: Extremely preterm neonates in PROP were exposed to high doses of medications at levels known to generate significant adverse effects. With limited evidence for efficacy, there is an urgent need for controlled trials in this vulnerable patient population.

Material community deprivation and hospital utilization during the first year of life: an urban population-based cohort study.

PURPOSE: The purpose of the study was to conduct an individual-level analysis of hospital utilization during the first year of life to test the hypothesis that community material deprivation increases health care utilization. METHODS: We used a population-based perinatal data repository based on linkage of electronic health records from regional delivery hospitals to subsequent hospital utilization at the region's only dedicated children's hospital. Zero-inflated Poisson and Cox proportional hazards regression models were used to quantify the causal role of a census tract-based deprivation index on the total number, length, and time until hospital utilization during the first year of life. RESULTS: After adjusting for any neonatal intensive care unit admission, chronic complex conditions, race and ethnicity, insurance status, birth season, and very low birth weight, we found that a 10% increase in the deprivation index caused a 1.032-fold increase (95% confidence interval (CI), [1.025-1.040]) in post initial hospitalization length of stay, a 1.011-fold increase (95% CI, [1.002-1.021]) in number of post initial hospital encounters, and 1.022-fold increase (95% CI, [1.009-1.035]) in hazard for hospitalization utilization during the first year of life. CONCLUSIONS: Interventions designed to reduce material deprivation and income inequalities could significantly reduce infant hospital utilization.

Surveillance of Intrauterine Opioid Exposures Using Electronic Health Records.

The objective was to use population-based electronic health records for surveillance of intrauterine exposures to substances of abuse, including opioids, and to monitor changes in exposure rates over time. This retrospective, descriptive analysis utilized geocoded neonatal physician billing records representing intrauterine exposures to substances of abuse detected through universal maternal drug testing. Census tract-level exposure rates were identified among the newborn population of Hamilton County, Ohio between 2014 and 2016. Among 27,896 newborns, the authors detected an intrauterine opioid exposure rate of 37.9 per 1000 infants, with 10.5 per 1000 experiencing severe opioid withdrawal (neonatal abstinence syndrome). Individual data were mapped to 222 US census tracts. Tract-level opioid exposure rates ranged from 0.0 to 607.1 (median: 32.9) per 1000 live births. Secondary use of electronic health record data has potential to aid in intrauterine opioid exposure and other public health surveillance efforts without disrupting clinical workflows or placing an additional burden on limited resources. Surveillance of intrauterine opioid exposures may inform stakeholders and enable targeting of interventions and prevention strategies toward the highest risk populations.

Infant mortality in coroner/medical examiner investigations.

Infant mortality rate is generally regarded as a fundamental indicator of population health and is often used to validate public health interventions. Hamilton County, Ohio, has one of the highest rates in the nation. Most deaths that do not occur in the hospital fall under the jurisdiction of a coroner/medical examiner. We reviewed all infant deaths evaluated by the Hamilton County Coroner from 2006 to 2013 in order to identify opportunities for public health interventions. We predicted that the majority of these infant deaths were unintentional, but preventable. The eligible population included live born infants, who died less than one year of age. There were 217 cases of infant deaths during this time frame and 14 primary causes of death identified in this cohort. Sleep related deaths made up the majority of deaths (n = 141, 65%), a mean of 17.6 per year. This analysis identifies unsafe sleep patterns, particularly co-bedding and inappropriate sleep surface, as the most frequent contributing factors. Therefore, the coroner/medical examiner, working with public health and healthcare providers can generate information to drive targeted improvements in the outcome for infants.

Clinical and Cost Impact Analysis of a Novel Prognostic Test for Early Detection of Preterm Birth.

Objective The objective of this study was to evaluate the potential impact to the U.S. health care system by adopting a novel test that identifies women at risk for spontaneous preterm birth. Methods A decision-analytic model was developed to assess clinical and cost outcomes over a 1-year period. The use of a prognostic test to predict spontaneous preterm birth in a hypothetical population of women reflective of the U.S. population (predictive arm) was compared with the current baseline rate of spontaneous preterm birth and associated infant morbidity and mortality (baseline care arm). Results In a population of 3,528,593 births, our model predicts a 23.5% reduction in infant mortality (8,300 vs. 6,343 deaths) with use of the novel test. The rate of acute conditions at birth decreased from 11.2 to 8.1%; similarly, the rate of developmental disabilities decreased from 13.2 to 11.5%. The rate of spontaneous preterm birth decreased from 9.8 to 9.1%, a reduction of 23,430 preterm births. Direct medical costs savings was $511.7M (- 2.1%) in the first year of life. Discussion The use of a prognostic test for reducing spontaneous preterm birth is a dominant strategy that could reduce costs and improve outcomes. More research is needed once such a test is available to determine if these results are borne out upon real-world use.

Risk Prediction for Adverse Pregnancy Outcomes in a Medicaid Population.

BACKGROUND: Despite prior efforts to develop pregnancy risk prediction models, there remains a lack of evidence to guide implementation in clinical practice. The current aim was to develop and validate a risk tool grounded in social determinants theory for use among at-risk Medicaid patients. METHODS: This was a retrospective cohort study of 409 women across 17 Cincinnati health centers between September 2013 and April 2014. The primary outcomes included preterm birth, low birth weight, intrauterine fetal demise, and neonatal death. After random allocation into derivation and validation samples, a multivariable model was developed, and a risk scoring system was assessed and validated using area under the receiver operating characteristic curve (AUROC) values. RESULTS: The derived multivariable model (n=263) included: prior preterm birth, interpregnancy interval, late prenatal care, comorbid conditions, history of childhood abuse, substance use, tobacco use, body mass index, race, twin gestation, and short cervical length. Using a weighted risk score, each additional point was associated with an odds ratio of 1.57 for adverse outcomes, p<0.001, AUROC=0.79. In the validation sample (n=146), each additional point conferred an odds ratio of 1.20, p=0.03, AUROC=0.63. Using a cutoff of 20% probability for the outcome, sensitivity was 29%, with specificity 82%. Positive and negative predictive values were 22% and 85%, respectively. CONCLUSIONS: Risk scoring based on social determinants can discriminate pregnancy risk within a Medicaid population; however, performance is modest and consistent with prior prediction models. Future research is needed to evaluate whether implementation of risk scoring in Medicaid prenatal care programs improves clinical outcomes.