Publications by authors named "Edward F Bell"

153 Publications

Neonatal Intensive Care for Very Preterm Infants in China.

JAMA Netw Open 2021 Aug 2;4(8):e2118940. Epub 2021 Aug 2.

Division of Neonatology, Stead Family Department of Pediatrics, University of Iowa, Iowa City.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.18940DOI Listing
August 2021

Growth Rates of Infants Randomized to Continuous Positive Airway Pressure or Intubation After Extremely Preterm Birth.

J Pediatr 2021 Jun 19. Epub 2021 Jun 19.

National Institute of Child Health and Human Development, Bethesda, MD; Department of Global and Community Health, George Mason University, Fairfax, VA.

Objective: To evaluate the effects of early treatment with continuous positive airway pressure (CPAP) on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants.

Study Design: EPT infants (24-27 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks of postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks of PMA and follow-up outcomes at 18-22 months corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed.

Results: Growth data were analyzed for 810 of 1316 infants enrolled in SUPPORT (414 in the intervention group, 396 in the control group). The median gestational age was 26 weeks, and the mean birth weight was 839 g. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between the 2 groups. In a regression model, growth rates between birth and 36 weeks of PMA, as well as growth rates during multiple intervals from birth to day 7, days 7-14, days 14-21, days 21-28, day 28 to 32 weeks PMA, and 32-36 weeks PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of having a Bayley-III cognitive score <85 at 18-22 months corrected age (P = .002).

Conclusions: EPT infants randomized to early CPAP did not have higher in-hospital growth rates than infants randomized to early intubation.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.026DOI Listing
June 2021

Should Vitamin A Injections to Prevent Bronchopulmonary Dysplasia or Death Be Reserved for High-Risk Infants? Reanalysis of the National Institute of Child Health and Human Development Neonatal Research Network Randomized Trial.

J Pediatr 2021 May 15. Epub 2021 May 15.

Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA.

Objective: To determine whether infants at higher risk of bronchopulmonary dysplasia (BPD) or death benefit more from vitamin A therapy than those at lower risk.

Study Design: We conducted a post hoc reanalysis of a landmark phase III randomized controlled trial conducted from January 1996 to July 1997 at 14 university-affiliated neonatal intensive care units in the US. Data analysis was performed from October 2019 to October 2020. Infants born weighing 401-1000 g and receiving respiratory support at 24 hours of age were assigned to intramuscular vitamin A 5000 IU or sham procedure 3 times weekly for 4 weeks. The primary outcome was BPD, defined as use of supplemental oxygen, or death at 36 weeks postmenstrual age. An externally validated model for predicting BPD or death was used to estimate the risk of these outcomes for each infant.

Results: As previously reported, 222 of 405 infants (54.8%) assigned vitamin A therapy and 248 of 402 infants (61.7%) in the control group developed BPD or died (relative risk [RR], 0.89 [95% CI, 0.80-0.99]; risk difference [RD], -6.9% [95% CI, -13.0 to -0.7]). The predicted individual risks of BPD or death ranged from 7.1% to 98.6% (median, 61.5%; mean, 60.9%). The effect of vitamin A therapy on BPD or death depended on infants' risk of the primary outcome (P = .03 for interaction): for example, a RR of 0.73 (RD, -14.5%) for infants with a 25% predicted risk and a RR of 0.96 (RD, -1.0%) for infants with a 75% risk. There was no difference in the decrease in vitamin A deficiency across risk groups.

Conclusions: Contrary to expectations, the effect of vitamin A therapy on BPD or death was greater for lower risk than higher risk infants.

Trial Registration: ClinicalTrials.gov NCT01203488.
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http://dx.doi.org/10.1016/j.jpeds.2021.05.022DOI Listing
May 2021

Sex-specific cytokine responses and neurocognitive outcome after blood transfusions in preterm infants.

Pediatr Res 2021 Apr 28. Epub 2021 Apr 28.

Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Background: The objective of this study was to determine sex-specific differences in inflammatory cytokine responses to red blood cell (RBC) transfusion in preterm infants in the neonatal period and their relationship to later neurocognitive status.

Methods: Infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled in the Transfusion of Prematures (TOP) trial. The total number of transfusions was used as a marker of transfusion status. Nineteen cytokines and biomarkers were analyzed from 71 infants longitudinally during the neonatal period. Twenty-six infants completed the Bayley Scales of Infant & Toddler Development, 3rd Edition (Bayley-III) at 12 months' corrected age.

Results: Nine cytokine levels were significantly elevated in proportion to the number of transfusions received. Of those, one cytokine showed a sex-specific finding (p = 0.004): monocyte chemoattractant protein-1, MCP-1, rose substantially in females (8.9% change per additional transfusion), but not in males (-0.8% change). Higher concentrations of MCP-1 exclusively were associated with worse Bayley-III scores: decreased cognitive raw scores (p = 0.0005) and motor scaled scores (p < 0.0001).

Conclusions: This study provides evidence of a sex-specific difference in the inflammatory response to RBC transfusions during neonatal life, with MCP-1 levels rising only in females and inversely correlating with neurocognitive status at 12 months old.

Impact: It is important to understand the risk factors for abnormal neurodevelopment in preterm infants, including anemia and RBC transfusion, in order to improve outcomes and provide potential targets for therapy. Our study investigates and provides the first evidence of sex-specific differences in inflammatory cytokine responses to RBC transfusions in preterm infants in the neonatal period, and their relationship to later cognitive outcomes. This study critically suggests that different transfusion thresholds may have a sex-specific effect on neurodevelopment: females have worse cognitive outcomes with increased number of transfusions, while males have worse outcomes with lower number of transfusions.
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http://dx.doi.org/10.1038/s41390-021-01536-0DOI Listing
April 2021

Red cell transfusion thresholds for preterm infants: finally some answers.

Authors:
Edward F Bell

Arch Dis Child Fetal Neonatal Ed 2021 Apr 27. Epub 2021 Apr 27.

Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA

Extremely low birthweight infants become anaemic during their care in the neonatal intensive care unit because of the physiological anaemia experienced by all newborn infants compounded by early umbilical cord clamping, blood loss by phlebotomy for laboratory monitoring and delayed erythropoiesis. The majority of these infants receive transfusions of packed red blood cells, usually based on haemoglobin values below a certain threshold. The haemoglobin or haematocrit thresholds used to guide transfusion practices vary with infant status and among institutions and practitioners. Previous smaller studies have not given clear guidance with respect to the haemoglobin thresholds that should trigger transfusions or even if this is the best way to decide when to transfuse an infant. Two large clinical trials of similar design comparing higher and lower haemoglobin thresholds for transfusing extremely low birthweight infants were recently published, the ETTNO and TOP trials. These trials found reassuringly conclusive and concordant results. Within the range of haemoglobin transfusion thresholds studied, there was no difference in the primary outcome (which was the same in both studies), neurodevelopmental impairment at 2 years' corrected age or death before assessment, in either study. In addition, there was no difference in either study in either of the components of the primary outcome. In conclusion, haemoglobin transfusion thresholds within the ranges used in these trials, 11-13 g/dL for young critically ill or ventilated infants and 7-10 g/dL for stable infants not requiring significant respiratory support, can be safely used without expecting adverse consequences on survival or neurodevelopment.
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http://dx.doi.org/10.1136/archdischild-2020-320495DOI Listing
April 2021

Eligibility Criteria and Representativeness of Randomized Clinical Trials That Include Infants Born Extremely Premature: A Systematic Review.

J Pediatr 2021 Aug 21;235:63-74.e12. Epub 2021 Apr 21.

Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH; Ohio Perinatal Research Network at Nationwide Children's Hospital, Columbus, OH; Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH; The Heart Center, Nationwide Children's Hospital, Columbus, OH. Electronic address:

Objective: To assess the eligibility criteria and trial characteristics among contemporary (2010-2019) randomized clinical trials (RCTs) that included infants born extremely preterm (<28 weeks of gestation) and to evaluate whether eligibility criteria result in underrepresentation of high-risk subgroups (eg, infants born at <24 weeks of gestation).

Study Design: PubMed and Scopus were searched January 1, 2010, to December 31, 2019, with no language restrictions. RCTs with mean or median gestational ages at birth of <28 weeks of gestation were included. The study followed the PRISMA guidelines; outcomes were registered prospectively. Data extraction was performed independently by multiple observers. Study quality was evaluated using a modified Jadad scale.

Results: Among RCTs (n = 201), 32 552 infants were included. Study participant characteristics, interventions, and outcomes were highly variable. A total of 1603 eligibility criteria were identified; rationales were provided for 18.8% (n = 301) of criteria. Fifty-five RCTs (27.4%) included infants <24 weeks of gestation; 454 (1.4%) infants were identified as <24 weeks of gestation.

Conclusions: The present study identifies sources of variability across RCTs that included infants born extremely preterm and reinforces the critical need for consistent and transparent policies governing eligibility criteria.
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http://dx.doi.org/10.1016/j.jpeds.2021.04.028DOI Listing
August 2021

The relationship of neurodevelopmental impairment to concurrent early childhood outcomes of extremely preterm infants.

J Perinatol 2021 Mar 23. Epub 2021 Mar 23.

Stead Family Department of Pediatrics, University of Iowa, Iowa, IA, USA.

Objective: Determine how neurodevelopmental impairment (NDI) relates to concurrent outcomes for children born extremely preterm.

Study Design: Retrospective cohort study children born 22 0/7-26 6/7 weeks' gestation at NICHD Neonatal Research Network hospitals. Outcomes were ascertained at 18-22 months' corrected age.

Result: Of 6562 children, 2618 (40%) died and 441 (7%) had no follow-up. Among the remaining 3483 children, 825 (24%), 1576 (45%), 657 (19%), and 425 (12%) had no, potential/mild, moderate, and severe NDI, respectively. Rehospitalization, respiratory medications, surgery, and medical support services were associated with greater NDI severity but affected >10% of children without NDI. Rehospitalization occurred in 40% of children with no NDI (mean (SD): 1.7 (1.3) episodes).

Conclusion: Medical, functional, and social outcomes at 18-22 months' corrected age were associated with NDI; however, many children without NDI were affected. These data should contribute to counseling families and the design of studies for childhood outcomes beyond NDI.
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http://dx.doi.org/10.1038/s41372-021-00999-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985590PMC
March 2021

Breast Milk for Term and Preterm Infants-Own Mother's Milk or Donor Milk?

Nutrients 2021 Jan 28;13(2). Epub 2021 Jan 28.

Department of Obstetrics and Gynecology, University of Pécs Medical School, 7624 Pécs, Hungary.

Hormones are important biological regulators, controlling development and physiological processes throughout life. We investigated pituitary hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and total protein levels during the first 6 months of lactation. Breast milk samples were collected every fourth week of lactation from mothers who gave birth to preterm ( = 14) or term ( = 16) infants. Donor milk is suggested when own mother's milk is not available; therefore, we collected breast milk samples before and after Holder pasteurization (HoP) from the Breast Milk Collection Center of Pécs, Hungary. Three infant formulas prepared in the Neonatal Intensive Care Unit of the University of Pécs were tested at three different time points. Our aim was to examine the hormone content of own mother's milk and donor milk. There were no significant changes over time in the concentrations of any hormone. Preterm milk had higher PRL (28.2 ± 2.5 vs 19.3 ± 2.3 ng/mL) and LH (36.3 ± 8.8 vs 15.9 ± 4.1 mIU/L) concentrations than term milk during the first 6 months of lactation. Total protein and FSH concentrations did not differ between preterm and term breast milk. Holder pasteurization decreased the PRL concentration (30.4 ± 1.8 vs 14.4 ± 0.6 ng/mL) and did not affect gonadotropin levels of donor milk. Infant formulas have higher total protein content than breast milk but do not contain detectable levels of pituitary hormones. Differences were detected in the content of pituitary hormones produced for preterm and term infants. Divergence between feeding options offers opportunities for improvement of nutritional guidelines for both hospital and home feeding practices.
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http://dx.doi.org/10.3390/nu13020424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912320PMC
January 2021

Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions.

Arch Dis Child Fetal Neonatal Ed 2021 Jan 21. Epub 2021 Jan 21.

Pediatrics, Neonatology, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, Texas, USA.

Objective: Determine risk of death or neurodevelopmental impairment (NDI) in infants with late-onset sepsis (LOS) versus late-onset, antibiotic-treated, blood culture-negative conditions (LOCNC).

Design: Retrospective cohort study.

Setting: 24 neonatal centres.

Patients: Infants born 1/1/2006-31/12/2014, at 22-26 weeks gestation, with birth weight 401-1000 g and surviving >7 days were included. Infants with early-onset sepsis, necrotising enterocolitis, intestinal perforation or both LOS and LOCNC were excluded.

Exposures: LOS and LOCNC were defined as antibiotic administration for ≥5 days with and without a positive blood/cerebrospinal fluid culture, respectively. Infants with these diagnoses were also compared with infants with neither condition.

Outcomes: Death or NDI was assessed at 18-26 months corrected age follow-up. Modified Poisson regression models were used to estimate relative risks adjusting for covariates occurring ≤7 days of age.

Results: Of 7354 eligible infants, 3940 met inclusion criteria: 786 (20%) with LOS, 1601 (41%) with LOCNC and 1553 (39%) with neither. Infants with LOS had higher adjusted relative risk (95% CI) for death/NDI (1.14 (1.05 to 1.25)) and death before follow-up (1.71 (1.44 to 2.03)) than those with LOCNC. Among survivors, risk for NDI did not differ between the two groups (0.99 (0.86 to 1.13)) but was higher for LOCNC infants (1.17 (1.04 to 1.31)) compared with unaffected infants.

Conclusions: Infants with LOS had higher risk of death, but not NDI, compared with infants with LOCNC. Surviving infants with LOCNC had higher risk of NDI compared with unaffected infants. Improving outcomes for infants with LOCNC requires study of the underlying conditions and the potential impact of antibiotic exposure.
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http://dx.doi.org/10.1136/archdischild-2020-320664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292446PMC
January 2021

Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants.

N Engl J Med 2020 12;383(27):2639-2651

From the Department of Pediatrics, University of Pennsylvania, and Children's Hospital of Philadelphia, Philadelphia (H.K., B.S., A.S.C.); the Department of Pediatrics, University of Iowa, Iowa City (E.F.B., K.J.J., J.A.W.); the Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto (S.R.H., V.Y.C.), and the Department of Pediatrics, University of California, Los Angeles, Los Angeles (U.D.) - both in California; the Biostatistics and Epidemiology Division, RTI International, Research Triangle Park (S.T., M.M.C.), and the Department of Pediatrics, Duke University School of Medicine, Durham (C.M.C.) - both in North Carolina; the Biostatistics and Epidemiology Division, RTI International, Rockville (J.E.N., A.D.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda (R.D.H.) - both in Maryland; the Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, RI (B.R.V., A.R.L.); the Division of Neonatology, University of Alabama at Birmingham, Birmingham (W.A.C.); the University of Rochester School of Medicine and Dentistry, Rochester, NY (C.T.D., M.F.C.); the Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston (K.A.K.), and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (M.H.W.); the University of New Mexico Health Sciences Center, Albuquerque (R.K.O.); the Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt Lake City (R.K.O., B.A.Y.); the Department of Pediatrics, Indiana University School of Medicine, Indianapolis (B.B.P., G.M.S.); Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati (B.B.P., K.S.), the Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland (M.C.W.), and Nationwide Children's Hospital and the Department of Pediatrics, Ohio State University College of Medicine, Columbus (R.S.); the Department of Pediatrics, Dalhousie University, Halifax, NS, Canada (R.K.W.); the Department of Neonatology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston (J.A.F.Z.); the Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO (W.E.T.); Emory University School of Medicine, Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta (R.M.P.); the Department of Pediatrics, Wayne State University, Detroit (S.C.); and the College of Health and Human Services, George Mason University, Fairfax, VA (R.D.H.).

Background: Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia.

Methods: We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity.

Results: A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively.

Conclusions: In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).
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http://dx.doi.org/10.1056/NEJMoa2020248DOI Listing
December 2020

Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial.

J Pediatr 2021 03 13;230:106-111.e6. Epub 2020 Nov 13.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Pregnancy and Perinatology Branch, Bethesda, MD; George Mason University, Fairfax, VA.

Objective: To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours.

Study Design: Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age.

Results: Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively.

Conclusions: MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia.

Trial Registration: Clinicaltrials.gov: NCT00614744.
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http://dx.doi.org/10.1016/j.jpeds.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914162PMC
March 2021

Withholding or withdrawing life-sustaining treatment in extremely low gestational age neonates.

Arch Dis Child Fetal Neonatal Ed 2021 May 20;106(3):238-243. Epub 2020 Oct 20.

Dean's Office, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Objective: To identify sociodemographic and clinical factors associated with withholding or withdrawing life-sustaining treatment (WWLST) for extremely low gestational age neonates.

Design: Observational study of prospectively collected registry data from 19 National Institute of Child Health and Human Development Neonatal Research Network centres on neonates born at 22-28 weeks gestation who died >12 hours through 120 days of age during 2011-2016. Sociodemographic and clinical factors were compared between infants who died following WWLST and without WWLST.

Results: Of 1168 deaths, 67.1% occurred following WWLST. Withdrawal of assisted ventilation (97.4%) was the primary modality. WWLST rates were inversely proportional to gestational age. Life-sustaining treatment was withheld or withdrawn more often for non-Hispanic white infants than for non-Hispanic black infants (72.7% vs 60.4%; 95% CI 1.00 to 1.92) or Hispanic infants (72.7% vs 67.2%; 95% CI 1.32 to 3.72). WWLST rates varied across centres (38.6-92.6%; p<0.001). The centre with the highest rate had adjusted odds 4.89 times greater than the average (95% CI 1.18 to 20.18). The adjusted odds of WWLST were higher for infants with necrotiing enterocolitis (OR 1.77, 95% CI 1.21 to 2.59) and severe brain injury (OR 1.98, 95% CI 1.44 to 2.74).

Conclusions: Among infants who died, WWLST rates varied widely across centres and were associated with gestational age, race, ethnicity, necrotiing enterocolitis, and severe brain injury. Further exploration is needed into how race, centre, and approaches to care of infants with necrotiing enterocolitis and severe brain injury influence WWLST.
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http://dx.doi.org/10.1136/archdischild-2020-318855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055718PMC
May 2021

In-hospital mortality and morbidity among extremely preterm infants in relation to maternal body mass index.

J Perinatol 2021 May 6;41(5):1014-1024. Epub 2020 Oct 6.

Department of Pediatrics, Wayne State University, Detroit, MI, USA.

Objective: The objective of this paper is to compare in-hospital survival and survival without major morbidities in extremely preterm infants in relation to maternal body mass index (BMI).

Methods: This retrospective cohort study included extremely preterm infants (gestational age 22-28 weeks). This study was conducted at National Institute of Child Health and Human Development Neonatal Research Network sites. Primary outcome was survival without any major morbidity.

Results: Maternal BMI data were available for 2415 infants. Survival without any major morbidity was not different between groups: 30.8% in the underweight/normal, 28.1% in the overweight, and 28.5% in the obese (P = 0.65). However, survival was lower in the obese group (76.5%) compared with overweight group (83.2%) (P = 0.02). Each unit increase in maternal BMI was associated with decreased odds of infant survival (P < 0.01).

Conclusions: Survival without any major morbidity was not associated with maternal obesity. An increase in maternal prepregnancy BMI was associated with decreased odds of infant survival.
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http://dx.doi.org/10.1038/s41372-020-00847-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021608PMC
May 2021

Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.

Am J Obstet Gynecol 2021 02 31;224(2):158-174. Epub 2020 Jul 31.

Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH.

Objective: The objective of this study was to provide a systematic review and meta-analysis to quantify prognosis and identify factors associated with variations in reported mortality estimates among infants who were born at 22 weeks of gestation and provided proactive treatment (resuscitation and intensive care).

Data Sources: PubMed, Scopus, and Web of Science databases, with no language restrictions, were searched for articles published from January 2000 to February 2020.

Study Eligibility Criteria: Reports on live-born infants who were delivered at 22 weeks of gestation and provided proactive care were included. The primary outcome was survival to hospital discharge; secondary outcomes included survival without major morbidity and survival without neurodevelopmental impairment. Because we expected differences across studies in the definitions for various morbidities, multiple definitions for composite outcomes of major morbidities were prespecified. Neurodevelopmental impairment was based on Bayley Scales of Infant Development II or III. Data extractions were performed independently, and outcomes agreed on a priori.

Study Appraisal And Synthesis Methods: Methodological quality was assessed using the Quality in Prognostic Studies tool. An adapted version of the Grading of Recommendations Assessment, Development and Evaluation approach for prognostic studies was used to evaluate confidence in overall estimates. Outcomes were assessed as prevalence and 95% confidence intervals. Variabilities across studies attributable to heterogeneity were estimated with the I statistic; publication bias was assessed with the Luis Furuya-Kanamori index. Data were pooled using the inverse variance heterogeneity model.

Results: Literature searches returned 21,952 articles, with 2034 considered in full; 31 studies of 2226 infants who were delivered at 22 weeks of gestation and provided proactive neonatal treatment were included. No articles were excluded for study design or risk of bias. The pooled prevalence of survival was 29.0% (95% confidence interval, 17.2-41.6; 31 studies, 2226 infants; I=79.4%; Luis Furuya-Kanamori index=0.04). Survival among infants born to mothers receiving antenatal corticosteroids was twice the survival of infants born to mothers not receiving antenatal corticosteroids (39.0% vs 19.5%; P<.01). The overall prevalence of survival without major morbidity, using a definition that includes any bronchopulmonary dysplasia, was 11.0% (95% confidence interval, 8.0-14.3; 10 studies, 374 infants; I=0%; Luis Furuya-Kanamori index=3.02). The overall rate of survival without moderate or severe impairment was 37.0% (95% confidence interval, 14.6-61.5; 5 studies, 39 infants; I=45%; Luis Furuya-Kanamori index=-0.15). Based on the year of publication, survival rates increased between 2000 and 2020 (slope of the regression line=0.09; standard error=0.03; P<.01). Studies were highly diverse with regard to interventions and outcomes reported.

Conclusion: The reported survival rates varied greatly among studies and were likely influenced by combining observational data from disparate sources, lack of individual patient-level data, and bias in the component studies from which the data were drawn. Therefore, pooled results should be interpreted with caution. To answer fundamental questions beyond the breadth of available data, multicenter, multidisciplinary collaborations, including alignment of important outcomes by stakeholders, are needed.
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http://dx.doi.org/10.1016/j.ajog.2020.07.051DOI Listing
February 2021

Outcomes Following Post-Hemorrhagic Ventricular Dilatation among Infants of Extremely Low Gestational Age.

J Pediatr 2020 Jul 30. Epub 2020 Jul 30.

College of Health and Human Services, George Mason University, Fairfax, VA.

Objective: To assess outcomes following post-hemorrhagic ventricular dilatation (PHVD) among infants born at ≤26 weeks of gestation.

Study Design: Observational study of infants born April 1, 2011, to December 31, 2015, in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and categorized into 3 groups: PHVD, intracranial hemorrhage without ventricular dilatation, or normal head ultrasound. PHVD was treated per center practice. Neurodevelopmental impairment at 18-26 months was defined by cerebral palsy, Bayley Scales of Infant and Toddler Development, 3rd edition, cognitive or motor score <70, blindness, or deafness. Multivariable logistic regression examined the association of death or impairment, adjusting for neonatal course, center, maternal education, and parenchymal hemorrhage.

Results: Of 4216 infants, 815 had PHVD, 769 had hemorrhage without ventricular dilatation, and 2632 had normal head ultrasounds. Progressive dilatation occurred among 119 of 815 infants; the initial intervention in 66 infants was reservoir placement and 53 had ventriculoperitoneal shunt placement. Death or impairment occurred among 68%, 39%, and 28% of infants with PHVD, hemorrhage without dilatation, and normal head ultrasound, respectively; aOR (95% CI) were 4.6 (3.8-5.7) PHVD vs normal head ultrasound scan and 2.98 (2.3-3.8) for PHVD vs hemorrhage without dilatation. Death or impairment was more frequent with intervention for progressive dilatation vs no intervention (80% vs 65%; aOR 2.2 [1.38-3.8]). Death or impairment increased with parenchymal hemorrhage, intervention for PHVD, male sex, and surgery for retinopathy; odds decreased with each additional gestational week.

Conclusions: PHVD was associated with high rates of death or impairment among infants with gestational ages ≤26 weeks; risk was further increased among those with progressive ventricular dilation requiring intervention.
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http://dx.doi.org/10.1016/j.jpeds.2020.07.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855243PMC
July 2020

Survey of practices in relation to chronic pulmonary hypertension in neonates in the Canadian Neonatal Network and the National Institute of Child Health and Human Development Neonatal Research Network.

Pulm Circ 2020 Jul-Sep;10(3):2045894020937126. Epub 2020 Jul 16.

Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada.

Current knowledge gaps pertaining to diagnosis and management of neonatal chronic pulmonary hypertension (cPH) may result in significant variability in clinical practice. The objective of the study is to understand cPH management practices in neonatal intensive care units affiliated with the Canadian Neonatal Network (CNN) and National Institute of Child Health and Human Development Neonatal Research Network (NRN). A 32-question survey seeking practice details for cPH evaluation, diagnostic criteria, conservative measures, pharmacotherapeutics, and follow-up was e-mailed to a designated physician at each center. Responses were described as frequency (percentage) and compared between CNN and NRN, where appropriate. Overall response rate was 67% (CNN 20/28 (71%), NRN 9/15 (60%)). While 8 (28%) centers had standardized management protocols, 17 (59%) routinely evaluate high-risk patients; moderate-severe chronic lung disease being the commonest indication. While interventricular septal flattening on echocardiography was the commonest listed diagnostic criterion, several adjunctive indices were also identified. Asymptomatic neonates with cPH were managed expectantly (routine care) in 50% of sites, and using various conservative measures in others. Pulmonary vasodilators were prescribed for symptomatic cases, with 60% of sites using them early (86% reporting any use). Seventy-five percent of sites use inhaled nitric oxide and sildenafil citrate as first- and second-line agents, respectively. Use of standard protocols, cardiac catheterization, and conservative measures for asymptomatic cases was more common in NRN units ( < 0.05). While there is relative homogeneity in patient identification and diagnostic criteria used for neonatal cPH, significant interunit inconsistencies still exists in routine evaluation, use of additional investigations, management of asymptomatic cases, frequency and type of conservative measures, and choice of pulmonary vasodilators.
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http://dx.doi.org/10.1177/2045894020937126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366415PMC
July 2020

Precision medicine in neonatal hemodynamics: need for prioritization of mechanism of illness and defining population of interest.

J Perinatol 2020 09 27;40(9):1446-1449. Epub 2020 Jul 27.

Division of Neonatology, Department of Pediatrics, University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA.

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http://dx.doi.org/10.1038/s41372-020-0741-yDOI Listing
September 2020

Racial/Ethnic Disparities Among Extremely Preterm Infants in the United States From 2002 to 2016.

JAMA Netw Open 2020 06 1;3(6):e206757. Epub 2020 Jun 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Importance: Racial/ethnic disparities in quality of care among extremely preterm infants are associated with adverse outcomes.

Objective: To assess whether racial/ethnic disparities in major outcomes and key care practices were changing over time among extremely preterm infants.

Design, Setting, And Participants: This observational cohort study used prospectively collected data from 25 US academic medical centers. Participants included 20 092 infants of 22 to 27 weeks' gestation with a birth weight of 401 to 1500 g born at centers participating in the National Institute of Child Health and Human Development Neonatal Research Network from 2002 to 2016. Of these infants, 9316 born from 2006 to 2014 were eligible for follow-up at 18 to 26 months' postmenstrual age (excluding 5871 infants born before 2006, 2594 infants born after 2014, and 2311 ineligible infants including 64 with birth weight >1000 g and 2247 infants with gestational age >26 6/7 weeks), of whom 745 (8.0%) did not have known follow-up outcomes at 18 to 26 months.

Main Outcomes And Measures: Rates of mortality, major morbidities, and care practice use over time were evaluated using models adjusted for baseline characteristics, center, and birth year. Data analyses were conducted from 2018 to 2019.

Results: In total, 20 092 infants with a mean (SD) gestational age of 25.1 (1.5) weeks met the inclusion criteria and were available for the primary outcome: 8331 (41.5%) black infants, 3701 (18.4%) Hispanic infants, and 8060 (40.1%) white infants. Hospital mortality decreased over time in all groups. The rate of improvement in hospital mortality over time did not differ among black and Hispanic infants compared with white infants (black infants went from 35% to 24%, Hispanic infants went from 32% to 27%, and white infants went from 30% to 22%; P = .59 for race × year interaction). The rates of late-onset sepsis among black infants (went from 37% to 24%) and Hispanic infants (went from 45% to 23%) were initially higher than for white infants (went from 36% to 25%) but decreased more rapidly and converged during the most recent years (P = .02 for race × year interaction). Changes in rates of other major morbidities did not differ by race/ethnicity. Death before follow-up decreased over time (from 2006 to 2014: black infants, 14%; Hispanic infants, 39%, white infants, 15%), but moderate-severe neurodevelopmental impairment increased over time in all racial/ethnic groups (increase from 2006 to 2014: black infants, 70%; Hispanic infants, 123%; white infants, 130%). Rates of antenatal corticosteroid exposure (black infants went from 72% to 90%, Hispanic infants went from 73% to 83%, and white infants went from 86% to 90%; P = .01 for race × year interaction) and of cesarean delivery (black infants went from 45% to 59%, Hispanic infants went from 49% to 59%, and white infants went from 62% to 63%; P = .03 for race × year interaction) were initially lower among black and Hispanic infants compared with white infants, but these differences decreased over time.

Conclusions And Relevance: Among extremely preterm infants, improvements in adjusted rates of mortality and most major morbidities did not differ by race/ethnicity, but rates of neurodevelopmental impairment increased in all groups. There were narrowing racial/ethnic disparities in important care practices, including the use of antenatal corticosteroids and cesarean delivery.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287569PMC
June 2020

Association of Antenatal Corticosteroids and Magnesium Sulfate Therapy With Neurodevelopmental Outcome in Extremely Preterm Children.

Obstet Gynecol 2020 06;135(6):1377-1386

Department of Pediatrics, the University of Alabama at Birmingham, Birmingham, Alabama; Statistics and Epidemiology Unit, RTI International, Research Triangle Park, North Carolina; the Department of Pediatrics, Children's Hospital of Michigan and Hutzel Women's Hospital, Wayne State University, Detroit, Michigan; the Department of Pediatrics, University of Iowa, Iowa City, Iowa; the Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California; the Department of Pediatrics, UT Southwestern, Dallas, Texas; the Department of Obstetrics and Gynecology and Center for Women's Reproductive Health, University of Alabama at Birmingham, Birmingham, Alabama; the Department of Global and Community Health, George Mason University, Fairfax, Virginia; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland.

Objective: To test the primary hypothesis that extremely preterm children antenatally exposed to both magnesium sulfate and antenatal corticosteroids have a lower rate of severe neurodevelopmental impairment or death compared with those exposed to antenatal corticosteroids alone.

Methods: This was a prospective observational study of children born at 22 0/7-26 6/7 weeks of gestation from 2011 to 2014 at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hospitals (N=3,093). The primary outcome was severe neurodevelopmental impairment or death at 18-26 months of corrected age follow-up based on exposure to antenatal corticosteroids and magnesium sulfate or antenatal corticosteroids alone. Secondary outcomes included components of severe neurodevelopmental impairment by exposure group and comparisons of severe neurodevelopmental impairment or death between children exposed to both antenatal corticosteroids and magnesium sulfate with those exposed to magnesium sulfate alone or to neither antenatal corticosteroids nor magnesium sulfate. Logistic regression models adjusted for background characteristics.

Results: Children exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of severe neurodevelopmental impairment or death (813/2,239, 36.3%) compared with those exposed to antenatal corticosteroids alone (225/508, 44.3%; adjusted odds ratio [aOR] 0.73; 95% CI 0.58-0.91), magnesium sulfate alone (47/89, 53%; aOR 0.49; 95% CI 0.29-0.82), or neither therapy (121/251; 48.2%; aOR 0.66, 95% CI 0.49-0.89). Similarly, children exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of death compared with either or neither therapy, but the rate of severe neurodevelopmental impairment among survivors did not differ between exposure groups.

Conclusion: In children born between 22 0/7 and 26 6/7 weeks of gestation, exposure to both antenatal corticosteroids and magnesium sulfate was associated with lower rates of severe neurodevelopmental impairment or death and death compared with exposure to antenatal corticosteroids alone.

Clinical Trial Registration: ClinicalTrials.gov, NCT00063063.
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http://dx.doi.org/10.1097/AOG.0000000000003882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278037PMC
June 2020

Impact of Early-Onset Sepsis and Antibiotic Use on Death or Survival with Neurodevelopmental Impairment at 2 Years of Age among Extremely Preterm Infants.

J Pediatr 2020 06;221:39-46.e5

Department of Pediatrics, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX.

Objective: To evaluate the hypothesis that early-onset sepsis increases risk of death or neurodevelopmental impairment (NDI) among preterm infants; and that among infants without early-onset sepsis, prolonged early antibiotics alters risk of death/NDI.

Study Design: Retrospective cohort study of infants born at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2014) at 22-26 weeks of gestation and birth weight 401-1000 g. Early-onset sepsis defined as growth of a pathogen from blood or cerebrospinal fluid culture ≤72 hours after birth. Prolonged early antibiotics was defined as antibiotics initiated ≤72 hours and continued ≥5 days without culture-confirmed infection, necrotizing enterocolitis, or spontaneous perforation. Primary outcome was death before follow-up or NDI assessed at 18-26 months corrected age. Poisson regression was used to estimate adjusted relative risk (aRR) and CI for early-onset sepsis outcomes. A propensity score for receiving prolonged antibiotics was derived from early clinical factors and used to match infants (1:1) with and without prolonged antibiotic exposure. Log binomial models were used to estimate aRR for outcomes in matched infants.

Results: Among 6565 infants, those with early-onset sepsis had higher aRR (95% CI) for death/NDI compared with infants managed with prolonged antibiotics (1.18 [1.06-1.32]) and to infants without prolonged antibiotics (1.23 [1.10-1.37]). Propensity score matching was achieved for 4362 infants. No significant difference in death/NDI (1.04 [0.98-1.11]) was observed with or without prolonged antibiotics among the matched cohort.

Conclusions: Early-onset sepsis was associated with increased risk of death/NDI among extremely preterm infants. Among matched infants without culture-confirmed infection, prolonged early antibiotic administration was not associated with death/NDI.
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http://dx.doi.org/10.1016/j.jpeds.2020.02.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248124PMC
June 2020

Early-Onset Neonatal Sepsis 2015 to 2017, the Rise of Escherichia coli, and the Need for Novel Prevention Strategies.

JAMA Pediatr 2020 07 6;174(7):e200593. Epub 2020 Jul 6.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

Importance: Early-onset sepsis (EOS) remains a potentially fatal newborn condition. Ongoing surveillance is critical to optimize prevention and treatment strategies.

Objective: To describe the current incidence, microbiology, morbidity, and mortality of EOS among a cohort of term and preterm infants.

Design, Setting, And Participants: This prospective surveillance study included a cohort of infants born at a gestational age (GA) of at least 22 weeks and birth weight of greater than 400 g from 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from April 1, 2015, to March 31, 2017. Data were analyzed from June 14, 2019, to January 28, 2020.

Main Outcomes And Measures: Early-onset sepsis defined by isolation of pathogenic species from blood or cerebrospinal fluid culture within 72 hours of birth and antibiotic treatment for at least 5 days or until death.

Results: A total of 235 EOS cases (127 male [54.0%]) were identified among 217 480 newborns (1.08 [95% CI, 0.95-1.23] cases per 1000 live births). Incidence varied significantly by GA and was highest among infants with a GA of 22 to 28 weeks (18.47 [95% CI, 14.57-23.38] cases per 1000). No significant differences in EOS incidence were observed by sex, race, or ethnicity. The most frequent pathogens were Escherichia coli (86 [36.6%]) and group B streptococcus (GBS; 71 [30.2%]). E coli disease primarily occurred among preterm infants (68 of 131 [51.9%]); GBS disease primarily occurred among term infants (54 of 104 [51.9%]), with 24 of 45 GBS cases (53.3%) seen in infants born to mothers with negative GBS screening test results. Intrapartum antibiotics were administered to 162 mothers (68.9%; 110 of 131 [84.0%] preterm and 52 of 104 [50.0%] term), most commonly for suspected chorioamnionitis. Neonatal empirical antibiotic treatment most frequently included ampicillin and gentamicin. All GBS isolates were tested, but only 18 of 81 (22.2%) E coli isolates tested were susceptible to ampicillin; 6 of 77 E coli isolates (7.8%) were resistant to both ampicillin and gentamicin. Nearly all newborns with EOS (220 of 235 [93.6%]) displayed signs of illness within 72 hours of birth. Death occurred in 38 of 131 infected infants with GA of less than 37 weeks (29.0%); no term infants died. Compared with earlier surveillance (2006-2009), the rate of E coli infection increased among very low-birth-weight (401-1500 g) infants (8.68 [95% CI, 6.50-11.60] vs 5.07 [95% CI, 3.93-6.53] per 1000 live births; P = .008).

Conclusions And Relevance: In this study, EOS incidence and associated mortality disproportionately occurred in preterm infants. Contemporary cases have demonstrated the limitations of current GBS prevention strategies. The increase in E coli infections among very low-birth-weight infants warrants continued study. Ampicillin and gentamicin remained effective antibiotics in most cases, but ongoing surveillance should monitor antibiotic susceptibilities of EOS pathogens.
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http://dx.doi.org/10.1001/jamapediatrics.2020.0593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199167PMC
July 2020

Pituitary Glycoprotein Hormones in Human Milk before and after Pasteurization or Refrigeration.

Nutrients 2020 Mar 4;12(3). Epub 2020 Mar 4.

Departments of Neonatology and Obstetrics & Gynecology, University of Pécs Medical School, 7624 Pécs, Hungary.

Our aims were to investigate the presence of pituitary glycoprotein hormones in preterm and donor milk, and to examine the effects of Holder pasteurization and refrigeration on the levels of these hormones. We measured follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) in milk samples from mothers who delivered prematurely ( = 27) and in samples of mothers who delivered at term and donated milk to the Mother's Milk Bank of Iowa ( = 30). The gonadotropins and TSH were present in similar amounts within human milk produced for preterm and term infants. FSH increased 21% after refrigeration ( < 0.05), while LH declined by 39% ( < 0.05). Holder pasteurization decreased LH by 24% ( < 0.05) and increased TSH by 17% ( < 0.05). Holder pasteurization followed by refrigeration resulted in a 21% increase in FSH and a 41% decrease in LH (both < 0.05), resulting in more than a 3-fold increase in donor milk FSH:LH ratios ( < 0.05 versus fresh donor milk). Despite structural similarities, the gonadotropins are differentially impacted by Holder pasteurization and refrigeration, and this results in marked alterations in the relative amount of FSH and LH that may be administered to preterm infants, potentially swinging hormonal balance towards ovarian hyperstimulation in females and hypogonadism in males.
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http://dx.doi.org/10.3390/nu12030687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146501PMC
March 2020

Assessment of an Updated Neonatal Research Network Extremely Preterm Birth Outcome Model in the Vermont Oxford Network.

JAMA Pediatr 2020 05 4;174(5):e196294. Epub 2020 May 4.

Office of Research, George Mason University College of Health and Human Services, Fairfax, Virginia.

Importance: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) extremely preterm birth outcome model is widely used for prognostication by practitioners caring for families expecting extremely preterm birth. The model provides information on mean outcomes from 1998 to 2003 and does not account for substantial variation in outcomes among US hospitals.

Objective: To update and validate the NRN extremely preterm birth outcome model for most extremely preterm infants in the United States.

Design, Setting, And Participants: This prognostic study included 3 observational cohorts from January 1, 2006, to December 31, 2016, at 19 US centers in the NRN (derivation cohort) and 637 US centers in Vermont Oxford Network (VON) (validation cohorts). Actively treated infants born at 22 weeks' 0 days' to 25 weeks' 6 days' gestation and weighing 401 to 1000 g, including 4176 in the NRN for 2006 to 2012, 45 179 in VON for 2006 to 2012, and 25 969 in VON for 2013 to 2016, were studied. VON cohorts comprised more than 85% of eligible US births. Data analysis was performed from May 1, 2017, to March 31, 2019.

Exposures: Predictive variables used in the original model, including infant sex, birth weight, plurality, gestational age at birth, and exposure to antenatal corticosteroids.

Main Outcomes And Measures: The main outcome was death before discharge. Secondary outcomes included neurodevelopmental impairment at 18 to 26 months' corrected age and measures of hospital resource use (days of hospitalization and ventilator use).

Results: Among 4176 actively treated infants in the NRN cohort (48% female; mean [SD] gestational age, 24.2 [0.8] weeks), survival was 63% vs 62% among 3702 infants in the era of the original model (47% female; mean [SD] gestational age, 24.2 [0.8] weeks). In the concurrent (2006-2012) VON cohort, survival was 66% among 45 179 actively treated infants (47% female; mean [SD] gestational age, 24.1 [0.8] weeks) and 70% among 25 969 infants from 2013 to 2016 (48% female; mean [SD] gestational age, 24.1 [0.8] weeks). Model C statistics were 0.74 in the 2006-2012 validation cohort and 0.73 in the 2013-2016 validation cohort. With the use of decision curve analysis to compare the model with a gestational age-only approach to prognostication, the updated model showed a predictive advantage. The birth hospital contributed equally as much to prediction of survival as gestational age (20%) but less than the other factors combined (60%).

Conclusions And Relevance: An updated model using well-known factors to predict survival for extremely preterm infants performed moderately well when applied to large US cohorts. Because survival rates change over time, the model requires periodic updating. The hospital of birth contributed substantially to outcome prediction.
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http://dx.doi.org/10.1001/jamapediatrics.2019.6294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052789PMC
May 2020

Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes.

J Perinatol 2020 04 4;40(4):616-627. Epub 2020 Feb 4.

Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, USA.

Objective: To determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI).

Study Design: Cohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks' postmenstrual age was used to produce adjusted odds ratios (aOR).

Results: Compared with infants in the reference group (22-28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8 and 49 but higher among infants treated at DOL 50-63 (aOR 1.77, 95% CI 1.03-3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44-6.48). The aOR for NDI did not vary significantly by age of PNS exposure.

Conclusion: For infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.
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http://dx.doi.org/10.1038/s41372-020-0594-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101070PMC
April 2020

Behavior Profiles at 2 Years for Children Born Extremely Preterm with Bronchopulmonary Dysplasia.

J Pediatr 2020 04 31;219:152-159.e5. Epub 2020 Jan 31.

Department of Pediatrics, Stanford University, Palo Alto, CA.

Objective: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).

Study Design: We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.

Results: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P < .001) and pervasive developmental problems (P < .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values < .05).

Conclusions: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.
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http://dx.doi.org/10.1016/j.jpeds.2019.12.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096270PMC
April 2020

Hormone levels in preterm and donor human milk before and after Holder pasteurization.

Pediatr Res 2020 10 30;88(4):612-617. Epub 2020 Jan 30.

Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Background: After birth, breastfeeding is the exclusive source of hormonal signaling between mother and infant. Hospitalized infants often receive donor milk when their own mother's milk is unavailable.

Methods: The presence of insulin, leptin, cortisol, progesterone, and testosterone was examined in samples from milk bank donors and mothers of preterm infants. We further investigated the effect of Holder pasteurization (HoP) on hormone levels.

Results: Comparing nonpasteurized samples, leptin levels were nearly threefold higher in milk from mothers of preterm infants versus donated milk, and regardless of milk source, leptin levels were significantly decreased by HoP. Insulin concentrations were also decreased by HoP, and among mothers of preterm infants, obesity was associated with significantly higher content of leptin and insulin. While combined use of donor milk and HoP was associated with cortisol levels nearly threefold higher than those in nonpasteurized own mother's milk, progesterone and testosterone content did not differ by source or pasteurization.

Conclusions: The hormonal composition of breast milk is impacted by HoP and maternal obesity. Compared to nonpasteurized maternal milk, use of pasteurized donor milk dramatically decreases the intake of leptin while increasing the intake of cortisol. Further research is necessary to define optimal breast milk processing practices.
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http://dx.doi.org/10.1038/s41390-020-0789-6DOI Listing
October 2020

Validation of the Postnatal Growth and Retinopathy of Prematurity Screening Criteria.

JAMA Ophthalmol 2020 01;138(1):31-37

Perelman School of Medicine, Scheie Eye Institute, University of Pennsylvania, Philadelphia.

Importance: The first Postnatal Growth and Retinopathy of Prematurity Study (G-ROP-1) developed new screening criteria with 100% sensitivity for type 1 retinopathy of prematurity (ROP) and 30% reduction of infants requiring examinations in a retrospective development cohort of 7483 infants from 29 North American hospitals in 2006-2012. Infants meeting 1 or more of the following criteria undergo examinations: gestational age less than 28 weeks or birth weight less than 1051 g; weight gain less than 120 g during age 10 to 19 days, weight gain less than 180 g during age 20 to 29 days, or weight gain less than 170 g during age 30 to 39 days; or hydrocephalus.

Objective: To evaluate the generalizability of the G-ROP screening criteria in a new cohort of at-risk infants.

Design, Setting, And Participants: This prospective validation cohort study (G-ROP-2) was conducted at 41 hospitals in the United States and Canada (25 G-ROP-1 hospitals and 16 new hospitals) from September 8, 2015, to June 13, 2017, among 3981 premature infants at risk for ROP and with known ROP outcomes.

Main Outcomes And Measures: Sensitivity for Early Treatment for Retinopathy of Prematurity Study type 1 ROP and potential reduction in infants receiving examinations.

Results: Among the 3981 infants in the study (1878 girls and 2103 boys; median gestational age, 28 weeks [range, 22-35 weeks]; median birth weight, 1072 g [range, 350-4080 g]; 1966 white; 942 black; 321 Latino; 120 Asian; 22 Native Hawaian or Pacific Islander; and 25 American Indian or Alaskan Native), the G-ROP criteria correctly predicted 219 of 219 cases of type 1 ROP (sensitivity, 100%; 95% CI, 98.3%-100%), while reducing the number of infants undergoing examinations by 35.6% (n = 1418). In a combined G-ROP-1 and G-ROP-2 cohort of 11 463 infants, the G-ROP criteria predicted 677 of 677 cases of type 1 ROP (sensitivity, 100%; 95% CI, 99.4%-100%), reducing the number of infants receiving examinations by 32.5% (n = 3730), while current criteria (birth weight <1501 g or gestational age ≤30 weeks 0 days) predicted 674 of 677 type 1 cases (sensitivity, 99.6%; 95% CI, 98.7%-99.8%).

Conclusions And Relevance: This study found that the G-ROP screening criteria were generalizable on validation and, if used clinically in the United States and Canada, could reduce the number of infants receiving examinations. The large G-ROP cohorts provide evidence-based screening criteria that have higher sensitivity and higher specificity (fewer infants receiving examinations) for type 1 ROP than currently recommended guidelines.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.4517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865315PMC
January 2020

Long-term outcome of brain structure in female preterm infants: possible associations of liberal versus restrictive red blood cell transfusions.

J Matern Fetal Neonatal Med 2019 Nov 13:1-8. Epub 2019 Nov 13.

Department of Psychiatry, University of Iowa, Iowa City, IA, USA.

Preterm infants who receive differential red blood cell (RBC) transfusions at birth may show brain structure differences across development, including abnormalities in white matter (WM) structure and organization. This study investigated long-term outcomes of brain structure in female infants born preterm, at an average age of 13 years old, who received red blood cell (RBC) transfusions in the neonatal period according to a liberal or restrictive approach. Results from this study will increase understanding of the effects of transfusion on the developing brain. This follow-up study included female preterm infants who participated in a clinical trial and had been randomized at birth to either a liberal or restrictive hematocrit threshold. Brain structures were measured in childhood using structural magnetic resonance imaging (MRI) scans. Due to the low number of females in the restrictive transfusion group at follow-up, additional females were recruited for inclusion. Main outcome measures included cerebral and subcortical brain region volumes. Total intracranial volume was significantly decreased in females who were randomized to higher average hematocrit levels at birth. Infants in the liberal transfusion group had proportionately smaller volumes in all measures of regional cerebral WM and subcortical brain volumes, reaching significance for temporal lobe WM and caudate volumes. Female premature infants who received a liberal transfusion threshold at birth had decreased WM volumes, which suggests the potential long-term neurodevelopmental risks associated with liberal transfusion practices.
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http://dx.doi.org/10.1080/14767058.2019.1683157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269074PMC
November 2019

Outcomes at 18 to 22 Months of Corrected Age for Infants Born at 22 to 25 Weeks of Gestation in a Center Practicing Active Management.

J Pediatr 2020 02 9;217:52-58.e1. Epub 2019 Oct 9.

Division of Neonatology, Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA. Electronic address:

Objective: To assess the outcomes in actively managed extremely preterm infants after admission to a neonatal intensive care unit.

Study Design: Retrospective cohort of 255 infants born at 22-25 weeks of gestation between 2006 and 2015 at a single study institution. Infants were excluded for congenital anomaly, death in delivery room, or parental request for palliation (n = 7). Neurodevelopmental outcomes were analyzed for 169 of 214 survivors (78.9%) at 18-22 months of corrected age. Outcomes were evaluated using the Mann-Whitney U, χ, or Fisher exact test, where appropriate. In addition, cognitive scores of the Bayley Scales of Infant-Toddler Development (3rd edition) were assessed using generalized estimating equations.

Results: Seventy infants born at 22-23 weeks of gestation (22 weeks, n = 20; 23 weeks, n = 50) and 178 infants born at 24-25 weeks of gestation (24 weeks, n = 79; 25 weeks, n = 99 infants) were included. Survival to hospital discharge of those surviving to NICU admission was 78% (55/70; 95% CI, 69%-88%) at 22-23 weeks and 89% (159/178; 95% CI, 84%-93% at 24-25 weeks; P = .02). No or mild neurodevelopmental impairment in surviving infants was 64% (29/45; 95% CI, 50%-77%) at 22-23 weeks and 76% (94/124; 95% CI, 68%-83%; P = .16) at 24-25 weeks.

Conclusions: Although survival was lower in infants born at 22-23 weeks than at 24-25 weeks of gestation, the majority of survivors in both groups had positive outcomes with no or mild neurodevelopmental impairments. Further evaluation of school performance is warranted.
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http://dx.doi.org/10.1016/j.jpeds.2019.08.028DOI Listing
February 2020
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