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1.  Stopping guidelines for an effectiveness trial: what should the protocol specify? 
Trials  2016;17:240.
Despite long-standing problems in decisions to stop clinical trials, stopping guidelines are often vague or unspecified in the trial protocol. Clear, well-conceived guidelines are especially important to assist the data monitoring committees for effectiveness trials.
Main text
To specify better stopping guidelines in the protocol for such trials, the clinical investigators and trial statistician should carefully consider the following kinds of questions:How should the relative importance of the treatment benefits and hazards be assessed?For decisions to stop a trial for benefit:What would be the minimum clinically important difference for the study population?How should the probability that the benefit exceeds that difference be assessed?When should the interim analyses include data from other trials?Would the evidence meet state-of-the-art standards for treatment recommendations and practice guidelines?Should less evidence be required to stop the trial for harm than for benefit?When should conventional stopping guidelines for futility be used for comparative effectiveness trials?
Both clinical and statistical expertise are required to address such challenging questions for effectiveness trials. Their joint consideration by clinical investigators and statisticians is needed to define better stopping guidelines before starting the trial.
PMCID: PMC4862046  PMID: 27165260
Clinical trials; Effectiveness trials; Stopping guidelines; Data monitoring committees; Futility
2.  Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012 
JAMA  2015;314(10):1039-1051.
Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.
To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.
Design, Setting, Participants
Prospective registry of 34,636 infants 22–28 weeks’ gestational age (GA) and 401–1500 gram birthweight born at 26 Network centers, 1993–2012.
Extremely preterm birth.
Main Outcomes
Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were: severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes, adjusting for study center, race/ethnicity, GA, birthweight for GA, and sex.
Use of antenatal corticosteroids increased from 1993 to 2012 (348/1431 [24%] to 1674/1919 [87%], p<0.001), as did cesarean delivery (625/1431 [44%] to 1227/1921 [64%], p<0.001). Delivery room intubation decreased from 1144/1433 (80%) in 1993 to 1253/1922 (65%) in 2012 (p<0.001). After increasing in the 1990s, postnatal steroid use declined to 141/1757 (8%) in 2004 (p<0.001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 120/1666 (7%) in 2002 to 190/1756 (11%) in 2012 (p<0.001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each GA (median GA 26 weeks, 109/296 [37%] to 85/320 [27%], adjusted relative risk [aRR]: 0.93 [95% CI, 0.92–0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants 26–27 weeks (26 weeks, 130/258 [50%] to 164/297 [55%], p<0.001). Survival increased between 2009 and 2012 for infants 23 weeks (41/152 [27%] to 50/150 [33%], aRR: 1.09 [95% CI, 1.05–1.14]) and 24 weeks (156/248 [63%] to 174/269 [65%], aRR: 1.05 [95% CI, 1.03–1.07]), with smaller relative increases for infants 25 and 27 weeks and no change for infants 22, 26 and 28 weeks. Survival without major morbidity increased approximately 2% per year for infants 25–28 weeks with no change for infants 22–24 weeks.
Conclusions and Relevance
Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks and survival without major morbidity increased for infants 25–28 weeks. These findings may be valuable in counselling families and developing novel interventions.
PMCID: PMC4787615  PMID: 26348753
3.  Developmental Outcomes of Very Preterm Infants with Tracheostomies 
The Journal of pediatrics  2014;164(6):1303-1310.e2.
To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.
Study design
Retrospective cohort study from 16 centers of the NICHD Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N=8,683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI, a composite of one or more of: developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed impact of timing, by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.
Tracheostomies were associated with all neonatal morbidities examined, and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without [odds ratio (OR) adjusted for center 7.0 (95%CI, 5.2-9.5)]. After adjustment for potential confounders, odds of death or NDI remained higher [OR 3.3 (95%CI, 2.4-4.6)], but odds of death alone were lower [OR 0.4 (95%CI, 0.3-0.7)], among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life [adjusted OR 0.5 (95%CI, 0.3-0.9)].
Tracheostomy in preterm infants is associated with adverse developmental outcomes, and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.
PMCID: PMC4035374  PMID: 24472229
newborn; very low birth weight infant; neurodevelopmental impairment; tracheotomy; bronchopulmonary dysplasia; prematurity
4.  Immunogenicity of Haemophilus influenzae Type b Protein Conjugate Vaccines in Very Low Birth Weight Infants 
PMCID: PMC3960569  PMID: 24569312
Infant; premature; infant; very low birth weight; Haemophilus influenzae vacines; immunization; vaccines
5.  Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants 
Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500g,VLBW) with and without blood stream infection (BSI) during their birth hospitalization.
Patients and Methods
Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4, and 6 months after birth with blood drawn 4–6 weeks after 3rd dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with birth-weight groups and other confounding factors identified in the primary study.
244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody ≥0.35μg/mL.
BSI was not associated with reduced odds of WHO-defined protective PCV7 responses in VLBWs.
PMCID: PMC3722279  PMID: 23370608
VLBW; immune response; vaccine; sepsis; blood stream infection
6.  Immunogenicity of Trivalent Influenza Vaccine in Extremely-Low-Birth-Weight, Premature versus Term Infants 
Influenza vaccine immunogenicity in premature infants is incompletely characterized.
To assess the immunogenicity of trivalent, inactivated influenza vaccine (TIV) in extremely low-birth-weight (ELBW, ≤1000 grams birth weight), premature (<30 weeks gestation) infants. We hypothesized that geometric mean titers (GMT) of influenza antibody would be lower in premature than in full-term (≥37 week) infants.
In this prospective, multicenter study, former premature and full-term infants ages, 6–17 months, received 2 doses of TIV during the 2006–7 or 2007–8 influenza seasons. Sera were drawn before dose 1 and 4–6 weeks after dose 2. Antibody was measured by hemagglutination inhibition.
Over two years, 41 premature and 42 full-term infants were enrolled; 36 and 33 of these infants, respectively, had post-vaccination titers available. Premature infants weighed less (mean 1.3 – 1.8 kg difference) at the time of immunization than full-term infants. Pre-vaccination titers did not differ between groups. Premature infants had higher post-vaccination antibody GMT than full-term infants to H1 (2006–7, 1:513 v. 1:91, P=0.03; 2007–8, 1:363 v. 1:189, P=0.02) and B/Victoria (2006–7, 1:51 v. 1:10, P=0.02). More premature than full-term infants had antibody titers ≥ 1:32 to B/Victoria (85% v. 60%, p=0.04) in 2007–8. Two (5%) premature and 8 (19%) full-term infants had adverse events, primarily fever, within 72 hours after vaccination. No child had medically-diagnosed influenza.
Former premature infants had antibody responses to two TIV doses greater than or equal to those of full-term children. Two TIV doses are immunogenic and well tolerated in ELBW, premature infants 6–17 months old.
PMCID: PMC3090695  PMID: 21273938
Premature infant; very low birth weight infant; influenza vaccines; immunization; vaccines
The heptavalent pneumococcal-CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (VLBW, ≤1500 grams) infants.
To assess PCV-7 immunogenicity in VLBW, premature infants. We hypothesized that the frequency of post-vaccine antibody concentrations ≥0.15 µg/mL would vary directly with birth weight.
This was a multi-center observational study. Infants 401–1500 grams birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 NICHD Neonatal Research Network centers. Infants received PCV-7 at 2, 4 and 6 months after birth and had blood drawn 4–6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.
Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 ± 2.2 (mean ± standard deviation) weeks gestation and 1008 ± 282 grams birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001–1500 grams birth weight were more likely than those 401–1000 grams to achieve antibody concentrations ≥0.15 µg/mL against the least two immunogenic serotypes (6B: 96% v. 85%, P = 0.003 and 23F: 97% v. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw and Caucasian race were each independently associated with antibody concentrations <0.35 µg/mL against serotypes 6B and/or 23F.
When compared with larger premature infants, infants weighing ≤1000 grams at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.
PMCID: PMC2949965  PMID: 20234331
Infant, premature; infant, very low birth weight; pneumococcal vaccines; immunization; vaccines
9.  Cytokines Associated with Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants 
Pediatrics  2009;123(4):1132-1141.
Inflammation mediated by cytokines may be important in the pathogenesis of bronchopulmonary dysplasia and the competing outcome of death in extremely low birth weight infants.
To develop multi-variable logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at 36w post-menstrual age using clinical and cytokine data from the first 28 days.
1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development had 25 cytokines measured from blood collected within 4 h of birth and on days 3, 7, 14, and 21. Stepwise regression using peak values of the 25 cytokines and 15 clinical variables identified variables associated with BPD/death. Multi-variable logistic regression was done for bronchopulmonary dysplasia/death using variables selected by stepwise regression. Similar analyses were also done using average cytokine values from days 0–21, days 0–3, and from days 14–21.
Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. Combining results from all models, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukins-1β, -6, -8, -10, and interferon-γ and lower concentrations of interleukin-17, RANTES, and tumor necrosis factor-β. Compared to models with only clinical variables, addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude.
The overall pattern of cytokines suggests bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T-lymphocytes.
PMCID: PMC2903210  PMID: 19336372
Logistic models; Infant; premature; Predictive value of tests
10.  Risk Factors for Umbilical Venous Catheter-Associated Thrombosis in Very Low Birth Weight Infants 
Pediatric blood & cancer  2009;52(1):75-79.
Thrombosis in neonates is a rare but serious occurrence, usually associated with central catheterization. The objective of this study was to investigate the risk factors associated with catheter related thrombosis in very low birth weight (VLBW) infants.
The present retrospective study was performed using data from a randomized trial of duration of umbilical venous catheters (UVC) placement among infants <1250 g birth weight. Twenty-two cases of UVC-associated thrombosis were identified in this sample. The remaining study sample (n=188) served as the comparison group. Data on thrombosis, platelets, gestational age, birth weight, hematocrit, serum sodium, maternal preeclampsia, blood group, infant of diabetic mother and demographic factors were collected using database and record review.
Among the total subjects (n=210), 112 (53%) were males and 126 (60%) were Caucasians, with mean gestational age of 27.7 ± 2.1 weeks (standard deviation) and mean birth weight of 923 ± 195 grams. Bivariate analysis revealed significant association of thrombosis with hematocrit >55% in the first week (odds ratio [OR] 5.4; 95% confidence interval [CI] 2.0-14.6; p=0.0003), being small for gestational age (OR, 2.9; 95% CI, 1.2-7.4; p=0.02) and maternal preeclampsia (OR, 3.97; 95% CI, 1.6-9.84; p=0.0017). In multivariate logistic regression analysis, only hematocrit >55% was independently associated with thrombus (OR, 3.7; 95% CI 1.1-11.8; p=0.03).
This study demonstrates a significant, independent association between elevated hematocrit and development of UVC-associated thrombosis. Careful monitoring for catheter-associated thrombosis may be indicated in VLBW infants who have hematocrit >55% in the first week of life.
PMCID: PMC2585148  PMID: 18680150
neonate; thrombosis; risk factors; umbilical venous catheters

Results 1-10 (10)