Abstract
Objective:
To characterize the association between sepsis and postnatal weight growth when accounting for the degree of growth restriction present at birth.
Design:
Retrospective matched cohort study using data from the Postnatal Growth and Retinopathy of Prematurity study. Participants were born with birth weights <1500g or gestational ages <32 weeks between 2006–2011 at 29 neonatal centers in the US and Canada. Sepsis was defined as a culture-confirmed blood, cerebrospinal fluid bacterial or fungal infection before 36 weeks’ postmenstrual age. Growth was assessed as the change in weight z-score between birth and 36 weeks’ postmenstrual age.
Results:
Of 4,785 eligible infants, 813 (17%) developed sepsis and 693 (85%) were matched 1:1 to controls. Sepsis was associated with a greater decline in weight z-score (mean difference −0.09, 95% CI [−0.14, −0.03]). Postnatal weight growth failure (decline in weight z-score >1) was present in 237 (34%) infants with sepsis and 179 (26%) controls (adjusted odds ratio 1.49, 95% CI [1.12, 1.97]). Longitudinal growth trajectories showed similar initial changes in weight z-scores between infants with and without sepsis. By three weeks after sepsis onset, there was a greater decline in weight z-scores relative to birth values in those with sepsis than without sepsis (delta z-score −0.89 vs −0.77; mean difference −0.12, 95% CI −0.18, −0.05). This significant difference persisted until 36 weeks’ or discharge.
Conclusion:
Infants with sepsis had similar early weight growth trajectories as infants without sepsis, but developed significant deficits in weight that were not apparent until several weeks after the onset of sepsis.
Introduction
Very preterm infants are at high risk for multiple neonatal morbidities including sepsis and postnatal growth failure.1–3 Sepsis is a leading cause of mortality among this population.4 Postnatal growth failure is associated with increased risk of later adverse outcomes, including neurodevelopmental impairment in childhood5–8 and cardiovascular disease, diabetes, and obesity in adulthood.9,10
Prior studies demonstrate an association between sepsis and postnatal growth failure among preterm infants.5,11 It is unclear whether this apparent relationship will persist after accounting for the degree of growth restriction present at birth. The temporal association between sepsis and growth is also poorly described. For instance, it is uncertain whether poor prenatal or early postnatal growth are antecedent events that predispose infants to develop sepsis or whether subsequent post-sepsis growth failure occurs. Improved understanding of the determinants of postnatal growth is important to identify infants at high risk for poor growth and to develop strategies and interventions that prevent and treat growth failure.12,13 Better characterization of growth trajectories among infants with and without sepsis, after accounting for intrauterine growth, may inform the nature and timing of such interventions.14
The objectives of this study were to examine the association between sepsis and postnatal weight growth failure in very preterm infants using definitions that account for growth status at birth, and to compare growth trajectory patterns over time between infants with and without sepsis during the birth hospitalization. We hypothesized that infants who develop sepsis will demonstrate worse post-infection weight growth when compared to similar infants without sepsis.
Patients and Methods
Data Source and Study Population
We performed a secondary matched analysis using data from the multicenter Postnatal Growth and Retinopathy of Prematurity (G-ROP) study.15,16 G-ROP enrolled infants at 29 neonatal centers in the US and Canada who underwent eye examinations and had a known outcome for retinopathy. Clinical data including frequent weight measurements were collected at regular intervals from birth. The original study was approved by the institutional review board at the Children’s Hospital of Philadelphia (12–009727).
We analyzed infants born between January 2006 and December 2011, with birth weights <1500g or gestational ages <32 weeks, who survived to 36 weeks’ postmenstrual age (PMA) or were discharged between 34 and 36 weeks’ PMA. All evaluated infants had at least 1 non-birthweight weight entry within 14 days after birth, at least 20 total weights, and a final weight at ≥34 weeks’ PMA. Infants with known chromosomal abnormalities, syndromic diagnoses, or surgical necrotizing enterocolitis were excluded.
Study Exposure and Outcome Definitions
Sepsis was defined as a culture-confirmed blood or cerebrospinal fluid infection from a bacterial or fungal organism before 36 weeks’ PMA. Suspected contaminants, and “culture-negative sepsis” episodes were not considered sepsis events.
We analyzed the outcome of postnatal weight growth relative to growth status at birth in multiple ways.2 First, we assessed change in weight z-score from birth to 36 weeks’ PMA or discharge, if it occurred between 34 and 36 weeks’ PMA, as a continuous variable. Second, we characterized poor postnatal weight growth as a dichotomous outcome using three previously reported cut-offs for growth failure: decrease in weight z-score greater than 1 (i.e. a change in z-score values <−1), 1.5, and 2 from birth to 36 weeks’ PMA or discharge.17 Third, we performed a longitudinal comparison of delta z-score values before and after sepsis onset. Weight z-scores were calculated using sex-specific median and standard deviation (SD) values using Olsen growth curves: (observed weight - expected weight) / SD.18 The expected weight at each PMA was defined as the median birth weight at the corresponding gestational age.18 For example, if a baby was discharged at 34 weeks’ PMA, the discharge weight was compared to the median BW at 34 weeks’ GA.18 Delta z-scores were calculated by subtracting the weight z-score at birth from the z-score at 36 weeks PMA or discharge (if between 34 and 36 weeks’ PMA), consistent with previous reports.17
We assessed for differences in rates of enteral feeding in the week before and after sepsis onset between the two groups. Caloric and volume intake data were not available.
Statistical Analysis
To minimize confounding, infants with sepsis were matched 1:1 to infants without sepsis by sex, completed gestation weeks, birth weight (within 100g), delivery mode, and race/ethnicity. Descriptive statistics and standardized mean differences were calculated to compare characteristics of infants with sepsis and their matched controls.
Univariable and multivariable logistic and linear mixed effects models were used to evaluate the association between sepsis and postnatal growth outcomes. Models included random intercepts for both center-level clustering and case-control matching to adjust for their correlations. Multivariable models were adjusted for birth weight and gestational age as continuous variables because these are known risk factors for growth failure and exact matching was not performed for these covariates. An interaction term between sepsis status and the timing of sepsis onset (first 3 days vs after 3 days) in the infected infant of the matched pair was added to assess for effect modification by the occurrence of “early” vs “late” onset sepsis. A post-hoc analysis compared the risk for decrease in weight z-score >1 between infants with 1 episode of sepsis to those with 2 or more episodes. All analyses that considered the time of sepsis onset used data from the first sepsis episode.
We assessed longitudinal differences in weight growth before and after sepsis onset between the matched groups using locally estimated scatterplot smoothing (LOESS). The day of sepsis diagnosis in the infected infant defined the time point of sepsis onset for each matched pair. As these plots demonstrated non-linear temporal changes in delta z-score values, we compared delta z-scores between the groups at weekly intervals using mean differences and corresponding 95% confidence intervals. We only included days with at least 100 weight data points for each group to enable reasonably unbiased estimates of the mean delta z-scores.
All statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC).
Results
Study Cohort
The G-ROP study evaluated 7,483 infants with a known outcome for retinopathy.16 Among the original cohort, 4,785 infants were eligible for inclusion in this analysis, including 813 (17%) infants who developed sepsis and 3,972 (83%) who did not (Figure 1). Of these, 693 (85%) with a history of sepsis were successfully matched to 693 without sepsis. Significant differences in the measured baseline characteristics between the groups were resolved by matching (Table 1). Among the 693 matched infants with sepsis, 51 had early-onset sepsis and 642 had late-onset sepsis. On average, the first sepsis episode occurred 20.3 (SD 15.3) days after birth, with a range of 0 to 89 days. A total of 124 (18%) infants had more than 1 sepsis episode.
Figure 1:
Patient Flow Diagram
CSF (cerebrospinal fluid); GA (gestational age); PMA (postmenstrual age)
Flow diagram demonstrating patients included in the analysis.
Table 1:
Comparison of Original and Matched Samples
| Original Sample |
Matched Sample* |
|||||
|---|---|---|---|---|---|---|
| Characteristics | With Sepsis (N=813) | Without Sepsis (N=3972) | SMD | With Sepsis (N=693) | Without Sepsis (N=693) | SMD |
| BW (g) - mean (SD) | 847.9(250.5) | 1028.0(263.1) | 0.70 | 859.8(244.9) | 861.9(245.8) | 0.01 |
| BW z-score - mean (SD) | −0.5(1.0) | −0.5(0.9) | 0.00 | −0.5(0.9) | −0.5(0.9) | 0.00 |
| Birth length (cm) - mean(SD) | 33.6(3.5) | 36.0(3.5) | 0.67 | 33.8(3.5) | 34.0(3.4) | 0.06 |
| Birth HC (cm) - mean(SD) | 23.6(2.4) | 25.2(2.3) | 0.68 | 23.7(2.4) | 23.7(2.2) | 0.03 |
| GA (weeks) - mean(SD) | 26.4(2.0) | 28.1(2.1) | 0.80 | 26.5(2.0) | 26.5(2.0) | 0.01 |
| 1 minute APGAR score - mean(SD) | 4.2(2.4) | 5.0(2.5) | 0.32 | 4.3(2.4) | 4.3(2.5) | 0.01 |
| 5 minute APGAR score - mean(SD) | 6.5(2.1) | 7.1(1.9) | 0.28 | 6.6(2.0) | 6.5(2.1) | 0.02 |
| Female sex (%) | 400(49) | 1963(49) | 0.00 | 333(48) | 333(48) | 0.00 |
| Maternal ethnicity Hispanic or Latino (%) | 75(9) | 278(7) | 0.10 | 41(6) | 41(6) | 0.00 |
| Maternal race | 0.19 | 0.00 | ||||
| White/Caucasian (%) | 358(44) | 1949(49) | 326(47) | 326(47) | ||
| Black/African American (%) | 304(37) | 1277(32) | 276(40) | 276(40) | ||
| Others (%) | 151(19) | 746(19) | 91(13) | 91(13) | ||
| Vaginal delivery (%) | 302(37) | 1268(32) | 0.11 | 244(35) | 244(35) | 0.00 |
| Multiple gestation (%) | 196(24) | 1090(27) | 0.08 | 175(25) | 168(24) | 0.02 |
| Gestational diabetes (%) | 44(5) | 295(7) | 0.08 | 31(4) | 41(6) | 0.11 |
| Chorioamnionitis (%) | 120(15) | 516(13) | 0.07 | 103(15) | 129(19) | 0.12 |
| Prenatal steroids (%) | 615(76) | 3162(80) | 0.10 | 525(76) | 550(79) | 0.08 |
BW=birth weight; cm=centimeters; g=grams; GA=gestational age; HC=head circumference; SD=standard deviation; SMD=standardized mean difference. Standardized mean differences are expressed as absolute values.
Among the 1,386 infants in the matched cohort, 1,196 (86%) had a final weight determination at 36 weeks’ PMA and 190 (14%) had a final weight measured between 34 and 36 weeks’ PMA. A similar proportion of infants were discharged between 34 and 36 weeks’ PMA in both groups (13% of infants with sepsis and 15% of infants without sepsis; difference of 2%, 95% CI −1%, 6%).
Sepsis was associated with a greater decline in weight z-score between birth and 36 weeks’ PMA or discharge when considering the outcome as continuous variable, (mean difference −0.09, 95% CI [−0.14, −0.03]) (Table 2). In total, 237 (34%) infants with sepsis versus 179 (26%) without sepsis demonstrated a decline in weight z-score >1 from birth to 36 weeks PMA. In the adjusted analysis, sepsis was associated with a 49% increase in the odds of growth failure defined by this threshold (adjusted odds ratio (aOR) 1.49, 95% CI 1.12, 1.97). The direction and magnitude of the association between sepsis and poor weight growth was similar when growth failure was defined using a decline in z-score >1.5 and >2, although the confidence intervals for the adjusted odds ratios for the >1.5 cutoff narrowly included the point of equivalence (Table 2.)
Table 2:
Univariable and multivariable analysis for association between sepsis and postnatal weight growth
| Outcome | With Sepsis (N = 693) | Without Sepsis (N = 693) | P valuea | With Sepsis Compared to Without Sepsis |
|
|---|---|---|---|---|---|
| Unadjusted Mean Difference (95% CI)b | Adjusted Mean Difference (95% CI)b,c | ||||
| Delta z-scored: Mean (SE) | −0.73 (0.05) | −0.65 (0.05) | −0.09 (−0.14, −0.03) | −0.09 (−0.14, −0.03) | |
| Postnatal growth failure | Unadjusted OR (95% CI)e | Adjusted OR (95% CI)c,e | |||
| ~Decrease in z-score > 1 | 237 (34%) | 179 (26%) | <0.001 | 1.40 (1.09, 1.79) | 1.49 (1.12, 1.97) |
| ~Decrease in z-score > 1.5 | 92 (13%) | 69 (10%) | 0.02 | 1.37 (0.98, 1.93) | 1.41 (0.95, 2.10) |
| ~Decrease in z-score > 2 | 40 (5%) | 24 (4%) | 0.04 | 1.64 (0.97, 2.76) | 1.94 (1.06, 3.57) |
CI=confidence interval; OR=odds ratio; SE=standard error
P-value calculated using McNemar test.
Linear mixed effects model with clinic and matched pairs modelled as random intercepts.
Adjusted for birth weight and gestational age.
Calculated as z-score at 36 weeks’ postmenstrual age or discharge minus the z-score at birth.
Logistic regression model with clinic and matched pairs modelled as random intercepts.
A post-hoc analysis suggested greater risk of growth failure, defined as a decline in weight z-score >1, among infants with 2 or more sepsis episodes (aOR 1.77, 95% CI 1.07, 2.91) than 1 sepsis episode (aOR 1.43, 95% CI 1.06, 1.92). There was no evidence of a significant subgroup effect when stratifying the cohort by the timing of sepsis (early-onset vs late-onset) for any of the study outcomes.
Figure 2 graphs the longitudinal weight growth trajectories before and after the time point of sepsis onset in the two study groups. While both groups demonstrated declines in weight z- scores over time, a more severe decrease in weight gain emerged after sepsis onset in those with sepsis. Comparisons of the delta z-scores at weekly intervals show similar growth patterns between the groups until three weeks after the diagnosis of sepsis, at which point the delta z- score values were significantly lower in the infected group through nine weeks after sepsis onset (Table 3).
Figure 2:
Delta weight z-score comparison between infants with and without sepsis
Comparison of delta weight z-score before, at, and after sepsis episode time point between matched subjects with and without sepsis. The day of the sepsis onset was assigned for each matched pair according to the day of sepsis diagnosis in the infected infant. Only days with at least 100 weight data points for each group are shown and not all data points include matched pairs, as some pairs only had weight data in one group at certain time points. The daily values for the two groups (shown as o and +) represent means of the actual measurements, and the lines for the two groups represents the estimates determined from the locally estimated scatterplot smoothing (LOESS) analysis.
Table 3:
Comparison of delta z-score at weekly intervals between infants with sepsis and matched infants without sepsis
| Paired Subjects with Delta Z-score (N) |
Mean (SD) for Delta Z-score |
||||
|---|---|---|---|---|---|
| Days since sepsis episode time point | With Sepsis (N=693) | Without Sepsis (N=693) | With Sepsis | Without Sepsis | Mean Difference (95% CI) |
| −35 days | 94 | 94 | −0.53 (0.61) | −0.64 (0.62) | 0.11 (−0.02, 0.24) |
| −28 days | 154 | 154 | −0.57 (0.66) | −0.60 (0.61) | 0.03 (−0.07, 0.13) |
| −21 days | 234 | 234 | −0.56 (0.61) | −0.58 (0.59) | 0.02 (−0.05, 0.10) |
| −14 days | 352 | 352 | −0.60 (0.60) | −0.64 (0.57) | 0.03(−0.03, 0.10) |
| −7 days | 516 | 516 | −0.68 (0.60) | −0.65 (0.57) | −0.03 (−0.08, 0.02) |
| 0 days | 614 | 614 | −0.73 (0.59) | −0.67 (0.60) | −0.06 (−0.11, −0.01) |
| 7 days | 594 | 594 | −0.76 (0.63) | −0.73 (0.60) | −0.03 (−0.09, 0.03) |
| 14 days | 569 | 569 | −0.81 (0.64) | −0.76 (0.64) | −0.05 (−0.11, 0.005) |
| 21 days | 550 | 550 | −0.89 (0.68) | −0.77 (0.71) | −0.12 (−0.18, −0.05) |
| 28 days | 492 | 492 | −0.93 (0.68) | −0.79 (0.73) | −0.14 (−0.21, −0.07) |
| 35 days | 426 | 426 | −0.94 (0.74) | −0.81 (0.72) | −0.13 (−0.21, −0.05) |
| 42 days | 371 | 371 | −0.99 (0.77) | −0.81 (0.74) | −0.18 (−0.26, −0.10) |
| 49 days | 286 | 286 | −1.02 (0.79) | −0.84 (0.72) | −0.17 (−0.27, −0.07) |
| 56 days | 206 | 206 | −1.02 (0.77) | −0.85 (0.81) | −0.18 (−0.30, −0.06) |
| 63 days | 138 | 138 | −1.06 (0.73) | −0.89 (0.85) | −0.17 (−0.33, −0.01 |
CI=confidence interval; SD=standard deviation
Only matched infants who both had weight data at the time point were included. Paired t test was used to calculate the 95% CI of mean difference.
Although the G-ROP dataset includes limited information on nutritional intake, review of the available data suggests potentially relevant differences in the rates of enteral feeding before and after sepsis onset in the two study groups. In the week before the diagnosis of sepsis, a similar number of infants were receiving at least some form of enteral nutrition (456 (65.8%) who developed sepsis vs 481 (69%) without sepsis; 4% difference, 95% CI −1.3, 8.5). One week after sepsis onset, 455 (65.7%) infants with sepsis received enteral feedings compared to 587 (85%) without sepsis (19% difference, 95% CI 14.6, 23.5).
Discussion
Prior studies demonstrating an association between sepsis and postnatal weight growth failure infrequently accounted for the presence and severity of growth restriction at birth, which may bias the estimated association between these two postnatal morbidities.5,11 Moreover, the temporal relationship between sepsis and growth failure is not well established. To address these knowledge gaps, we conducted a matched cohort study that examined the association between sepsis and postnatal weight growth trajectories in very preterm infants. We assessed for changes in weight z-scores relative to birth indices to account for each infant’s growth status at the time of delivery. Our results suggest there is a significant, negative relationship between sepsis and postnatal weight growth. Furthermore, a post-hoc analysis indicates a dose-response relationship may exist whereby additional episodes of sepsis predispose infants to higher risk of growth failure. Notably, our examination of longitudinal weight growth patterns between matched infants with and without sepsis showed similar growth in the weeks immediately prior to the time of sepsis diagnosis. However, significant differences in weight growth were apparent by approximately 3 weeks following the onset of sepsis and persisted for at least 2 months after the diagnosis of sepsis.
In a cohort of over 6,000 preterm infants, Stoll et al. found that infection occurring in the newborn period was associated with impaired growth at 36 weeks’ PMA and during early childhood.5 This prior study defined small for gestational age and growth failure using growth cutoffs of less than the 10th percentile and adjusted the analyses for birth weight and gestational age.5 This approach provided important information about the potential association between sepsis and poor weight gain, but it may not fully account for the relationship between intrauterine and extrauterine growth. It is also unclear from these data whether sepsis increases the risk of growth failure and/or whether infants destined to have poor growth are at increased risk of sepsis.2,13 We observed similar early weight growth patterns among infants who developed sepsis and matched controls who did not, but divergent patterns with significantly worse growth in the infected infants after the diagnosis of sepsis. This suggests that sepsis is likely an antecedent event that predisposes to poor subsequent growth.
Understanding growth trajectories in preterm infants is important for setting standards for optimal growth and weight gain, identifying infants at risk for impaired growth due to high-risk morbidities, and monitoring the effects of therapeutic interventions. Longitudinal growth curves of very preterm infants reported by Ehrenkranz et al. showed that infants with major morbidities gained weight more slowly than infants without.11 Our results are congruent, and offer further insight into the association between sepsis and postnatal weight growth.
Our findings also have important clinical implications. Clinicians should be aware that very preterm infants who develop sepsis are at greater risk of poor postnatal weight gain and that in some infants this growth failure may be severe. It is biologically plausible that sepsis interferes with optimal growth. Infections trigger inflammation, increased metabolic demand, and may lead clinicians to reduce patients’ enteral feedings and nutrient intake.19 Strategies to optimize growth among high-risk infants, particularly following sepsis onset, require continued study.20
Our analyses also advance understanding of the complex relationship between sepsis and postnatal weight growth. Visual display of longitudinal growth patterns reveals several key findings. Extrauterine weight gain, when gauged according to intrauterine growth curves, decreased over time among infants who developed sepsis and matched controls who did not. Moreover, weight gain was generally similar between the groups in the weeks immediately prior to and after the time of sepsis diagnosis. However, we do observe a slight but not statistically significant worsening of the growth trajectory 1–2 weeks before sepsis onset followed by a modest uptick in growth 1–2 weeks after the sepsis diagnosis among the infected infants. These subtle changes in growth patterns may represent early signs of emerging physiologic instability followed by a “pseudo- improvement” in growth related to fluid resuscitation and third-spacing of intravascular volume. On average, it was not until three weeks after the diagnosis of sepsis that clear separation in growth between the groups was observed. Collectively, these findings raise concern that initial weight gain after sepsis onset may provide false reassurance and lead to delayed initiation of nutritional interventions until the full extent of the prolonged growth disparity becomes apparent in later weeks. As such, prophylactic administration of additional calories in the days or weeks after sepsis onset may be a fruitful area for future study. Lastly, it appears there may be early signs of catch-up weight gain at the end of the study period in the sepsis group. While these findings are reassuring, prior data suggest that growth failure associated with sepsis may persist into early childhood.5
The strengths of this study include the large and heterogeneous population of very preterm infants. More than 98% of infants had >20 weight measurements, which enabled a robust analysis of weight trajectories that accounted for growth status at birth. Our study does have limitations. All weights were assessed in reference to Olsen curves which define intrauterine, not extrauterine growth standards.21 Longitudinal length and head circumference data were not available nor was detailed information on nutritional or caloric intake. Future studies that collect robust nutrition data will enable an important mechanistic analysis to identify potential causes of our novel findings. We were unable to assess for growth outcomes after the study end point at 36 weeks’ PMA and our study data do not inform how deficits in growth after sepsis may affect long term growth and development. Lastly, as evolution of care over time may affect infant morbidity rates and growth patterns, replication of our findings using more contemporary data may have utility.
Conclusions
We found that sepsis was associated with an increased risk of poor postnatal weight growth in very preterm infants. Notably, infants with sepsis had similar early growth trajectories as infants without sepsis, but developed significant deficits in growth that were not apparent until several weeks after the onset of sepsis. Strategies and interventions to optimize growth among preterm infants with sepsis should be an area of future study.
What is already known on this topic:
Sepsis predisposes preterm infants to significant morbidities including poor growth and development. The temporal relationship between sepsis and postnatal growth, however, is not well established, and prior studies infrequently accounted for growth status at birth.
What this study adds:
Sepsis was associated with an increased risk of poor postnatal weight growth in very preterm infants. Infants with sepsis had similar early weight growth trajectories as those without, but developed significant deficits in growth that were not apparent until several weeks after the onset of sepsis.
Acknowledgements
We acknowledge Matthew Devine, BS (Division of Neonatology, Children’s Hospital of Philadelphia), for assistance with creating a computer macro to calculate z-score for weight based on Olsen growth curves (no compensation was provided; written permission for inclusion in Acknowledgment section was granted). The Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study Group collaborators appear at the end of the article.
Funding:
Dustin Flannery was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health grant T32HD060550, an Agency for Healthcare Research and Quality grant K08HS027468, and by a Pilot Grant from the Children’s Hospital of Philadelphia Office of Faculty Development. Erik Jensen was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health grant K23HL136843. Laura Tomlinson, Yinxi Yu, Gui-shuang Ying, and Gil Binenbaum were supported by the National Eye Institute of the National Institutes of Health grants R01EY021137–01A1 and R21EY029776–01. The funding organizations had no role in the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscripts; or decision to submit the manuscript for publication.
Collaborators: The Postnatal Growth and ROP (G-ROP) Study Group. The G-ROP Study Group investigators include the following: Office of Study Chair: The Children’s Hospital of Philadelphia: Gil Binenbaum, MD, MSCE (Principal Investigator [PI]), Lauren A. Tomlinson, BS (Project Manager), Trang B. Duros, Anh Nguyen. Data Coordinating Center - University of Pennsylvania Perelman School of Medicine: Gui-shuang Ying, PhD (PI), Maureen G. Maguire, PhD, Mary Brightwell-Arnold, BA, SCP, James Shaffer, MS, Yinxi Yu, MS, Maria Blanco BS, Trina Brown BS, Christopher P. Helker, MSPH. Clinical Centers: Emory University School of Medicine (Children’s Healthcare of Atlanta): Amy Hutchinson, MD (PI), Carrie Young, RN. University of Colorado Denver (University of Colorado Hospital, Children’s Hospital Colorado): Emily McCourt, MD (PI), Anne Lynch, MD (Co-I), Jennifer Cathcart, MPH, Ashlee Cerda, MPH, Levi Bonnell, MPH, Tamara Thevarajah, MS. Albany Medical College: Gerard P. Barry, MD (PI), Marilyn Fisher, MD, MS (Co-I), Maria V. Battaglia, BS, MS, Alex M. Drach. BA, Kevin Hughes, BA. Lehigh Valley Hospital: Nachammai Chinnakaruppan, MD (PI), Andrew Meyer, MD (PI), Christina Gogal, BS, CCRC, Cynthia Beitler, BS, MT,BB (ASCP), CCRC, Lauri Centolanza, BS, MT (ASCP), Keith T. Moyer, MS, Mary Sobotor CLA-ASCP, CCRC. Johns Hopkins University (Johns Hopkins Hospital): Pamela Donohue, ScD (PI), Michael X. Repka, MD (Co-I), Jennifer A. Shepard, CRNP, Megan Doherty, NNP. University at Buffalo (Women & Children’s Hospital of Buffalo): James D. Reynolds, MD (PI), Erin Connelly. Medical University of South Carolina: Edward Cheeseman, MD, MBA (PI), Kinsey Shirer, RN, Carol Bradham, COA, CCRC, Allison McAlpine, Sudeep Sunthankar. University of Illinois at Chicago: Javaneh Abbasian, MD (PI), Janet Lim, MD. Cincinnati Children’s Hospital Medical Center (Cincinnati Children’s Hospital Medical Center, Good Samaritan Hospital, and University of Cincinnati Medical Center): Michael Yang, MD (PI), Patricia Cobb, MS, Elizabeth L. Alfano. Nationwide Children’s Hospital (Nationwide Children’s Hospital, Riverside Methodist Hospital, Grant Medical Center, Doctors Hospital): David Rogers, MD (PI), Rachel E. Reem, MD, Amanda Schreckengost, MA, Rae R. Fellows, M.Ed., CCRC, Kaitlyn Loh, Madeline A. McGregor, Thabit Mustafa, Ivy Dean, Rachel Miller, Tess Russell, Rebecca Stattler, Sara Maletic, Theran Jake Selph. Kapi’olani Medical Center for Women and Children: David Young, MD (PI), Andrea Siu, MPH, RAC, Michele Kanemori, George Kingston. University of Texas at Houston (Children’s Memorial Hermann Hospital): Megan Geloneck, MD (PI), Robert Feldman (PI), Ted Baker, Laura Baker, Ephrem Melese, MD. Indiana University (Riley Hospital for Children at Indiana University Health): Kathryn Haider, MD (PI), Jingyun Wang, PhD (PI), Elizabeth Hynes, RNC-NIC, CLC. University of Iowa (University of Iowa Stead Family Children’s Hospital): Edward F. Bell, MD (PI), Alina V. Dumitrescu, MD (Co-I), Jonathan M. Klein, MD (Co-I), Gretchen A. Cress, RN, MPH, Avanthi S. Ajjarapu, Kristine Berge, MSN, Eric Boeshart, Morgan Dorsey, Bethany M. Funk, Grace Hach, Claire L. Johnson, Kevin Kurian, Emily Miller, Angela C. Platt. Queen’s University (Kingston Health Sciences Center): Christine Law, MD (PI), Andrew Gissing. Loma Linda University (Loma Linda University Children’s Hospital): Leila Khazaeni, MD (PI), Jennifer Dunbar, MD (CoI), Kelley Hawkins, Sharon Lee, RN, Lily Sung, Carly Leggitt. University of Louisville (Norton Children’s Hospital): Aparna Ramasubramanian, MD (PI), Rahul Bhola, MD (PI), Michelle Bottorff, COA, CCRC, Neviana Dimova, MD, MS, Rachel Keith, PhD, MSN, NP-C, Laura Thomas RN, BSN, CCRN. University of Minnesota (Masonic Children’s Hospital, formerly University of Minnesota - Amplatz Children’s Hospital): Jill Anderson, MD (PI), Raymond G. Areaux, Jr., MD (Co-I), Ann Marie Holleschau, BA, CCRP, Jordan Gross, Andrea Kramer. Vanderbilt Eye Institute and Vanderbilt University Medical Center: (Monroe Carell Jr. Children’s Hospital at Vanderbilt): David Morrison, MD (PI), Sean Donahue, MD, PhD (Co-I), Carsyn Saige Wilkins, Neva Fukuda, CO, Sandy Owings, COA, CCRP, Scott Ruark. University of Oklahoma (The Children’s Hospital at OU Medical Center / The University of Oklahoma Health Sciences Center): R. Michael Siatkowski, MD (PI), Faizah Bhatti, MD (Co-I), Vanessa Bergman, COT, CCRC, Karen Corff, APRN, NNP, Kari Harkey, RNC-NIC, Amy Manfredo, APRN-CNP, Ashley Helmbrecht, DNP, APRN-CNP, Shrenik Talsania, MBBS, MPH, CPH, Terri Whisenhunt, MS, RN. University of Nebraska (Nebraska Medicine): Donny Suh, MD, FAAP (PI), Ann Anderson Berry, MD, PhD (Co-I), Denise Lynes APRN-CNS, MSN, Kelly C. Erikson, MPH. The Children’s Hospital of Philadelphia (The Children’s Hospital of Philadelphia, Hospital of the University of Pennsylvania, Pennsylvania Hospital): Gil Binenbaum, MD, MSCE (PI), Soraya Abbasi, MD (PI), Haresh Kirpalani, MD, MSc, Graham E. Quinn MD, MSCE, Lindsay Dawson, MD, Lauren A. Tomlinson, BS. University of Pittsburgh (Children’s Hospital of Pittsburgh, Magee Women Hospital of UPMC): Christin Sylvester, MD (PI), Kanwal Nischal, MD (PI), Lauren Runkel, MA. Rhode Island Hospital (Women and Infants Hospital of Rhode Island): Wendy S. Chen, MD, PhD (PI), Deidrya Jackson. Saint Louis University (Cardinal Glennon Children’s Hospital): Bradley Davitt, MD (PI), Dawn Govreau, COT, Linda Breuer, LPN, September Noonan, RN. University of Utah (Primary Children’s Hospital and University of Utah Hospital): Robert Hoffman, MD (PI), Joanna Beachy, MD, PhD, Kelliann Farnsworth, COT, Katie Jo Farnsworth, CRC, Deborah Harrison, MS, Ashlie Bernhisel, Bonnie Carlstrom. University of California San Francisco (UCSF Benioff Children’s Hospital and Zuckerberg San Francisco General Hospital, formerly San Francisco General Hospital): Alejandra G. de Alba Campomanes, MD, MPH (PI), Yizhuo Bastea-Forte, Lucia Rivera Sanchez, Jacquelyn Kemmer, Alexandra Neiman, Sarah Sitati-Ng’Anda MD. Seattle Children’s Hospital (Seattle Children’s Hospital, University of Washington Medical Center): Kristina Tarczy-Hornoch, MD, D.Phil, (PI), Francine Baran, MD (PI), Lauren Eaton. The Hospital for Sick Children (Sick Kids), Toronto: Nasrin Najm-Tehrani, MB BCh, MSc, FRCS Ed (Ophth), FRCSC (PI), Tanya Grossi, Maram Isaac, Robin Knighton. Los Angeles Biomedical Research Institute (Harbor-UCLA Medical Center): Monica Ralli Khitri, MD (PI), Madeline Del Signore, RN. Crozer-Chester Medical Center (Crozer Chester Medical Center, Delaware County Memorial Hospital): Cynthia Dembofsky, MD (PI), Andrew Meyer, MD (PI), Karen Flaherty, Tracey Harris, Jamie Heeneke. Nemours/Alfred I. duPont Hospital for Children: Dorothy Hendricks, MD (PI), Christopher M. Fecarotta, MD (PI), Alicia Olivant Fisher, MS, Mark Paullin, MS. Cost- Effectiveness Component: Beth Israel Deaconess Medical Center: John Zupancic, MD, MS, ScD (PI). Executive Committee: Alejandra de Alba Campomanes, MD MPH, Edward F. Bell, MD, Gil Binenbaum, MD, MSCE, Pamela Donohue, ScD, Maureen Maguire, PhD, David Morrison, MD, Graham E. Quinn, MD, MSCE, Michael X. Repka, MD, David L. Rogers, MD, Lauren A. Tomlinson BS, Michael Yang, MD, Gui-shuang Ying, PhD.
Footnotes
Competing Interests: None declared.
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
Clinical Trial Registration (if any): N/A
References
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