Original Article
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life: Risk Assessment Jane B. Taylor, MD1,2 Mitzi A. Go, MD2 Michael F. Nyp, DO1 Jennifer Legino, BS2 Michael Norberg, MDiv1 Hongying Dai, PhD1,3 William E. Truog, MD1 1 Department of Pediatrics, University of Missouri-Kansas City School
of Medicine, Kansas City, Missouri 2 Department of Pediatrics, University of Kansas School of Medicine at the University of Kansas Medical Center, Kansas City, Kansas 3 Department of Research Development and Clinical Investigation, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri
Address for correspondence Jane B. Taylor, MD, Pediatric Pulmonology Office, 2401 Gillham Rd., Kansas City, MO, 64108 (e-mail: [email protected]).
Abstract
Keywords
► prematurity ► rehospitalization ► bronchopulmonary dysplasia ► dysphagia ► respiratory infection ► pulmonary hypertension
Objective This study aims to determine risk factors for rehospitalization in extremely premature infants. Study Design A retrospective cohort study of 157 infants born < 29 weeks’ gestational age assessing risk factors for rehospitalization through 2 years of life. Results Multivariable logistic regression showed that an increasing number of respiratory infections (odds ratio [OR]: 1.8 [1.1–3.1] per infection p ¼ 0.03) and inhaled steroid use at 1 year (OR: 4.0 [1.3–12.1] p ¼ 0.01) were predictive of hospital readmission. Diuretic (OR: 27 [1.01–1,000] p ¼ 0.04) and oxygen (OR: 32 [3.1–333] p ¼ 0.004) use at 1 year were predictive of pediatric intensive care unit admission. The number of respiratory infections (OR: 2.8 [1.7–4.5] p < 0.0001) with reflux/aspiration necessitating G-tube/Nissen fundoplication surgical intervention with or without G-tubes alone (OR: 21.3 [2.9–166.7] p ¼ 0.02 and OR: 22.7 [CI, 2.4–200] p ¼ 0.04) was predictive of increased number of rehospitalizations. Conclusions Key modifiable risk factors identified were reflux/aspiration and ongoing respiratory infections. Critical time periods for diuretic, oxygen, and inhaled steroid use in this population occurred at the age of 1 year.
Management for extremely premature infants (born < 29 weeks’ gestational age [GA]) after neonatal intensive care unit (NICU) discharge is variable and lacks national guidelines1–3 with little research to determine risk factors for rehospitalization in a population that has an estimated rehospitalization rate of over 70% with common respiratory infections.4,5 In the United States, one in eight children is born prematurely and more than 90% of infants born > 24 weeks’ GA are surviving.6 Lung disease secondary to prematurity, which is not always associated with the relative severity of an
infant’s bronchopulmonary dysplasia (BPD) determined at 36 weeks’ GA or the extent of respiratory support needed in the NICU, can deteriorate over time.7 Respiratory complications in premature infants are common, and increasing subsequent viral infections in the first year of life have been shown to significantly increase pulmonary morbidity in premature infants8 with many initial viral respiratory infections undetected before NICU discharge.9 Multiple concurrent viral coinfections in childhood also increase health care utilization in children.10
received March 12, 2015 accepted after revision May 7, 2015
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1555123. ISSN 0735-1631.
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Am J Perinatol
The initial impact of prematurity on the US economy is approximately $26.2 billion per year ($51,600 per infant).11,12 However, this figure does not take into account the health care utilization that occurs subsequent to NICU discharge. It is critical to remember that premature infants’ lung physiology does not fully normalize over time. Recent studies, in which serial infant pulmonary function tests were performed, did not provide evidence for any significant “catch up” of lung growth in premature infants during the first year of life.13,14 Studies in teenagers/adults with extreme prematurity at birth showed persistent abnormalities in lung function as evidenced by increased air trapping, increased residual volume, increased incidence of airway hyper-reactivity, and a faster decline in lung function in adulthood.14–19 These problems, in turn, lead to increased morbidity and the need for increased medical utilization well past childhood and ultimately over a lifetime.7,20 We hypothesize that identification of clinical events in the patient’s NICU course and shortly afterward can predict risk for early rehospitalization and increased pulmonary morbidity over time.8,11 Identifying these risk factors will allow for development of more precise management protocols, necessary for continued cost-effective management of this rapidly growing patient population.
Methods Center for Infant Pulmonary Disorders (CIPD) Data Repository: The Infant Pulmonary Disorders Data Repository (IPDR) is located at Children’s Mercy Hospitals and Clinics, Kansas City, MO (CMH). It provided deidentified data for this study according to the process approved by the Institutional Review Board at CMH. Participants are included in the database upon admission to the NICU and followed over the first 6 years of life, or until death or loss to follow-up (LFU). There were a total of 184 infants born < 29 weeks’ gestation. Study inclusion criteria were as follows: (1) Infants in the IPDR born less than 29 weeks’ gestation who were (2) admitted to CMH less than 24 hours of life who (3) did not have any major structural anomalies of a major organ system (i.e., congenital heart disease, diaphragmatic hernia, and giant omphalocele). A total of 157 of the 184 infants in the IPDR met the inclusion criteria. The data set from 2008 through 2010 was compared and found to be similar to the national neonatal research network data set.21,22
Study Design A retrospective cohort design was used to evaluate clinical factors during NICU admission and in the first 2 years of life to assess for risk factors for rehospitalization, and the severity of rehospitalization, in extremely premature infants through their second birthday. Variables The clinical variables selected as potential risk factors included the categorical variables of the following: (1) BPD status: based on criteria outlined by Ehrenkranz et al23; (2) breast milk ingestion: any breast milk intake at NICU discharge, 6 months, 1 year, and 2 years of age; (3) transient pulmonary hypertension (PHTN): echocardiographic eviAmerican Journal of Perinatology
Taylor et al.
dence of PHTN, medication use for PHTN that stopped before NICU discharge; (4) persistent pulmonary hypertension: echocardiographic evidence of PHTN, medication use for PHTN that continued after NICU discharge; (5) post NICU pulmonary hypertension: echocardiographic evidence of PHTN, medication use for PHTN that occurred after NICU discharge; (6) transient adrenal insufficiency: signs/symptoms of hypocortisolism-persistent hypotension > 48 hours despite presser support during a time of infection/stress, persistent hypoglycemia > 48 hours, failed ACTH stimulation test which required hydrocortisone therapy in the NICU; (7) presence of persistent adrenal insufficiency: signs/symptoms of hypocortisolism-persistent hypotension > 48 hours despite presser support during a time of infection/stress, persistent hypoglycemia > 48 hours, failed ACTH stimulation test which required hydrocortisone therapy past NICU discharge; (8) tobacco exposure in the home; (9) reflux: diagnosed by an upper gastrointestinal study, pH probe or pediatric gastrointestinal subspecialist, pH probe or pediatric gastrointestinal subspecialist, (10) steroid use in the NICU (systemic or inhaled), (11) gender, (12) diuretic, inhaled steroid or oxygen use at the time of NICU discharge, 6 month, 1 year, and 2 years of age; and (13) swallowing dysfunction with dysphagia and aspiration: diagnosed by abnormal swallow study, occupational therapy/speech evaluation by a speech pathologist that specializes in swallowing dysfunction, or clinical course that resulted in a nasogastric tube (NG tube) being placed for > 1 month or placement of a gastrointestinal tube (G-tube) with/without a Nissen fundoplication stomach wrap procedure to reduce reflux. The continuous variables evaluated were as follows: (1) birth weight; (2) increasing number of respiratory infections: increased nasal secretions/cough/pulmonary secretions supporting lab work (chest radiograph [CXR], respiratory viral polymerase chain reaction [PCR], complete blood count [CBC] with differential) that led to worsening respiratory status as determined by increased respiratory rate, increased oxygen requirement, and increased suctioning. The outcome variables included hospital readmission, number of hospital readmissions, and severity of hospital admissions (general pediatric floor vs. intensive care unit). All variables of interest were determined through extensive medical record reviews of each participant’s NICU discharge summaries, NICU procedure notes, radiology records, emergency room (ER) notes, Special Care Clinic (NICU long-term follow-up) notes, subspecialty clinic notes, and laboratory results. Study Population We included all infants enrolled in the CIPD Data Repository that met the above inclusion criteria from January 1, 2008, through December 31, 2010, and followed them through their second birthday (through December 31, 2012). We excluded infants who died < 36 weeks’ corrected GA and excluded tracheostomy and ventilator-dependent infants (of which there was 1).
Data Analysis For our statistical analysis, we used the SAS programming version 9.2 software package (SAS Institute, Inc, Cary, NC) and
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Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 1 Comparison of CIPD data repository with a national database: patient demographic information n
BW (g) mean SD
GA (wk) mean SD
Male (%)
Hispanic (%)
Black (%)
Antenatal steroids (%)
National
3,629
897 203
26.7 1.9
51.1
17.4
39.9
66
Local
158
906 235.3
26.1 1.6
63.5
8.8
41.5
64
SPSS 20 (IBM Corporation, Armonk, NY). We calculated summary statistics (mean, standard deviation, median, interquartile range, and percentage) for demographics and performed univariate analysis for risk factor variables and outcome variables among subjects with rehospitalization and subjects without rehospitalization for the CIPD cohort born between 2008 and 2010. We compared subjects between these two groups using the t-test, chi-square test, and Fisher exact test. We further analyzed subjects in the rehospitalization group by looking at those infants receiving intensive care unit (ICU) and those requiring multiple hospitalizations. Finally, we performed multivariate logistic regression to detect the presence of possible associations between our selected clinical variables (BPD, inhaled steroid use, dysphagia, etc.) and susceptibility for rehospitalization. The odds ratio (OR) and 95% confidence interval for OR were determined for each risk factor. Multivariate logistic regression models using step-wise model selection created predictive models for rehospitalization and pediatric intensive care unit (PICU) hospitalization. An ordinal logistic regression model using backward selection was used to create a multivariate predictive model for the number of hospital readmissions. Performance of the predictive model was assessed by the cstatistic, percentage of concordance, and cross validation.
Results Basic demographic information on gender, GA, and birth weight was collected on each infant in the CIPD cohort. Comparison to a large national NICU data set (►Table 1) revealed similar demographics and outcomes.21,22 Of the 184 live-born premature infants in the CIPD Data Repository, 158 infants were initially identified meeting study inclusion criteria for consideration in this study. The one patient who was trach/vent dependent was excluded after major airway anomalies were identified, leaving a total of 157 infants. Overall, 15 infants died < 36 weeks corrected GA, leaving a total of 142 infants at the time of NICU discharge. Overall, 39 infants were LFU by their second birthday, and 7 infants died before their second birthday (see ►Fig. 1). There were 96 infants followed through 2 years of age. Overall, 60 infants were readmitted to the hospital after NICU discharge (42%, 60/142). Of these patients, 26 were readmitted to the hospital on multiple occasions (18%, 26/142) and 15 (10%, 15/142) were admitted to the PICU with a mean PICU admission age of 13 months. In the LFU group, 11 infants had been hospitalized before being LFU (28%, 11/39). In the 2-year cohort, 44 infants had been hospitalized (45%, 44/96). In the cohort of infants
who died after NICU discharge, five infants had been rehospitalized (71%, 5/7). Univariate analysis was performed on the selected clinical variables during NICU admission and after NICU discharge to determine the risk factors for rehospitalization in this patient population (►Table 2). The significant variables were dysphagia (OR, 3.8; p ¼ 0.0002), PHTN in the NICU (OR, 2.3; p ¼ 0.004), PHTN post NICU (OR,1.49; p ¼ 0.02), transient adrenal insufficiency (OR, 2.3; p ¼ 0.004), chronic adrenal insufficiency (OR, 6.1; p ¼ 0.02), systemic steroid use in the NICU (OR, 4.3; p ¼ 0.0008), inhaled steroid (iSter) use at 6 months, 1 year, and 2 years (OR: 14.7; p ¼ 0.002, OR: 4.1; p ¼ 0.002, and OR: 4.3; p ¼ 0.001), birth weight (OR, two for each decrease of 2 g in weight; p ¼ 0.03), subsequent number of respiratory infections (OR, 2.1 for each subsequent infection; p ¼ 0.0003), and oxygen use at 1 year of age (OR, 5.8; p ¼ 0.002). Breast milk at NICU discharge had a protective effect (OR, 0.3; p ¼ 0.007). Tobacco exposure, diuretic use (at any time point), and BPD were not significant risk factors for readmission. The Bonferroni adjusted p value was calculated (p value number of variables [27]) to conservatively exclude potential false-positives and the significant variables that remained were dysphagia (p ¼ 0.005), oxygen use at 1 year (p ¼ 0.05), steroid use in the NICU (p ¼ 0.02),
184 Infants in the CIPD Registry
157 Infants Met Inclusion Criteria 15 infants died
142 Infants Discharged from the NICU 7 infants died 23 infants LFU
112 Infants at 1 years of age 0 infants died 16 infants LFU
96 Infants at 2 years of age Fig. 1 Patient flow diagram over the 2-year study period. LFU, lost to follow-up. American Journal of Perinatology
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Abbreviations: CIPD, Center for Infant Pulmonary Disorders; GA, gestational age; SD, standard deviation.
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 2 Univariate analysis comparing risk factors and rehospitalization rates in infants enrolled in the CIPD Data Repository from January 1, 2008 through December 31, 2010 who were clinically followed for their first 2 years of life (through December 31, 2012)
Tobacco exposure (n ¼ 157)
OR
p Value
36 (36)
64 (64)
0.77 (0.40–1.51)
0.45
Female
24 (42.1)
33 (57.9)
Yes
4 (22.2)
14 (77.8)
0.42 (0.13–1.35)
0.2
No
56 (40.3)
83 (59.7) 3.85(1.86–7.99)
0.0002
2.35 (1.04–5.32)
0.04
Infty (1.49–Infty)
0.02
0.30 (0.12–0.74)
0.007
0.28 (0.06–1.39)
0.18
0 (0–4.44)
0.5
1.75 (0.74–4.12)
0.2
1.61 (0.64–4.06)
0.31
5.48 (0.59–50.64)
0.17
1.82 (0.92–3.58)
0.08
1.87 (0.91–3.86)
0.09
5.83 (1.78–19.09)
0.002
Infty (2.29–Infty)
0.004
4.39 (1.76–10.99)
0.0008
4.0 (1.31–12.16)
0.01
2.82 (0.50–15.94)
0.4
14.78 (1.83–119.45)
0.002
0.05
4.07 (1.65–10.05)
0.002
0.05
4.36 (1.77–10.76)
0.001
0.03
Male
Dysphagia/abnormal OPM (n ¼ 157)
Yes
27(61.4)
17 (38.6)
No
33 (29.2)
80 (70.8)
NICU PHTN (n ¼ 157)
Yes
16 (55.2)
13 (44.8)
No
44 (34.4)
84 (65.6)
PHTN post D/C (n ¼ 157) BM at NICU D/C (n ¼ 141) BM at 6 mo (n ¼ 125) BM at 1 y (n ¼ 114) D at NICU D/C (n ¼ 141) D at 6 mo (n ¼ 125) D at 1 y (n ¼ 114) O2 at NICU D/C (n ¼ 141) O2 at 6 mo (n ¼ 125) O2 at 1 y (n ¼ 114) O2 at 2 y (n ¼ 95) Steroid in NICU (n ¼ 157) iSter in NICU (n ¼ 154) iSter at NICU D/C (n ¼ 141) iSter at 6 mo (n ¼ 125) iSter at 1 y (n ¼ 114) iSter at 2 y (n ¼ 96)
American Journal of Perinatology
p Value
Readmit ¼ No, n (%)
Yes
4 (100)
0 (0)
No
56 (36.6)
97 (63.4)
Yes
7 (21.9)
25 (78.1)
No
53 (48.6)
56 (51.4)
Yes
2 (20)
8 (80)
No
54 (47.0)
61 (63.0)
Yes
0 (0)
2 (100)
No
50 (44.6)
62 (55.4)
Yes
14 (53.9)
12 (46.2)
No
46 (40)
69 (60)
Yes
12 (54.4)
10 (45.5)
No
44 (42.7)
59 (57.3)
Yes
4 (80)
1 (20)
No
46 (42.2)
63 (57.8)
Yes
31 (50.8)
30 (49.2)
No
29 (36.3)
51 (63.7)
Yes
28 (53.9)
24 (46.1)
No
28 (38.4)
45 (61.6)
Yes
14 (77.8)
4 (22.2)
No
36 (37.50)
60 (62.5)
Yes
7 (100)
0 (0)
No
38 (43.2)
50 (56.8)
Yes
17 (68)
8 (32)
No
43 (32.6)
89 (67.4)
Yes
11 (68.8)
5 (31.2)
No
49 (35.5)
89 (64.5)
Yes
4 (66.7)
2 (33.3)
No
56 (41.5)
79 (58.5)
Yes
10 (90.9)
1 (9.1)
No
46 (40.4)
68 (59.7)
Yes
20 (69.0)
9 (31.0)
No
30 (35.3)
55 (64.7)
Yes
24 (70.6)
10 (29.4)
No
22 (35.5)
40 (64.5)
0.005
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Gender (n ¼ 157)
a
Readmit ¼ Yes, n (%)
Exposure
0.05
0.02
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 2 (Continued) Readmit ¼ No, n (%)
OR
p Value
Transient AI (n ¼ 154)
Yes
15 (53.6)
13 (46.4)
2.34 (1.01–5.39)
0.04
Chronic AI (n ¼ 154)
No
39 (33.1)
79 (66.9)
Yes
6 (75)
2 (25)
6.08 (1.17–31.50)
0.02
No
39 (33.1)
79 (66.9)
Number of resp infections (n ¼ 144)
No
17 (26.6)
47 (73.4)
0.0003
1
21 (40.4)
31 (59.6)
2.09 (1.4–3.12) for each infection
2
11 (58.0)
8 (42.1)
3
5 (100)
0 (0)
BPD severity (n ¼ 157)
1.37 (0.99–1.91)
0.059
GA (n ¼ 157)
0.84 (0.68–1.03)
0.1
Change in birth weight (g) (n ¼ 157%)
0.998 (0.997–1.0) per for each g of wt change
0.03
4
3 (75)
1 (25)
No
10 (35.7)
18 (64.3)
Mild
12 (31.6)
26 (68.4)
Moderate
21 (46.7)
24 (53.3)
Severe
17 (54.8)
14 (45.2)
22
1 (100)
0 (0)
23
5 (50)
5 (50)
24
8 (44.4)
10 (55.6)
25
8 (38.1)
13 (61.9)
26
12 (46.2)
14 (53.8)
27
15 (33.3)
30 (66.7)
28
11 (30.6)
25 (69.4)
1g
a
p Value
0.008
Abbreviations: AI, adrenal insufficiency; BM, breast milk; BPD, bronchopulmonary dysplasia; CIPD, Center for Infant Pulmonary Disorders; D, diuretics; GA, gestational age; iSter, inhaled steroids; NICU, neonatal intensive care unit; O2, oxygen; OPM, oral pharyngeal motility study; PHTN, pulmonary hypertension. Note: p values for both original chi-square analysis and Bonferroni adjusted p values are reported. a Bonferroni adjusted p values.
inhaled steroid use at 6 months (p ¼ 0.05), 1 year (p ¼ 0.05), and 2 years (p ¼ 0.03) and number of respiratory infections (p ¼ 0.008). Univariate analysis was then performed on the selected variables to determine if any were risk factors for rehospitalization to the PICU. Significant variables were a history of pulmonary HTN in the NICU (OR, 3.83; p ¼ 0.04), oxygen use at 1 year of life (OR, 7.5; p ¼ 0.008), oxygen use at 2 years of life (OR, 8.27; p ¼ 0.03), and increasing number of respiratory infections with significance occurring with more than three infections in the first year of life (OR, 2.04; p ¼ 0.02) (►Table 3). Three logistic regression models were then created for the outcome variables of (1) rehospitalization, (2) PICU hospitalization, and (3) number of rehospitalizations (►Table 4). The first two variables were categorical, so a multivariable model using logistic regression with step-wise model selection was performed using the aforementioned variables for the first two models. The issue of collinearity between variables was approached by using the step-wise modeling approach and calculating the variance inflation factor (VIF) for each variable and using factors for the step-wise model that had a VIF of two
or less. The third model for the number of rehospitalizations used an ordinal logistic regression model using a backward model selection with the aforementioned variables. The issue of collinearity between variables was approached by using the backward modeling approach and only using variables with a VIF of two or less. For model 1, both number of respiratory infections (OR, 1.8; p ¼ 0.03) and inhaled steroid use at 1 year of age (OR, 4.0; p ¼ 0.01) were predictive for hospital readmission. For model 2, both diuretic (OR, 27; p ¼ 0.04) and oxygen use (OR, 32; p ¼ 0.004) at 1 year of age were predictive for PICU admission. The third model showed that an increasing number of respiratory infections (OR, 2.8; p < 0.0001) and a history of reflux and feeding problems as determined by surgical intervention with a Nissen fundoplication G-tube insertion (OR, 21; p ¼ 0.02 and OR, 23; p ¼ 0.04) were predictive of multiple rehospitalizations.
Discussion This study looked at clinical factors during NICU admission and shortly afterward as potential risk factors for American Journal of Perinatology
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Readmit ¼ Yes, n (%)
Exposure
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Exposure
Readmit ICU ¼ Yes, n (%)
Readmit ICU ¼ No, n (%)
Readmit ICU
p Value
7 (20)
28 (80)
0.47 (0.14–1.54)
0.21
0.95 (0.09–9.92)
1
1.44 (0.44–4.7)
0.54
3.83 (1.07–13.66)
0.04
10.5 (1–11.36)
0.049
0.54 (0.06–5.06)
1
2.71 (0.16–46.4)
0.48
1.89 (0.51–6.94)
0.48
3.67 (0.95–14.15)
0.07
3.89 (0.48–31.52)
0.22
1.73 (0.52–5.69)
0.55
2.88 (0.82–10.02)
0.09
7.5 (1.71–32.9)
0.008
8.27 (1.4–48.53)
0.03
0.94 (0.25–3.53)
1
0.58 (0.11–3.06)
0.71
0.95 (0.09–9.92)
1
1.14 (0.25–5.16)
1
2.22 (0.57–8.68)
0.3
2.12 (0.46–9.84)
0.46
0.88 (0.20–3.86)
1
Gender (N ¼ 58)
Male Female
8 (34.8)
15 (65.2)
Tobacco exposure (N ¼ 58)
Yes
1 (25)
3 (75)
No
14 (25.9)
40 (34.1)
Yes
8 (29.6)
19 (70.1)
No
7 (22.6)
24 (77.4)
Yes
7 (46.7)
8 (53.3)
No
8 (18.6)
35 (81.4)
Dysphagia/abnormal OPM (N ¼ 58) NICU PHTN (N ¼ 58) PHTN post D/C (N ¼ 58) BM at NICU D/C (N ¼ 58) BM at 6 mo (N ¼ 54) D at NICU D/C (N ¼ 58) D at 6 mo (N ¼ 54) D at 1 y (N ¼ 48) O2 at NICU D/C (N ¼ 58) O2 at 6 mo (N ¼54) O2 at 1 y (N ¼ 48) O2 at 2 y (N ¼ 43) Steroid in NICU (N ¼ 58) iSter in NICU (N ¼ 58) iSter at NICU D/C (N ¼ 58) iSter at 6 mo (N ¼ 54) iSter at 1 y (N ¼ 48) iSter at 2 y (N ¼ 44) Transient AI (N ¼ 52)
American Journal of Perinatology
Yes
3 (75)
1 (25)
No
12 (22.2)
42 (77.8)
Yes
1 (16.67)
5 (88.3)
No
14 (26.9)
38 (73.1)
Yes
1 (50)
1 (50)
No
14 (26.9)
38 (73.1)
Yes
5 (35.7)
9 (64.3)
No
10 (22.7)
33 (77.3)
Yes
6 (50)
6 (50)
No
9 (21.4)
33 (78.6)
Yes
2 (50)
2 (50)
No
9 (20.5)
35 (79.5)
Yes
9 (31)
20 (69)
No
6 (20.7)
23 (79.3)
Yes
10 (38.5)
16 (61.5)
No
5 (17.9)
23 (82.1)
Yes
7 (50)
7 (50)
No
4 (11.8)
30 (88.2)
Yes
4 (57.1)
3 (42.9)
No
5 (13.9)
31 (86.1)
Yes
4 (25)
12 (75)
No
11 (26.2)
31 (73.8)
Yes
2 (18.2)
9 (81.8)
No
13 (27.7)
34 (72.3)
Yes
1 (25)
3 (75)
No
14 (25.9)
40 (74.1)
Yes
3 (30)
7 (70)
No
12 (27.3)
32 (72.7)
Yes
6 (31.6)
13 (68.4)
No
5 (17.2)
24 (82.8)
Yes
6 (26.1)
17 (73.9)
No
3 (14.3)
18 (85.7)
Yes
3 (21.4)
11 (78.6)
No
9 (23.7)
29 (76.3)
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Table 3 Univariate subgroup analysis of risk factors for PICU hospitalization in infants enrolled in the CIPD Data Repository from January 1, 2008 through December 31, 2010 who were clinically followed for their first 2 years of lifea
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Exposure
Readmit ICU ¼ Yes, n (%)
Readmit ICU ¼ No, n (%)
Readmit ICU
p Value
3.22 (0.55–18.85)
0.32
2.04 (1.35–3.09)
0.02
1.43 (0.79–2.60)
0.24
0.87 (0.61–1.24)
0.45
Chronic AI (N ¼ 44)
Yes
3 (50)
3 (50)
No
9 (23.7)
29 (76.3)
Number of resp infections (N ¼ 55)
0–2
9 (19.1)
38 (80.9)
3þ
5 (62.5)
3 (37.5)
No
1 (10)
9 (90)
BPD severity (N ¼ 58)
GA (N ¼ 58)
Mild
3 (25)
9 (75)
Moderate
6 (30)
14 (70)
Severe
5 (31.3)
11 (68.8)
22
0 (0)
1 (100)
23
3 (60)
2 (40)
24
1 (12.5)
7 (87.5)
25
4 (50)
4 (50)
26
2 (18.2)
9 (81.9)
27
1 (7.1)
13 (92.9)
28
4 (36.4)
7 (63.6)
Abbreviations: AI, adrenal insufficiency; BM, breast milk; BPD, bronchopulmonary dysplasia; CIPD, Center for Infant Pulmonary Disorders; D, diuretics; iSter, inhaled steroids; GA, gestational age; iSter, inhaled steroids; O2, oxygen; OPM, oral pharyngeal motility study; PHTN, pulmonary hypertension; PICU, pediatric intensive care unit. a Through December 31, 2012.
rehospitalization, PICU admission, and recurrent rehospitalizations in a cohort of extremely premature infants (< 29 weeks’ GA) over the first 2 years of life. Recent literature has shown that there are over 100,000 hospitalizations a year in the United States for term infants in the perinatal period.24 Late preterm infants (GA between 34 and 36 weeks) may be at a threefold risk for rehospitalization.25,26 Currently, no literature has been published on the rehospitalization risks for extremely premature infants (< 29 weeks’ gestation), but literature has shown that premature infants in general (< 36 weeks) are at increased risk for rehospitalization from pulmonary infections.10,26–28 To date, no study has looked at general modifiable risk factors for rehospitalization in extremely premature infants (< 29 weeks’ GA) that potentially can be addressed to prevent further health care utilization and promote improved outcomes in this patient population. In our study, the clinical factors identified as risk factors for hospital readmission using univariate analysis are listed in ►Table 2. The three most significant risk factors were reflux/dysphagia, inhaled steroid use (at 6 and 12 months of age), and number of intercurrent respiratory infections by 12 months of age. Surprisingly, BPD was not a risk factor for readmission in this study. However, the prevalence of BPD was high in both the readmitted and non-readmitted populations (82% readmission and 77% non-readmission), making it impossible to detect a difference in our small cohort. Breast milk ingestion at the time of NICU discharge showed a small protective effect for infants. However, most infants were placed on formula by 6 months of age because of the poor maternal supply or nutritional/feeding issues, so this
trend could not be adequately followed in our population. The risk factors identified for PICU readmission (►Table 3) were a history of PHTN in the NICU, prolonged oxygen use, and increasing number of respiratory infections. Our findings support the theory that ongoing inflammatory conditions on an already immature pulmonary parenchymal/vascular bed lead to ongoing morbidity and mortality in this patient population. The multivariate analysis of our outcome variables with identification of reflux/aspiration and ongoing respiratory infections as key risk factors allows for future interventions in this population. Also, identified critical time periods for diuretic, oxygen, and inhaled steroid use will allow physicians to better categorize at-risk infants in the future. The average PICU admission was at 13 months and the critical time period for diuretic/oxygen/inhaled steroid use was at 1 year of age. Our study design has several strengths. We evaluated infants born recently (2008–2010) and followed them for the first 2 years of life (through 2012). This study design minimized the variability in patient care as the same group of physicians and center care protocols were consistently used and the recent time frame of the cohort limited the impact of changing technology and medical therapies on this patient population. While the CIPD data set is comparable to the neonatal data registry in gender distribution, BPD outcomes, GA distribution, and birth weight distribution,21,22 our data set differs from the national registry in that it follows the infants past NICU discharge into childhood, allowing for further research into risk factors for hospital readmission and severity of readmission in this rapidly growing patient American Journal of Perinatology
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Table 3 (Continued)
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 4 Two stepwise logistic regression models looking at the two outcome variables of re-admission and PICU admission (4A and 4B). One ordinal backward logistic regression model looking at the outcome variable of number of readmissions (4C) (A) Rehospitalization (c-statistic ¼ 0.71). Effect
β Estimate
p Value
Intercept
0.30 0.38
0.43
Number of resp infections
0.58 0.27
0.03
1.8 (1.1–3.1)
iSter at 1 y
0.70 0.28
0.01
4.0 (1.3–12.1)
Effect
β Estimate
p Value
Odds ratio (95% CI)
Intercept
0.15 0.76
0.85
D at 1 y
1.65 0.84
0.04
27 (1.01–1,000)
O2 at 1 y
1.74 0.60
0.004
32 (3.1–333) Odds ratio (95% CI)
Odds ratio (95% CI)
(B) PICU readmission (c-statistic ¼ 0.87)
Effect
β Estimate
p Value
Intercept 1 vs. 0
0.003 0.486
0.99
Intercept 2 vs. 0
1.45 0.52
0.01
Intercept 3 vs. 0
3.03 0.62
< 0.0001
Intercept 4 vs. 0
3.24 0.64
< 0.0001
Intercept 5 vs. 0
3.49 0.67
< 0.0001
Intercept 9 vs. 0
4.16 0.79
< 0.0001
Intercept 10 vs. 0
4.67 0.91
< 0.0001
Intercept 11 vs. 0
5.46 1.15
< 0.0001
Number of resp infections
1.03 0.25
< 0.0001
NF/GT vs. None/NG
1.0 0.4
0.02
21.3 (2.9–166.7)
NF/GT vs. GT
1.1 0.5
0.04
22.7 (2.4–200)
NF/GT after NICU DC
2.8 (1.7–4.5)
0.01
Abbreviations: CI, confidence interval; D: diuretics; GT, gastrostomy tube; iSter, inhaled steroid; NF/GT, Nissen fundoplication and G-tube; NG, nasogastric tube; O2, oxygen.
population. Our study also required access to the patient’s medical record through the first 2 years of life with special emphasis being placed on ER, hospital, laboratory/imaging studies, OR, and primary care provider records. This center is the only tertiary referral center for children with complex illness in this geographic region and hospitalizes 86% of pediatric cases and close to 100% of high-risk cases (unpublished CMH demographic data). While we did lose some subjects to follow-up because they moved out of state, most local infants remained within this medical system, which reduced potential LFU. Over 73% of our cohort was successfully followed for the duration of the study. Our study design had several limitations relevant to the evaluation of these results. All infants were from a single center, so the findings may not be generalizable to the population of extremely premature infants at large. Another limitation is that our study spanned the first 2 years of the life for each subject, and as is true of any study design, obtaining long-term data are challenging because some patients are LFU. In our data set, 39 of 142 infants (27%) were LFU by 2 years of age. Another limitation of the study is our definition American Journal of Perinatology
of a respiratory infection which did vary between the inpatient NICU and outpatient settings. While the infants were in the NICU, we had control over their management; however, once they were discharged into the community, the type of work-up obtained varied. Also, they were not evaluated on a daily basis after NICU discharge and it is likely that mild respiratory infections went unnoticed by caregivers. Also, our center administered Synagis (AstraZeneca Pharmaceuticals LP, Wilmington, DE) 48 to 72 hours before discharge between the months of November and March, following American Academy of Pediatrics recommendations. However, subjects also received Synagis later at their local pediatrician’s office, so compliance data were not always available and were based on family report. Finally, the largest limitation of this study is the small sample size. Extreme prematurity is a rare event and we have only had the technology to support this patient population recently. Therefore, long-term data on this group is currently lacking. Our small sample size leads to the potential for bias and widens the band of the confidence interval. The small sample size also only allows for detection of risk factors that
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(C) Number of Rehospitalization (c-statistic ¼0.72)
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
2 Palm K, Simoneau T, Sawicki G, Rhein L. Assessment of current
3
4 5
6
7
8
Conclusion Currently, local management strategies vary significantly in this patient population and standardized national guidelines do not exist for patient management post NICU discharge.1–3 This retrospective cohort analysis identified some key risk factors for rehospitalization, multiple hospitalizations, and PICU admission. Multivariate analysis identified the following two modifiable key risk factors: reflux/aspiration and ongoing respiratory infections in the first 12 months of life. It also identified a critical time period for oxygen, diuretic, and inhaled steroid use at 1 year of age. Awareness of these risk factors, as well as knowledge of the critical time periods for diuretic, oxygen, and inhaled steroid use in this population, will allow physicians to better identify at-risk infants over time to intervene to prevent increased morbidity and health care utilization. Ultimately, larger retrospective studies are needed to produce risk stratification models for these infants that can be tested in large prospective multicenter studies looking at long-term interventions and outcomes based on these models.
9
10
11
12
13
14
15
Acknowledgments This research project is part of the Center for Infant and Pulmonary Disorders (CIPD) Data Repository at Children’s Mercy Hospital and Clinics (CMH), funded in part through two external grants (NIH/NHLBI U-O1HL94338 and NICHD NRN U-10 HD068284) and two intramural funding sources (Cooper Connor Endowed Fund for Pulmonary Research and the Sosland Family Endowment for Neonatal Research). Manuscript support was provided by the Medical Writing Center at Children’s Mercy Hospital and Clinics.
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17
18
19
20
References 1 Groothuis JR, Makari D. Definition and outpatient management of
the very low-birth-weight infant with bronchopulmonary dysplasia. Adv Ther 2012;29(4):297–311
21
strategies for weaning premature infants from supplemental oxygen in the outpatient setting. Adv Neonatal Care 2011;11(5): 349–356 Rhein LM, Konnikova L, McGeachey A, Pruchniewski M, Smith VC. The role of pulmonary follow-up in reducing health care utilization in infants with bronchopulmonary dysplasia. Clin Pediatr (Phila) 2012;51(7):645–650 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163(7):1723–1729 Drysdale SB, Wilson T, Alcazar M, et al. Lung function prior to viral lower respiratory tract infections in prematurely born infants. Thorax 2011;66(6):468–473 Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126(3):443–456 Anand D, Stevenson CJ, West CR, Pharoah PO. Lung function and respiratory health in adolescents of very low birth weight. Arch Dis Child 2003;88(2):135–138 Taylor JB, Nyp MF, Norberg M, et al. Impact of intercurrent respiratory infections on lung health in infants born
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life: Risk Assessment Jane B. Taylor, MD1,2 Mitzi A. Go, MD2 Michael F. Nyp, DO1 Jennifer Legino, BS2 Michael Norberg, MDiv1 Hongying Dai, PhD1,3 William E. Truog, MD1 1 Department of Pediatrics, University of Missouri-Kansas City School
of Medicine, Kansas City, Missouri 2 Department of Pediatrics, University of Kansas School of Medicine at the University of Kansas Medical Center, Kansas City, Kansas 3 Department of Research Development and Clinical Investigation, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri
Address for correspondence Jane B. Taylor, MD, Pediatric Pulmonology Office, 2401 Gillham Rd., Kansas City, MO, 64108 (e-mail: [email protected]).
Abstract
Keywords
► prematurity ► rehospitalization ► bronchopulmonary dysplasia ► dysphagia ► respiratory infection ► pulmonary hypertension
Objective This study aims to determine risk factors for rehospitalization in extremely premature infants. Study Design A retrospective cohort study of 157 infants born < 29 weeks’ gestational age assessing risk factors for rehospitalization through 2 years of life. Results Multivariable logistic regression showed that an increasing number of respiratory infections (odds ratio [OR]: 1.8 [1.1–3.1] per infection p ¼ 0.03) and inhaled steroid use at 1 year (OR: 4.0 [1.3–12.1] p ¼ 0.01) were predictive of hospital readmission. Diuretic (OR: 27 [1.01–1,000] p ¼ 0.04) and oxygen (OR: 32 [3.1–333] p ¼ 0.004) use at 1 year were predictive of pediatric intensive care unit admission. The number of respiratory infections (OR: 2.8 [1.7–4.5] p < 0.0001) with reflux/aspiration necessitating G-tube/Nissen fundoplication surgical intervention with or without G-tubes alone (OR: 21.3 [2.9–166.7] p ¼ 0.02 and OR: 22.7 [CI, 2.4–200] p ¼ 0.04) was predictive of increased number of rehospitalizations. Conclusions Key modifiable risk factors identified were reflux/aspiration and ongoing respiratory infections. Critical time periods for diuretic, oxygen, and inhaled steroid use in this population occurred at the age of 1 year.
Management for extremely premature infants (born < 29 weeks’ gestational age [GA]) after neonatal intensive care unit (NICU) discharge is variable and lacks national guidelines1–3 with little research to determine risk factors for rehospitalization in a population that has an estimated rehospitalization rate of over 70% with common respiratory infections.4,5 In the United States, one in eight children is born prematurely and more than 90% of infants born > 24 weeks’ GA are surviving.6 Lung disease secondary to prematurity, which is not always associated with the relative severity of an
infant’s bronchopulmonary dysplasia (BPD) determined at 36 weeks’ GA or the extent of respiratory support needed in the NICU, can deteriorate over time.7 Respiratory complications in premature infants are common, and increasing subsequent viral infections in the first year of life have been shown to significantly increase pulmonary morbidity in premature infants8 with many initial viral respiratory infections undetected before NICU discharge.9 Multiple concurrent viral coinfections in childhood also increase health care utilization in children.10
received March 12, 2015 accepted after revision May 7, 2015
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1555123. ISSN 0735-1631.
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Am J Perinatol
The initial impact of prematurity on the US economy is approximately $26.2 billion per year ($51,600 per infant).11,12 However, this figure does not take into account the health care utilization that occurs subsequent to NICU discharge. It is critical to remember that premature infants’ lung physiology does not fully normalize over time. Recent studies, in which serial infant pulmonary function tests were performed, did not provide evidence for any significant “catch up” of lung growth in premature infants during the first year of life.13,14 Studies in teenagers/adults with extreme prematurity at birth showed persistent abnormalities in lung function as evidenced by increased air trapping, increased residual volume, increased incidence of airway hyper-reactivity, and a faster decline in lung function in adulthood.14–19 These problems, in turn, lead to increased morbidity and the need for increased medical utilization well past childhood and ultimately over a lifetime.7,20 We hypothesize that identification of clinical events in the patient’s NICU course and shortly afterward can predict risk for early rehospitalization and increased pulmonary morbidity over time.8,11 Identifying these risk factors will allow for development of more precise management protocols, necessary for continued cost-effective management of this rapidly growing patient population.
Methods Center for Infant Pulmonary Disorders (CIPD) Data Repository: The Infant Pulmonary Disorders Data Repository (IPDR) is located at Children’s Mercy Hospitals and Clinics, Kansas City, MO (CMH). It provided deidentified data for this study according to the process approved by the Institutional Review Board at CMH. Participants are included in the database upon admission to the NICU and followed over the first 6 years of life, or until death or loss to follow-up (LFU). There were a total of 184 infants born < 29 weeks’ gestation. Study inclusion criteria were as follows: (1) Infants in the IPDR born less than 29 weeks’ gestation who were (2) admitted to CMH less than 24 hours of life who (3) did not have any major structural anomalies of a major organ system (i.e., congenital heart disease, diaphragmatic hernia, and giant omphalocele). A total of 157 of the 184 infants in the IPDR met the inclusion criteria. The data set from 2008 through 2010 was compared and found to be similar to the national neonatal research network data set.21,22
Study Design A retrospective cohort design was used to evaluate clinical factors during NICU admission and in the first 2 years of life to assess for risk factors for rehospitalization, and the severity of rehospitalization, in extremely premature infants through their second birthday. Variables The clinical variables selected as potential risk factors included the categorical variables of the following: (1) BPD status: based on criteria outlined by Ehrenkranz et al23; (2) breast milk ingestion: any breast milk intake at NICU discharge, 6 months, 1 year, and 2 years of age; (3) transient pulmonary hypertension (PHTN): echocardiographic eviAmerican Journal of Perinatology
Taylor et al.
dence of PHTN, medication use for PHTN that stopped before NICU discharge; (4) persistent pulmonary hypertension: echocardiographic evidence of PHTN, medication use for PHTN that continued after NICU discharge; (5) post NICU pulmonary hypertension: echocardiographic evidence of PHTN, medication use for PHTN that occurred after NICU discharge; (6) transient adrenal insufficiency: signs/symptoms of hypocortisolism-persistent hypotension > 48 hours despite presser support during a time of infection/stress, persistent hypoglycemia > 48 hours, failed ACTH stimulation test which required hydrocortisone therapy in the NICU; (7) presence of persistent adrenal insufficiency: signs/symptoms of hypocortisolism-persistent hypotension > 48 hours despite presser support during a time of infection/stress, persistent hypoglycemia > 48 hours, failed ACTH stimulation test which required hydrocortisone therapy past NICU discharge; (8) tobacco exposure in the home; (9) reflux: diagnosed by an upper gastrointestinal study, pH probe or pediatric gastrointestinal subspecialist, pH probe or pediatric gastrointestinal subspecialist, (10) steroid use in the NICU (systemic or inhaled), (11) gender, (12) diuretic, inhaled steroid or oxygen use at the time of NICU discharge, 6 month, 1 year, and 2 years of age; and (13) swallowing dysfunction with dysphagia and aspiration: diagnosed by abnormal swallow study, occupational therapy/speech evaluation by a speech pathologist that specializes in swallowing dysfunction, or clinical course that resulted in a nasogastric tube (NG tube) being placed for > 1 month or placement of a gastrointestinal tube (G-tube) with/without a Nissen fundoplication stomach wrap procedure to reduce reflux. The continuous variables evaluated were as follows: (1) birth weight; (2) increasing number of respiratory infections: increased nasal secretions/cough/pulmonary secretions supporting lab work (chest radiograph [CXR], respiratory viral polymerase chain reaction [PCR], complete blood count [CBC] with differential) that led to worsening respiratory status as determined by increased respiratory rate, increased oxygen requirement, and increased suctioning. The outcome variables included hospital readmission, number of hospital readmissions, and severity of hospital admissions (general pediatric floor vs. intensive care unit). All variables of interest were determined through extensive medical record reviews of each participant’s NICU discharge summaries, NICU procedure notes, radiology records, emergency room (ER) notes, Special Care Clinic (NICU long-term follow-up) notes, subspecialty clinic notes, and laboratory results. Study Population We included all infants enrolled in the CIPD Data Repository that met the above inclusion criteria from January 1, 2008, through December 31, 2010, and followed them through their second birthday (through December 31, 2012). We excluded infants who died < 36 weeks’ corrected GA and excluded tracheostomy and ventilator-dependent infants (of which there was 1).
Data Analysis For our statistical analysis, we used the SAS programming version 9.2 software package (SAS Institute, Inc, Cary, NC) and
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Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 1 Comparison of CIPD data repository with a national database: patient demographic information n
BW (g) mean SD
GA (wk) mean SD
Male (%)
Hispanic (%)
Black (%)
Antenatal steroids (%)
National
3,629
897 203
26.7 1.9
51.1
17.4
39.9
66
Local
158
906 235.3
26.1 1.6
63.5
8.8
41.5
64
SPSS 20 (IBM Corporation, Armonk, NY). We calculated summary statistics (mean, standard deviation, median, interquartile range, and percentage) for demographics and performed univariate analysis for risk factor variables and outcome variables among subjects with rehospitalization and subjects without rehospitalization for the CIPD cohort born between 2008 and 2010. We compared subjects between these two groups using the t-test, chi-square test, and Fisher exact test. We further analyzed subjects in the rehospitalization group by looking at those infants receiving intensive care unit (ICU) and those requiring multiple hospitalizations. Finally, we performed multivariate logistic regression to detect the presence of possible associations between our selected clinical variables (BPD, inhaled steroid use, dysphagia, etc.) and susceptibility for rehospitalization. The odds ratio (OR) and 95% confidence interval for OR were determined for each risk factor. Multivariate logistic regression models using step-wise model selection created predictive models for rehospitalization and pediatric intensive care unit (PICU) hospitalization. An ordinal logistic regression model using backward selection was used to create a multivariate predictive model for the number of hospital readmissions. Performance of the predictive model was assessed by the cstatistic, percentage of concordance, and cross validation.
Results Basic demographic information on gender, GA, and birth weight was collected on each infant in the CIPD cohort. Comparison to a large national NICU data set (►Table 1) revealed similar demographics and outcomes.21,22 Of the 184 live-born premature infants in the CIPD Data Repository, 158 infants were initially identified meeting study inclusion criteria for consideration in this study. The one patient who was trach/vent dependent was excluded after major airway anomalies were identified, leaving a total of 157 infants. Overall, 15 infants died < 36 weeks corrected GA, leaving a total of 142 infants at the time of NICU discharge. Overall, 39 infants were LFU by their second birthday, and 7 infants died before their second birthday (see ►Fig. 1). There were 96 infants followed through 2 years of age. Overall, 60 infants were readmitted to the hospital after NICU discharge (42%, 60/142). Of these patients, 26 were readmitted to the hospital on multiple occasions (18%, 26/142) and 15 (10%, 15/142) were admitted to the PICU with a mean PICU admission age of 13 months. In the LFU group, 11 infants had been hospitalized before being LFU (28%, 11/39). In the 2-year cohort, 44 infants had been hospitalized (45%, 44/96). In the cohort of infants
who died after NICU discharge, five infants had been rehospitalized (71%, 5/7). Univariate analysis was performed on the selected clinical variables during NICU admission and after NICU discharge to determine the risk factors for rehospitalization in this patient population (►Table 2). The significant variables were dysphagia (OR, 3.8; p ¼ 0.0002), PHTN in the NICU (OR, 2.3; p ¼ 0.004), PHTN post NICU (OR,1.49; p ¼ 0.02), transient adrenal insufficiency (OR, 2.3; p ¼ 0.004), chronic adrenal insufficiency (OR, 6.1; p ¼ 0.02), systemic steroid use in the NICU (OR, 4.3; p ¼ 0.0008), inhaled steroid (iSter) use at 6 months, 1 year, and 2 years (OR: 14.7; p ¼ 0.002, OR: 4.1; p ¼ 0.002, and OR: 4.3; p ¼ 0.001), birth weight (OR, two for each decrease of 2 g in weight; p ¼ 0.03), subsequent number of respiratory infections (OR, 2.1 for each subsequent infection; p ¼ 0.0003), and oxygen use at 1 year of age (OR, 5.8; p ¼ 0.002). Breast milk at NICU discharge had a protective effect (OR, 0.3; p ¼ 0.007). Tobacco exposure, diuretic use (at any time point), and BPD were not significant risk factors for readmission. The Bonferroni adjusted p value was calculated (p value number of variables [27]) to conservatively exclude potential false-positives and the significant variables that remained were dysphagia (p ¼ 0.005), oxygen use at 1 year (p ¼ 0.05), steroid use in the NICU (p ¼ 0.02),
184 Infants in the CIPD Registry
157 Infants Met Inclusion Criteria 15 infants died
142 Infants Discharged from the NICU 7 infants died 23 infants LFU
112 Infants at 1 years of age 0 infants died 16 infants LFU
96 Infants at 2 years of age Fig. 1 Patient flow diagram over the 2-year study period. LFU, lost to follow-up. American Journal of Perinatology
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Abbreviations: CIPD, Center for Infant Pulmonary Disorders; GA, gestational age; SD, standard deviation.
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 2 Univariate analysis comparing risk factors and rehospitalization rates in infants enrolled in the CIPD Data Repository from January 1, 2008 through December 31, 2010 who were clinically followed for their first 2 years of life (through December 31, 2012)
Tobacco exposure (n ¼ 157)
OR
p Value
36 (36)
64 (64)
0.77 (0.40–1.51)
0.45
Female
24 (42.1)
33 (57.9)
Yes
4 (22.2)
14 (77.8)
0.42 (0.13–1.35)
0.2
No
56 (40.3)
83 (59.7) 3.85(1.86–7.99)
0.0002
2.35 (1.04–5.32)
0.04
Infty (1.49–Infty)
0.02
0.30 (0.12–0.74)
0.007
0.28 (0.06–1.39)
0.18
0 (0–4.44)
0.5
1.75 (0.74–4.12)
0.2
1.61 (0.64–4.06)
0.31
5.48 (0.59–50.64)
0.17
1.82 (0.92–3.58)
0.08
1.87 (0.91–3.86)
0.09
5.83 (1.78–19.09)
0.002
Infty (2.29–Infty)
0.004
4.39 (1.76–10.99)
0.0008
4.0 (1.31–12.16)
0.01
2.82 (0.50–15.94)
0.4
14.78 (1.83–119.45)
0.002
0.05
4.07 (1.65–10.05)
0.002
0.05
4.36 (1.77–10.76)
0.001
0.03
Male
Dysphagia/abnormal OPM (n ¼ 157)
Yes
27(61.4)
17 (38.6)
No
33 (29.2)
80 (70.8)
NICU PHTN (n ¼ 157)
Yes
16 (55.2)
13 (44.8)
No
44 (34.4)
84 (65.6)
PHTN post D/C (n ¼ 157) BM at NICU D/C (n ¼ 141) BM at 6 mo (n ¼ 125) BM at 1 y (n ¼ 114) D at NICU D/C (n ¼ 141) D at 6 mo (n ¼ 125) D at 1 y (n ¼ 114) O2 at NICU D/C (n ¼ 141) O2 at 6 mo (n ¼ 125) O2 at 1 y (n ¼ 114) O2 at 2 y (n ¼ 95) Steroid in NICU (n ¼ 157) iSter in NICU (n ¼ 154) iSter at NICU D/C (n ¼ 141) iSter at 6 mo (n ¼ 125) iSter at 1 y (n ¼ 114) iSter at 2 y (n ¼ 96)
American Journal of Perinatology
p Value
Readmit ¼ No, n (%)
Yes
4 (100)
0 (0)
No
56 (36.6)
97 (63.4)
Yes
7 (21.9)
25 (78.1)
No
53 (48.6)
56 (51.4)
Yes
2 (20)
8 (80)
No
54 (47.0)
61 (63.0)
Yes
0 (0)
2 (100)
No
50 (44.6)
62 (55.4)
Yes
14 (53.9)
12 (46.2)
No
46 (40)
69 (60)
Yes
12 (54.4)
10 (45.5)
No
44 (42.7)
59 (57.3)
Yes
4 (80)
1 (20)
No
46 (42.2)
63 (57.8)
Yes
31 (50.8)
30 (49.2)
No
29 (36.3)
51 (63.7)
Yes
28 (53.9)
24 (46.1)
No
28 (38.4)
45 (61.6)
Yes
14 (77.8)
4 (22.2)
No
36 (37.50)
60 (62.5)
Yes
7 (100)
0 (0)
No
38 (43.2)
50 (56.8)
Yes
17 (68)
8 (32)
No
43 (32.6)
89 (67.4)
Yes
11 (68.8)
5 (31.2)
No
49 (35.5)
89 (64.5)
Yes
4 (66.7)
2 (33.3)
No
56 (41.5)
79 (58.5)
Yes
10 (90.9)
1 (9.1)
No
46 (40.4)
68 (59.7)
Yes
20 (69.0)
9 (31.0)
No
30 (35.3)
55 (64.7)
Yes
24 (70.6)
10 (29.4)
No
22 (35.5)
40 (64.5)
0.005
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Gender (n ¼ 157)
a
Readmit ¼ Yes, n (%)
Exposure
0.05
0.02
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 2 (Continued) Readmit ¼ No, n (%)
OR
p Value
Transient AI (n ¼ 154)
Yes
15 (53.6)
13 (46.4)
2.34 (1.01–5.39)
0.04
Chronic AI (n ¼ 154)
No
39 (33.1)
79 (66.9)
Yes
6 (75)
2 (25)
6.08 (1.17–31.50)
0.02
No
39 (33.1)
79 (66.9)
Number of resp infections (n ¼ 144)
No
17 (26.6)
47 (73.4)
0.0003
1
21 (40.4)
31 (59.6)
2.09 (1.4–3.12) for each infection
2
11 (58.0)
8 (42.1)
3
5 (100)
0 (0)
BPD severity (n ¼ 157)
1.37 (0.99–1.91)
0.059
GA (n ¼ 157)
0.84 (0.68–1.03)
0.1
Change in birth weight (g) (n ¼ 157%)
0.998 (0.997–1.0) per for each g of wt change
0.03
4
3 (75)
1 (25)
No
10 (35.7)
18 (64.3)
Mild
12 (31.6)
26 (68.4)
Moderate
21 (46.7)
24 (53.3)
Severe
17 (54.8)
14 (45.2)
22
1 (100)
0 (0)
23
5 (50)
5 (50)
24
8 (44.4)
10 (55.6)
25
8 (38.1)
13 (61.9)
26
12 (46.2)
14 (53.8)
27
15 (33.3)
30 (66.7)
28
11 (30.6)
25 (69.4)
1g
a
p Value
0.008
Abbreviations: AI, adrenal insufficiency; BM, breast milk; BPD, bronchopulmonary dysplasia; CIPD, Center for Infant Pulmonary Disorders; D, diuretics; GA, gestational age; iSter, inhaled steroids; NICU, neonatal intensive care unit; O2, oxygen; OPM, oral pharyngeal motility study; PHTN, pulmonary hypertension. Note: p values for both original chi-square analysis and Bonferroni adjusted p values are reported. a Bonferroni adjusted p values.
inhaled steroid use at 6 months (p ¼ 0.05), 1 year (p ¼ 0.05), and 2 years (p ¼ 0.03) and number of respiratory infections (p ¼ 0.008). Univariate analysis was then performed on the selected variables to determine if any were risk factors for rehospitalization to the PICU. Significant variables were a history of pulmonary HTN in the NICU (OR, 3.83; p ¼ 0.04), oxygen use at 1 year of life (OR, 7.5; p ¼ 0.008), oxygen use at 2 years of life (OR, 8.27; p ¼ 0.03), and increasing number of respiratory infections with significance occurring with more than three infections in the first year of life (OR, 2.04; p ¼ 0.02) (►Table 3). Three logistic regression models were then created for the outcome variables of (1) rehospitalization, (2) PICU hospitalization, and (3) number of rehospitalizations (►Table 4). The first two variables were categorical, so a multivariable model using logistic regression with step-wise model selection was performed using the aforementioned variables for the first two models. The issue of collinearity between variables was approached by using the step-wise modeling approach and calculating the variance inflation factor (VIF) for each variable and using factors for the step-wise model that had a VIF of two
or less. The third model for the number of rehospitalizations used an ordinal logistic regression model using a backward model selection with the aforementioned variables. The issue of collinearity between variables was approached by using the backward modeling approach and only using variables with a VIF of two or less. For model 1, both number of respiratory infections (OR, 1.8; p ¼ 0.03) and inhaled steroid use at 1 year of age (OR, 4.0; p ¼ 0.01) were predictive for hospital readmission. For model 2, both diuretic (OR, 27; p ¼ 0.04) and oxygen use (OR, 32; p ¼ 0.004) at 1 year of age were predictive for PICU admission. The third model showed that an increasing number of respiratory infections (OR, 2.8; p < 0.0001) and a history of reflux and feeding problems as determined by surgical intervention with a Nissen fundoplication G-tube insertion (OR, 21; p ¼ 0.02 and OR, 23; p ¼ 0.04) were predictive of multiple rehospitalizations.
Discussion This study looked at clinical factors during NICU admission and shortly afterward as potential risk factors for American Journal of Perinatology
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Readmit ¼ Yes, n (%)
Exposure
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Exposure
Readmit ICU ¼ Yes, n (%)
Readmit ICU ¼ No, n (%)
Readmit ICU
p Value
7 (20)
28 (80)
0.47 (0.14–1.54)
0.21
0.95 (0.09–9.92)
1
1.44 (0.44–4.7)
0.54
3.83 (1.07–13.66)
0.04
10.5 (1–11.36)
0.049
0.54 (0.06–5.06)
1
2.71 (0.16–46.4)
0.48
1.89 (0.51–6.94)
0.48
3.67 (0.95–14.15)
0.07
3.89 (0.48–31.52)
0.22
1.73 (0.52–5.69)
0.55
2.88 (0.82–10.02)
0.09
7.5 (1.71–32.9)
0.008
8.27 (1.4–48.53)
0.03
0.94 (0.25–3.53)
1
0.58 (0.11–3.06)
0.71
0.95 (0.09–9.92)
1
1.14 (0.25–5.16)
1
2.22 (0.57–8.68)
0.3
2.12 (0.46–9.84)
0.46
0.88 (0.20–3.86)
1
Gender (N ¼ 58)
Male Female
8 (34.8)
15 (65.2)
Tobacco exposure (N ¼ 58)
Yes
1 (25)
3 (75)
No
14 (25.9)
40 (34.1)
Yes
8 (29.6)
19 (70.1)
No
7 (22.6)
24 (77.4)
Yes
7 (46.7)
8 (53.3)
No
8 (18.6)
35 (81.4)
Dysphagia/abnormal OPM (N ¼ 58) NICU PHTN (N ¼ 58) PHTN post D/C (N ¼ 58) BM at NICU D/C (N ¼ 58) BM at 6 mo (N ¼ 54) D at NICU D/C (N ¼ 58) D at 6 mo (N ¼ 54) D at 1 y (N ¼ 48) O2 at NICU D/C (N ¼ 58) O2 at 6 mo (N ¼54) O2 at 1 y (N ¼ 48) O2 at 2 y (N ¼ 43) Steroid in NICU (N ¼ 58) iSter in NICU (N ¼ 58) iSter at NICU D/C (N ¼ 58) iSter at 6 mo (N ¼ 54) iSter at 1 y (N ¼ 48) iSter at 2 y (N ¼ 44) Transient AI (N ¼ 52)
American Journal of Perinatology
Yes
3 (75)
1 (25)
No
12 (22.2)
42 (77.8)
Yes
1 (16.67)
5 (88.3)
No
14 (26.9)
38 (73.1)
Yes
1 (50)
1 (50)
No
14 (26.9)
38 (73.1)
Yes
5 (35.7)
9 (64.3)
No
10 (22.7)
33 (77.3)
Yes
6 (50)
6 (50)
No
9 (21.4)
33 (78.6)
Yes
2 (50)
2 (50)
No
9 (20.5)
35 (79.5)
Yes
9 (31)
20 (69)
No
6 (20.7)
23 (79.3)
Yes
10 (38.5)
16 (61.5)
No
5 (17.9)
23 (82.1)
Yes
7 (50)
7 (50)
No
4 (11.8)
30 (88.2)
Yes
4 (57.1)
3 (42.9)
No
5 (13.9)
31 (86.1)
Yes
4 (25)
12 (75)
No
11 (26.2)
31 (73.8)
Yes
2 (18.2)
9 (81.8)
No
13 (27.7)
34 (72.3)
Yes
1 (25)
3 (75)
No
14 (25.9)
40 (74.1)
Yes
3 (30)
7 (70)
No
12 (27.3)
32 (72.7)
Yes
6 (31.6)
13 (68.4)
No
5 (17.2)
24 (82.8)
Yes
6 (26.1)
17 (73.9)
No
3 (14.3)
18 (85.7)
Yes
3 (21.4)
11 (78.6)
No
9 (23.7)
29 (76.3)
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Table 3 Univariate subgroup analysis of risk factors for PICU hospitalization in infants enrolled in the CIPD Data Repository from January 1, 2008 through December 31, 2010 who were clinically followed for their first 2 years of lifea
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Exposure
Readmit ICU ¼ Yes, n (%)
Readmit ICU ¼ No, n (%)
Readmit ICU
p Value
3.22 (0.55–18.85)
0.32
2.04 (1.35–3.09)
0.02
1.43 (0.79–2.60)
0.24
0.87 (0.61–1.24)
0.45
Chronic AI (N ¼ 44)
Yes
3 (50)
3 (50)
No
9 (23.7)
29 (76.3)
Number of resp infections (N ¼ 55)
0–2
9 (19.1)
38 (80.9)
3þ
5 (62.5)
3 (37.5)
No
1 (10)
9 (90)
BPD severity (N ¼ 58)
GA (N ¼ 58)
Mild
3 (25)
9 (75)
Moderate
6 (30)
14 (70)
Severe
5 (31.3)
11 (68.8)
22
0 (0)
1 (100)
23
3 (60)
2 (40)
24
1 (12.5)
7 (87.5)
25
4 (50)
4 (50)
26
2 (18.2)
9 (81.9)
27
1 (7.1)
13 (92.9)
28
4 (36.4)
7 (63.6)
Abbreviations: AI, adrenal insufficiency; BM, breast milk; BPD, bronchopulmonary dysplasia; CIPD, Center for Infant Pulmonary Disorders; D, diuretics; iSter, inhaled steroids; GA, gestational age; iSter, inhaled steroids; O2, oxygen; OPM, oral pharyngeal motility study; PHTN, pulmonary hypertension; PICU, pediatric intensive care unit. a Through December 31, 2012.
rehospitalization, PICU admission, and recurrent rehospitalizations in a cohort of extremely premature infants (< 29 weeks’ GA) over the first 2 years of life. Recent literature has shown that there are over 100,000 hospitalizations a year in the United States for term infants in the perinatal period.24 Late preterm infants (GA between 34 and 36 weeks) may be at a threefold risk for rehospitalization.25,26 Currently, no literature has been published on the rehospitalization risks for extremely premature infants (< 29 weeks’ gestation), but literature has shown that premature infants in general (< 36 weeks) are at increased risk for rehospitalization from pulmonary infections.10,26–28 To date, no study has looked at general modifiable risk factors for rehospitalization in extremely premature infants (< 29 weeks’ GA) that potentially can be addressed to prevent further health care utilization and promote improved outcomes in this patient population. In our study, the clinical factors identified as risk factors for hospital readmission using univariate analysis are listed in ►Table 2. The three most significant risk factors were reflux/dysphagia, inhaled steroid use (at 6 and 12 months of age), and number of intercurrent respiratory infections by 12 months of age. Surprisingly, BPD was not a risk factor for readmission in this study. However, the prevalence of BPD was high in both the readmitted and non-readmitted populations (82% readmission and 77% non-readmission), making it impossible to detect a difference in our small cohort. Breast milk ingestion at the time of NICU discharge showed a small protective effect for infants. However, most infants were placed on formula by 6 months of age because of the poor maternal supply or nutritional/feeding issues, so this
trend could not be adequately followed in our population. The risk factors identified for PICU readmission (►Table 3) were a history of PHTN in the NICU, prolonged oxygen use, and increasing number of respiratory infections. Our findings support the theory that ongoing inflammatory conditions on an already immature pulmonary parenchymal/vascular bed lead to ongoing morbidity and mortality in this patient population. The multivariate analysis of our outcome variables with identification of reflux/aspiration and ongoing respiratory infections as key risk factors allows for future interventions in this population. Also, identified critical time periods for diuretic, oxygen, and inhaled steroid use will allow physicians to better categorize at-risk infants in the future. The average PICU admission was at 13 months and the critical time period for diuretic/oxygen/inhaled steroid use was at 1 year of age. Our study design has several strengths. We evaluated infants born recently (2008–2010) and followed them for the first 2 years of life (through 2012). This study design minimized the variability in patient care as the same group of physicians and center care protocols were consistently used and the recent time frame of the cohort limited the impact of changing technology and medical therapies on this patient population. While the CIPD data set is comparable to the neonatal data registry in gender distribution, BPD outcomes, GA distribution, and birth weight distribution,21,22 our data set differs from the national registry in that it follows the infants past NICU discharge into childhood, allowing for further research into risk factors for hospital readmission and severity of readmission in this rapidly growing patient American Journal of Perinatology
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Table 3 (Continued)
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
Taylor et al.
Table 4 Two stepwise logistic regression models looking at the two outcome variables of re-admission and PICU admission (4A and 4B). One ordinal backward logistic regression model looking at the outcome variable of number of readmissions (4C) (A) Rehospitalization (c-statistic ¼ 0.71). Effect
β Estimate
p Value
Intercept
0.30 0.38
0.43
Number of resp infections
0.58 0.27
0.03
1.8 (1.1–3.1)
iSter at 1 y
0.70 0.28
0.01
4.0 (1.3–12.1)
Effect
β Estimate
p Value
Odds ratio (95% CI)
Intercept
0.15 0.76
0.85
D at 1 y
1.65 0.84
0.04
27 (1.01–1,000)
O2 at 1 y
1.74 0.60
0.004
32 (3.1–333) Odds ratio (95% CI)
Odds ratio (95% CI)
(B) PICU readmission (c-statistic ¼ 0.87)
Effect
β Estimate
p Value
Intercept 1 vs. 0
0.003 0.486
0.99
Intercept 2 vs. 0
1.45 0.52
0.01
Intercept 3 vs. 0
3.03 0.62
< 0.0001
Intercept 4 vs. 0
3.24 0.64
< 0.0001
Intercept 5 vs. 0
3.49 0.67
< 0.0001
Intercept 9 vs. 0
4.16 0.79
< 0.0001
Intercept 10 vs. 0
4.67 0.91
< 0.0001
Intercept 11 vs. 0
5.46 1.15
< 0.0001
Number of resp infections
1.03 0.25
< 0.0001
NF/GT vs. None/NG
1.0 0.4
0.02
21.3 (2.9–166.7)
NF/GT vs. GT
1.1 0.5
0.04
22.7 (2.4–200)
NF/GT after NICU DC
2.8 (1.7–4.5)
0.01
Abbreviations: CI, confidence interval; D: diuretics; GT, gastrostomy tube; iSter, inhaled steroid; NF/GT, Nissen fundoplication and G-tube; NG, nasogastric tube; O2, oxygen.
population. Our study also required access to the patient’s medical record through the first 2 years of life with special emphasis being placed on ER, hospital, laboratory/imaging studies, OR, and primary care provider records. This center is the only tertiary referral center for children with complex illness in this geographic region and hospitalizes 86% of pediatric cases and close to 100% of high-risk cases (unpublished CMH demographic data). While we did lose some subjects to follow-up because they moved out of state, most local infants remained within this medical system, which reduced potential LFU. Over 73% of our cohort was successfully followed for the duration of the study. Our study design had several limitations relevant to the evaluation of these results. All infants were from a single center, so the findings may not be generalizable to the population of extremely premature infants at large. Another limitation is that our study spanned the first 2 years of the life for each subject, and as is true of any study design, obtaining long-term data are challenging because some patients are LFU. In our data set, 39 of 142 infants (27%) were LFU by 2 years of age. Another limitation of the study is our definition American Journal of Perinatology
of a respiratory infection which did vary between the inpatient NICU and outpatient settings. While the infants were in the NICU, we had control over their management; however, once they were discharged into the community, the type of work-up obtained varied. Also, they were not evaluated on a daily basis after NICU discharge and it is likely that mild respiratory infections went unnoticed by caregivers. Also, our center administered Synagis (AstraZeneca Pharmaceuticals LP, Wilmington, DE) 48 to 72 hours before discharge between the months of November and March, following American Academy of Pediatrics recommendations. However, subjects also received Synagis later at their local pediatrician’s office, so compliance data were not always available and were based on family report. Finally, the largest limitation of this study is the small sample size. Extreme prematurity is a rare event and we have only had the technology to support this patient population recently. Therefore, long-term data on this group is currently lacking. Our small sample size leads to the potential for bias and widens the band of the confidence interval. The small sample size also only allows for detection of risk factors that
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(C) Number of Rehospitalization (c-statistic ¼0.72)
Rehospitalization in Infants Born < 29 Weeks’ Gestation during the First 2 Years of Life
2 Palm K, Simoneau T, Sawicki G, Rhein L. Assessment of current
3
4 5
6
7
8
Conclusion Currently, local management strategies vary significantly in this patient population and standardized national guidelines do not exist for patient management post NICU discharge.1–3 This retrospective cohort analysis identified some key risk factors for rehospitalization, multiple hospitalizations, and PICU admission. Multivariate analysis identified the following two modifiable key risk factors: reflux/aspiration and ongoing respiratory infections in the first 12 months of life. It also identified a critical time period for oxygen, diuretic, and inhaled steroid use at 1 year of age. Awareness of these risk factors, as well as knowledge of the critical time periods for diuretic, oxygen, and inhaled steroid use in this population, will allow physicians to better identify at-risk infants over time to intervene to prevent increased morbidity and health care utilization. Ultimately, larger retrospective studies are needed to produce risk stratification models for these infants that can be tested in large prospective multicenter studies looking at long-term interventions and outcomes based on these models.
9
10
11
12
13
14
15
Acknowledgments This research project is part of the Center for Infant and Pulmonary Disorders (CIPD) Data Repository at Children’s Mercy Hospital and Clinics (CMH), funded in part through two external grants (NIH/NHLBI U-O1HL94338 and NICHD NRN U-10 HD068284) and two intramural funding sources (Cooper Connor Endowed Fund for Pulmonary Research and the Sosland Family Endowment for Neonatal Research). Manuscript support was provided by the Medical Writing Center at Children’s Mercy Hospital and Clinics.
16
17
18
19
20
References 1 Groothuis JR, Makari D. Definition and outpatient management of
the very low-birth-weight infant with bronchopulmonary dysplasia. Adv Ther 2012;29(4):297–311
21
strategies for weaning premature infants from supplemental oxygen in the outpatient setting. Adv Neonatal Care 2011;11(5): 349–356 Rhein LM, Konnikova L, McGeachey A, Pruchniewski M, Smith VC. The role of pulmonary follow-up in reducing health care utilization in infants with bronchopulmonary dysplasia. Clin Pediatr (Phila) 2012;51(7):645–650 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163(7):1723–1729 Drysdale SB, Wilson T, Alcazar M, et al. Lung function prior to viral lower respiratory tract infections in prematurely born infants. Thorax 2011;66(6):468–473 Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126(3):443–456 Anand D, Stevenson CJ, West CR, Pharoah PO. Lung function and respiratory health in adolescents of very low birth weight. Arch Dis Child 2003;88(2):135–138 Taylor JB, Nyp MF, Norberg M, et al. Impact of intercurrent respiratory infections on lung health in infants born
