Respiratory Hospitalizations and Rehospitalizations in Infants Born Late Preterm

Abstract

The impact of late preterm (LPT) birth, born at 34-0/7 to 36-6/7, on respiratory morbidity beyond the neonatal period is still a subject of controversy. It is currently not yet established whether LPT infants are at increased risks for recurrent severe respiratory illnesses requiring hospitalizations. Records of LPT and full term (FT) patients <2 years of age admitted during the year 2012 to the hospital due to a respiratory illness were reviewed. The clinical course and rate of readmissions of children born (LPT, 34–36 weeks) with (FT, ≥37 weeks) who were hospitalized with a respiratory illness in early childhood were compared. Four hundred eight-six patients met inclusion criteria: 51 (10.5%) LPT and 435 (89.5%) FT. The groups had similar preadmission clinical demographic characteristics. The LPT group had a significantly increased risk for recurrent hospitalization due to respiratory illnesses in the year following the index admission (odds ratio = 2.69, 95% confidence interval = 1.32–5.48, P = 0.006), and rehospitalizations occurring at an earlier age when compared to FT (9.3 ± 3.3 versus. 13.1 ± 7.8 months, P = 0.02). Other outcome indices such as hospital length of stay, medical treatment during hospitalization, and microbiological diagnosis were similar between groups (P > 0.1). LPT infants hospitalized for a respiratory illness during the first 2 years of life are at increased risk for further respiratory hospitalizations. A prospective study is required to identify risk factors for respiratory morbidity in LPT born children.

Introduction

In the past two decades, the rate of prematurity has been increasing in developed countries. Of these preterm infants, the majority (74%) are born late preterm (LPT) (born 34⁰/₇ to 36⁶/₇ weeks' gestation)¹ and account for the fastest growing subset of premature infants.² The impact of LPT infants on health resources has attracted considerable interest and research regarding short- and long-term morbidity and outcomes.^3,4 Compared with term-born neonates, LPT infants are at an increased risk to suffer from respiratory morbidity after birth, including respiratory distress syndrome, transient tachypnea of the newborn, and apneas.^5,6 However, the characteristics of respiratory morbidity beyond the neonatal period is not as well established.^4,7

Although several studies in the last few years have addressed late pulmonary morbidity in these infants, the findings are inconsistent. Most studies on respiratory morbidity of LPT infants have reported increased rates of late pulmonary morbidity, especially preschool wheeze and asthma,^8–13 and others have found a reduced pulmonary function at school age in LPT infants.^14–16 However, several studies have failed to find a significant association between late prematurity and late respiratory morbidity.^17–19 Such discrepancies could be related to differences in the classification of late prematurity (ie, the inclusion of moderate preterm infants, born 32–35 or 36 weeks gestation, in the LPT cohort), differences in methods of asthma diagnosis, and/or the inherent limitations of retrospective studies.¹⁴ Recently, a large propensity score study concluded that the reported risk of late pulmonary morbidity among LPT infants may be ascribed to differences in covariates and not the prematurity itself.¹⁸ Thus, the characteristics of late respiratory morbidity in LPT are not fully established, but it is evident that long-term pulmonary morbidity correlates with the degree of prematurity.^8,11,12

It has been previously shown that early and moderate preterm infants have increased rates of respiratory hospitalizations, respiratory syncytial virus (RSV)-related hospitalizations, resource utilization, and complications during hospitalization.^13,20–22 However, respiratory hospitalizations in LPT infants have not been assessed.

The aim of this study was to investigate the consequence of late prematurity on respiratory hospitalizations in the first 2 years of life. This may help develop preventive therapy, improve resource utilization, and save costs.

Materials and Methods

The study was approved by the Institutional Board Review for clinical studies.

Patients

All patients under the age of 2 years admitted to the Pediatric Departments of the Hadassah Hebrew University Medical Center in Jerusalem for respiratory illness during the year 2012 were included in the study.

Initial case identification was based on the International Classification of Diseases, Ninth Revision (ICD-9)-coded diagnosis of upper respiratory tract infection, lower respiratory tract infection, pneumonia, bronchiolitis, asthma, and respiratory failure as recorded by the physicians in the pediatric units, as specified in the discharge summary (the computerized database system at our center uses the ICD-9 codes in patients' files).

Study design

Medical records were reviewed to confirm the presence of respiratory illness as the primary reason for admission. Inclusion criterion was gestational age at birth of 34 weeks and above. Exclusion criteria were unrecorded gestation age at birth, primary reason for admission other than a respiratory illness, and patients with heart or pulmonary congenital malformations. Patients suffering from other chronic medical conditions (ie, neurological disorders, hematological disorders, renal disorders, endocrinological disorders, and gastrointestinal disorders) were not excluded from the study. Patients with a prior diagnosis of asthma or prior respiratory morbidity were not excluded from the study since prior diagnosis of asthma at this age, as recorded by a general pediatrician, often reflects recurrent respiratory symptoms, which also might be a consequence of prematurity. Patients with Down syndrome (trisomy 21) were excluded from the study regardless of presence or absence of congenital malformations. Our pediatric ward operates a national outpatient center for Down syndrome; therefore a high admission rate of patients suffering from this genetic disorder was expected. Current data strongly suggest that Down syndrome is a major risk factor for severe respiratory illnesses during the first years of life.^23,24 Thus, to avoid bias, these patients were excluded.

The following data were retrieved from patients' charts from their first respiratory admission during the studied year (index hospitalization): gestational age at birth, sex, chronologic age at admission, chronic disabilities and nonpulmonary diseases, medications and duration of symptoms before admission, symptoms and laboratory indices on presentation (as recorded in the emergency room computerized chart), results of microbiological studies, hospitalization course, and diagnosis at discharge. Importantly, since patients' files are recorded by residents and general pediatricians and an accurate diagnosis of asthma at <2 years of age is often difficult, we considered a computerized diagnosis of asthma as a “wheezing illness” and not a separate entity. Other “wheezing illnesses” included charted diagnosis of bronchiolitis and wheezing.

Resource utilization during the hospital stay was also recoded, including type and duration of medication and oxygen therapy during hospitalization, ancillary studies (cultures, sweat tests, echocardiograms, bronchoscopy, and radiological studies), and medical care prescribed at hospital discharge.

In addition, for each patient, any readmission due to a respiratory illness (determined according to the same coding procedures as the index admission) during the year following discharge from the index hospitalization was also recorded. The institutions' computerized data base was used to identify patients' rehospitalizations. Patients were stratified into one of two groups by gestational age at birth: LPT (34–36 ⁶/₇ weeks gestation) and full term (FT) (≥37 weeks gestation).

Study end points

Major outcome measures included total hospital length of stay (LOS) and the number of readmissions due to an acute respiratory illness in the year following discharge from the index hospitalization. Minor outcome measures included duration of fever and duration of supplemental oxygen treatment.

Statistical analysis

Results were summarized as means and standard deviations for continuous variables and percentages for nominal variables. Bivariate comparisons between the LPT and FT groups for continuous variables used the t-test in case of normal distributions and the Mann–Whitney test in case of nonnormal distributions. For nominal variables, the Wald Chi-Square test or Fisher's exact test was used where necessary. Multivariate logistic regression models were used to evaluate the influence of covariates on major outcomes. Covariates used in the multivariate model included the following: gestational age at birth (LPT or FT), chronic nonrespiratory illness, chronic respiratory illness (bronchopulmonary dysplasia and asthma), age at index hospitalization, cause of admission at index hospitalization, oxygen support during index hospitalization, index hospitalization LOS (as a continuous variable), and treatment with chronic respiratory medication following the index hospitalization. The statistical analysis was performed using SAS^® 9.3 Software (Cary, NC).

Results

During the study period, 584 children under the age of 2 years were admitted to the pediatric ward for acute respiratory illness; no mortality was recorded. Ninety-eight children were excluded from the study: 53 children lacked a record of gestational age at birth in their medical charts, 29 were born early preterm (<34 weeks gestation), and 16 children had Down syndrome. Thus, the final study cohort included 486 children, of whom 435 (89.5%) were born FT and 51 (10.5%) were born LPT.

As shown in Table 1, regarding the index hospitalization, the FT and LPT groups were similar in terms of demographic, preadmission clinical characteristics, chronic illnesses, and clinical and laboratory parameters at presentation. The causes of admission and organisms responsible for infectious illnesses were also similar in both groups (Tables 1 and 2). A wheezing illness, either asthma or acute bronchiolitis, was the most common cause for admission in both groups (72.6% and 72.5% in FT and LPT children, respectively). RSV was the most common identified infectious cause in both groups, 47.5% and 43.9% in the FT and LPT groups. respectively (Table 2). Altogether, an infectious viral agent was identified in 63.7% of the FT and 51.2% of the LPT children.

Table 1.

Patient Characteristics at Presentation at Index Hospitalization

	Full term (n = 435)	Late preterm (n = 51)	P
Gestational age at birth	39.6 [1.0]	35.1 [0.9]	<0.001
Age (months)	8.3 [6.4]	7.5 [4.7]	0.26
Sex (% male)	56.3	62.7	0.38
Duration of fever before admission (days)	1.6 [2.4] n = 429^b	1.3 [1.8] n = 49^b	0.35
Chronic medical treatment	33 (7.6)	5 (9.8)	0.58
Prior respiratory morbidity^a	53 (12.2)	2 (3.9)	0.08
Chronic medical conditions^a	22 (5.1)	4 (7.8)	0.40
Cause of admission
Bronchiolitis	224 (51.5)	30 (58.8)	0.34
Asthma	92 (21.1)	7 (13.7)	0.22
URTI	37 (8.5)	6 (11.8)	0.44
Pneumonia	61 (14)	6 (11.8)	0.65
Other	21 (4.8)	2 (3.9)	0.77
Indices on admission
Patients with fever	425 (97.7)	49 (96)	0.94
Oxygen saturation at room air (%)	92 [5.8]	93 [3.8]	0.12
WBC (10⁹/L)	14.23 [7] n = 403^b	13.23 [6.8] n = 46^b	0.35
CRP (mg/dL)	3.4 [5.5] n = 279^b	1.97 [3] n = 36^b	0.10

See text for details.

number of patients tested.

Data presented as n (%) or mean [ ± Standard Deviation].

CRP, C reactive protein; WBC, white blood cells.

Table 2.

Viral Respiratory Pathogens Identified During the Index Hospitalization

	Full term (n = 364^a)	Late preterm (n = 41^a)	P
Nonidentified	132 (36.3)	20 (48.8)	0.12
RSV	173 (47.5)	18 (43.9)	0.66
HMPV	25 (6.9)	1 (2.4)	0.30
Adenovirus	16 (4.4)	1 (2.4)	0.56
Parainfluenza	10 (2.7)	1 (2.4)	0.91
Other	8 (2.2)	0 (0)	0.64

number of patients tested.

HMPV, human metapneumovirus; RSV, respiratory syncytial virus.

Outcomes

Hospital LOS and all measured variables assessing the clinical course and the severity of the respiratory illness during the index hospitalization were similar in both groups (Table 3). In the year following the index hospitalization, when compared to FT, LPT patients had a significantly increased risk for rehospitalizations due to respiratory illness, [12 (19%) rehospitalization in LPT patients versus. 38 (8%) rehospitalizations in FT patients, odds ratio (OR) = 2.69, 95% confidence interval (CI) = 1.32–5.48, (P = 0.006)] (Table 4). Other identified risk factors for readmission due to acute respiratory illness were having a respiratory or nonrespiratory chronic illness and a relative prolonged LOS during the index admission. When multiple covariates were introduced into the multivariate regression models, late prematurity still remained a significant risk factor for readmission due to acute respiratory illness (adjusted OR = 2.24, 95% CI = 1.06–4.7, P = 0.035). A relative prolonged LOS in the index admission was also still a significant risk factor for readmission after multivariate regression analysis (adjusted OR = 1.006, 95% CI = 1.002–1.011, P = 0.008). Furthermore, even though the age during the index hospitalization was similar between the LPT and FT groups, rehospitalizations in the LPT group occurred at a significantly early age compared to the FT group (9.3 ± 3.3 months versus. 13.1 ± 7.8 months, P = 0.02), and at a shorter interval from index hospitalization (3.1 ± 0.8 months versus. 5.3 ± 0.6 months p = 0.05). All other measured variables assessing the clinical course and the severity of the respiratory illness during the rehospitalization were similar in both groups (Table 4).

Table 3.

Clinical Course During Index Hospitalization and Discharge

	Full term (n = 435)	Late preterm (n = 51)	P
LOS, days	4.08 [1.98]	4.24 [2.47]	0.67
Duration of fever, days	1.39 [0.66]	1.39 [0.6]	0.96
Admission to the PICU	17 (4)	2 (4)	0.99
Treatment
Supplemental oxygen	215 (49.8)	26 (51)	0.87
Duration of oxygen treatment, days	2.9 [1.9]	3.38 [2.4]	0.23
Antibiotic treatment	213 (49)	26 (51)	0.78
Duration of antibiotic treatment, days	3.77 [1.8]	3.35 [1.5]	0.25
Systemic steroid treatment,	182 (41.8)	25 (49)	0.37
Duration of steroid treatment, days	3.46 [1.7]	3.08 [1.4]	0.31
Bronchodilator treatment	370 (85.1)	42 (82.4)	0.61
Treatment with diuretics	4 (1)	1 (2)	0.23
Treatment with antireflux medications	26 (6)	3 (5.9)	0.97
Ancillary studies
CXR	384 (88)	45 (88)	0.35
HRCT chest	1 (0.2)	1 (2)	0.07
Bronchoscopy	2 (0.5)	1 (2)	0.20
Echocardiogram	9 (2.1)	3 (5.9)	0.10
Sweat test	15 (3.4)	0 (0)	0.18
PCR for pertussis	48 (11)	7 (13.7)	0.57
Recommended treatment at discharge
Supplemental oxygen	2 (0.5)	1 (2)	0.20
Bronchodilator treatment	137 (31.6)	12 (23.5)	0.23
Antibiotic treatment	130 (30)	15 (29.4)	0.92
Systemic steroid treatment	131 (30.2)	12 (23.5)	0.32
Inhaled corticosteroid treatment	24 (5.5)	2 (3.9)	0.63
Treatment with montelukast	39 (9)	3 (5.9)	0.45
Treatment with diuretics	1 (0.2)	1 (2)	0.07
Antireflux medication	15 (3.5)	1 (2)	0.57

Data presented as n (%) or mean [ ± SD].

LOS, length of stay; PICU, pediatric intensive care unit.

Table 4.

Characteristics of Rehospitalizations Due to a Respiratory Illness in the Year Following the Index Hospitalization

	Full term (n = 435)	Late preterm (n = 51)	P
Total number of rehospitalization^a	38 (8)	12 (19)	0.006
Number of patients rehospitalized	34 (7.8)	8 (15.7)	0.06
Average number of rehospitalizations	1.1 [0.36]	1.5 [0.76]	0.23
Interval between index and rehospitalization (months)	3.1 [0.8]	5.3 [0.6]	0.05
Age at rehospitalization (months)	13.1 [7.8]	9.3 [3.3]	0.02
Rehospitalization due to a wheezing illness	27 (71)	10 (83)	0.4
LOS in rehospitalization (days)	3.71 [3.16]	3.83 [3.51]	0.91

Number of rehospitalization in the year following index hospitalization.

Data presented as n (%) or mean [ ± SD].

Discussion

Our study findings demonstrate that when compared to FT, infants born LPT are at an increased risk for rehospitalization due to a respiratory illness (mainly wheezing or bronchiolitis) during the first 2 years of life. Nonetheless, the severity of illness during the index hospitalization and also rehospitalization was not found to be significantly different from that of FT infants.

To the best of our knowledge, this is the first study evaluating the impact of late prematurity on respiratory hospitalization in the first 2 years of life, outside the perinatal period. Furthermore, the finding of an increased risk for recurrent respiratory hospitalizations in LPT infants with a similar clinical hospitalization course as FT infants has not been described elsewhere. Other studies have also reported higher rates of recurrent respiratory hospitalizations up to 2- to 3-fold in LPT infants,²⁵ but have dealt primarily with the higher rates of recurrent hospitalizations due to acute RSV infections.^26,27 These studies demonstrated that LPT infants required more admissions during the first few months of life.^25,28 The data collected in this study examined respiratory hospitalizations over a wider age range. Thus, this study reinforces the finding of ongoing respiratory morbidity in children born LPT beyond the first few months of life.

In contrast to our findings of comparable course and resource utilization during respiratory hospitalizations in LPT and FT infants, other studies have described an increased risk for severe respiratory illness in LPT infants. A recent prospective study found that children under 2 years of age born 31–36 weeks gestation are at an increased risk for admission to the pediatric intensive care unit (PICU) for community-acquired alveolar pneumonia.⁹ Other studies have shown an increased use of medical resources^25,29 and complications^21,22 during the first year of life in the LPT infants compared to FT infants. In addition, Gunville et al. reported that children born LPT and admitted to the PICU during the first 2 of life for respiratory illness have a more severe clinical course that manifests in longer hospitalization stay, more use of medical resources, and higher costs compared to children born FT.³⁰ Some of these studies reporting respiratory morbidity in late prematurity included infants born more prematurely (31–34 weeks of gestational age).^{9,13,14,21,22,25,29} Early and late respiratory morbidity correlate with the extent of prematurity; thus the inclusion of infants born early during pregnancy may explain the discrepancies between our results and the results in these studies. The cutoff point of 34 weeks of gestation for late prematurity may be artificial, but is important for determining policies regarding preventive treatment strategies and resource utilization.

The most common cause for hospitalization and rehospitalization in our study was a “wheezing illness” (medical chart diagnosis of asthma, wheezing, or bronchiolitis). This finding is consistent with studies showing the increased incidence of asthma in LPT children^8,10–13 and may indicate the need to consider starting asthma preventive therapy in LPT children hospitalized with a first episode of an acute wheezing illness.

There are several limitations to this study. First, the observational retrospective design may have resulted in missing or incomplete data and medical registration errors; we were unable to assess important prenatal and postnatal information such as maternal smoking during pregnancy, postnatal second hand smoke exposure, and duration of breast feeding. Second, this study was conducted in a single medical center and thus lacks information about hospitalizations from other medical centers during the study period. The main strength of this study is related to the definition of late prematurity in our inclusion criteria (born 34⁰/₇–36⁶/₇ weeks gestation), which made it possible to focus specifically on this group of patients without introducing the bias of earlier gestational ages, sometimes referred to as “moderate preterm”. In addition, the assessment of readmissions in the year following hospitalization allows for a broader clinical perspective on the long-term outcomes of these children.

We presented evidence for late pulmonary morbidity in infants born LPT. Our findings suggest that late prematurity is a major risk factor for recurrent hospitalization due to “wheezing illness” in the first 2 years of life. Further studies are required to assess the benefit of preventive treatments.

Footnotes

Acknowledgment

The project was supported by internal departmental funds.

Author Disclosure Statement

No competing financial interests exist.

References

Goldenberg

, Culhane

, Iams

, Romero

. Epidemiology and causes of preterm birth. Lancet, 2008; 371:75–84.

Mathews

, MacDorman

. Infant mortality statistics from the 2006 period linked birth/infant death data set. Natl Vital Stat Rep, 2010; 58:1–31.

Raju

, Higgins

, Stark

, Leveno

. Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics, 2006; 118:1207–1214.

Kugelman

, Colin

. Late preterm infants: near term but still in a critical developmental time period. Pediatrics, 2013; 132:741–751.

Consortium on Safe L, Hibbard

, Wilkins

, et al. Respiratory morbidity in late preterm births. Jama, 2010; 304:419–425.

Young

, Korgenski

, Buchi

. Early readmission of newborns in a large health care system. Pediatrics, 2013; 131:e1538–e1544.

Kotecha

, Dunstan

, Kotecha

. Long term respiratory outcomes of late preterm-born infants. Semi Fetal Neonatal Med, 2012; 17:77–81.

Harju

, Keski-Nisula

, Georgiadis

, Raisanen

, Gissler

, Heinonen

. The burden of childhood asthma and late preterm and early term births. J Pediatr, 2014; 164:295–299 e291.

Greenberg

, Dagan

, Shany

, Bar-Ziv

, Givon-Lavi

. Increased risk for respiratory syncytial virus-associated, community-acquired alveolar pneumonia in infants born at 31–36 weeks of gestation. Pediatr Infect Dis J, 2014; 33:381–386.

10.

Goyal

, Fiks

, Lorch

. Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics, 2011; 128:e830–e838.

11.

Boyle

, Poulsen

, Field

, et al. Effects of gestational age at birth on health outcomes at 3 and 5 years of age: population based cohort study. BMJ, 2012; 344:e896.

12.

Vogt

, Lindstrom

, Braback

, Hjern

. Preterm birth and inhaled corticosteroid use in 6- to 19-year-olds: a Swedish national cohort study. Pediatrics, 2011; 127:1052–1059.

13.

Vrijlandt

, Kerstjens

, Duiverman

, Bos

, Reijneveld

. Moderately preterm children have more respiratory problems during their first 5 years of life than children born full term. Am J Respir Crit Care Med, 2013; 187:1234–1240.

14.

Colin

, McEvoy

, Castile

. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks' gestational age. Pediatrics, 2010; 126:115–128.

15.

Kotecha

, Watkins

, Paranjothy

, Dunstan

, Henderson

, Kotecha

. Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents. Thorax, 2012; 67:54–61.

16.

McEvoy

, Venigalla

, Schilling

, Clay

, Spitale

, Nguyen

. Respiratory function in healthy late preterm infants delivered at 33–36 weeks of gestation. J Pediatr, 2013; 162:464–469.

17.

Abe

, Shapiro-Mendoza

, Hall

, Satten

. Late preterm birth and risk of developing asthma. J Pediatr, 2010; 157:74–78.

18.

Voge

, Katusic

, Qin

, Juhn

. Risk of asthma in late preterm infants: a propensity score approach. J Allergy Clin Immunol pract, 2015.

19.

Crump

, Winkleby

, Sundquist

. Risk of asthma in young adults who were born preterm: a Swedish national cohort study. Pediatrics, 2011; 127:e913–e920.

20.

Boyce

, Mellen

, Mitchel

Jr. , Wright

, Griffin

. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr, 2000; 137:865–870.

21.

Willson

, Landrigan

, Horn

, Smout

. Complications in infants hospitalized for bronchiolitis or respiratory syncytial virus pneumonia. J pediatr, 2003; 143(5 Suppl):S142–S149.

22.

Horn

, Smout

. Effect of prematurity on respiratory syncytial virus hospital resource use and outcomes. J Pediatr, 2003; 143(5 Suppl):S133–S141.

23.

Bloemers

, van Furth

, Weijerman

, et al. Down syndrome: a novel risk factor for respiratory syncytial virus bronchiolitis—a prospective birth-cohort study. Pediatrics, 2007; 120:e1076–e1081.

24.

, Lanctot

, Bont

, et al. Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. Pediatrics, 2014; 133:1031–1037.

25.

McLaurin

, Hall

, Jackson

, Owens

, Mahadevia

. Persistence of morbidity and cost differences between late-preterm and term infants during the first year of life. Pediatrics, 2009; 123:653–659.

26.

Drysdale

, Milner

, Greenough

. Respiratory syncytial virus infection and chronic respiratory morbidity—is there a functional or genetic predisposition?. Acta Paediatr, 2012; 101:1114–1120.

27.

Resch

, Paes

. Are late preterm infants as susceptible to RSV infection as full term infants?. Early Hum Dev, 2011; 87 Suppl 1:S47–S49.

28.

Oddie

, Hammal

, Richmond

, Parker

. Early discharge and readmission to hospital in the first month of life in the Northern Region of the UK during 1998: a case cohort study. Arch Dis Child, 2005; 90:119–124.

29.

Bird

, Bronstein

, Hall

, Lowery

, Nugent

, Mays

. Late preterm infants: birth outcomes and health care utilization in the first year. Pediatrics, 2010; 126:e311–e319.

30.

Gunville

, Sontag

, Stratton

, Ranade

, Abman

, Mourani

. Scope and impact of early and late preterm infants admitted to the PICU with respiratory illness. J Pediatr, 2010; 157:209–214 e201.