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Early-term birth is a risk factor for wheezing in childhood: A cross-sectional population study
Early-term birth is a risk factor for wheezing in childhood: A cross-sectional population study Martin O. Edwards, BM, MRCPCH,a Sarah J. Kotecha, BSc, SRD,a John Lowe, BSc,a Louise Richards, MSc,b W. John Watkins, PhD,a and Sailesh Kotecha, PhD, FRCPCHa Cardiff, United Kingdom Background: Early term–born (37-38 weeks’ gestation) infants have increased respiratory morbidity during the neonatal period compared with full term–born (39-42 weeks’ gestation) infants, but longer-term respiratory morbidity remains unclear. Objective: We assessed whether early term–born children have greater respiratory symptoms and health care use in childhood compared with full term–born children. Methods: We surveyed 1- to 10-year-old term-born children (n 5 13,361). Questionnaires assessed respiratory outcomes with additional data gathered from national health databases. Results: Of 2,845 eligible participants, 545 were early term–born and 2,300 were full term–born. Early term–born children had higher rates of admission to the neonatal unit (odds ratio [OR], 1.7; 95% CI, 1.2-2.5) and admission to the hospital during their first year of life (OR, 1.6; 95% CI, 1.2-2.1). Forty-eight percent of early term–born children less than 5 years old reported wheeze ever compared with 39% of full term–born children (OR, 1.5; 95% CI, 1.1-1.9), and 26% versus 17% reported recent wheezing (OR, 1.7; 95% CI, 1.3-2.4). Early term–born children older than 5 years reported higher rates of wheeze ever (OR, 1.4; 95% CI, 1.05-1.8) and recent wheezing over the last 12 months than full-term control subjects (OR, 1.4; 95% CI, 1.02-2.0). Increased rates of respiratory symptoms in early term–born children persisted when family history of atopy and delivery by means of cesarean sections were included in logistic regression models. Conclusion: Early term–born children had significantly increased respiratory morbidity and use of health care services when compared with full term–born children, even when stratified by mode of delivery and family history of atopy. (J Allergy Clin Immunol 2015;nnn:nnn-nnn.) Key words: Cesarean section, asthma, wheezing, gestational age, atopy, bronchodilators
From athe Department of Child Health, Cardiff University School of Medicine, and bthe NHS Wales Informatics Service, Cardiff. Supported in part by Mason Medical Research Foundation and CYPRN. Disclosure of potential conflict of interest: M. O. Edwards has received research support from the Mason Medical Research Foundation and the Children and Young People’s Research Network (CYPRN Wales) and has received travel support from CYPRN Wales. S. Kotecha has consultant arrangements with VoluSense Norway and has received research support from the Medical Research Council, the European Union Framework Programme 7, and the Welsh government. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication December 9, 2014; revised April 29, 2015; accepted for publication May 7, 2015. Corresponding author: Sailesh Kotecha, PhD, FRCPCH, Department of Child Health, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: [email protected]. 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2015.05.005
Abbreviations used CS: Cesarean section OR: Odds ratio VD: Vaginal delivery WIMD: Welsh Index of Multiple Deprivation
Recently, the American College of Obstetricians and Gynecologists has redefined full-term delivery as 39 to 41 weeks’ gestation, and early-term deliveries are defined as 37 to 38 weeks’ gestation.1 This is due to evidence of increased morbidity in the neonatal period of infants born before 39 weeks’ gestation2-4 and due to increased mortality in infancy, childhood, and young adulthood of those born at 37 to 38 weeks’ gestation compared with those born at full term.5 However, there are limited data on the long-term respiratory outcomes of children and adults born early term, although some recent studies have focused on the respiratory outcomes of the late preterm population (34-36 weeks’ gestation).6-8 Some of these studies have included early-term birth in their analyses,9 but data beyond 5 years of age are very limited. In England and Wales 139,352 (nearly 19%) of the 726,572 live births in 2012 were early-term births.10 Several studies have shown increased admissions to neonatal units for infants born early term, especially those delivered by means of elective cesarean section (CS).11,12 In 2012, nearly a quarter of all CSs in England were performed at 37 to 38 weeks’ gestation, which accounted for a third of all early-term deliveries.13 Only a small proportion of these early term–born infants need to have respiratory morbidity in the long term to result in a marked burden on health care services. Infants born early term by means of elective CS have been shown to have greater respiratory morbidity when compared with infants delivered by means of vaginal delivery (VD).14,15 A recent meta-analysis reported an increased risk of asthma in childhood after delivery by means of either elective or emergency CS.16 Because they also noted that ‘‘the risk of asthma was also higher in children born by instrumental vaginal delivery,’’ it is important to explore alternative explanations for future risk of wheeze, including the relative immaturity of the infants at birth, namely early-term birth (ie, 37-38 weeks’ gestation). Other possible explanations include neonatal respiratory morbidity, such as transient tachypnea of the newborn, especially in those delivered by means of CS,17 or family history of atopy because it might modify the risk of childhood respiratory symptoms, but there are few reports assessing its role in early term–born children. We examined the combined effect of early-term birth, mode of delivery, and family history of atopy on respiratory morbidity in childhood. We also hypothesized that children born early term 1
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TABLE I. Characteristics of responders less than 5 years of age, comparing early-term with full-term birth
Gestational age (wk), mean (95% CI) Birth weight (kg), mean (95% CI) Male sex (%) WIMD score, median Age (y), mean (95% CI) Maternal age (y) at time of delivery, mean (95% CI) Ethnicity, white (%) Family history of atopy (%) Mother smoked in pregnancy (%) Mode of delivery (CS or not [%]) Mode of delivery (elective CS/emergency CS/instrumental/NVD [%])
Early term (n 5 272)
Full term (n 5 1123)
37.7* (37.6-37.7) 3.10* (3.05-3.16) 147 (54) 977 2.3 (2.2-2.4) 30.5 (29.7-31.2) 232/253 (91.7) 65 (23.9) 30 (11) 97/262 (37)* 55 (21)*/42 (16)/29 (11)/136 (52)*
40.1 (40.0-40.1) 3.55 (3.52-3.57) 592 (52.7) 1009 2.2 (2.2-2.3) 30.3 (29.9-30.6) 984/1056 (93.2) 314 (28 [OR, 0.8; 95% CI, 0.6-1.1]) 101 (9) 279/1087 (25.7) 117 (11)/162 (15)/134 (12)/674 (62)
NVD, Normal vaginal delivery. *P < .05. OR for early-term against full-term birth.
have increased respiratory morbidity in childhood compared with full term–born control subjects. Furthermore, we postulated that the effect of gestational age on any respiratory morbidity would remain significant, even with the inclusion of mode of delivery and family history of atopy as confounding factors.
METHODS Respiratory and Neurological Outcomes of Children born Preterm Study We conducted a cross-sectional population-based study of children in Wales to explore the association between gestational age at birth and the risk of respiratory illness, hospital admissions, and other health-related outcomes in the first 10 years of life. In brief, we invited 13,361 preterm-born children and 13,361 term-born matched control subjects in 2013, with birth dates from January 1, 2003, to December 31, 2011, to complete a survey on respiratory and neurological health-based outcomes. Additional information was available from national health database systems. The South East Wales Research Ethics Committee approved the study.
Gestation groups and participants Gestational age at birth was used to categorize the children into early-term (37-38 weeks’ gestation) and full-term (39-42 weeks’ gestation) categories. The gestational age was based on maternal reporting of the last menstrual period and antenatal ultrasound scans. Standardized z scores were calculated for birth weight by correction for sex and gestational age at birth with the LMS method18; participants with a birth weight outside of 63.5 SDs were excluded because these weights were deemed implausible. Of the 2851 term-born (37-42 weeks’ gestation) participants in the Respiratory and Neurological Outcomes of Children born Preterm Study, 4 were excluded for having implausible birth weights, and 2 were excluded for missing birth weights. Anonymized data on birth weight, gestational age at birth, social status, and sex were available for the whole population from the National Health Service Wales Informatics Service, which manages health care databases in Wales. Additional perinatal information, such as date of birth, mode of delivery, maternal details, and admissions to the neonatal unit, was also available for the participants.
Statistical analysis x2 Tests and Mann-Whitney U tests were used to compare differences between the characteristics of the responders and nonresponders and between the early term– and full term–born participants. A P value of less than .05 was considered statistically significant. Missing responses in the questionnaires
were coded as negative responses, but analyses were also conducted by coding the missing responses as missing values. The results were essentially unchanged. Two different sets of questionnaires based on validated surveys were mailed to families with children less than 5 years of age19,20 and children 5 years of age and older.21,22 Main outcomes of interest focused on respiratory symptoms based on parental responses. Some of the data have been analyzed after separation into these 2 age groups to allow for the different questions being assessed. Univariate logistic regression analysis was used to investigate differences between the 2 gestational groups for health-related outcomes, such as wheezing ever, use of inhalers, and hospital admissions. Multivariable logistic regression analyses were performed to adjust for mode of delivery at birth (CS delivery or VD) only and then to adjust for confounding factors, which included the Welsh Index of Multiple Deprivation score (WIMD; an area-based measure of multiple deprivation), sex, maternal smoking during pregnancy, family history of atopy, ethnicity, and maternal age at time of delivery in a single model by using main effects only. More detailed models that included additional factors, such as intrauterine growth restriction, current maternal smoking, and maternal history of asthma, were also performed, but because their contribution was small to the overall effect size, only the factors with the most significant contributions are presented. In secondary analyses, using logistic regression modeling, we stratified the children by mode of delivery and compared the differences in rates of wheezing and neonatal admissions between children born early term and children born full term. We also compared differences in rates of wheezing between children born early term who did or did not have a family history of atopy with children born full term who did or did not have a family history of atopy. The statistical analysis was performed with PAWS/SPSS software (version 18.0; IBM, Chicago, Ill).
RESULTS Characteristics of responders From 13,361 term-born children invited to take part, 2,845 (21.3%) were included in the analyses after exclusion of 6 respondents. Responders had similar characteristics to nonresponders except for higher WIMD scores (Tables I and II and see Tables E1 and E2 in this article’s Online Repository at www. jacionline.org). Comparing early term–born children (both age groups) with full term–born control subjects did not show a statistically significant difference for sex, age, WIMD score, ethnicity, maternal smoking during pregnancy, or maternal age at time of birth. The early term–born children had a significantly higher rate of CS delivery, particularly those delivered by means of elective CS, compared with the full term–born control subjects (37% vs 25.7% in the group of subjects <5 years of age with odds ratios
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TABLE II. Characteristics of responders 5 years of age or older, comparing early-term with full-term birth
Gestational age (wk), mean (95% CI) Birth weight (kg), mean (95% CI) Male sex (%) WIMD score, median Age (y), mean (95% CI) Maternal age (y) at time of delivery, mean (95% CI) Ethnicity, white (%) Family history of atopy (%) Mother smoked in pregnancy (%) Mode of delivery (CS or not [%]) Mode of delivery (elective CS/emergency CS/instrumental/NVD [%])
Early term (n 5 273)
Full term (n 5 1177)
37.7* (37.6-37.7) 3.13* (3.08-3.19) 142 (52) 1111 7.1 (6.9-7.3) 31.0 (30.3-31.7) 228/239 (95.4) 75 (27.5)* 33 (12.1) 106/245 (43.3)* 64 (26)*/42 (17)/25 (10)/114 (47)*
40.1 (40.0-40.1) 3.53 (3.51-3.56) 623 (52.9) 1117 7.2 (7.1-7.3) 30.3 (29.9-30.6) 973/1023 (95.1) 253 (21.5 [OR, 1.4; 95% CI, 1.0-1.9]) 150 (12.7) 235/1045 (22.5) 90 (9)/145 (14)/129 (12)/681 (65)
NVD, Normal vaginal delivery. *P < .05.
[ORs] of 1.7 [95% CI, 1.3-2.3] and 43.3% vs 22.5% in the group of subjects 5 years of age and older with ORs of 2.6 [95% CI, 2.03.5]). Rates of family history of atopy were 23.9% and 28% (OR, 0.8; 95% CI, 0.6-1.1) for the less than 5-year age group and 27.5% and 21.5% (OR, 1.4; 95% CI, 1.0-1.9) for the 5 years and older age group for those born early term and full term, respectively.
Children less than 5 years of age The prevalence of wheeze ever was 48.2% in the early term– born children less than 5 years of age and 39% in the full term– born control subjects, with an OR of 1.5 (95% CI, 1.1-1.9; Table III). Similar results were noted for the following respiratory outcomes: recent wheeze (OR, 1.7; 95% CI, 1.3-2.4), recent daytime coughing (OR, 1.7; 95% CI, 1.3-2.2), and recent chest infections (OR, 1.3; 95% CI, 1.0-1.8). Early term–born children also had twice the odds of inhaler medication use (OR, 2.0; 95% CI, 1.4-2.9), higher neonatal unit admission rates in the first 28 days of life (OR, 1.7; 95% CI, 1.2-2.5), and higher admission rates to the hospital in the first year of life (OR, 1.6; 95% CI, 1.22.1). The adjusted ORs for all respiratory symptoms, treatment with any inhaler, and admissions to the neonatal unit or hospital remained similar to the unadjusted results when mode of delivery alone or when all confounding factors were included in the analysis.
Children 5 years of age and older The prevalence of wheeze ever in children 5 years of age and older was 33.3% in the early term–born children and 26.4% in the full term–born control subjects (OR, 1.4; 95% CI, 1.05-1.8; Table IV). Similar results were noted for recent wheeze (OR, 1.4; 95% CI, 1.02-2.0), doctor’s diagnosis of asthma (OR, 1.4; 95% CI, 1.0-2.1), exercise-induced wheezing (OR, 1.8; 95% CI, 1.22.8), and chest infection over the last year (OR, 1.7; 95% CI, 1.2-2.3). It should be noted that children born early term had higher inhaler medication use (OR, 1.6; 95% CI, 1.1-2.3), treatment with antibiotics over the last year (OR, 1.7; 95% CI, 1.32.2), admissions to the neonatal unit in the first 28 days of life (OR, 1.5; 95% CI, 1.1-2.1), and admissions to the hospital in the first year of life (OR, 1.6; 95% CI, 1.2-2.1). For all results, when adjusted for mode of delivery, the ORs were unchanged or marginally lower compared with unadjusted ORs. When
TABLE III. Childhood wheezing, family history, inhaler use, and hospital admissions for all children less than 5 years of age (unadjusted and adjusted ORs) Early term (n 5 272)*
Admission to neonatal unit in first 28 d of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Admission to hospital in first year of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Recent daytime cough (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Chest infections over the last year (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Inhaler medication use (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI)
55 (20.2) 1.7 1.7 1.8 105 1.6 1.6 1.6 131 1.5 1.4 1.5 71 1.7 1.7 1.7 163 1.7 1.7 1.8 98 1.3 1.3 1.3 51 2.0 2.1 2.1
(1.2-2.5) (1.2-2.4) (1.3-2.5) (38.6) (1.2-2.1) (1.2-2.1) (1.2-2.1) (48.2) (1.1-1.9) (1.1-1.9) (1.1-1.9) (26.1) (1.3-2.4) (1.3-2.4) (1.3-2.4) (59.9) (1.3-2.2) (1.3-2.2) (1.3-2.3) (36) (1.0-1.8) (0.99-1.7) (1.0-1.8) (18.8) (1.4-2.9) (1.4-3.0) (1.4-3.0)
Full term (n 5 1123)*
143 (12.7) P 5 .002 P 5 .004 P 5 .001 316 (28.1) P 5 .001 P 5 .002 P 5 .001 438 (39) P 5 .006 P 5 .010 P 5 .005 189 (16.8) _ .001 P< P 5 .001 P 5 .001 527 (46.9) _ .001 P< _ .001 P< _ .001 P< 333 (29.7) P 5 .042 P 5 .052 P 5 .053 115 (10.2) _ .001 P< _ .001 P< _ .001 P<
*Participants with birth weights of less than or greater than 3.5 SDs or with unknown gestational age were excluded from the analysis. Adjusted for mode of delivery (CS or not). àAdjusted for family history of atopy, sex, maternal smoking during pregnancy, ethnicity, WIMD score, and maternal age at time of birth.
adjustment was made for all confounding factors, the results remained similar. The lower limits of some of the CIs for results for the older children were close to 1, with most showing statistical significance (P <.05); however, a doctor’s diagnosis of asthma was marginal (unadjusted P 5 .049, not significant after adjustments; Table IV).
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TABLE IV. Childhood wheezing, family history, inhaler use, and hospital admissions for all children 5 years of age and older (unadjusted and adjusted ORs) Early term (n 5 273)*
Admission to neonatal unit in first 28 d of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Admission to hospital in first year of life (%) OR (95%CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Doctor’s diagnosis of asthma (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Exercise-induced wheezing (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Inhaler medication use, any (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Chest infections over last year (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Treatment with antibiotics over last year of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI)
79 (28.9) 1.5 1.4 1.7 126 1.6 1.4 1.8 91 1.4 1.4 1.4 52 1.4 1.4 1.4 44 1.4 1.4 1.4 35 1.8 1.7 1.7 41 1.6 1.5 1.5 65 1.7 1.6 1.6 135
(1.1-2.1) (1.0-1.8) (1.2-2.2) (46.2) (1.2-2.1) (1.1-1.9) (1.4-2.4) (33.3) (1.05-1.8) (1.03-1.9) (1.0-1.8) (19) (1.02-2.0) (0.98-2.0) (0.93-1.9) (16.1) (1.0-2.1) (0.96-2.0) (0.9-2.0) (12.8) (1.2-2.8) (1.1-2.6) (1.2-2.7) (15) (1.1-2.3) (1.0-2.2) (1.0-2.2) (23.8) (1.2-2.3) (1.1-2.2) (1.1-2.2) (49.5)
1.7 (1.3-2.2) 1.6 (1.2-2.1) 1.6 (1.2-2.1)
Full term (n 5 1177)*
248 (21.1) P 5 .005 P 5 .045 P 5 .001 411 (34.9) P 5 .001 P 5 .007 _ .001 P< 311 (26.4) P 5 .020 P 5 .031 P 5 .043 165 (14) P 5 .037 P 5 .065 P 5 .110 138 (11.7) P 5 .049 P 5 .079 P 5 .110 87 (7.4) P 5 .004 P 5 .013 P 5 .015 118 (10) P 5 .018 P 5 .039 P 5 .036 187 (15.9) P 5 .002 P 5 .007 P 5 .007 437 (37.1)
FIG 1. Prevalence of wheeze ever for early term– and full term–born children delivered by means of CS or VD. Bars denote the percentage of term-born children having wheeze ever who were delivered by means of CS (white bars) or VD (gray bars). Only relevant ORs between groups are shown.
_ .001 P< P 5 .001 _ .001 P<
*Participants with birth weights of less than or greater than 3.5 SDs or with unknown gestational age were excluded from analysis. Adjusted for mode of delivery (CS or not). àAdjusted for family history of atopy, sex, maternal smoking during pregnancy, ethnicity, WIMD score, and maternal age at time of birth.
Prevalence of respiratory symptoms for mode of delivery and family history of atopy In our stratified analysis by mode of delivery and family history of atopy, the results for children less than 5 years of age and those 5 years of age and older were similar, and therefore both age groups were analyzed together. The odds of wheezing were significantly different between the early term– and full term–born groups for all subjects combined (OR, 1.4; 95% CI, 1.2-1.8). However, there was not a significant difference in the odds of wheezing between those delivered by means of CS and those delivered by means of VD (OR, 1.2; 95% CI, 0.99-1.42). On further evaluation of the interaction between these 2 factors, early term–born children who were delivered by means of CS had marginally increased risk of wheeze ever than term-born children delivered by means of CS (OR, 1.3; 95% CI, 0.95-1.8; Fig 1), and those delivered by means of
FIG 2. Neonatal unit admissions for early term– and full term–born children delivered by means of CS or VD. Bars denote the percentage of term-born children having wheeze ever who were delivered by means of CS (white bars) or VD (gray bars). Only relevant ORs between groups are shown.
VD were significantly different between the groups (OR, 1.5; 95% CI, 1.1-1.9). However, there was no significant difference in the odds of wheezing between children born early term by means of CS and children born early term by means of VD (OR, 1.1; 95% CI, 0.7-1.5) or between children born full term by means of CS and children born full term by means of VD (OR, 1.2; 95% CI, 0.9-1.4). These results strongly suggest that the mode of delivery has limited association with wheeze ever when comparing children born early term and those born full term. However, early term–born infants delivered by means of either VD or CS had greater rates of neonatal admission compared with full term–born infants delivered by means of VD (OR, 1.5; 95% CI, 1.1-2.0) or CS (OR, 1.4; 95% CI, 0.99-2.1; Fig 2). Furthermore, early term–born children with or without a family history
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TABLE VI. Wheezing in children 5 years of age and older, comparing birth by CS with birth by VD CS (n 5 341)
FIG 3. Prevalence of wheeze ever for term-born children with or without atopy. Bars denote the percentage of term-born children having wheeze ever who have a family history of atopy (white bars) or not (gray bars). Only relevant ORs between groups are shown.
TABLE V. Wheezing in children less than 5 years of age, comparing birth by CS with birth by VD CS (n 5 376)
Admission to neonatal unit (%) OR (95% CI) Adjusted* OR (95% CI) Admission to hospital in first year of life (%) OR (95% CI) Adjusted* OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted* OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted* OR (95% CI)
OR for VD early-term/ (n 5 973) full-term birth
69 1.5 1.4 131
(18.4) (1.1-2.1) (1.0-2.0) (34.8)
126 (12.9) P 5 .012 P 5 .027 279 (28.7)
1.7 (1.2-2.4) P 5 .004
1.3 1.3 164 1.2 1.1 75 1.1 1.1
(1.0-1.7) (0.99-1.7) (43.6) (0.9-1.5) (0.9-1.4) (19.9) (0.8-1.5) (0.8-1.4)
P 5 .028 P 5 .060 385 (39.6) P 5 .180 P 5 .270 177 (18.2) P 5 .460 P 5 .690
P < .001
1.6 (1.2-2.2)
1.4 (1.1-1.9) P 5 .010 1.7 (1.2-2.4) P < .001
*Adjusted for gestational age group at birth.
of atopy were both associated with increased risk of wheeze ever (with a family history: OR, 1.4; 95% CI, 1.0-2.1; without a family history: OR, 1.4; 95% CI, 1.1-1.8; Fig 3), suggesting that atopy is unlikely to play a part in the increased rates of respiratory symptoms in early term–born children. We next used a multivariable model to assess the role of mode of delivery in future development of wheezing in the 2 age groups (Tables Vand VI). When rates of wheezing were analyzed in children less than 5 years of age comparing birth by means of CS versus VD, the difference was not significant for wheeze ever (1.2; 95% CI, 0.9-1.5) and recent wheezing over the last 3 months (1.1; 95% CI, 0.8-1.5) but was significant for admission to the neonatal unit (1.5; 95% CI, 1.1-2.1) and admission to the hospital in the first year of life (1.3; 95% CI, 1.0-1.7). These results remained essentially unchanged after adjustment for gestational group at birth (Table V). In children 5 years of age and older, when relating birth by means of CS versus by means of VD to rates of wheezing, the
Admission to neonatal unit (%) OR (95% CI) Adjusted* OR (95% CI) Admission to hospital in first year of life (%) OR (95% CI) Adjusted* OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted* OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted* OR (95% CI) Doctor’s diagnosis of asthma (%) OR (95% CI) Adjusted* OR (95% CI)
VD OR for early-term/ (n 5 949) full-term birth
107 (31.4)
182 (19.2)
1.3 (1.0-1.8)
1.9 (1.5-2.6) 1.8 (1.4-2.4) 164 (48.1)
_ .001 P< _ .001 P< 317 (33.4)
P 5 .085
1.8 1.7 102 1.2 1.1 59 1.3 1.2 50
_ .001 P< _ .001 P< 252 (26.6) P 5 .230 P 5 .420 132 (13.9) P 5 .130 P 5 .250 115 (12.1)
(1.4-2.4) (1.3-2.3) (29.9) (0.9-1.6) (0.8-1.5) (17.3) (0.9-1.8) (0.9-1.7) (14.7)
1.2 (0.9-1.8) P 5 .230 0.99 (0.89-1.1) P 5 .820
1.5 (1.1-2.0) P 5 .006 1.4 (1.0-1.9) P 5 .030 1.5 (1.0-2.1) P 5 .040 1.4 (0.9-2.1) P 5 .070
*Adjusted for gestational age group at birth.
difference was not significant for wheeze ever (1.2; 95% CI, 0.91.6) and recent wheezing over the last 12 months (1.3; 95% CI, 0.9-1.8) but was significant for admission to a neonatal unit (1.9; 95% CI, 1.5-2.6) and admission to the hospital in the first year of life (1.8; 95% CI, 1.4-2.4). The results remained the same after adjustment for gestational age at birth (Table VI).
DISCUSSION The aim of this cross-sectional study was to collect data on respiratory-related outcomes for children who were born early or full term. Our results show that early term–born children up to 10 years of age had up to 70% greater risk of respiratory symptoms and up to 50% greater inhaler use than similarly aged term-born children. Early term–born children aged 5 years or greater also had increased risk of chest infections and antibiotic use when compared with those born at full term. The risk of respiratory symptoms and treatment with inhalers throughout childhood seemed to be largely independent of atopy and mode of delivery. We also confirm previous reports of the increased admission to neonatal units of early term–born infants, which was partially explained by greater delivery by means of CS.4,11 There have been few studies assessing the long-term respiratory health outcomes of children born early term. Goyal et al23 have shown increased risk of respiratory illness in those born late preterm (35-36 weeks’ gestation) and early term (3738 weeks’ gestation) in early childhood (up to 18 months of age). Boyle et al9 and Paranjothy et al24 have both reported increased risk of respiratory disease in children born early term up to 5 years of age, which we have confirmed. Our study extends these observations by collecting respiratory morbidity and treatment data for early term–born children. The data suggest that respiratory symptoms continue into early school years for early term–born children when compared with full term– born children and that these children are receiving increased treatment with inhaler medication. Harju et al25 also assessed the effect of gestational age at birth and the risk of having asthma in childhood and showed that early
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term and late preterm deliveries contribute most to the additional cases of asthma compared with those born at 39 to 40 weeks’ gestation, although they only assessed the risk of medically diagnosed asthma by relying on registry-collected data and were unable to comment on symptoms or severity. We have shown that early term–born children have more wheezing than full term– born control subjects, and this remained significant when sex, mode of delivery, and family history of atopy were included in the analysis. Whether the increased prevalence of respiratory symptoms is due to a ‘‘traditional’’ asthma diagnosis or is a consequence of earlier delivery and hence marginally earlier stage of lung growth and development remains to be seen. Our data did not show an association between early-term birth and a doctor’s diagnosis of asthma, and therefore the long-term diagnostic implications of early-term birth will need further evaluation. Our study has shown that more than a third of children born at 37 to 38 weeks’ gestation are delivered by means of CS (nearly 60% of which were elective), which has previously been shown to be an independent risk factor for later respiratory disease.26 However, our results did not find a difference between children delivered by means of CS compared with those delivered by means of VD for respiratory symptoms throughout childhood, which was similar to 2 previous studies.27,28 Children born early term by means of CS or VD had higher rates of wheezing compared with children born full term by means of VD and marginally increased rates for children born early term by means of CS compared with children born full term by means of CS. However, there was no difference in rates between children born early term by means of CS and those born early term by means of VD, and results were the same for full term–born children, which suggests that birth by means of CS, unlike previous observations, does not substantially affect later respiratory outcomes. In contrast, early term–born or full term–born infants delivered by means of CS were associated with greater admissions to the neonatal unit when compared with those born early term or full term and delivered by means of VD. Furthermore, the results stratified by age group have shown that those delivered by means of CS have increased neonatal admissions and admissions to the hospital in the first year of life compared with those delivered by means of VD, with the results remaining unchanged after adjustments for gestation. Tita et al2 and Wilmink et al29 both showed similar findings in their studies and supported the call to delay elective CS until after 38 weeks’ gestation. However, their results were unadjusted for gestation, although De Luca et al30 and Parikh et al11 both also showed that infants born secondary to CS have increased neonatal problems with adjustment for gestational age at birth, including those at 37 to 38 weeks’ gestation. A recent review of the literature by Kuzniewicz et al31 concluded that there are limited data on health care use by children born early term; our data showed that these children have increased treatment with inhalers, treatment with antibiotics, and hospital admissions. It would appear that children born early term are being treated more frequently for their increased respiratory symptoms with inhalers and have increased antibiotic use and hospital admissions. Although the early-term group had increased use of bronchodilators, it will be important to ensure that this treatment is appropriate, which will require investigation of the underlying mechanisms of increased wheeze we have reported in early term–born children. There are no previous reports on the differences in treatment of children born early term and full term, which suggests that clinicians need to consider the
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importance of gestational age at birth when reviewing all children with respiratory symptoms. There is growing recognition that not only children born preterm but also those born early term are at greater risk of poorer respiratory health in later life,32 and thus deliveries should be delayed to 39 weeks’ gestation unless medically indicated. Our results support the view that full-term delivery should be redefined as 39 to 41 weeks’ gestation,1,33 thus avoiding delivery at 38 weeks’ gestation or less and potentially decreasing future respiratory morbidity. The mechanisms underlying these recurrent respiratory symptoms in children born early term is not known but might be related to delivery at a marginally earlier stage of lung growth and development when surfactant production might not be optimal. This could be secondary to a structural immaturity because infants born at only a few weeks’ gestation early are still in the saccular stage of lung development,34 and therefore these children might have symptoms relating to reduced lung capacity. However, respiratory symptoms might be secondary to a functional problem, such as respiratory distress syndrome or transient tachypnea of the newborn, caused by reduced surfactant production and/or poor lung fluid clearance before birth.35 Further studies to understand the underlying mechanisms are required. If the respiratory symptoms in childhood are secondary to a functional abnormality at the time of birth, there is the potential to prevent neonatal respiratory morbidities with the use of antenatal maternal corticosteroids. It has been suggested that for medically indicated CS before 39 weeks’ gestation, mothers should receive antenatal glucocorticoids to decrease the risks of neonatal morbidity.36 Corticosteroid administration to the mother before elective CS at term appears to decrease neonatal respiratory symptoms in the neonatal period, most likely through their effects on clearance of lung fluid and enhanced surfactant production.30,36 Whether routine use of antenatal steroids in early term–born infants can prevent future risk of wheezing is speculative.37
Limitations Data were gathered from parent-completed questionnaires and hospital database records, and therefore we were able to analyze multiple health outcomes. However, this analysis was limited by the lack of data on indications for delivery before 39 weeks’ gestation. Indications, such as maternal sepsis and prolonged rupture of the membranes, can also result in increased rates of admissions and could affect longer-term respiratory outcomes.38 However, although these indications might be an important factor for a select group of babies who are delivered early by means of CS, our results show that the future risk for wheezing disorders was independent of mode of delivery. There was lack of information on maternal disease (although maternal age, which is strongly associated with increasing maternal disease, was included in multivariable logistic analyses) and for maternal treatment with antenatal corticosteroids (although this treatment is not _37 weeks’ routinely used in the United Kingdom for infants born > gestation). Questionnaires were completed by families with similar characteristics, except for higher rates of deprivation for the nonresponders, which could lead to an underestimation of respiratory morbidity; however, because the comparison was between those born at different gestational ages, the results are likely to remain robust. Because only very few cases had missing data, the data are unlikely to affect the main conclusions. It is often suggested that gestational age should be used as a
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continuous variable in analyses; however, we believe our analysis supports the notion of grouped gestational ages into categories, such as early term, late preterm, and term.33
Conclusion Our data suggest that delivery at 37 to 38 weeks’ gestation is associated with increased respiratory symptoms throughout childhood and increased use of health care services (neonatal admissions, admissions in the first year of life, and inhaler and antibiotic use). These findings appeared to be independent of atopy and of delivery by means of CS, suggesting that alternative mechanisms (eg, immaturity of the lungs) than those for asthma (ie, the hygiene hypothesis) might be responsible for the increased rates of wheeze noted in this group of children. The underlying mechanisms need to be clarified so that targeted therapy can be sought. It is clear from our data that delivery at 37 to 38 weeks’ gestation should be avoided, as recommended by the United Kingdom’s National Institute for Health and Care Excellence,39 unless medically indicated. We thank all the children and their families who took part in this study, the team at NWIS, and the following pediatric consultants for supporting this study: Dr G. Morris, Dr S. Papworth, Dr P. Stutchfield, Dr I. Barnard, Dr I. AlMuzaffar, Dr P. Pitchaikani, and Dr I. Prosser.
Key messages d
Early-term birth is associated with increased risk of respiratory morbidity in early and late childhood.
d
Wheezing associated with early-term birth appears to be independent of delivery by means of CS and of family history of atopy.
REFERENCES 1. American College of Obstetricians and Gynecologists. American Congress of Obstetricians and Gynecologists committee opinion no. 579: definition of term pregnancy. Obstet Gynecol 2013;122:1139-40. 2. Tita AT, Landon MB, Spong CY, Lai Y, Leveno KJ, Varner MW, et al. Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med 2009;360:111-20. 3. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 561: nonmedically indicated early-term deliveries. Obstet Gynecol 2013;121:911-5. 4. Fleischman AR, Oinuma M, Clark SL. Rethinking the definition of ‘‘term pregnancy’’. Obstet Gynecol 2010;116:136-9. 5. Crump C, Sundquist K, Winkleby MA, Sundquist J. Early-term birth (37-38 weeks) and mortality in young adulthood. Epidemiology 2013;24:270-6. 6. Hibbard J, Wilkins I, Sun L, Gregory K, Haberman S, Hoffman M, et al. Respiratory morbidity in late preterm births. JAMA 2010;304:419-25. 7. Kotecha SJ, Watkins WJ, Paranjothy S, Dunstan FD, Henderson AJ, Kotecha S. Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents. Thorax 2012;67:54-61. 8. Kotecha SJ, Dunstan FD, Kotecha S. Long term respiratory outcomes of late preterm-born infants. Semin Fetal Neonatal Med 2012;17:77-81. 9. Boyle EM, Poulsen G, Field DJ, Kurinczuk JJ, Wolke D, Alfirevic Z, 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. 10. Office for National Statistics. Office for National Statistics 2012: births and deaths in England and Wales (provisional), 2011. Newport: Office for National Statistics; 2011. 11. Parikh LI, Reddy UM, M€annist€o T, Mendola P, Sjaarda L, Hinkle S, et al. Neonatal outcomes in early term birth. Am J Obstet Gynecol 2014;211:265. 12. Sengupta S, Carrion V, Shelton J, Wynn RJ, Ryan RM, Singhal K, et al. Adverse neonatal outcomes associated with early-term birth. JAMA Pediatr 2013;167: 1053-9.
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13. Hospital Episode Statistics Analysis Health and Social Care Information Center. NHS Maternity Statistics 2012-13. London (United Kingdom): National Health Service; 2013. 14. Hansen A, Wisborg K, Uldbjerg N, Henriksen T. Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study. BMJ 2008;336: 85-7. 15. Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB. Elective caesarean section and respiratory morbidity in the term and near-term neonate. Acta Obstet Gynecol Scand 2007;86:389-94. 16. Huang L, Chen Q, Zhao Y, Wang W, Fang F, Bao Y. Is elective cesarean section associated with a higher risk of asthma? A meta-analysis. J Asthma 2015;52:16-25. 17. Adams M, Doull I. Birth by caesarean section and asthma. Clin Exp Allergy 2008; 38:554-6. 18. Pan H, Cole TJ. LMSgrowth, a Microsoft Excel add-in to access growth references based on the LMS method. Available at: http://www.healthforallchildren.co.uk/ 2012. Accessed January 2015. 19. Trinick R, Southern KW, McNamara PS. Assessing the Liverpool Respiratory Symptom Questionnaire in children with cystic fibrosis. Eur Respir J 2012;39: 899-905. 20. Powell CV, McNamara P, Solis A, Shaw NJ. A parent completed questionnaire to describe the patterns of wheezing and other respiratory symptoms in infants and preschool children. Arch Dis Child 2002;87:376-9. 21. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8:483-91. 22. Joshi S, Powell T, Watkins WJ, Drayton M, Williams EM, Kotecha S. Exerciseinduced bronchoconstriction in school-aged children who had chronic lung disease in infancy. J Pediatr 2013;162:813-8.e1. 23. Goyal NK, Fiks AG, Lorch SA. Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 2011;128:e830-8. 24. Paranjothy S, Dunstan F, Watkins WJ, Hyatt M, Demmler JC, Lyons RA, et al. Gestational age, birth weight, and risk of respiratory hospital admission in childhood. Pediatrics 2013;132:e1562-9. 25. Harju M, Keski-Nisula L, Georgiadis L, R€ais€anen S, Gissler M, Heinonen S. The burden of childhood asthma and late preterm and early term births. J Pediatr 2014; 164:295-9.e1. 26. Roduit C, Scholtens S, de Jongste JC, Wijga AH, Gerritsen J, Postma DS, et al. Asthma at 8 years of age in children born by caesarean section. Thorax 2009;64:107-13. 27. Werner A, Ramlau-Hansen CH, Jeppesen SK, Thulstrup AM, Olsen J. Caesarean delivery and risk of developing asthma in the offspring. Acta Paediatr 2007;96:595-6. 28. Menezes AM, Hallal PC, Matijasevich AM, Barros AJ, Horta BL, Araujo CL, et al. Caesarean sections and risk of wheezing in childhood and adolescence: data from two birth cohort studies in Brazil. Clin Exp Allergy 2011;41:218-23. 29. Wilmink FA, Hukkelhoven CW, Lunshof S, Mol BW, van der Post JA, Papatsonis DN. Neonatal outcome following elective cesarean section beyond 37 weeks of gestation: a 7-year retrospective analysis of a national registry. Am J Obstet Gynecol 2010;202:250.e1-8. 30. De Luca R, Boulvain M, Irion O, Berner M, Pfister RE. Incidence of early neonatal mortality and morbidity after late-preterm and term cesarean delivery. Pediatrics 2009;123:e1064-71. 31. Kuzniewicz MW, Parker SJ, Schnake-Mahl A, Escobar GJ. Hospital readmissions and emergency department visits in moderate preterm, late preterm, and early term infants. Clin Perinatol 2013;40:753-75. 32. Ananth CV, Friedman AM, Gyamfi-Bannerman C. Epidemiology of moderate preterm, late preterm and early term delivery. Clin Perinatol 2013;40:601-10. 33. Marlow N. Full term; an artificial concept. Arch Dis Child Fetal Neonatal Ed 2012; 97:F158-9. 34. Joshi S, Kotecha S. Lung growth and development. Early human development 2007;83:789-94. 35. Edwards MO, Kotecha SJ, Kotecha S. Respiratory distress of the term newborn infant. Paediatr Respir Rev 2013;14:29-36. 36. Stutchfield P, Whitaker R, Russell I. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ 2005;331:662. 37. Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S, Doull IJ. Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean section (ASTECS trial). Arch Dis Child Fetal Neonatal Ed 2013;98: F195-200. 38. Bendiks M, Kopp MV. The relationship between advances in understanding the microbiome and the maturing hygiene hypothesis. Curr Allergy Asthma Rep 2013;13: 487-94. 39. National Institute for Health and Care Excellence. CG132 caesarean section: NICE guidelines. Available at: http://guidance.nice.org.uk/CG132/NICEGuidance/ pdf/English2013. Accessed January 2015.
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TABLE E1. Characteristics of nonresponders less than 5 years of age, comparing early-term with full-term birth
Gestational age (wk), mean (95% CI) Birth weight (kg), mean (95% CI) Male sex (%) WIMD score, median Age (y), mean (95% CI) *P < .05.
Early term (n 5 1005)
Full term (n 5 4521)
37.7 (37.7-37.7) 3.13 (3.10-3.16) 551 (54.8) 741* 2.95 (2.90-3.00)*
40.1 (40.1-40.2) 3.52 (3.51-3.53) 2463 (54.5) 748* 3.00 (2.98-3.03)*
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TABLE E2. Characteristics of nonresponders 5 years of age and older, comparing early-term with full-term birth Early term (n 5 944)
Full term (n 5 3982)
Gestational age (wk), mean 37.7 (37.7-37.8) 40.1 (40.1-40.1) (95% CI) Birth weight (kg), mean (95% CI) 3.111 (3.08-3.14) 3.509 (3.49-3.52) Male sex (%) 544 (57.6) 2160 (54.2) WIMD score, median 742* 825* Age (y), mean (95% CI) 7.89 (7.78-7.99)* 7.90 (7.85-7.95)* *P < .05.
From athe Department of Child Health, Cardiff University School of Medicine, and bthe NHS Wales Informatics Service, Cardiff. Supported in part by Mason Medical Research Foundation and CYPRN. Disclosure of potential conflict of interest: M. O. Edwards has received research support from the Mason Medical Research Foundation and the Children and Young People’s Research Network (CYPRN Wales) and has received travel support from CYPRN Wales. S. Kotecha has consultant arrangements with VoluSense Norway and has received research support from the Medical Research Council, the European Union Framework Programme 7, and the Welsh government. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication December 9, 2014; revised April 29, 2015; accepted for publication May 7, 2015. Corresponding author: Sailesh Kotecha, PhD, FRCPCH, Department of Child Health, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: [email protected]. 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2015.05.005
Abbreviations used CS: Cesarean section OR: Odds ratio VD: Vaginal delivery WIMD: Welsh Index of Multiple Deprivation
Recently, the American College of Obstetricians and Gynecologists has redefined full-term delivery as 39 to 41 weeks’ gestation, and early-term deliveries are defined as 37 to 38 weeks’ gestation.1 This is due to evidence of increased morbidity in the neonatal period of infants born before 39 weeks’ gestation2-4 and due to increased mortality in infancy, childhood, and young adulthood of those born at 37 to 38 weeks’ gestation compared with those born at full term.5 However, there are limited data on the long-term respiratory outcomes of children and adults born early term, although some recent studies have focused on the respiratory outcomes of the late preterm population (34-36 weeks’ gestation).6-8 Some of these studies have included early-term birth in their analyses,9 but data beyond 5 years of age are very limited. In England and Wales 139,352 (nearly 19%) of the 726,572 live births in 2012 were early-term births.10 Several studies have shown increased admissions to neonatal units for infants born early term, especially those delivered by means of elective cesarean section (CS).11,12 In 2012, nearly a quarter of all CSs in England were performed at 37 to 38 weeks’ gestation, which accounted for a third of all early-term deliveries.13 Only a small proportion of these early term–born infants need to have respiratory morbidity in the long term to result in a marked burden on health care services. Infants born early term by means of elective CS have been shown to have greater respiratory morbidity when compared with infants delivered by means of vaginal delivery (VD).14,15 A recent meta-analysis reported an increased risk of asthma in childhood after delivery by means of either elective or emergency CS.16 Because they also noted that ‘‘the risk of asthma was also higher in children born by instrumental vaginal delivery,’’ it is important to explore alternative explanations for future risk of wheeze, including the relative immaturity of the infants at birth, namely early-term birth (ie, 37-38 weeks’ gestation). Other possible explanations include neonatal respiratory morbidity, such as transient tachypnea of the newborn, especially in those delivered by means of CS,17 or family history of atopy because it might modify the risk of childhood respiratory symptoms, but there are few reports assessing its role in early term–born children. We examined the combined effect of early-term birth, mode of delivery, and family history of atopy on respiratory morbidity in childhood. We also hypothesized that children born early term 1
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TABLE I. Characteristics of responders less than 5 years of age, comparing early-term with full-term birth
Gestational age (wk), mean (95% CI) Birth weight (kg), mean (95% CI) Male sex (%) WIMD score, median Age (y), mean (95% CI) Maternal age (y) at time of delivery, mean (95% CI) Ethnicity, white (%) Family history of atopy (%) Mother smoked in pregnancy (%) Mode of delivery (CS or not [%]) Mode of delivery (elective CS/emergency CS/instrumental/NVD [%])
Early term (n 5 272)
Full term (n 5 1123)
37.7* (37.6-37.7) 3.10* (3.05-3.16) 147 (54) 977 2.3 (2.2-2.4) 30.5 (29.7-31.2) 232/253 (91.7) 65 (23.9) 30 (11) 97/262 (37)* 55 (21)*/42 (16)/29 (11)/136 (52)*
40.1 (40.0-40.1) 3.55 (3.52-3.57) 592 (52.7) 1009 2.2 (2.2-2.3) 30.3 (29.9-30.6) 984/1056 (93.2) 314 (28 [OR, 0.8; 95% CI, 0.6-1.1]) 101 (9) 279/1087 (25.7) 117 (11)/162 (15)/134 (12)/674 (62)
NVD, Normal vaginal delivery. *P < .05. OR for early-term against full-term birth.
have increased respiratory morbidity in childhood compared with full term–born control subjects. Furthermore, we postulated that the effect of gestational age on any respiratory morbidity would remain significant, even with the inclusion of mode of delivery and family history of atopy as confounding factors.
METHODS Respiratory and Neurological Outcomes of Children born Preterm Study We conducted a cross-sectional population-based study of children in Wales to explore the association between gestational age at birth and the risk of respiratory illness, hospital admissions, and other health-related outcomes in the first 10 years of life. In brief, we invited 13,361 preterm-born children and 13,361 term-born matched control subjects in 2013, with birth dates from January 1, 2003, to December 31, 2011, to complete a survey on respiratory and neurological health-based outcomes. Additional information was available from national health database systems. The South East Wales Research Ethics Committee approved the study.
Gestation groups and participants Gestational age at birth was used to categorize the children into early-term (37-38 weeks’ gestation) and full-term (39-42 weeks’ gestation) categories. The gestational age was based on maternal reporting of the last menstrual period and antenatal ultrasound scans. Standardized z scores were calculated for birth weight by correction for sex and gestational age at birth with the LMS method18; participants with a birth weight outside of 63.5 SDs were excluded because these weights were deemed implausible. Of the 2851 term-born (37-42 weeks’ gestation) participants in the Respiratory and Neurological Outcomes of Children born Preterm Study, 4 were excluded for having implausible birth weights, and 2 were excluded for missing birth weights. Anonymized data on birth weight, gestational age at birth, social status, and sex were available for the whole population from the National Health Service Wales Informatics Service, which manages health care databases in Wales. Additional perinatal information, such as date of birth, mode of delivery, maternal details, and admissions to the neonatal unit, was also available for the participants.
Statistical analysis x2 Tests and Mann-Whitney U tests were used to compare differences between the characteristics of the responders and nonresponders and between the early term– and full term–born participants. A P value of less than .05 was considered statistically significant. Missing responses in the questionnaires
were coded as negative responses, but analyses were also conducted by coding the missing responses as missing values. The results were essentially unchanged. Two different sets of questionnaires based on validated surveys were mailed to families with children less than 5 years of age19,20 and children 5 years of age and older.21,22 Main outcomes of interest focused on respiratory symptoms based on parental responses. Some of the data have been analyzed after separation into these 2 age groups to allow for the different questions being assessed. Univariate logistic regression analysis was used to investigate differences between the 2 gestational groups for health-related outcomes, such as wheezing ever, use of inhalers, and hospital admissions. Multivariable logistic regression analyses were performed to adjust for mode of delivery at birth (CS delivery or VD) only and then to adjust for confounding factors, which included the Welsh Index of Multiple Deprivation score (WIMD; an area-based measure of multiple deprivation), sex, maternal smoking during pregnancy, family history of atopy, ethnicity, and maternal age at time of delivery in a single model by using main effects only. More detailed models that included additional factors, such as intrauterine growth restriction, current maternal smoking, and maternal history of asthma, were also performed, but because their contribution was small to the overall effect size, only the factors with the most significant contributions are presented. In secondary analyses, using logistic regression modeling, we stratified the children by mode of delivery and compared the differences in rates of wheezing and neonatal admissions between children born early term and children born full term. We also compared differences in rates of wheezing between children born early term who did or did not have a family history of atopy with children born full term who did or did not have a family history of atopy. The statistical analysis was performed with PAWS/SPSS software (version 18.0; IBM, Chicago, Ill).
RESULTS Characteristics of responders From 13,361 term-born children invited to take part, 2,845 (21.3%) were included in the analyses after exclusion of 6 respondents. Responders had similar characteristics to nonresponders except for higher WIMD scores (Tables I and II and see Tables E1 and E2 in this article’s Online Repository at www. jacionline.org). Comparing early term–born children (both age groups) with full term–born control subjects did not show a statistically significant difference for sex, age, WIMD score, ethnicity, maternal smoking during pregnancy, or maternal age at time of birth. The early term–born children had a significantly higher rate of CS delivery, particularly those delivered by means of elective CS, compared with the full term–born control subjects (37% vs 25.7% in the group of subjects <5 years of age with odds ratios
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TABLE II. Characteristics of responders 5 years of age or older, comparing early-term with full-term birth
Gestational age (wk), mean (95% CI) Birth weight (kg), mean (95% CI) Male sex (%) WIMD score, median Age (y), mean (95% CI) Maternal age (y) at time of delivery, mean (95% CI) Ethnicity, white (%) Family history of atopy (%) Mother smoked in pregnancy (%) Mode of delivery (CS or not [%]) Mode of delivery (elective CS/emergency CS/instrumental/NVD [%])
Early term (n 5 273)
Full term (n 5 1177)
37.7* (37.6-37.7) 3.13* (3.08-3.19) 142 (52) 1111 7.1 (6.9-7.3) 31.0 (30.3-31.7) 228/239 (95.4) 75 (27.5)* 33 (12.1) 106/245 (43.3)* 64 (26)*/42 (17)/25 (10)/114 (47)*
40.1 (40.0-40.1) 3.53 (3.51-3.56) 623 (52.9) 1117 7.2 (7.1-7.3) 30.3 (29.9-30.6) 973/1023 (95.1) 253 (21.5 [OR, 1.4; 95% CI, 1.0-1.9]) 150 (12.7) 235/1045 (22.5) 90 (9)/145 (14)/129 (12)/681 (65)
NVD, Normal vaginal delivery. *P < .05.
[ORs] of 1.7 [95% CI, 1.3-2.3] and 43.3% vs 22.5% in the group of subjects 5 years of age and older with ORs of 2.6 [95% CI, 2.03.5]). Rates of family history of atopy were 23.9% and 28% (OR, 0.8; 95% CI, 0.6-1.1) for the less than 5-year age group and 27.5% and 21.5% (OR, 1.4; 95% CI, 1.0-1.9) for the 5 years and older age group for those born early term and full term, respectively.
Children less than 5 years of age The prevalence of wheeze ever was 48.2% in the early term– born children less than 5 years of age and 39% in the full term– born control subjects, with an OR of 1.5 (95% CI, 1.1-1.9; Table III). Similar results were noted for the following respiratory outcomes: recent wheeze (OR, 1.7; 95% CI, 1.3-2.4), recent daytime coughing (OR, 1.7; 95% CI, 1.3-2.2), and recent chest infections (OR, 1.3; 95% CI, 1.0-1.8). Early term–born children also had twice the odds of inhaler medication use (OR, 2.0; 95% CI, 1.4-2.9), higher neonatal unit admission rates in the first 28 days of life (OR, 1.7; 95% CI, 1.2-2.5), and higher admission rates to the hospital in the first year of life (OR, 1.6; 95% CI, 1.22.1). The adjusted ORs for all respiratory symptoms, treatment with any inhaler, and admissions to the neonatal unit or hospital remained similar to the unadjusted results when mode of delivery alone or when all confounding factors were included in the analysis.
Children 5 years of age and older The prevalence of wheeze ever in children 5 years of age and older was 33.3% in the early term–born children and 26.4% in the full term–born control subjects (OR, 1.4; 95% CI, 1.05-1.8; Table IV). Similar results were noted for recent wheeze (OR, 1.4; 95% CI, 1.02-2.0), doctor’s diagnosis of asthma (OR, 1.4; 95% CI, 1.0-2.1), exercise-induced wheezing (OR, 1.8; 95% CI, 1.22.8), and chest infection over the last year (OR, 1.7; 95% CI, 1.2-2.3). It should be noted that children born early term had higher inhaler medication use (OR, 1.6; 95% CI, 1.1-2.3), treatment with antibiotics over the last year (OR, 1.7; 95% CI, 1.32.2), admissions to the neonatal unit in the first 28 days of life (OR, 1.5; 95% CI, 1.1-2.1), and admissions to the hospital in the first year of life (OR, 1.6; 95% CI, 1.2-2.1). For all results, when adjusted for mode of delivery, the ORs were unchanged or marginally lower compared with unadjusted ORs. When
TABLE III. Childhood wheezing, family history, inhaler use, and hospital admissions for all children less than 5 years of age (unadjusted and adjusted ORs) Early term (n 5 272)*
Admission to neonatal unit in first 28 d of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Admission to hospital in first year of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Recent daytime cough (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Chest infections over the last year (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Inhaler medication use (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI)
55 (20.2) 1.7 1.7 1.8 105 1.6 1.6 1.6 131 1.5 1.4 1.5 71 1.7 1.7 1.7 163 1.7 1.7 1.8 98 1.3 1.3 1.3 51 2.0 2.1 2.1
(1.2-2.5) (1.2-2.4) (1.3-2.5) (38.6) (1.2-2.1) (1.2-2.1) (1.2-2.1) (48.2) (1.1-1.9) (1.1-1.9) (1.1-1.9) (26.1) (1.3-2.4) (1.3-2.4) (1.3-2.4) (59.9) (1.3-2.2) (1.3-2.2) (1.3-2.3) (36) (1.0-1.8) (0.99-1.7) (1.0-1.8) (18.8) (1.4-2.9) (1.4-3.0) (1.4-3.0)
Full term (n 5 1123)*
143 (12.7) P 5 .002 P 5 .004 P 5 .001 316 (28.1) P 5 .001 P 5 .002 P 5 .001 438 (39) P 5 .006 P 5 .010 P 5 .005 189 (16.8) _ .001 P< P 5 .001 P 5 .001 527 (46.9) _ .001 P< _ .001 P< _ .001 P< 333 (29.7) P 5 .042 P 5 .052 P 5 .053 115 (10.2) _ .001 P< _ .001 P< _ .001 P<
*Participants with birth weights of less than or greater than 3.5 SDs or with unknown gestational age were excluded from the analysis. Adjusted for mode of delivery (CS or not). àAdjusted for family history of atopy, sex, maternal smoking during pregnancy, ethnicity, WIMD score, and maternal age at time of birth.
adjustment was made for all confounding factors, the results remained similar. The lower limits of some of the CIs for results for the older children were close to 1, with most showing statistical significance (P <.05); however, a doctor’s diagnosis of asthma was marginal (unadjusted P 5 .049, not significant after adjustments; Table IV).
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TABLE IV. Childhood wheezing, family history, inhaler use, and hospital admissions for all children 5 years of age and older (unadjusted and adjusted ORs) Early term (n 5 273)*
Admission to neonatal unit in first 28 d of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Admission to hospital in first year of life (%) OR (95%CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Doctor’s diagnosis of asthma (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Exercise-induced wheezing (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Inhaler medication use, any (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Chest infections over last year (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI) Treatment with antibiotics over last year of life (%) OR (95% CI) Adjusted OR (95% CI) Adjustedà OR (95% CI)
79 (28.9) 1.5 1.4 1.7 126 1.6 1.4 1.8 91 1.4 1.4 1.4 52 1.4 1.4 1.4 44 1.4 1.4 1.4 35 1.8 1.7 1.7 41 1.6 1.5 1.5 65 1.7 1.6 1.6 135
(1.1-2.1) (1.0-1.8) (1.2-2.2) (46.2) (1.2-2.1) (1.1-1.9) (1.4-2.4) (33.3) (1.05-1.8) (1.03-1.9) (1.0-1.8) (19) (1.02-2.0) (0.98-2.0) (0.93-1.9) (16.1) (1.0-2.1) (0.96-2.0) (0.9-2.0) (12.8) (1.2-2.8) (1.1-2.6) (1.2-2.7) (15) (1.1-2.3) (1.0-2.2) (1.0-2.2) (23.8) (1.2-2.3) (1.1-2.2) (1.1-2.2) (49.5)
1.7 (1.3-2.2) 1.6 (1.2-2.1) 1.6 (1.2-2.1)
Full term (n 5 1177)*
248 (21.1) P 5 .005 P 5 .045 P 5 .001 411 (34.9) P 5 .001 P 5 .007 _ .001 P< 311 (26.4) P 5 .020 P 5 .031 P 5 .043 165 (14) P 5 .037 P 5 .065 P 5 .110 138 (11.7) P 5 .049 P 5 .079 P 5 .110 87 (7.4) P 5 .004 P 5 .013 P 5 .015 118 (10) P 5 .018 P 5 .039 P 5 .036 187 (15.9) P 5 .002 P 5 .007 P 5 .007 437 (37.1)
FIG 1. Prevalence of wheeze ever for early term– and full term–born children delivered by means of CS or VD. Bars denote the percentage of term-born children having wheeze ever who were delivered by means of CS (white bars) or VD (gray bars). Only relevant ORs between groups are shown.
_ .001 P< P 5 .001 _ .001 P<
*Participants with birth weights of less than or greater than 3.5 SDs or with unknown gestational age were excluded from analysis. Adjusted for mode of delivery (CS or not). àAdjusted for family history of atopy, sex, maternal smoking during pregnancy, ethnicity, WIMD score, and maternal age at time of birth.
Prevalence of respiratory symptoms for mode of delivery and family history of atopy In our stratified analysis by mode of delivery and family history of atopy, the results for children less than 5 years of age and those 5 years of age and older were similar, and therefore both age groups were analyzed together. The odds of wheezing were significantly different between the early term– and full term–born groups for all subjects combined (OR, 1.4; 95% CI, 1.2-1.8). However, there was not a significant difference in the odds of wheezing between those delivered by means of CS and those delivered by means of VD (OR, 1.2; 95% CI, 0.99-1.42). On further evaluation of the interaction between these 2 factors, early term–born children who were delivered by means of CS had marginally increased risk of wheeze ever than term-born children delivered by means of CS (OR, 1.3; 95% CI, 0.95-1.8; Fig 1), and those delivered by means of
FIG 2. Neonatal unit admissions for early term– and full term–born children delivered by means of CS or VD. Bars denote the percentage of term-born children having wheeze ever who were delivered by means of CS (white bars) or VD (gray bars). Only relevant ORs between groups are shown.
VD were significantly different between the groups (OR, 1.5; 95% CI, 1.1-1.9). However, there was no significant difference in the odds of wheezing between children born early term by means of CS and children born early term by means of VD (OR, 1.1; 95% CI, 0.7-1.5) or between children born full term by means of CS and children born full term by means of VD (OR, 1.2; 95% CI, 0.9-1.4). These results strongly suggest that the mode of delivery has limited association with wheeze ever when comparing children born early term and those born full term. However, early term–born infants delivered by means of either VD or CS had greater rates of neonatal admission compared with full term–born infants delivered by means of VD (OR, 1.5; 95% CI, 1.1-2.0) or CS (OR, 1.4; 95% CI, 0.99-2.1; Fig 2). Furthermore, early term–born children with or without a family history
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TABLE VI. Wheezing in children 5 years of age and older, comparing birth by CS with birth by VD CS (n 5 341)
FIG 3. Prevalence of wheeze ever for term-born children with or without atopy. Bars denote the percentage of term-born children having wheeze ever who have a family history of atopy (white bars) or not (gray bars). Only relevant ORs between groups are shown.
TABLE V. Wheezing in children less than 5 years of age, comparing birth by CS with birth by VD CS (n 5 376)
Admission to neonatal unit (%) OR (95% CI) Adjusted* OR (95% CI) Admission to hospital in first year of life (%) OR (95% CI) Adjusted* OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted* OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted* OR (95% CI)
OR for VD early-term/ (n 5 973) full-term birth
69 1.5 1.4 131
(18.4) (1.1-2.1) (1.0-2.0) (34.8)
126 (12.9) P 5 .012 P 5 .027 279 (28.7)
1.7 (1.2-2.4) P 5 .004
1.3 1.3 164 1.2 1.1 75 1.1 1.1
(1.0-1.7) (0.99-1.7) (43.6) (0.9-1.5) (0.9-1.4) (19.9) (0.8-1.5) (0.8-1.4)
P 5 .028 P 5 .060 385 (39.6) P 5 .180 P 5 .270 177 (18.2) P 5 .460 P 5 .690
P < .001
1.6 (1.2-2.2)
1.4 (1.1-1.9) P 5 .010 1.7 (1.2-2.4) P < .001
*Adjusted for gestational age group at birth.
of atopy were both associated with increased risk of wheeze ever (with a family history: OR, 1.4; 95% CI, 1.0-2.1; without a family history: OR, 1.4; 95% CI, 1.1-1.8; Fig 3), suggesting that atopy is unlikely to play a part in the increased rates of respiratory symptoms in early term–born children. We next used a multivariable model to assess the role of mode of delivery in future development of wheezing in the 2 age groups (Tables Vand VI). When rates of wheezing were analyzed in children less than 5 years of age comparing birth by means of CS versus VD, the difference was not significant for wheeze ever (1.2; 95% CI, 0.9-1.5) and recent wheezing over the last 3 months (1.1; 95% CI, 0.8-1.5) but was significant for admission to the neonatal unit (1.5; 95% CI, 1.1-2.1) and admission to the hospital in the first year of life (1.3; 95% CI, 1.0-1.7). These results remained essentially unchanged after adjustment for gestational group at birth (Table V). In children 5 years of age and older, when relating birth by means of CS versus by means of VD to rates of wheezing, the
Admission to neonatal unit (%) OR (95% CI) Adjusted* OR (95% CI) Admission to hospital in first year of life (%) OR (95% CI) Adjusted* OR (95% CI) Wheeze ever (%) OR (95% CI) Adjusted* OR (95% CI) Recent wheeze (%) OR (95% CI) Adjusted* OR (95% CI) Doctor’s diagnosis of asthma (%) OR (95% CI) Adjusted* OR (95% CI)
VD OR for early-term/ (n 5 949) full-term birth
107 (31.4)
182 (19.2)
1.3 (1.0-1.8)
1.9 (1.5-2.6) 1.8 (1.4-2.4) 164 (48.1)
_ .001 P< _ .001 P< 317 (33.4)
P 5 .085
1.8 1.7 102 1.2 1.1 59 1.3 1.2 50
_ .001 P< _ .001 P< 252 (26.6) P 5 .230 P 5 .420 132 (13.9) P 5 .130 P 5 .250 115 (12.1)
(1.4-2.4) (1.3-2.3) (29.9) (0.9-1.6) (0.8-1.5) (17.3) (0.9-1.8) (0.9-1.7) (14.7)
1.2 (0.9-1.8) P 5 .230 0.99 (0.89-1.1) P 5 .820
1.5 (1.1-2.0) P 5 .006 1.4 (1.0-1.9) P 5 .030 1.5 (1.0-2.1) P 5 .040 1.4 (0.9-2.1) P 5 .070
*Adjusted for gestational age group at birth.
difference was not significant for wheeze ever (1.2; 95% CI, 0.91.6) and recent wheezing over the last 12 months (1.3; 95% CI, 0.9-1.8) but was significant for admission to a neonatal unit (1.9; 95% CI, 1.5-2.6) and admission to the hospital in the first year of life (1.8; 95% CI, 1.4-2.4). The results remained the same after adjustment for gestational age at birth (Table VI).
DISCUSSION The aim of this cross-sectional study was to collect data on respiratory-related outcomes for children who were born early or full term. Our results show that early term–born children up to 10 years of age had up to 70% greater risk of respiratory symptoms and up to 50% greater inhaler use than similarly aged term-born children. Early term–born children aged 5 years or greater also had increased risk of chest infections and antibiotic use when compared with those born at full term. The risk of respiratory symptoms and treatment with inhalers throughout childhood seemed to be largely independent of atopy and mode of delivery. We also confirm previous reports of the increased admission to neonatal units of early term–born infants, which was partially explained by greater delivery by means of CS.4,11 There have been few studies assessing the long-term respiratory health outcomes of children born early term. Goyal et al23 have shown increased risk of respiratory illness in those born late preterm (35-36 weeks’ gestation) and early term (3738 weeks’ gestation) in early childhood (up to 18 months of age). Boyle et al9 and Paranjothy et al24 have both reported increased risk of respiratory disease in children born early term up to 5 years of age, which we have confirmed. Our study extends these observations by collecting respiratory morbidity and treatment data for early term–born children. The data suggest that respiratory symptoms continue into early school years for early term–born children when compared with full term– born children and that these children are receiving increased treatment with inhaler medication. Harju et al25 also assessed the effect of gestational age at birth and the risk of having asthma in childhood and showed that early
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term and late preterm deliveries contribute most to the additional cases of asthma compared with those born at 39 to 40 weeks’ gestation, although they only assessed the risk of medically diagnosed asthma by relying on registry-collected data and were unable to comment on symptoms or severity. We have shown that early term–born children have more wheezing than full term– born control subjects, and this remained significant when sex, mode of delivery, and family history of atopy were included in the analysis. Whether the increased prevalence of respiratory symptoms is due to a ‘‘traditional’’ asthma diagnosis or is a consequence of earlier delivery and hence marginally earlier stage of lung growth and development remains to be seen. Our data did not show an association between early-term birth and a doctor’s diagnosis of asthma, and therefore the long-term diagnostic implications of early-term birth will need further evaluation. Our study has shown that more than a third of children born at 37 to 38 weeks’ gestation are delivered by means of CS (nearly 60% of which were elective), which has previously been shown to be an independent risk factor for later respiratory disease.26 However, our results did not find a difference between children delivered by means of CS compared with those delivered by means of VD for respiratory symptoms throughout childhood, which was similar to 2 previous studies.27,28 Children born early term by means of CS or VD had higher rates of wheezing compared with children born full term by means of VD and marginally increased rates for children born early term by means of CS compared with children born full term by means of CS. However, there was no difference in rates between children born early term by means of CS and those born early term by means of VD, and results were the same for full term–born children, which suggests that birth by means of CS, unlike previous observations, does not substantially affect later respiratory outcomes. In contrast, early term–born or full term–born infants delivered by means of CS were associated with greater admissions to the neonatal unit when compared with those born early term or full term and delivered by means of VD. Furthermore, the results stratified by age group have shown that those delivered by means of CS have increased neonatal admissions and admissions to the hospital in the first year of life compared with those delivered by means of VD, with the results remaining unchanged after adjustments for gestation. Tita et al2 and Wilmink et al29 both showed similar findings in their studies and supported the call to delay elective CS until after 38 weeks’ gestation. However, their results were unadjusted for gestation, although De Luca et al30 and Parikh et al11 both also showed that infants born secondary to CS have increased neonatal problems with adjustment for gestational age at birth, including those at 37 to 38 weeks’ gestation. A recent review of the literature by Kuzniewicz et al31 concluded that there are limited data on health care use by children born early term; our data showed that these children have increased treatment with inhalers, treatment with antibiotics, and hospital admissions. It would appear that children born early term are being treated more frequently for their increased respiratory symptoms with inhalers and have increased antibiotic use and hospital admissions. Although the early-term group had increased use of bronchodilators, it will be important to ensure that this treatment is appropriate, which will require investigation of the underlying mechanisms of increased wheeze we have reported in early term–born children. There are no previous reports on the differences in treatment of children born early term and full term, which suggests that clinicians need to consider the
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importance of gestational age at birth when reviewing all children with respiratory symptoms. There is growing recognition that not only children born preterm but also those born early term are at greater risk of poorer respiratory health in later life,32 and thus deliveries should be delayed to 39 weeks’ gestation unless medically indicated. Our results support the view that full-term delivery should be redefined as 39 to 41 weeks’ gestation,1,33 thus avoiding delivery at 38 weeks’ gestation or less and potentially decreasing future respiratory morbidity. The mechanisms underlying these recurrent respiratory symptoms in children born early term is not known but might be related to delivery at a marginally earlier stage of lung growth and development when surfactant production might not be optimal. This could be secondary to a structural immaturity because infants born at only a few weeks’ gestation early are still in the saccular stage of lung development,34 and therefore these children might have symptoms relating to reduced lung capacity. However, respiratory symptoms might be secondary to a functional problem, such as respiratory distress syndrome or transient tachypnea of the newborn, caused by reduced surfactant production and/or poor lung fluid clearance before birth.35 Further studies to understand the underlying mechanisms are required. If the respiratory symptoms in childhood are secondary to a functional abnormality at the time of birth, there is the potential to prevent neonatal respiratory morbidities with the use of antenatal maternal corticosteroids. It has been suggested that for medically indicated CS before 39 weeks’ gestation, mothers should receive antenatal glucocorticoids to decrease the risks of neonatal morbidity.36 Corticosteroid administration to the mother before elective CS at term appears to decrease neonatal respiratory symptoms in the neonatal period, most likely through their effects on clearance of lung fluid and enhanced surfactant production.30,36 Whether routine use of antenatal steroids in early term–born infants can prevent future risk of wheezing is speculative.37
Limitations Data were gathered from parent-completed questionnaires and hospital database records, and therefore we were able to analyze multiple health outcomes. However, this analysis was limited by the lack of data on indications for delivery before 39 weeks’ gestation. Indications, such as maternal sepsis and prolonged rupture of the membranes, can also result in increased rates of admissions and could affect longer-term respiratory outcomes.38 However, although these indications might be an important factor for a select group of babies who are delivered early by means of CS, our results show that the future risk for wheezing disorders was independent of mode of delivery. There was lack of information on maternal disease (although maternal age, which is strongly associated with increasing maternal disease, was included in multivariable logistic analyses) and for maternal treatment with antenatal corticosteroids (although this treatment is not _37 weeks’ routinely used in the United Kingdom for infants born > gestation). Questionnaires were completed by families with similar characteristics, except for higher rates of deprivation for the nonresponders, which could lead to an underestimation of respiratory morbidity; however, because the comparison was between those born at different gestational ages, the results are likely to remain robust. Because only very few cases had missing data, the data are unlikely to affect the main conclusions. It is often suggested that gestational age should be used as a
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continuous variable in analyses; however, we believe our analysis supports the notion of grouped gestational ages into categories, such as early term, late preterm, and term.33
Conclusion Our data suggest that delivery at 37 to 38 weeks’ gestation is associated with increased respiratory symptoms throughout childhood and increased use of health care services (neonatal admissions, admissions in the first year of life, and inhaler and antibiotic use). These findings appeared to be independent of atopy and of delivery by means of CS, suggesting that alternative mechanisms (eg, immaturity of the lungs) than those for asthma (ie, the hygiene hypothesis) might be responsible for the increased rates of wheeze noted in this group of children. The underlying mechanisms need to be clarified so that targeted therapy can be sought. It is clear from our data that delivery at 37 to 38 weeks’ gestation should be avoided, as recommended by the United Kingdom’s National Institute for Health and Care Excellence,39 unless medically indicated. We thank all the children and their families who took part in this study, the team at NWIS, and the following pediatric consultants for supporting this study: Dr G. Morris, Dr S. Papworth, Dr P. Stutchfield, Dr I. Barnard, Dr I. AlMuzaffar, Dr P. Pitchaikani, and Dr I. Prosser.
Key messages d
Early-term birth is associated with increased risk of respiratory morbidity in early and late childhood.
d
Wheezing associated with early-term birth appears to be independent of delivery by means of CS and of family history of atopy.
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13. Hospital Episode Statistics Analysis Health and Social Care Information Center. NHS Maternity Statistics 2012-13. London (United Kingdom): National Health Service; 2013. 14. Hansen A, Wisborg K, Uldbjerg N, Henriksen T. Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study. BMJ 2008;336: 85-7. 15. Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB. Elective caesarean section and respiratory morbidity in the term and near-term neonate. Acta Obstet Gynecol Scand 2007;86:389-94. 16. Huang L, Chen Q, Zhao Y, Wang W, Fang F, Bao Y. Is elective cesarean section associated with a higher risk of asthma? A meta-analysis. J Asthma 2015;52:16-25. 17. Adams M, Doull I. Birth by caesarean section and asthma. Clin Exp Allergy 2008; 38:554-6. 18. Pan H, Cole TJ. LMSgrowth, a Microsoft Excel add-in to access growth references based on the LMS method. Available at: http://www.healthforallchildren.co.uk/ 2012. Accessed January 2015. 19. Trinick R, Southern KW, McNamara PS. Assessing the Liverpool Respiratory Symptom Questionnaire in children with cystic fibrosis. Eur Respir J 2012;39: 899-905. 20. Powell CV, McNamara P, Solis A, Shaw NJ. A parent completed questionnaire to describe the patterns of wheezing and other respiratory symptoms in infants and preschool children. Arch Dis Child 2002;87:376-9. 21. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8:483-91. 22. Joshi S, Powell T, Watkins WJ, Drayton M, Williams EM, Kotecha S. Exerciseinduced bronchoconstriction in school-aged children who had chronic lung disease in infancy. J Pediatr 2013;162:813-8.e1. 23. Goyal NK, Fiks AG, Lorch SA. Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 2011;128:e830-8. 24. Paranjothy S, Dunstan F, Watkins WJ, Hyatt M, Demmler JC, Lyons RA, et al. Gestational age, birth weight, and risk of respiratory hospital admission in childhood. Pediatrics 2013;132:e1562-9. 25. Harju M, Keski-Nisula L, Georgiadis L, R€ais€anen S, Gissler M, Heinonen S. The burden of childhood asthma and late preterm and early term births. J Pediatr 2014; 164:295-9.e1. 26. Roduit C, Scholtens S, de Jongste JC, Wijga AH, Gerritsen J, Postma DS, et al. Asthma at 8 years of age in children born by caesarean section. Thorax 2009;64:107-13. 27. Werner A, Ramlau-Hansen CH, Jeppesen SK, Thulstrup AM, Olsen J. Caesarean delivery and risk of developing asthma in the offspring. Acta Paediatr 2007;96:595-6. 28. Menezes AM, Hallal PC, Matijasevich AM, Barros AJ, Horta BL, Araujo CL, et al. Caesarean sections and risk of wheezing in childhood and adolescence: data from two birth cohort studies in Brazil. Clin Exp Allergy 2011;41:218-23. 29. Wilmink FA, Hukkelhoven CW, Lunshof S, Mol BW, van der Post JA, Papatsonis DN. Neonatal outcome following elective cesarean section beyond 37 weeks of gestation: a 7-year retrospective analysis of a national registry. Am J Obstet Gynecol 2010;202:250.e1-8. 30. De Luca R, Boulvain M, Irion O, Berner M, Pfister RE. Incidence of early neonatal mortality and morbidity after late-preterm and term cesarean delivery. Pediatrics 2009;123:e1064-71. 31. Kuzniewicz MW, Parker SJ, Schnake-Mahl A, Escobar GJ. Hospital readmissions and emergency department visits in moderate preterm, late preterm, and early term infants. Clin Perinatol 2013;40:753-75. 32. Ananth CV, Friedman AM, Gyamfi-Bannerman C. Epidemiology of moderate preterm, late preterm and early term delivery. Clin Perinatol 2013;40:601-10. 33. Marlow N. Full term; an artificial concept. Arch Dis Child Fetal Neonatal Ed 2012; 97:F158-9. 34. Joshi S, Kotecha S. Lung growth and development. Early human development 2007;83:789-94. 35. Edwards MO, Kotecha SJ, Kotecha S. Respiratory distress of the term newborn infant. Paediatr Respir Rev 2013;14:29-36. 36. Stutchfield P, Whitaker R, Russell I. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ 2005;331:662. 37. Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S, Doull IJ. Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean section (ASTECS trial). Arch Dis Child Fetal Neonatal Ed 2013;98: F195-200. 38. Bendiks M, Kopp MV. The relationship between advances in understanding the microbiome and the maturing hygiene hypothesis. Curr Allergy Asthma Rep 2013;13: 487-94. 39. National Institute for Health and Care Excellence. CG132 caesarean section: NICE guidelines. Available at: http://guidance.nice.org.uk/CG132/NICEGuidance/ pdf/English2013. Accessed January 2015.
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J ALLERGY CLIN IMMUNOL NNN 2015
TABLE E1. Characteristics of nonresponders less than 5 years of age, comparing early-term with full-term birth
Gestational age (wk), mean (95% CI) Birth weight (kg), mean (95% CI) Male sex (%) WIMD score, median Age (y), mean (95% CI) *P < .05.
Early term (n 5 1005)
Full term (n 5 4521)
37.7 (37.7-37.7) 3.13 (3.10-3.16) 551 (54.8) 741* 2.95 (2.90-3.00)*
40.1 (40.1-40.2) 3.52 (3.51-3.53) 2463 (54.5) 748* 3.00 (2.98-3.03)*
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J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn
TABLE E2. Characteristics of nonresponders 5 years of age and older, comparing early-term with full-term birth Early term (n 5 944)
Full term (n 5 3982)
Gestational age (wk), mean 37.7 (37.7-37.8) 40.1 (40.1-40.1) (95% CI) Birth weight (kg), mean (95% CI) 3.111 (3.08-3.14) 3.509 (3.49-3.52) Male sex (%) 544 (57.6) 2160 (54.2) WIMD score, median 742* 825* Age (y), mean (95% CI) 7.89 (7.78-7.99)* 7.90 (7.85-7.95)* *P < .05.