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Long term respiratory outcomes of late preterm-born infants
Seminars in Fetal & Neonatal Medicine 17 (2012) 77e81
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Long term respiratory outcomes of late preterm-born infants Sarah J. Kotecha a, Frank D. Dunstan b, Sailesh Kotecha a, * a b
Department of Child Health, School of Medicine, Cardiff University, Cardiff, UK Primary Care and Public Health, School of Medicine, Cardiff University, Neuadd Meirionnydd, Cardiff, UK
s u m m a r y Keywords: Late preterm Lung growth Lung physiology Pulmonary function Respiratory
In recent years, the rate of preterm births has risen in many industrialised countries with late preterm births forming a substantial proportion of the preterm births. Late preterm infants are delivered at the immature saccular stage of lung development when surfactant and antioxidant systems are still developing. It is now increasingly recognised that late preterm infants have increased respiratory morbidity in the neonatal period. In addition, late preterm infants are at an increased risk of lower respiratory tract infections in infancy from respiratory viruses such as respiratory syncytial virus. There is a paucity of data reporting lung function in infancy and childhood in late preterm born children. The available data suggest that children born late preterm may be at risk of decreased lung function in later life. However, further studies are required to assess the medium and long term respiratory consequences of late preterm birth. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
extracorporeal membrane oxygenation (ECMO), nitric oxide (NO)] but it seems reasonable to call this group ‘near term’ infants. Infants born at 33e34 weeks’ gestation have been poorly studied thus far. It is increasingly recognised that these babies may have greater morbidity than previously thought and we suggest that it is this group of babies who are referred to as ‘late preterm’-born infants.
This review discusses the somewhat limited data available on the short and long term respiratory outcomes of late preterm births. We have defined a late preterm birth for the purpose of this review as a birth occurring between 33 and 36 weeks’ gestation. The following topics are discussed: (i) the increasing rate of late preterm births in developed countries; (ii) the stage of lung development at birth of late preterm infants and implications for their future lung function; (iii) the short and long term respiratory outcomes of late preterm births.
2. Definitions There are different definitions of ‘late preterm’, complicating interpretation. Prematurity is defined as <37 weeks’ gestation and most research has been conducted on those who were born at 32 weeks, often called extremely preterms, but those born 32 weeks’ gestation should be termed very preterm and extreme prematurity should be restricted to those born at 28 weeks’ gestation. Due to improved survival, more focus recently has been on those born at 28 weeks’ gestation. Infants born at 35e36 weeks’ gestation are often included in studies largely focusing on term-born infants [e.g.
* Corresponding author. Department of Child Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Tel.: þ44 (0) 2920 744187; fax: þ44 (0) 2920 744283. E-mail address: [email protected] (S.J. Kotecha). 1744-165X/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.01.004
3. Epidemiology According to a European-wide study of births in 2004, the percentage of live births between 32 and 36 weeks varied from around 5% in Finland and Sweden to 8% in Germany and Austria.1 There is some evidence of increases in the rate of late preterm births, partly due to the increases in the rate of multiple births; w40% of multiple births are in the late preterm period in Scotland and Northern Ireland, compared to the 6% of singletons who are born at <37 weeks’ gestation.2 In recent years, the rates of preterm birth have risen in many industrialised countries. For example in the USA, the rate has increased from 9.5% in 1981 to 12.7% in 2005.3 Of these, 20% occurred at 32e33 weeks’ gestation and 60e70% at 34e36 weeks’ gestation.3 Hence late preterm births form a substantial proportion of the preterm births. Data from the National Center for Health Statistics on singleton deliveries in the USA showed that the rate of late preterm deliveries at 34e36 weeks’ gestation rose by 20%, from 6.8% to 8.1%, between 1990 and 2006.4 In Scotland, the rate of singleton live births at 33e36 weeks increased from 4.3% in 1985e1989 to 4.9% in 2000e2003.5 In Wales, the percentage of singleton live births at 33e36 weeks actually decreased from 5% in 1999e2003 to 4.7% in 2005e2009
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(our data). In England, longitudinal data are not widely available; however, in 2004 the rate was w6%.1 Data from the USA showed that the mothers who were younger (aged <20 years) and older (40 years) were the most likely to have a late preterm baby when only singleton deliveries were studied.4 They note that the reasons for the increase in the rate of late preterm births are unclear but that the management of labour and delivery has changed over this time period. Two studies suggest that the increasing use of induction of labour and performing caesarean sections at 34e36 weeks’ gestation have had an influence on the increasing rate of late preterm births.6,7 A recent review suggests that the factors which have contributed most to the increasing incidence of late preterm births include women becoming pregnant later in life, increased demand for assisted reproductive technology, and a rise in multiple gestation pregnancies along possibly with the increasing use of induction of labour and caesarean sections.8 A population-based cohort study in British Columbia, Canada, of >95,000 singleton births between 33 and 40 weeks’ gestation also noted maternal factors which were more common in late preterm births (33e36 weeks’ gestation) compared with term births.9 Chorioamnionitis, hypertension, diabetes, thrombophilia, primigravida, teenage pregnancy and prelabour rupture of membranes were all more common in the late-preterm group. It is often wrongly assumed that the vast majority of late preterm-born children do not have any significant morbidity besides feeding problems, and they are often likened to term-born children. However, it is increasingly recognised that late preterm infants born at 34e36 weeks’ gestation have higher mortality and morbidity rates in infancy than term infants. The results obtained from an American study using period-linked birth/infant death files for 1995e2002 showed that early (0e6 days of life), late (7e27 days of late), and post-neonatal (28e364 days of life) death rates were six, three and two times higher respectively in infants born at 34e36 weeks’ gestation compared to term infants.10 The abovementioned cohort study in British Columbia, Canada of >95,000 singleton births between 33 and 40 weeks’ gestation reported that the perinatal mortality rate was 8 times greater, the neonatal mortality rate was 5.5 times greater, and the infant mortality rate was 3.5 times greater in the late preterm group (33e36 weeks’ gestation) compared with the term group.9 The risk of death was greatest during the first few days of life. In the USA in 2005, infant mortality was 7.30 per 1000 live births in those born late preterm at 34e36 weeks’ gestation, three times the rate of infant mortality at term (2.43 per 1000 live births).11 In England and Wales, in 2007e2008 the rate was 8.99 per 1000 in those born at 33e36 weeks compared to 1.78 per 1000 in those born at term.12 Evidence suggests that late preterm infants are also at risk of a broad range of short and long term morbidities and the body of evidence to support this continues to grow. A recent publication suggests that preterm birth at 35e36 weeks’ gestation, along with admission to a neonatal intensive care unit (NICU), has measurable associated cognitive risk when compared with children born at term.13 They found a greater risk of cognitive deficit in those with admission to a NICU compared to those without admission indicating that neonatal morbidities contribute to subtle cognitive defects. A systematic review in 2011, of infants born at 34e36 weeks’ gestation, suggested that, compared with term infants, late preterms are at an increased risk of adverse developmental outcomes and academic difficulties up to 7 years of age.14 In addition, late preterm infants are delivered at an immature stage of lung development which leads to a higher frequency of respiratory distress syndrome (RDS) and higher rates of rehospitalisation in the neonatal period.15 A recent publication noted: ‘the reviewed articles demonstrate that the respiratory vulnerability of preterm
Fig. 1. Respiratory morbidity in late preterm births. , transient tachypnoea of the newborn; , transient tachypnoea of the newborn; OR, odds ratio; CI, confidence interval. (Adapted with permission from The Consortium on Safe Labour, J Am Med Assoc 2010, Vol. 304, pp. 419e425.)
infants born at 32 to 36 weeks’ gestational age, usually considered to be at low risk for subsequent respiratory problems, is more similar to that of very preterm infants than that of term infants.’16 Despite the large number of late preterm births, the emphasis of the majority of the research studies so far has been on very preterm infants, i.e. those born at 32 weeks’ gestation.16 A workshop convened by the National Institute of Child Health and Human Development recognised the importance of preterm infants born beyond 32 weeks’ gestation but identified the lack of outcome data for this significant population.17 It has been noted in the USA that the raised levels of late preterm births are recognised as an important public health issue.4 4. Lung development Late preterm infants are born during the third trimester of pregnancy when the rate of lung maturation is the greatest.18 The lung develops in a programmed process and disruption of this process at any stage may lead to a lung that functions less effectively and is susceptible to injury.19 Late preterm infants are born at the late saccular stage of development20,21 when surfactant and antioxidant systems are still relatively immature (or still developing). During this stage, the number of bronchi increases, saccules invaginate to form alveoli, the air spaces are surrounded by capillaries and surfactant is produced.21 All these developments lead to a rapid increase in lung volume and surface area.18 Early delivery may alter their subsequent alveolar development, as has been suggested for extremely preterm infants.22 After late preterm birth, the immature lung may be linked to a lack of surfactant, poor gas exchange and delayed intrapulmonary fluid absorption manifesting in mild to moderate respiratory disease, i.e. RDS or transient tachypnoea of the newborn (TTN).23,24 5. Neonatal outcomes It is now increasingly recognised that late preterm infants have increased respiratory morbidity in the neonatal period.25 A retrospective collection of data from across the USA on >200,000 deliveries between 2002 and 2008 reported that preterm infants of 34e36 weeks’ gestation had increased respiratory morbidity in the neonatal period, especially neonatal RDS, TTN and pneumonia (Fig. 1).25 Of these, 36.5% were admitted to a NICU compared with 7.2% of term infants. Moreover 28.8% of these late preterm infants
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admitted to a NICU had respiratory illness compared with 15.6% of the term infants admitted to a NICU. In the above-mentioned population-based cohort study in British Columbia, investigating singleton births between 33 and 40 weeks’ gestation, it was reported that infants born late preterm at 33e36 weeks’ gestation needed resuscitation more frequently at birth than the term group. Neonatal respiratory morbidity, defined as respiratory distress due to RDS, TTN or other conditions that caused clinical respiratory distress, was 4.4 times greater [95% confidence interval (CI): 4.2e4.6] and neonatal infections were 5.2 times more common (95% CI: 4.6e5.9) in the preterm group. In addition, the mean length of neonatal hospital stay was longer in the late preterm group, 142 h compared with 57 h in the term group.9 Another study of >150,000 singleton births between 34 and 41 weeks’ gestation showed that rates of severe respiratory disorders in neonates, defined as respiratory distress syndrome requiring mechanical ventilation and/or nasal continuous positive airway pressure (nCPAP), increased with decreasing gestational age (0.28% at 39e41 weeks to 19.8% at 34 weeks).26 This study demonstrates that infants born late preterm at 34e36 weeks’ gestation are more likely to require respiratory support. Interventions such as mechanical ventilation and oxygen therapy are well known to promote pulmonary injury and inflammation in infancy leading to abnormal lung growth and development.27 The interpretation is further complicated by the fact that mechanical ventilation and other respiratory interventions are more likely to be instituted in infants with underlying lung disease which may already identify them as candidates for future lung abnormalities. Such issues may be resolved by urgently needed longitudinal studies in infancy. 6. Prevention of respiratory disease in late preterm-born infants The use of antenatal steroids to decrease the incidence of respiratory disorders in late preterm infants has been studied.28e30 In 1972, Liggins et al. reported a randomised controlled trial of betamethasone in mothers in whom premature delivery, before 37 weeks’ gestation, was planned or threatened.29 They noted that in infants live-born at 32e36 weeks’ gestation the betamethasone group had an RDS incidence of 4.7% whereas the control group had an incidence of 6.9%. A Cochrane review evaluating antenatal corticosteroids versus placebo or no treatment for accelerating fetal lung maturity in women at risk of preterm birth concluded that RDS was significantly reduced in treated infants born before 36 weeks (relative risk: 0.54; 95% CI: 0.41e0.72).30 By contrast, a recent small study suggested that antenatal corticosteroids at 34e36 weeks of pregnancy may not reduce the incidence of respiratory disorders in newborn infants.28 Further work is required to establish the efficiency of antenatal steroids in late preterm-born infants to prevent respiratory disorders in the neonatal period, while ensuring that there are no associated neurodevelopmental consequences. 7. Childhood outcomes Since late preterms are delivered at an early stage of lung development, they may be at risk of respiratory illnesses in infancy or early childhood especially from viruses such as respiratory syncytial virus (RSV).18 In a cohort study, the estimated number of RSV hospitalisations during the first year of life was 57 per 1000 for children born at 33 to <36 weeks compared with 30 per 1000 for children born at term without underlying medical condition.31 Preliminary data from an Italian cohort study suggest that hospitalisations for lower respiratory tract infections were slightly more frequent in the 33e37 weeks’ gestation group compared to the 38 weeks’ gestation group (4.4% in infants born between 33 and 34
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weeks, 4.6% in infants born between 35 and 37 weeks, and 3.5% in infants born 38 weeks).32 A report by Gunville et al.33 studied the clinical course and outcomes of children <2 years of age who were born at <32, 32e35, and 36 weeks’ gestation and admitted to a paediatric intensive care unit (PICU) for any respiratory illness. A total of 271 children met the inclusion criteria of which 17.3%, 12.2% and 70.5% were <32, 32e35 and 36 week gestation children respectively. The median lengths of PICU stay were 6.3, 7.1 and 3.7 days in the <32, 32e35 and 36 week gestation children respectively. They concluded that both preterm groups of children form a large number of PICU admissions for respiratory illnesses and have far larger resource utilization than term infants. In two historical cohort studies not specifically investigating outcomes of late preterm births, it has been reported that some respiratory infections in infancy may lead to decreased lung function in later life.34,35 Both studies noted that pneumonia or bronchitis in early childhood was associated with deficits in lung function in late adult life, suggesting that early respiratory infections in late preterm infants may lead to reduced lung function in later life; although these observations may be due to pre-existing abnormalities of lung growth and development. Clearly further evidence is required to assess whether preventative or prophylactic treatment against RSV should be routine or targeted in late preterm infants. Some recent data investigating the development of asthma in children monitored up to 18 months of age, suggest that late preterm birth at 34e36 weeks’ gestation could possibly be an important risk factor for the development of asthma when compared with children born at 39e42 week’s gestation.36 Escobar et al. reported that late preterm birth at 34e36 weeks’ gestation was associated with an increased risk of recurrent wheeze in the third year of life when compared with children born at 38e40 weeks.37 By contrast a Swedish national cohort study of >600,000 subjects failed to find an association between late preterm birth at 33e36 weeks’ gestation and asthma medications in young adults when compared with young adults born at term.38 However, wheeze associated with atopy needs to be differentiated from wheeze consequent on preterm birth.
8. Short term lung function outcomes Methodologies to assess lung growth and physiology in infancy or preschool children are currently limited although newer techniques such as the use of hyperpolarised helium39,40 and modern infant lung physiology methods show promise.41 Lung physiological measurements provide evidence of adequate lung function but there is a paucity of data reporting lung function in infancy in late preterm-born children,42 with most studies following preterm birth focusing on very preterm infants of 32 weeks’ gestation. In one of the few studies, Friedrich et al. compared healthy infants born at 30e34 weeks’ gestation with term controls, reporting decreased forced expiratory flow between 25% and 75% of forced vital capacity (FEF25e75) at 4 (P ¼ 0.022) and 16 months (P ¼ 0.027) of age but not decreased forced vital capacity (FVC) at 4 and 16 months of age.42 Furthermore, the measurements appeared to ‘track’ without showing any ‘catch-up’ between the two time periods. Hoo et al. studied the airway function, at w3 weeks of age and again at 1 year of age, of ‘healthy’ premature infants [mean gestational age (SD) of 33.2 (2.2) weeks], who did not have any respiratory illness in the neonatal period. They compared the maximal expiratory flow at functional respiratory capacity (V0max FRC) and noted normal values at 3 weeks of age (mean SD Zscore: 0.06 0.92) but significantly diminished values at 1 year of age [mean (95% CI) 2nde1st test: 1.94 (2.27, 1.60)]. There was a high correlation between the values found at 3 weeks and 1 year
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of age, again suggesting ‘tracking’ of lung function (Spearman correlation coefficient: 0.64).43
important public health measures such as the prevention of smoking which may prevent or delay the development of later chronic obstructive airway disease.
9. Long term respiratory outcomes In one of the few studies on later lung function of late pretermborn children, Todisco et al. studied children (mean age 11.6 years) who were born at 34e36 weeks’ gestation and compared them with their term-born siblings. None of the late preterm children had RDS or had been mechanically ventilated.44 Despite the fact that the mean values of the residual volume and residual volume/ total lung capacity of late preterms and their siblings were within the upper limits of normal, the late preterm children had significantly increased mean values compared with their siblings (P < 0.01). No significant difference was found for bronchial responsiveness between the two groups. They noted that maternal smoking during pregnancy was more prevalent in the preterm children with impaired respiratory functions. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we have recently shown that at 8e9 years of age, measures of forced expiratory spirometry are lower in children born at 33e34 weeks’ gestation compared with children born at term, and are of similar magnitude to those in the extremely preterm (25e32 weeks’ gestation) group, who had received a much higher proportion of respiratory intervention during the neonatal period.45 However, by 14e17 years measures of airway function in children born at 33e34 weeks’ gestation were similar to those in children born at term with the exception of FEF25e75. Hence improvements in lung function were seen between these ages, thus challenging the concept of tracking. We studied the effect of interventions in infancy and noted that children requiring mechanical ventilation in infancy at 25e32 and 33e34 weeks’ gestation had lower airway function (FEV1 and FEF25e75) at both ages compared to those not ventilated in infancy, although the numbers ventilated were small. By contrast, those children born at 35e36 weeks’ gestation had similar lung function to term control infants at both 8e9 and 14e17 years of age. In addition, we have also reported that children in the ALSPAC cohort born at term with intrauterine growth restriction (IUGR) have reduced lung function when compared with control children born at term without IUGR,46 thus suggesting that late preterm children also born with IUGR will have poorer lung function outcomes than those without IUGR.47
Practice points The rate of late preterm births has risen markedly in many industrialised countries in recent years. Late preterm infants are at an increased risk of mortality and respiratory morbidity during the neonatal period and infancy. There is a lack of data on lung function outcomes in infants, children and adults born late preterm. Available data suggest that late preterm infants are at an increased risk of a wide range of short and long term respiratory complications. The data studying lung function outcomes suggest that children born late preterm are at an increased risk of deficits in lung function in childhood.
Research directions Assess whether interventions such as using antenatal steroids decrease respiratory disease in the neonatal period without long term adverse outcomes. Objective longitudinal measurements of short and long term lung physiology of infants, children, and adults born late preterm. Long term respiratory follow-up on the clinical impact of being born late preterm. New techniques to assess lung growth and physiology in infancy and early childhood.
Conflict of interest statement None declared. Funding sources None.
10. Conclusion References In conclusion, late preterm infants are an increasing population in many countries, and are often not viewed as a high-risk population. However, they have increased mortality rates in infancy and are at an increased risk of a broad range of short and long term complications. Their early delivery may alter their subsequent lung development. Late preterm infants are at an increased risk of respiratory morbidity in the neonatal period with a higher incidence of respiratory interventions, such as mechanical ventilation, and an increased rate of early respiratory infections, all of which may impact negatively on later lung function. Although data on lung function in later life are lacking, and further studies are urgently needed, the available data suggest that children born late preterm may be at risk of decreased lung function later in life. Further work is urgently required to assess the medium and long term respiratory consequences of preterm birth especially in childhood and early adulthood. Discouragement of antenatal smoking and interventions such as the use of antenatal steroids may help prevent some of the possible adverse long term respiratory outcomes. In addition, it is important that late preterm-born children are identified, fully informed and educated about
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S.J. Kotecha et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 77e81 11. Mathews TJ, MacDorman MF. Division of Vital Statistics, Infant mortality statistics from the 2005 period linked birth/infant, death data set, National Vital Statistics Reports, Volume 57, Number 2, July 30, 2008. 12. Office for National Statistics. Gestation-specific infant mortality in England and Wales, 2007e2008. Available at: http://www.ons.gov.uk/ons/publications/rereference-tables.html?edition¼tcm%3A77-217113. 13. Baron IS, Erickson K, Ahronovick MD, Baker R, Litman FR. Cognitive deficit in preschoolers born late-preterm. Early Hum Dev 2011;87:115e9. 14. McGowan JE, Alderdice FA, Holmes VA, Johnston L. Early childhood development of late-preterm infants: a systematic review. Pediatrics 2011;127:1111e24. 15. Engle WA, Tomashek KM, Wallman C. “Late-preterm” infants: a population at risk. Pediatrics 2007;120:1390e401. 16. Colin AA, McEvoy C, Castile RG. Respiratory morbidity and lung function in preterm infants of 32 to 36 weeks’ gestational age. Pediatrics 2010;126:1115e28. 17. Raju TNK, Higgins RD, Stark AR, Leveno KJ. 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;118:1207e14. 18. Resch B, Paes B. Are late preterm infants as susceptible to RSV infection as full term infants? Early Hum Dev 2011;87S:S47e9. 19. Maritz GS, Morley CJ, Harding R. Early developmetal origins of impaired lung structure and function. Early Hum Dev 2005;81:763e71. 20. Kotecha S. Lung growth: implications for the newborn infants. Arch Dis Child Fetal Neonatal Ed 2000;82:F69e74. 21. Joshi S, Kotecha S. Lung growth and development. Early Hum Dev 2007;83:789e94. 22. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res 1999;46:641e3. 23. Escobar GJ, Clark RH, Greene JD. Short-term outcomes of infants born at 35 and 36 weeks’ gestation: we need to ask more questions. Semin Perinatol 2006;30:28e33. 24. Jain L, Eaton DC. Physiology of fetal lung fluid clearance and the effect of labor. Semin Perinatol 2006;30:34e43. 25. Consortium on Safe Labour. Respiratory morbidity in late preterm births. JAMA 2010;304:419e25. 26. Gouyon J-B, Vintejoux A, Sagot P, et al, Burgundy Perinatal Network. Neonatal outcome associated with singleton birth at 34e41 weeks of gestation. Int J Epidemiol 2010;39:769e76. 27. Chakraborty M, McGreal EP, Kotecha S. Acute lung injury in neonates: mechanisms and management. Paediatr Respir Rev 2010;11:162e70. 28. Porto AMF, Coutinho IC, Correia JB, Ramos MM. Effectiveness of antenatal corticosteroids in reducing respiratory disorders in late preterm infants: randomised clinical trial. BMJ 2011;343:d1696. 29. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515. 30. Roberts D, Daziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. (Review.). Cochrane Database Syst Rev 2006;3:CD004454.
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31. Boyce TG, Mellen BG, Mitchel Jr EF, Wright PF, Griffin MR. Rates of hospitalization for respiratory syncytial virus infection among children in Medicaid. J Pediatr 2000;137:860e70. 32. Lanari M, Adorni F, Silvestri M, Coscia A, Musicco M, Italian Study Group on Risk Factors for RSV-related Hospitalization. The multicenter Italian birth cohort study on incidence and determinants of lower respiratory tract infection hospitalization in infants at 33 weeks GA or more: preliminary results. Early Hum Dev 2011;87S:S43e6. 33. Gunville CF, Sontag MK, Stratton KA, Ranade DJ, Abman SH, Mourani PM. Scope and impact of early and late preterm infants admitted to PICU with respiratory illness. J Pediatr 2010;157:209e14. 34. Shaheen SO, Sterne JAC, Tucker JS, Florey DC. Birth weight, childhood lower respiratory tract infection and adult lung function. Thorax 1998;53:549e53. 35. Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airway disease. BMJ 1991;303:671e5. 36. Goyal NK, Fiks AG, Lorch SA. Association of late-preterm birth with asthma in young children: practice-based study. Pediatrics 2011;128:e830e8. 37. Escobar GJ, Ragins A, Xu Li S, Prager L, Masaquel AS, Kipnis P. Recurrent wheezing in the third year of life among children born at 32 weeks’ gestation or later. Arch Pediatr Adolesc Med 2010;164:915e22. 38. Crump C, Winkley MA, Sundquist J, Sundquist K. Risk of asthma in young adults who were born preterm: a Swedish national cohort study. Pediatrics 2011;127:e913e20. 39. Sukstanskii AL, Conradi MS, Yablonskiy DA. 3He lung morphometry technique: accuracy analysis and pulse sequence optimization. J Magn Reson 2010;207:234e41. 40. Narayanan M, Owers-Bradley J, Beardsmore CS, et al. Alveolarization continues during childhood and adolescence: new evidence from 3He magnetic resonance. Am. J. Respir. Crit. Care Med. 2012;185:186e91. 41. Williams EM, Pickerd N, Eriksen M, Oygarden K, Kotecha S. Estimation of tidal ventilation in preterm and term newborn infants using electromagnetic inductance plethysmography. Physiol Meas 2011;32:1833e45. 42. Friedrich L, Pitrez PMC, Stein RT, Goldani M, Tepper R, Jones MH. Growth rate of lung function in healthy preterm infants. Am J Respir Crit Care Med 2007;176:1269e73. 43. Hoo AF, Dezateux C, Henschen M, Costeloe K, Stocks J. Development of airway function in infancy after preterm delivery. J Pediatr 2002;141:652e8. 44. Todisco T, de Benedictis FM, Iannacci L, et al. Mild prematurity and respiratory functions. Eur J Pediatr 1993;152:55e8. 45. 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;67:54e61. 46. Kotecha SJ, Watkins WJ, Heron J, Henderson AJ, Dunstan FD, Kotecha S. Spirometric lung function in school-age children. Effect of intrauterine growth retardation and catch-up growth. Am J Respir Crit Care Med 2010;181:969e74. 47. Lal MK, Manktelow BN, Drapers ES, Field D. Population based study. Chronic lung disease of prematurity and intrauterine growth retardation: a populationbased study. Pediatrics 2003;111:483e7.
Contents lists available at SciVerse ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Long term respiratory outcomes of late preterm-born infants Sarah J. Kotecha a, Frank D. Dunstan b, Sailesh Kotecha a, * a b
Department of Child Health, School of Medicine, Cardiff University, Cardiff, UK Primary Care and Public Health, School of Medicine, Cardiff University, Neuadd Meirionnydd, Cardiff, UK
s u m m a r y Keywords: Late preterm Lung growth Lung physiology Pulmonary function Respiratory
In recent years, the rate of preterm births has risen in many industrialised countries with late preterm births forming a substantial proportion of the preterm births. Late preterm infants are delivered at the immature saccular stage of lung development when surfactant and antioxidant systems are still developing. It is now increasingly recognised that late preterm infants have increased respiratory morbidity in the neonatal period. In addition, late preterm infants are at an increased risk of lower respiratory tract infections in infancy from respiratory viruses such as respiratory syncytial virus. There is a paucity of data reporting lung function in infancy and childhood in late preterm born children. The available data suggest that children born late preterm may be at risk of decreased lung function in later life. However, further studies are required to assess the medium and long term respiratory consequences of late preterm birth. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
extracorporeal membrane oxygenation (ECMO), nitric oxide (NO)] but it seems reasonable to call this group ‘near term’ infants. Infants born at 33e34 weeks’ gestation have been poorly studied thus far. It is increasingly recognised that these babies may have greater morbidity than previously thought and we suggest that it is this group of babies who are referred to as ‘late preterm’-born infants.
This review discusses the somewhat limited data available on the short and long term respiratory outcomes of late preterm births. We have defined a late preterm birth for the purpose of this review as a birth occurring between 33 and 36 weeks’ gestation. The following topics are discussed: (i) the increasing rate of late preterm births in developed countries; (ii) the stage of lung development at birth of late preterm infants and implications for their future lung function; (iii) the short and long term respiratory outcomes of late preterm births.
2. Definitions There are different definitions of ‘late preterm’, complicating interpretation. Prematurity is defined as <37 weeks’ gestation and most research has been conducted on those who were born at 32 weeks, often called extremely preterms, but those born 32 weeks’ gestation should be termed very preterm and extreme prematurity should be restricted to those born at 28 weeks’ gestation. Due to improved survival, more focus recently has been on those born at 28 weeks’ gestation. Infants born at 35e36 weeks’ gestation are often included in studies largely focusing on term-born infants [e.g.
* Corresponding author. Department of Child Health, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Tel.: þ44 (0) 2920 744187; fax: þ44 (0) 2920 744283. E-mail address: [email protected] (S.J. Kotecha). 1744-165X/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2012.01.004
3. Epidemiology According to a European-wide study of births in 2004, the percentage of live births between 32 and 36 weeks varied from around 5% in Finland and Sweden to 8% in Germany and Austria.1 There is some evidence of increases in the rate of late preterm births, partly due to the increases in the rate of multiple births; w40% of multiple births are in the late preterm period in Scotland and Northern Ireland, compared to the 6% of singletons who are born at <37 weeks’ gestation.2 In recent years, the rates of preterm birth have risen in many industrialised countries. For example in the USA, the rate has increased from 9.5% in 1981 to 12.7% in 2005.3 Of these, 20% occurred at 32e33 weeks’ gestation and 60e70% at 34e36 weeks’ gestation.3 Hence late preterm births form a substantial proportion of the preterm births. Data from the National Center for Health Statistics on singleton deliveries in the USA showed that the rate of late preterm deliveries at 34e36 weeks’ gestation rose by 20%, from 6.8% to 8.1%, between 1990 and 2006.4 In Scotland, the rate of singleton live births at 33e36 weeks increased from 4.3% in 1985e1989 to 4.9% in 2000e2003.5 In Wales, the percentage of singleton live births at 33e36 weeks actually decreased from 5% in 1999e2003 to 4.7% in 2005e2009
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(our data). In England, longitudinal data are not widely available; however, in 2004 the rate was w6%.1 Data from the USA showed that the mothers who were younger (aged <20 years) and older (40 years) were the most likely to have a late preterm baby when only singleton deliveries were studied.4 They note that the reasons for the increase in the rate of late preterm births are unclear but that the management of labour and delivery has changed over this time period. Two studies suggest that the increasing use of induction of labour and performing caesarean sections at 34e36 weeks’ gestation have had an influence on the increasing rate of late preterm births.6,7 A recent review suggests that the factors which have contributed most to the increasing incidence of late preterm births include women becoming pregnant later in life, increased demand for assisted reproductive technology, and a rise in multiple gestation pregnancies along possibly with the increasing use of induction of labour and caesarean sections.8 A population-based cohort study in British Columbia, Canada, of >95,000 singleton births between 33 and 40 weeks’ gestation also noted maternal factors which were more common in late preterm births (33e36 weeks’ gestation) compared with term births.9 Chorioamnionitis, hypertension, diabetes, thrombophilia, primigravida, teenage pregnancy and prelabour rupture of membranes were all more common in the late-preterm group. It is often wrongly assumed that the vast majority of late preterm-born children do not have any significant morbidity besides feeding problems, and they are often likened to term-born children. However, it is increasingly recognised that late preterm infants born at 34e36 weeks’ gestation have higher mortality and morbidity rates in infancy than term infants. The results obtained from an American study using period-linked birth/infant death files for 1995e2002 showed that early (0e6 days of life), late (7e27 days of late), and post-neonatal (28e364 days of life) death rates were six, three and two times higher respectively in infants born at 34e36 weeks’ gestation compared to term infants.10 The abovementioned cohort study in British Columbia, Canada of >95,000 singleton births between 33 and 40 weeks’ gestation reported that the perinatal mortality rate was 8 times greater, the neonatal mortality rate was 5.5 times greater, and the infant mortality rate was 3.5 times greater in the late preterm group (33e36 weeks’ gestation) compared with the term group.9 The risk of death was greatest during the first few days of life. In the USA in 2005, infant mortality was 7.30 per 1000 live births in those born late preterm at 34e36 weeks’ gestation, three times the rate of infant mortality at term (2.43 per 1000 live births).11 In England and Wales, in 2007e2008 the rate was 8.99 per 1000 in those born at 33e36 weeks compared to 1.78 per 1000 in those born at term.12 Evidence suggests that late preterm infants are also at risk of a broad range of short and long term morbidities and the body of evidence to support this continues to grow. A recent publication suggests that preterm birth at 35e36 weeks’ gestation, along with admission to a neonatal intensive care unit (NICU), has measurable associated cognitive risk when compared with children born at term.13 They found a greater risk of cognitive deficit in those with admission to a NICU compared to those without admission indicating that neonatal morbidities contribute to subtle cognitive defects. A systematic review in 2011, of infants born at 34e36 weeks’ gestation, suggested that, compared with term infants, late preterms are at an increased risk of adverse developmental outcomes and academic difficulties up to 7 years of age.14 In addition, late preterm infants are delivered at an immature stage of lung development which leads to a higher frequency of respiratory distress syndrome (RDS) and higher rates of rehospitalisation in the neonatal period.15 A recent publication noted: ‘the reviewed articles demonstrate that the respiratory vulnerability of preterm
Fig. 1. Respiratory morbidity in late preterm births. , transient tachypnoea of the newborn; , transient tachypnoea of the newborn; OR, odds ratio; CI, confidence interval. (Adapted with permission from The Consortium on Safe Labour, J Am Med Assoc 2010, Vol. 304, pp. 419e425.)
infants born at 32 to 36 weeks’ gestational age, usually considered to be at low risk for subsequent respiratory problems, is more similar to that of very preterm infants than that of term infants.’16 Despite the large number of late preterm births, the emphasis of the majority of the research studies so far has been on very preterm infants, i.e. those born at 32 weeks’ gestation.16 A workshop convened by the National Institute of Child Health and Human Development recognised the importance of preterm infants born beyond 32 weeks’ gestation but identified the lack of outcome data for this significant population.17 It has been noted in the USA that the raised levels of late preterm births are recognised as an important public health issue.4 4. Lung development Late preterm infants are born during the third trimester of pregnancy when the rate of lung maturation is the greatest.18 The lung develops in a programmed process and disruption of this process at any stage may lead to a lung that functions less effectively and is susceptible to injury.19 Late preterm infants are born at the late saccular stage of development20,21 when surfactant and antioxidant systems are still relatively immature (or still developing). During this stage, the number of bronchi increases, saccules invaginate to form alveoli, the air spaces are surrounded by capillaries and surfactant is produced.21 All these developments lead to a rapid increase in lung volume and surface area.18 Early delivery may alter their subsequent alveolar development, as has been suggested for extremely preterm infants.22 After late preterm birth, the immature lung may be linked to a lack of surfactant, poor gas exchange and delayed intrapulmonary fluid absorption manifesting in mild to moderate respiratory disease, i.e. RDS or transient tachypnoea of the newborn (TTN).23,24 5. Neonatal outcomes It is now increasingly recognised that late preterm infants have increased respiratory morbidity in the neonatal period.25 A retrospective collection of data from across the USA on >200,000 deliveries between 2002 and 2008 reported that preterm infants of 34e36 weeks’ gestation had increased respiratory morbidity in the neonatal period, especially neonatal RDS, TTN and pneumonia (Fig. 1).25 Of these, 36.5% were admitted to a NICU compared with 7.2% of term infants. Moreover 28.8% of these late preterm infants
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admitted to a NICU had respiratory illness compared with 15.6% of the term infants admitted to a NICU. In the above-mentioned population-based cohort study in British Columbia, investigating singleton births between 33 and 40 weeks’ gestation, it was reported that infants born late preterm at 33e36 weeks’ gestation needed resuscitation more frequently at birth than the term group. Neonatal respiratory morbidity, defined as respiratory distress due to RDS, TTN or other conditions that caused clinical respiratory distress, was 4.4 times greater [95% confidence interval (CI): 4.2e4.6] and neonatal infections were 5.2 times more common (95% CI: 4.6e5.9) in the preterm group. In addition, the mean length of neonatal hospital stay was longer in the late preterm group, 142 h compared with 57 h in the term group.9 Another study of >150,000 singleton births between 34 and 41 weeks’ gestation showed that rates of severe respiratory disorders in neonates, defined as respiratory distress syndrome requiring mechanical ventilation and/or nasal continuous positive airway pressure (nCPAP), increased with decreasing gestational age (0.28% at 39e41 weeks to 19.8% at 34 weeks).26 This study demonstrates that infants born late preterm at 34e36 weeks’ gestation are more likely to require respiratory support. Interventions such as mechanical ventilation and oxygen therapy are well known to promote pulmonary injury and inflammation in infancy leading to abnormal lung growth and development.27 The interpretation is further complicated by the fact that mechanical ventilation and other respiratory interventions are more likely to be instituted in infants with underlying lung disease which may already identify them as candidates for future lung abnormalities. Such issues may be resolved by urgently needed longitudinal studies in infancy. 6. Prevention of respiratory disease in late preterm-born infants The use of antenatal steroids to decrease the incidence of respiratory disorders in late preterm infants has been studied.28e30 In 1972, Liggins et al. reported a randomised controlled trial of betamethasone in mothers in whom premature delivery, before 37 weeks’ gestation, was planned or threatened.29 They noted that in infants live-born at 32e36 weeks’ gestation the betamethasone group had an RDS incidence of 4.7% whereas the control group had an incidence of 6.9%. A Cochrane review evaluating antenatal corticosteroids versus placebo or no treatment for accelerating fetal lung maturity in women at risk of preterm birth concluded that RDS was significantly reduced in treated infants born before 36 weeks (relative risk: 0.54; 95% CI: 0.41e0.72).30 By contrast, a recent small study suggested that antenatal corticosteroids at 34e36 weeks of pregnancy may not reduce the incidence of respiratory disorders in newborn infants.28 Further work is required to establish the efficiency of antenatal steroids in late preterm-born infants to prevent respiratory disorders in the neonatal period, while ensuring that there are no associated neurodevelopmental consequences. 7. Childhood outcomes Since late preterms are delivered at an early stage of lung development, they may be at risk of respiratory illnesses in infancy or early childhood especially from viruses such as respiratory syncytial virus (RSV).18 In a cohort study, the estimated number of RSV hospitalisations during the first year of life was 57 per 1000 for children born at 33 to <36 weeks compared with 30 per 1000 for children born at term without underlying medical condition.31 Preliminary data from an Italian cohort study suggest that hospitalisations for lower respiratory tract infections were slightly more frequent in the 33e37 weeks’ gestation group compared to the 38 weeks’ gestation group (4.4% in infants born between 33 and 34
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weeks, 4.6% in infants born between 35 and 37 weeks, and 3.5% in infants born 38 weeks).32 A report by Gunville et al.33 studied the clinical course and outcomes of children <2 years of age who were born at <32, 32e35, and 36 weeks’ gestation and admitted to a paediatric intensive care unit (PICU) for any respiratory illness. A total of 271 children met the inclusion criteria of which 17.3%, 12.2% and 70.5% were <32, 32e35 and 36 week gestation children respectively. The median lengths of PICU stay were 6.3, 7.1 and 3.7 days in the <32, 32e35 and 36 week gestation children respectively. They concluded that both preterm groups of children form a large number of PICU admissions for respiratory illnesses and have far larger resource utilization than term infants. In two historical cohort studies not specifically investigating outcomes of late preterm births, it has been reported that some respiratory infections in infancy may lead to decreased lung function in later life.34,35 Both studies noted that pneumonia or bronchitis in early childhood was associated with deficits in lung function in late adult life, suggesting that early respiratory infections in late preterm infants may lead to reduced lung function in later life; although these observations may be due to pre-existing abnormalities of lung growth and development. Clearly further evidence is required to assess whether preventative or prophylactic treatment against RSV should be routine or targeted in late preterm infants. Some recent data investigating the development of asthma in children monitored up to 18 months of age, suggest that late preterm birth at 34e36 weeks’ gestation could possibly be an important risk factor for the development of asthma when compared with children born at 39e42 week’s gestation.36 Escobar et al. reported that late preterm birth at 34e36 weeks’ gestation was associated with an increased risk of recurrent wheeze in the third year of life when compared with children born at 38e40 weeks.37 By contrast a Swedish national cohort study of >600,000 subjects failed to find an association between late preterm birth at 33e36 weeks’ gestation and asthma medications in young adults when compared with young adults born at term.38 However, wheeze associated with atopy needs to be differentiated from wheeze consequent on preterm birth.
8. Short term lung function outcomes Methodologies to assess lung growth and physiology in infancy or preschool children are currently limited although newer techniques such as the use of hyperpolarised helium39,40 and modern infant lung physiology methods show promise.41 Lung physiological measurements provide evidence of adequate lung function but there is a paucity of data reporting lung function in infancy in late preterm-born children,42 with most studies following preterm birth focusing on very preterm infants of 32 weeks’ gestation. In one of the few studies, Friedrich et al. compared healthy infants born at 30e34 weeks’ gestation with term controls, reporting decreased forced expiratory flow between 25% and 75% of forced vital capacity (FEF25e75) at 4 (P ¼ 0.022) and 16 months (P ¼ 0.027) of age but not decreased forced vital capacity (FVC) at 4 and 16 months of age.42 Furthermore, the measurements appeared to ‘track’ without showing any ‘catch-up’ between the two time periods. Hoo et al. studied the airway function, at w3 weeks of age and again at 1 year of age, of ‘healthy’ premature infants [mean gestational age (SD) of 33.2 (2.2) weeks], who did not have any respiratory illness in the neonatal period. They compared the maximal expiratory flow at functional respiratory capacity (V0max FRC) and noted normal values at 3 weeks of age (mean SD Zscore: 0.06 0.92) but significantly diminished values at 1 year of age [mean (95% CI) 2nde1st test: 1.94 (2.27, 1.60)]. There was a high correlation between the values found at 3 weeks and 1 year
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of age, again suggesting ‘tracking’ of lung function (Spearman correlation coefficient: 0.64).43
important public health measures such as the prevention of smoking which may prevent or delay the development of later chronic obstructive airway disease.
9. Long term respiratory outcomes In one of the few studies on later lung function of late pretermborn children, Todisco et al. studied children (mean age 11.6 years) who were born at 34e36 weeks’ gestation and compared them with their term-born siblings. None of the late preterm children had RDS or had been mechanically ventilated.44 Despite the fact that the mean values of the residual volume and residual volume/ total lung capacity of late preterms and their siblings were within the upper limits of normal, the late preterm children had significantly increased mean values compared with their siblings (P < 0.01). No significant difference was found for bronchial responsiveness between the two groups. They noted that maternal smoking during pregnancy was more prevalent in the preterm children with impaired respiratory functions. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we have recently shown that at 8e9 years of age, measures of forced expiratory spirometry are lower in children born at 33e34 weeks’ gestation compared with children born at term, and are of similar magnitude to those in the extremely preterm (25e32 weeks’ gestation) group, who had received a much higher proportion of respiratory intervention during the neonatal period.45 However, by 14e17 years measures of airway function in children born at 33e34 weeks’ gestation were similar to those in children born at term with the exception of FEF25e75. Hence improvements in lung function were seen between these ages, thus challenging the concept of tracking. We studied the effect of interventions in infancy and noted that children requiring mechanical ventilation in infancy at 25e32 and 33e34 weeks’ gestation had lower airway function (FEV1 and FEF25e75) at both ages compared to those not ventilated in infancy, although the numbers ventilated were small. By contrast, those children born at 35e36 weeks’ gestation had similar lung function to term control infants at both 8e9 and 14e17 years of age. In addition, we have also reported that children in the ALSPAC cohort born at term with intrauterine growth restriction (IUGR) have reduced lung function when compared with control children born at term without IUGR,46 thus suggesting that late preterm children also born with IUGR will have poorer lung function outcomes than those without IUGR.47
Practice points The rate of late preterm births has risen markedly in many industrialised countries in recent years. Late preterm infants are at an increased risk of mortality and respiratory morbidity during the neonatal period and infancy. There is a lack of data on lung function outcomes in infants, children and adults born late preterm. Available data suggest that late preterm infants are at an increased risk of a wide range of short and long term respiratory complications. The data studying lung function outcomes suggest that children born late preterm are at an increased risk of deficits in lung function in childhood.
Research directions Assess whether interventions such as using antenatal steroids decrease respiratory disease in the neonatal period without long term adverse outcomes. Objective longitudinal measurements of short and long term lung physiology of infants, children, and adults born late preterm. Long term respiratory follow-up on the clinical impact of being born late preterm. New techniques to assess lung growth and physiology in infancy and early childhood.
Conflict of interest statement None declared. Funding sources None.
10. Conclusion References In conclusion, late preterm infants are an increasing population in many countries, and are often not viewed as a high-risk population. However, they have increased mortality rates in infancy and are at an increased risk of a broad range of short and long term complications. Their early delivery may alter their subsequent lung development. Late preterm infants are at an increased risk of respiratory morbidity in the neonatal period with a higher incidence of respiratory interventions, such as mechanical ventilation, and an increased rate of early respiratory infections, all of which may impact negatively on later lung function. Although data on lung function in later life are lacking, and further studies are urgently needed, the available data suggest that children born late preterm may be at risk of decreased lung function later in life. Further work is urgently required to assess the medium and long term respiratory consequences of preterm birth especially in childhood and early adulthood. Discouragement of antenatal smoking and interventions such as the use of antenatal steroids may help prevent some of the possible adverse long term respiratory outcomes. In addition, it is important that late preterm-born children are identified, fully informed and educated about
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