Born just a few weeks early: does it matter?
- 1Hull York Medical School, University of Hull, Hull, UK
- 2Department of Health Sciences, University of Leicester, Leicester, UK
- Correspondence to Elaine M Boyle, Department of Health Sciences, University of Leicester, 22–28 Princess Road West, Leicester LE1 6TP, UK;
Contributors JDB performed the literature search, reviewed the literature and drafted the manuscript. EMB reviewed, revised and approved the final manuscript.
- Accepted 20 July 2011
- Published Online First 24 August 2011
Until recently, infants born at moderate preterm (32–33 weeks) and late preterm (34–36 weeks) gestations have gone largely unstudied. Since their outcomes were thought to be similar to those of infants born at 37 weeks and above, they have historically been managed in much the same way as infants born at term. However, accumulating data indicate that risks of morbidity and mortality are significantly greater in this group than previously believed. Since moderate and late preterm infants account for around 6% of all births, very large numbers of babies are potentially affected. Although their problems may be less obvious than those of extremely preterm infants, the population impact of long-term health and neurodevelopmental problems in this group will be substantial. This review summarises the current available literature, highlights gaps in knowledge and discusses the implications of late preterm birth for both clinical practice and research in the perinatal period and beyond.
The risk of morbidity and mortality associated with birth before 32 weeks of gestation has been extensively reported.1,–,4 To date, most research has centred on these infants, since the likelihood and severity of adverse outcomes are highest within this group. In contrast, there are relatively few published data focusing on outcomes of preterm infants born beyond 32 weeks of gestation.
Moderate and late preterm infants are defined as those born at 32–33 weeks and 34–36 weeks of gestation, respectively.5 In the UK, approximately 40 000 babies are born annually between 32 and 36 weeks of gestation, far exceeding the numbers born at ≤32 weeks (approximately 8000 per year).6 In the USA, the proportion of preterm births increased from 10.5% in 1990 to 12.6% of all births in 2005, a 20% increase.7 Late and moderate preterm births represent approximately 75% of preterm births and constituted two-thirds of this increase.7 This, therefore, appears to be a large and growing phenomenon.
Definitions have changed with time. Historically, these babies were classed as ‘near-term’ since their outcomes were not thought to differ substantially from those of infants born at ≥37 weeks. This may be attributed to the fact that they often look mature and have weights similar to term infants at birth. In keeping with this perception, there is currently no routine data collection in the UK for babies born moderate or late preterm, and they are not routinely followed up after birth if their neonatal course has been uncomplicated. Nevertheless, they are physiologically and metabolically immature and accumulating evidence suggests that they are at higher risk for adverse outcomes than previously believed. This review summarises current available literature and discusses the implications of late preterm birth in the neonatal period and beyond.
A number of studies have shown that late preterm infants, compared with their term counterparts, have a higher incidence of neonatal problems including respiratory distress,8,–,11 hypoglycaemia,12 ,13 thermal instability,11 ,14 jaundice,15 ,16 infection,17 apnoea18 and feeding difficulties.19 These result in a prolonged neonatal hospital stay20 and a higher proportion being rehospitalised compared with term infants.8 ,9 ,21
Respiratory morbidities including respiratory distress syndrome, transient tachypnoea of the newborn and respiratory infections are the most common neonatal problems in this group. Wang et al11 compared outcomes of infants born at 35–36 weeks of gestation between 1997 and 2000 and showed that 28.9% of late preterm infants experienced respiratory distress compared with 5.3% of term infants. Escobar et al8, in a multicentre, retrospective study of infants born between 2002 and 2004, also showed an increased risk in moderate and late preterm subgroups. In this study, 22.1% of infants born at 33–34 weeks, 8.3% of infants born at 35–36 weeks but only 2.9% of infants born at 37–42 weeks of gestation experienced respiratory distress. Researchers in other developed countries have consistently demonstrated similar increased risk although the magnitude varies between studies.9 ,10 ,21,–,23 The largest and most recent study reported on 233 844 infants from 19 hospitals in the USA, of which 19 334 were late preterm.24 Analysis controlled for mode of delivery, maternal medical conditions and birth weight and demonstrated a prevalence of 9% for respiratory morbidity in late preterm, compared with 1% in term infants.
Hypothermia and hypoglycaemia
Temperature regulation and glucose homeostasis are often poor, especially in the first hours after birth. Although prevention of hypothermia is part of routine newborn management, Wang et al found that 10% of late preterm infants required active management for hypothermia, compared with no term infants. Laptook and Jackson14 showed increased susceptibility to cold stress in infants of 34–37 weeks of gestation. These infants are also more likely to develop hypoglycaemia than are full term infants; almost two-thirds required support with intravenous fluids according to the study by Wang et al.11 In contrast to infants born at term, moderate and late preterm infants have limited glycogen reserves and are less able to mount a protective ketogenic response to hypoglycaemia.25 This may render them more susceptible to long-term neurological consequences of neonatal hypoglycaemic injury.
Feeding difficulties and jaundice
Most infants born at 32–33 weeks routinely have nasogastric feeds as total or supplemental enteral feeding. This is not always the case with those born at ≥34 weeks, despite the fact that suck and swallow coordination is still immature.19 Sleepiness and difficulty in establishing feeding and, in particular, breast feeding, are common and exacerbate problems of hypoglycaemia and jaundice. Frequently, little additional attention is paid to the risks of jaundice associated with only modest prematurity and these babies are often managed as healthy term infants. A study of cases reported to the Pilot Kernicterus Registry in the USA found that late preterm babies were over-represented, with breast feeding being a significant risk factor.15 ,16
The ‘minor’ morbidities, with which moderate and late preterm infants commonly present, are also recognised as potential indicators of systemic neonatal infection, so it is unsurprising that these babiesare investigated more frequently for suspected sepsis than term infants.11 Cohen-Wolkowiez et al17 reported that 69% of late preterm babies were screened for early onset infection, although only 0.4% had positive blood cultures. However, there is also evidence to suggest that these babies may be inherently susceptible to infection due to immunological immaturity.26 Khashu et al9 found that either suspected or proven infections were seen five times as frequently, while McIntire and Leveno27 reported significantly more sepsis evaluations and culture-proven sepsis in late preterm compared with term infants.
Worryingly, the observed increase in neonatal morbidity is also reflected in higher mortality.9 ,27 ,28 A Canadian population-based cohort study found a significantly increased risk of neonatal and infant death in moderate and late preterm infants.29 This was confirmed by Tomashek et al30, who demonstrated that early and late neonatal mortality were, respectively, six and three times higher and that infant mortality was three times higher than that of term born infants. Although a substantial number of early deaths in both groups were related to congenital anomalies, differences persisted after exclusion of infants with anomalies.
Escobar et al31 showed that babies of 35 and 36 weeks' gestation were more likely to be rehospitalised than infants of ≥37 weeks, in the first 2 weeks following discharge and during the next 6 months. In the UK, Oddie et al32 studied early discharge from neonatal care; readmission in the first month occurred in 6.3% of babies of 35–37 weeks' gestation compared with 3.4% and 2.4%, respectively, of those born at 38–40 and ≥40 weeks. McLaurin et al33 found that infants born at 33–36 weeks of gestation were twice as likely to be admitted during their first year, with respiratory and gastrointestinal disorders accounting for half of the admissions.33
Neonatal morbidities affecting moderate and late preterm infants have been highlighted by a number of retrospective studies, but little is known about later health outcomes. Respiratory outcomes have been investigated in a small number of studies, some of which suggest a continued risk of respiratory problems into infancy and childhood. Most have studied susceptibility of infants to respiratory infections such as bronchiolitis due to respiratory syncitial virus (RSV). Data suggest that RSV infection among moderate or late preterm infants shows patterns of susceptibility more like those seen in infants born before 32 weeks than those in term infants.34 There is some evidence that RSV infection in these infants is subsequently associated with a greater risk of wheezing in infancy.35 In a review of 24 studies, Colin et al36 postulated that preterm birth, even where there is no significant neonatal respiratory disease, may have adverse effects on lung growth and development leading to reduced pulmonary function and increased morbidity. However, although asthma is the leading cause of respiratory disease in children, Abe et al37 were unable to demonstrate an association between late preterm birth and a diagnosis of asthma in early childhood.
Neurodevelopmental and neurobehavioural outcomes
Studies of neurodevelopmental outcomes in late preterm infants are few. Petrini et al38 studied infants by gestational age and confirmed that children born late preterm are three times as likely as term born children to be diagnosed with cerebral palsy. They reported a modest association with long-term developmental delay or mental retardation. Moster et al39 found increased cerebral palsy and developmental disorders with increasing prematurity. Woythaler et al40 showed worse neurodevelopmental outcomes in late preterm infants, but also highlighted an association between socioeconomic factors and mental delay.
Cognitive impairment has been shown to be inversely related to gestational age.41 Studies of children at 342 and 643 years showed increased cognitive impairment and behavioural problems in late preterm infants compared with babies of ≥37 weeks. However, Baron et al44 have since published data suggesting that uncomplicated late preterm birth does not, in itself, increase the risk of later cognitive impairment. This is supported by results of a prospective study of 1298 children, of which 53 were born late preterm although this study recruited a greater proportion of affluent families than might be representative of the general population.45 Romeo et al46 compared neurodevelopmental outcome in late preterm infants and control infants of ≥37 weeks at 12 and 18 months corrected age and showed similar outcomes in the two groups. However, if these infants were assessed according to their chronological age, outcomes for those born late preterm were worse. This is a potentially important observation, since corrections for premature birth are rarely made at later assessment of infants born beyond 34 weeks of gestation.
It has previously been shown that very premature infants are at risk of poor school performance.41 ,47 Chyi et al48 also demonstrated poorer school performance in children born late preterm, compared with those born at ≥37 weeks. Recently, MacKay and colleagues49 have reported that the risk of having special educational needs has a strong, ‘dose-dependent’ relationship with gestation at birth; this effect spanned the whole range of gestational ages. Morse et al50 reported that healthy late preterm infants were at increased risk of developmental delay and school-related problems during the first 5 years of life. Other studies, however, have produced conflicting evidence suggesting that late preterm infants, born otherwise healthy, have no long-term problems at school.42 ,45
Costs associated with moderate and late preterm birth
Given the increased neonatal morbidity experienced by moderate and late preterm infants, the cost of initial birth hospitalisation is likely to be significantly higher than in term born infants, as reported by several studies.51,–,53 Information about health consequences and costs beyond the neonatal period is limited, however, and research has centred mainly on increased rates of hospital admissions. Among infants born in California between 1992 and 2000, 15% of preterm infants required readmission to hospital in their first year, with infants born at 35 weeks of gestation accounting for 25% of the total cost.54 McLaurin et al33 examined costs of rehospitalisation and other healthcare use among late preterm and term infants. They demonstrated increased healthcare utilisation during the first year for late preterm infants; Bird et al reported similar findings.33 ,55
The role of obstetric factors
The increasing rate of late preterm births is likely to be influenced by a number of factors that are currently not well understood. It is reasonable to suppose that both increasing numbers of spontaneous deliveries and increasing obstetric intervention for maternal and fetal complications at this gestation may have a role to play. The view that late preterm infants are at minimal risk for significant morbidity compared with very preterm infants, may have led to a trend towards earlier intervention in pregnancies complicated by maternal pregnancy-related illness.25 ,26 In addition, improved obstetric care at earlier gestations may allow prolongation of some pregnancies to a stage where the risk of neonatal morbidity is thought to be smaller. These factors, together with the influence of maternal choice regarding the timing of delivery, have led to increasing numbers of babies being born before term.
Obstetric management of spontaneous preterm labour and preterm prolonged rupture of membranes influences a number of preterm births. Beyond 34 weeks, threatened preterm labour is less aggressively managed than at earlier gestations.56 There are few studies examining the use of antenatal corticosteroids prior to late preterm delivery and only recently has the use of tocolytics been considered in obstetric guidelines for this group.57 Laughon et al58 found that the reason for late preterm birth was unknown in 6% of cases, with known precursors being spontaneous labour (28.9%), preterm prolonged rupture of membranes (32.3%) and obstetric, maternal or foetal condition (31.8%). Holland et al59 found that 8.2% of late preterm deliveries were elective, but that the majority were unavoidable.
Implications for clinical practice, research and public health
Research and resources have, in recent years, been directed towards very preterm babies; those born at 32–36 weeks have been largely ignored. However, emerging data consistently indicate that risks associated with birth at moderate and late preterm gestations have at best been poorly understood and at worst, remain unknown. It is perhaps time to redress the balance in order to both scrutinise and optimise obstetric and neonatal management.
There are large gaps in evidence with respect to the decision-making processes in threatened preterm labour. It is not known whether risk factors for delivery at 32–36 weeks are similar or different from those at <32 weeks. There is likely to be variation in practice and effects of strategies to deliver or to prolong pregnancy are not clear.
The available evidence suggests that we may be doing moderate and late preterm babies a disservice by treating them in the same way as those born at term. Neonatal management varies, with routine neonatal unit admission being the norm in some areas, but postnatal ward care or transitional care being common in others. Consequences associated with the place of postnatal care are not fully appreciated in this group and warrant exploration. A large number of infants born at 32 weeks and above are offered neither neonatal nor neurodevelopmental follow-up. Many now suggest that this may not be appropriate and recommend follow-up until at least 18 months of age,38 ,43 ,48 ,60 but the service implications of a change in favour of this approach are substantial. Most available data are focused on late preterm birth and data for deliveries at 32–33 weeks of gestation are particularly sparse. It is clear that severity of adverse outcomes increases with decreasing gestation at birth; however, numbers of affected babies substantially increase with increasing gestational age. There is currently a paucity of contemporary prospective studies in these babies to allow clarification of their outcomes by longitudinal evaluation. These are necessary to completely define the extent of the problem. However, the later public health and economic impact of large numbers of survivors, albeit with less obvious physical, neuropsychological, educational and behavioural difficulties than those seen in extremely preterm infants, should not be underestimated.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.