Health and developmental consequences of very preterm birth
Very preterm birth has immediate consequences for the newborn infant. Survival decreases markedly with decreasing gestational age (GA) at birth, from 93.6% at 27-31 weeks’ GA, 52.4% at 22-26 weeks, 31.2% at 24 weeks to <1.1% before 24 weeks’ GA according to data from France (Ancel, Goffinet, and the Epipage Writing Group 2015). Survival in the EPICE cohort was 91.0% at 30-31 weeks, 84.9% at 28-29 weeks, 70.5% at 26-27 weeks, 44.6% at 24-25 weeks and 4.2% at 22-23 weeks’ GA (Draper et al. 2017). Stillbirth and mortality rates differ across countries, and was 27.7% overall in the EPICE cohort, ranging between 19.9% to 35.9% by region (Draper et al. 2017). In addition to an increased risk of mortality, the immaturity of infants born VPT and other related perinatal characteristics expose them to a high risk of severe morbidities and complications in their first months of life that, in turn, increase their risks of future health and developmental problems (Saigal and Doyle 2008).
Perinatal morbidities and characteristics
Intrauterine growth and small for gestational age
Approximately one-third of infants born VPT in Europe have intrauterine growth restriction (IUGR) as measured by being born small for their gestational age (SGA) (Zeitlin et al. 2017). Growth restriction is one of the main causes of VPT birth and is also more frequent among VPT births due to other causes, such as maternal hypertensive disorders (Delorme et al. 2016). Compared to other infants born at the same gestational ages, infants with restricted growth face increased risks of perinatal death (Delorme et al. 2016; Monier et al. 2017; Zeitlin, El Ayoubi, et al. 2010) and respiratory morbidity (Monier et al. 2017; Zeitlin, El Ayoubi, et al. 2010), as well as of worse long-term cognitive outcomes (Sacchi et al. 2020). Definitions of SGA vary, and in the EPICE cohort it is defined as birthweight <10th centile for intrauterine norms for gestational age and sex, using references developed for the cohort to take into consideration its multi-country composition (Zeitlin et al. 2017).
Congenital anomalies are birth defects of prenatal origin of different levels of severity. Major anomalies, such as spina bifida and heart defects require medical interventions, whereas minor anomalies such as cup ear or undescended testicle have more limited social or cosmetic consequences (Centers for Disease Control and Prevention 2019). Congenital anomalies are more than five times more likely to be present among VPT compared to term-born infants; approximately 16% of infants born VPT have a congenital anomaly (Honein et al. 2009), and infants born preterm have up to a doubled risk of cardiovascular anomalies compared to term-born infants (Tanner, Sabrine, and Wren 2005), including congenital heart defects (Mustafa et al. 2020). The risk of mortality is higher especially in infants exposed to both preterm birth and cardiovascular anomalies (Tanner, Sabrine, and Wren 2005). Many studies exclude infants with severe congenital anomalies, because the long-term prognosis of the infant is highly related to the severity of the anomaly, in addition to conditions surrounding the preterm birth. However, children with minor congenital anomalies are not generally excluded from prognostic studies and the presence of an anomaly may affect both short and long-term outcomes.
Other perinatal characteristics
There are other perinatal characteristic related to VPT birth which can affect child outcomes that are often taken into consideration in prognostic models for short and longer term outcomes, such as multiple pregnancy (between 8 to 10 % of all multiples in Europe are born <32 weeks’ gestation) (Blondel et al. 2006), maternal pregnancy complications such as hypertensive disorders (a risk factor for preterm delivery and associated with restricted intrauterine growth) (Delorme et al. 2016), and infant sex, with males being at higher risk of death and some morbidities (Wolke, Johnson, and Mendonça 2019).
Neonatal morbidities and complications
The prevalence of severe neonatal morbidities (brain lesions, necrotising enterocolitis and retinopathy of prematurity) and bronchopulmonary dysplasia in preterm survivors varies across Europe, as shown in the EPICE cohort; between 10.4% (Ile-de-France, France) and 23.5% (Wielkopolska, Poland) in infants born <32 weeks of gestation (Edstedt Bonamy et al. 2019). The rates of neonatal morbidities increase with decreasing gestational age, from 40.8% among infants born at 22-26 weeks to 12.4% among those born between 27-31 weeks in France (Ancel, Goffinet, and the Epipage Writing Group 2015). These morbidities, as well as other complications emerging in the neonatal period have been associated with an increased risk of adverse long-term outcomes.
Cerebral lesions and white matter injuries
Cerebral lesions and white matter injuries, including severe intraventricular haemorrhage (IVH, grades III-IV are the most severe lesions) and cystic periventricular leukomalacia (cPVL) occur in an estimated 3.9% and 3.2% in children surviving VPT birth in Europe, respectively (Edstedt Bonamy et al. 2019). These neonatal morbidities may be fatal, and are two of the major risk factors for cerebral palsy (Marret et al. 2013; Ancel et al. 2006; Beaino et al. 2010; Gotardo et al. 2019). Children with cPVL have a pooled relative risk of 19.4 to develop cerebral palsy compared to children without, in a recent meta-analysis (Gotardo et al. 2019). Cerebral lesions in the neonatal period have also been associated with adverse effects on brain (Lemola 2015) and cognitive development (Beaino et al. 2011; Marret et al. 2013).
Retinopathy of prematurity
Retinopathy of prematurity (ROP) is a severe disorder of the eye that is unique to infants born preterm and is one of the major causes of blindness in children (Hartnett 2015). It is classified in five stages of which the most severe stages cause irreversible damage to the eye (Classification of Retinopathy of Prematurity Group 2005). Around 3.7% of children born VPT in Europe are estimated to develop ROP (stage 3+) (Edstedt Bonamy et al. 2019). In addition to an elevated risk of blindness, ROP also increases the risk of vision impairments after VPT birth particularly (Hirvonen et al. 2018), and has been associated with poor cognitive outcome (Johnson 2007).
Necrotising enterocolitis (NEC) is a severe bowel condition with an immediate threat to the neonate. Pooled estimates from a recent meta-analysis show that 7% of infants born extremely preterm may develop NEC during NICU hospitalisation (Alsaied, Islam, and Thalib 2020), of whom 20-40% need surgery, followed by a high mortality rate of up to 50% (Lin and Stoll 2006). Data from the EPICE cohort showed that 1.9% of the children born VPT in Europe had severe NEC requiring surgery or peritoneal drainage (Edstedt Bonamy et al. 2019). Survivors of NEC needing surgery have shown to have a higher risk of neurological and neuro-motor delays and poor growth (Federici and De Biagi 2019).
Bronchopulmonary dysplasia (BPD) is a condition that affects the immature lung, where the infant becomes reliant on artificial respiratory support (O’Reilly, Sozo, and Harding 2013). Severe BPD, when defined as need for oxygen (fraction of inspired oxygen >30%) or mechanical or non-invasive respiratory support at 36 weeks’ postmenstrual age, affects about 5.5% of children born VPT in European countries (Edstedt Bonamy et al. 2019). BPD increases the risk for being re-hospitalised because of respiratory infections in the first years of life (Laugier et al. 2017), developing asthma in childhood, and is one of the principal causes of impaired lung function or respiratory illness later in life (O’Reilly, Sozo, and Harding 2013). BPD has also been associated with poor cognitive outcomes at five years of age (Twilhaar et al. 2018). Due to the long-term consequences BPD has on respiratory health, there is reason for long-term follow-up until adulthood (Duijts et al. 2020).
Sepsis is a major complication of preterm birth with multiple short and long-term outcomes (McGovern et al. 2020). It is a condition caused by virus, bacteria or fungus, classified into early and late onset sepsis based on timing, depending on the definition (in utero, neonatal period before 72h of life, after 7 days of life, etc.) (Shane, Sánchez, and Stoll 2017). Sepsis has been less often included in studies of preterm birth-related outcomes, especially population-based studies relying on data collection from different neonatal units, because of the difficulty of defining sepsis, i.e. using clinical or treatment criteria (McGovern et al. 2020).
Health and development in childhood and early adolescence
Children born VPT have a higher risk of adverse long-term sequelae compared to their term-born peers, which increases with decreasing gestational age. The long-term consequences are heterogeneous, and sometimes multiple (Wolke, Johnson, and Mendonça 2019) and although well documented, remain unknown for the individual infant when they are discharged home from the neonatal unit. The risk of long-term chronic conditions in children born VPT is higher (Luu et al. 2016), including asthma (Been et al. 2014) and epilepsy (Hack et al. 2005; Crump et al. 2011), with an increasing risk with decreasing gestational age. However, most research focus on sensory, motor and neuro-cognitive outcomes, which may not be detected until the child starts school and is exposed to cognitive and social requirements.
The risk of sensory impairments increases with decreasing gestational age and with the presence of brain lesions (Hirvonen et al. 2018). Whereas the need for hearing aid is rare (<1%) (Larroque et al. 2011) the need for glasses is common. At the age of eight years, 41% of the children born VPT in the EPIPAGE cohort needed glasses, compared to 26% in the term control group (Larroque et al. 2011). A register-based study on over one million livebirths in Finland showed a seven-fold increased risk of hearing loss in children born VPT (2.5%) compared to term-born children (0.4%), and much higher rates of visual impairment and blindness (3.6% vs. 0.8%) and minor sensory or ophthalmologic disorders (12.9% vs 2.6%) (Hirvonen et al. 2018).
Cerebral palsy and motor development
Cerebral palsy (CP) is one of the main motor-related consequences of VPT birth (Wolke, Johnson, and Mendonça 2019). Cerebral palsy is a heterogeneous condition associated with severe motor problems and several developmental consequences, including intellectual disability, autism and epilepsy (MacLennan, Thompson, and Gecz 2015). Pooled prevalence of motor delay and CP have been estimated to 30.6% and 6.8% respectively in pre-school aged (5-5,5 year-old) children born VPT, with increasing prevalence with decreasing gestational age (Pascal et al. 2018). Oskoui et al. estimated the prevalence to 8.2% at <28 weeks and 4.3% at 28-31 weeks (Oskoui et al. 2013). Mild and moderate motor problems in children who do not develop CP is also common in children born preterm (40.5% at <37 weeks) (Williams, Lee, and Anderson 2010). These are referred to as developmental coordination disorder and include deficits in coordination, balance, fine and gross motor skills and visuo-motor integration, and poorer performance in these domains tend to persist into adolescence (Wolke, Johnson, and Mendonça 2019).
Cognitive delay and IQ
There is a large pool of evidence on the increased risk of cognitive delay in children born VPT (Johnson 2007; Lemola 2015; Sentenac, Boutron, et al. 2020; Wolke, Johnson, and Mendonça 2019), also in seemingly healthy children (Dall’oglio, Rossiello et al. 2010). Systematic reviews and meta-analyses have established that school-aged children born VPT have lower IQ scores compared to their term-born peers (Johnson 2007; Wolke, Johnson, and Mendonça 2019), sometimes with poorer results in boys compared to girls (Johnson 2007; Linsell et al. 2018). Low IQ scores (<2 SD) have been found in up to 25% of children born VPT, making it one of the main sequelae of VPT birth, which, in addition, does not seem to improve as the children grow older (Wolke, Johnson, and Mendonça 2019). A recent synthesis of all systematic reviews on cognitive delay showed a standardised mean difference of 11.6 to 12.9 IQ points lower for children born <32 weeks compared to term-born controls (Sentenac, Boutron, et al. 2020). Cognitive delay is more common in lower gestational ages; pooled prevalence of cognitive delay (until 5,5 years of age) has been estimated at 14.7% in children born VPT and 29.4% in children born extremely preterm (Pascal et al. 2018). This delay presents across several sub-domains, including executive functioning and processing speed (Brydges et al. 2018).
Language delay, school readiness and academic performance
There is also growing evidence on language delay (Sentenac, Johnson, et al. 2020), poor school readiness (Carter and Msall 2017) and lower academic performance later in life (Brydges et al. 2018) in children born preterm. School-aged children born VPT have worse performance especially in mathematics and spelling, need more special educational support and have poorer academic attainment at the end of compulsory schooling, suggesting they do not catch up with their peers (Wolke, Johnson, and Mendonça 2019).
Psychiatric, behavioural and social problems
An increased risk of psychiatric, behavioural and social problems, especially in early adolescence, have been documented (Wolke, Johnson, and Mendonça 2019). Attention deficit disorders and to some extent Autism spectrum disorders are the most commonly reported psychiatric disorders reported in VPT-born children and adolescents (Wolke, Johnson, and Mendonça 2019; Johnson 2007). Although less frequently studied, research also shows an increased risk in depressive and anxiety disorders and social withdrawal and peer relationship problems lasting into adulthood (Wolke, Johnson, and Mendonça 2019).
Follow-up of children born very preterm
What is follow-up and why is it important?
Follow-up programmes provide screening for emerging health and developmental problems in children born VPT, in order to enable early interventions (EI) and coordinate follow-up and care from a range of medical care providers after discharge home (EFCNI, van Kempen, et al. 2018). Follow-up also aims to inform and guide families, and help them know whether their child is developing normally, and facilitate school entry (Doyle et al. 2014). Their broader missions include gaining more knowledge on long-term outcomes after VPT birth and to provide data for benchmarking (Doyle et al. 2014). These programmes, that are more structured and specialised than routine primary care check-ups, are developed to regularly assess children across multiple domains, ideally covering physical and mental health, learning and cognition and quality of life (Doyle et al. 2014), but as guidelines have not been standardised and resources vary, so do follow-up programmes.
Early intervention (EI) programmes are multidisciplinary and heterogeneous, and aim to implement interventions as early as possible after suspicion of developmental delay (Benzies et al. 2013; Anderson, Treyvaud, and Spittle 2020). Interventions include, for instance, physiotherapy, support to enhance infant cognitive and social development, and family interventions to support parenting and infant-parent bonding (Spittle et al. 2015; Benzies et al. 2013; Anderson, Treyvaud, and Spittle 2020). EI has been shown to have positive effects on cognition and motor development in infancy (Spittle et al. 2015). Improvements in parental anxiety and depression have also been reported for EI programmes with parent-support and/or educational components, which, in turn, have been associated with improved short-term child outcomes (up to 24 months) (Benzies et al. 2013) such as behaviour (Anderson, Treyvaud, and Spittle 2020). There is also some evidence that EI programmes are most beneficial for children with more risk factors (such as lowest birth weights or with brain lesions) (Anderson, Treyvaud, and Spittle 2020) and from socially disadvantaged families in terms of early health (Waruingi, Iyer, and Collin 2015) and cognitive, language and motor outcomes (Spittle et al. 2018). There is some evidence that cognitive improvements persist until five years of age (Spittle et al. 2015), but research shows inconsistent results on long-term outcomes and there is a general lack of long-term evaluations of post-discharge EI programmes (Anderson, Treyvaud, and Spittle 2020). However, studies on Head Start programmes, i.e. pre-school programmes aimed at reducing social disparities in disadvantaged communities, suggest that the impact of interventions on school achievement, social and behavioural and health outcomes may show in school-age and early adulthood (Bauer and Schanzenbach 2016).
Effects of follow-up
There is a consensus that follow-up is important for the long-term management of VPT birth because it detects health and developmental problems early and permits timely referral for early intervention (EFCNI, van Kempen, et al. 2018). However very few published studies have evaluated the impact of routine neonatal follow-up programmes on child outcomes. Existing studies focus on specific outcomes, are short-term or single unit studies, and/or have been performed in non-European health care contexts. These studies suggest that follow-up programmes may improve access to care and improved health outcomes.
One of the few existing randomised controlled trials on follow-up programmes for high-risk infants (low birth-weight infants and infants needing mechanical ventilation at NICU) showed that enforced follow-up could reduce intensive care visits and minimise the risk of life threatening illnesses during the first year of life without increasing overall care costs (Broyles et al. 2000). The enforced programme included improved access to care through a follow-up home visit, a 24/7 phone line, and access five days per week to the follow-up clinic for both routine care and acute health problems (Broyles et al. 2000). A recent European study suggests that routine follow-up may improve outcomes in children with CP (lower risk of contractures, but no effect on cognitive, motor and speech delays) (Bufteac et al. 2020). Studies from Australia and the US suggest that follow-up facilitates access to early intervention services (Pritchard et al. 2013; Greene and Patra 2016). Greene and Patra (2016), assessed EI referrals of infants born <30 weeks’ gestation and/or with a birth weight (BW) <1000 g attending NICU follow-up with cognitive, language and motor assessments at 4, 8 and 20 months’ CA. Their results showed that the increased time enrolled in follow-up increased the likelihood of being referred to EI services, with a peak in referrals at one year of CA. Referrals between 12 and 20 months were associated with delayed language development, lower gestational age and higher postmenstrual age at discharge (Greene and Patra 2016).
However, implementing follow-up programmes comes with its challenges; 19% of the infants, who were less likely to have abnormal brain ultrasounds and lung abnormalities and older mothers, did not attend any follow-up appointments (Greene and Patra 2016). Furthermore, the timing of evaluations during follow-up was crucial for appropriate referral to EI services, as too early developmental screening in infants <1000 g BW may not yet detect developmental delay which may manifest later in the most immature infants (Greene and Patra 2016). Another study from the US also reported that non-attendance to follow-appointments and financing of these programmes were two major challenges, and that further improving the coordination of care could result in improved outcomes in the children (Bockli et al. 2014).
Recommendations and programmes for follow-up and care after very preterm birth
Until recently, there were no international recommendations for follow-up after VPT birth. Expert groups have previously outlined key components of follow-up programmes, recommendations for the follow-up of specific neonatal complications and local or regional recommendations for follow-up. A group of experts from Australia, New Zealand and the UK developed a framework for follow-up in 2014, outlining the main domains to be assessed, including general health, growth, feeding, sensory and neurological problems, motor skills, cardiovascular and respiratory health, metabolism, reproductive health, cognitive and language development, pre-academic skills, behaviour, social skills, daily functioning, self-esteem, parents’ mental health and parent-child interaction, family social support and impact on siblings (Doyle et al. 2014). However, while also suggesting time points and tools for assessments, the expert group acknowledged that the domains assessed and the methods and tools used will depend on the resources in units providing this follow-up, and that the timing and frequency of assessments will depend on the child’s age, health and development (Doyle et al. 2014). Recommendations also exist for specific preterm birth-related pathologies and complications, such as BPD; an expert group on BPD recommended in a recent publication that children with BPD should be followed until adulthood, by multidisciplinary teams including subspecialists such as paediatric cardiologists, ENT specialists, physiotherapists etc. (Duijts et al. 2020).
Follow-up programmes and recommendations in Europe: the SHIPS regions
National and regional follow-up programmes and recommendations in Europe vary largely in terms of content (timing, number and types of assessments, tools used for the assessments), and duration across countries, regions and even neonatal units and networks. This is illustrated by the follow-up programmes and recommendations in the SHIPS regions.
As part of the SHIPS project’s objectives and reporting to the European Commission, information was collected on national and regional follow-up policies and practices in all SHIPS study regions until 2017 and reported in two Deliverables, 3.2 and 4.1 (Johnson et al. 2016; Barros et al. 2018). This information is summarised in Table 1 below, where data has been completed for France and the UK for the most recent recommendations.
In 2017, national or regional follow-up programmes existed in all but four of the SHIPS study countries (Denmark, Portugal, Italy and the UK), where local programmes were in place and limited information was collected. All national and regional programmes involved neonatal units and hospitals and multidisciplinary teams. Follow-up programmes had been established as early as in the 1980’s, but recent updates to programmes or guidelines in many countries shows that this continues to be an important policy area. Some countries had no official guidance or policy on follow-up in 2017 (UK and France). Recommendations have since been issued in both countries.
Table of contents :
Chapter 1: Introduction
1.1 Aim and objectives
Chapter 2: State of the art
2.2 Health and developmental consequences of very preterm birth
2.3 Follow-up of children born very preterm
2.4 Post-discharge health care and health care needs
2.5 Equity in health and health care
Chapter 3: Methods
3.2 Data source and study population
3.4 Harmonising health care data
3.5 Analysis strategy: key points
3.6 Qualitative analyses
Chapter 4: Specialist health care services use in a European cohort of infants born very preterm
Chapter 5: Parents’ ratings of post-discharge healthcare for their children born very preterm and their suggestions for improvement: a European cohort study
Chapter 6: Follow-up after very preterm birth in Europe
Chapter 7: Elevated health care use at five years of age in children born very preterm in a European cohort: association with social circumstances and access to routine follow-up services
Chapter 8: Discussion
8.1 Summary of main findings
8.2 Europe, opportunities and challenges for research
8.3 Study design and methods
Chapter 9: Conclusion
9.1 Conclusions on main findings
9.2 Perspectives for future research
Appendix A1, Chapter 3. Coding scheme for free-text responses in SHIPS questionnaire
Appendix B1, Chapter 4. Figure SI: Flow-chart illustrating the participation in the study
Appendix B2, Chapter 4. Table SI: Specialist services as defined in each country specific questionnaire.
Appendix B3, Chapter 4. Table SII: Responder and non-responder characteristics
Appendix B4, Chapter 4. Table SIII: Use of specialist services by country using inversed probability weighting, sorted by total use of services
Appendix C1, Chapter 5. Supplemental Figure S1. Flowchart
Appendix C2, Chapter 5. Supplemental Table S1. Parents’ ratings of preterm birth-related healthcare by country, ordered by unweighted proportion of poor or fair ratings
Appendix C3, Chapter 5. Supplemental Table S2. Risk ratios of poor or fair ratings by sociodemographic characteristics and child health and development (A) without weights, (B) using inverse probability weights, and (C) inverse probability weights truncated at 95th percentile
Appendix D1, Chapter 6. Supplemental Table 1: Translations and back-translations for questions on routine follow-up by country
Appendix E1, Chapter 7. Supplemental Table 1: Services as defined in each country-specific five-year follow-up questionnaire
Appendix E2, Chapter 7. Supplemental Table 2. Cluster characteristics, examples of Hierarchical and K-means clustering
Appendix E3, Chapter 7. Supplemental Table 3. Total number of outpatient/inpatient visits and total number of specialist services visits during the past year in five year-old children born VPT, by perinatal and social factors and follow-up context
Appendix E4, Chapter 7. Supplemental Table 4: Risk ratios of elevated health care use at 5 years of age in children born VPT, by perinatal and social factors and follow-up context (Models III) without inverse probability weights
List of figures
List of tables