Abstract
Background A difficult birth at term (DBAT) may manifest as fetal acidosis and low Apgar scores and is often referred to as “perinatal asphyxia,” especially when infants show signs of neonatal encephalopathy (NE). In contrast to DBAT resulting in moderate-to-severe NE, which is associated with neurodevelopmental disorders, little is known about the prognosis of less severe forms of DBAT, with or without NE.
Objective The purpose of this study was to evaluate the International Classification of Functioning, Disability and Health, Children & Youth Version activity “mobility” and other neurodevelopmental sequelae in infants with DBAT at age 6 years.
Methods The index cohort (n=62; 35 boys, 27 girls) consisted of consecutive term infants with DBAT based on clinical criteria in a Dutch nonacademic hospital from 1999 to 2005. Neonatal encephalopathy was assessed according to the Sarnat grading system and excluded infants with severe NE. The matched reference cohort (n=81; 49 boys, 32 girls) consisted of healthy term infants. The primary outcome at 6 years was limited mobility (Movement Assessment Battery for Children score ≤15th percentile). Secondary outcomes included learning and behavioral problems and the presence of minor neurological dysfunction.
Results Three children developed cerebral palsy and were excluded from analyses. Children with DBAT more often had limited mobility than children without DBAT (risk ratio [RR]=2.44; 95% confidence interval [95% CI]=1.16, 5.14). The risk of limited mobility rose with increasing severity of NE (mild NE: RR=3.38; 95% CI=1.40, 8.16; moderate NE: RR=4.00; 95% CI=1.54, 10.40), and manual abilities especially were affected (RR=4.12; 95% CI=1.40, 12.14). Learning problems, need for physical therapy, and complex minor neurological dysfunction were more common in children with DBAT than in children without DBAT.
Conclusions Term infants who develop mild or moderate NE following DBAT are at increased risk for limited mobility at age 6 years. Routine monitoring of neuromotor development in these children is warranted.
In industrialized countries, 1 in 1,000 infants has a difficult birth at term (DBAT),1 which may manifest as an abnormal fetal cardiotocogram, fetal acidosis, and low Apgar scores.2,3 In clinical practice, such difficulties are often labeled as “perinatal asphyxia.” The criteria for perinatal asphyxia in clinical practice vary (ie, the cutoff of a low Apgar score may be 6 or 7 and that of fetal acidosis may be 7.0, 7.1, or 7.2). Gradually, it has become clear that perinatal asphyxia especially has clinical significance when it results in neonatal neurological dysfunction. The Sarnat grading system was introduced to classify the various degrees of neonatal neurological dysfunction following perinatal asphyxia in terms of mild, moderate, and severe neonatal encephalopathy (NE) (for details on the classification, see eTab. 1).4
Most evidence on developmental outcome following perinatal asphyxia is based on follow-up of infants with moderate-to-severe perinatal asphyxia. As these infants have a high risk for death or disability, they are often admitted or transferred to academic centers, where intensive treatment, including treatment for hypothermia,5 and brain monitoring with magnetic resonance imaging (MRI) belong to the possibilities.6–9 In contrast, long-term neurodevelopmental functioning of children with a DBAT, resulting in milder forms of perinatal asphyxia, with or without NE, has received relatively little attention. Most reviews that included children with mild forms of perinatal asphyxia suggested that impairment is uncommon in these children.6–9 Nevertheless, more recent studies suggest that these children may be at increased risk for problems in learning, behavioral, and memory domains.10–12 So far, knowledge regarding long-term motor outcome, particularly in terms of limitations in activities covered by the chapter “Mobility” of the International Classification of Functioning, Disability and Health, Children & Youth Version (ICF-CY),13 in infants with milder forms of perinatal asphyxia is lacking. The activity of mobility in the ICF-CY includes the skill to move around from one place to another and arm and hand use, such as the manipulation of objects and catching and throwing a ball.13
We, therefore, studied long-term limitations in mobility and other neurodevelopmental outcomes in term infants who were born in a nonacademic setting and had a difficult birth. The presence of a DBAT was based on the presence of at least 2 of the commonly applied clinical markers of DBAT (ie, an abnormal fetal cardiotocogram; a low Apgar score at 5 minutes; and fetal acidosis, expressed as a low value of the pH and a high value of the base excess of the umbilical blood). After birth, the degree of NE was assessed. Outcome at the age of 6 years of the infants with DBAT was compared with that of infants without DBAT using standardized tools to measure long-term limitations in mobility and other neurodevelopmental outcomes.
The primary aim of this study was to evaluate whether DBAT is associated with limited mobility at 6 years. A secondary aim was to evaluate associations between DBAT and academic achievement, behavior, and neurological condition at the age of 6 years. We added the secondary aim because limited academic achievement and behavioral problems often are comorbid conditions of limited mobility and information on academic achievement and behavior is relevant.14–17 The information on neurological condition would allow us to gain insight in the neural mechanisms underlying a potentially limited mobility. Special attention was paid to the predictive value of the presence and severity of NE for limited mobility in the absence of cerebral palsy (CP).
Participants and Method
In order to understand the nature of our study group, we first summarize the Dutch health care system for obstetrical guidance, as it is different from that in most other industrialized countries.18,19 Women with an uncomplicated pregnancy deliver either at home or in the outpatient clinic of a regional hospital under the guidance of a midwife. In case of imminent complications, women are admitted to clinical obstetrical care under surveillance of a gynecologist. If DBAT occurs and results in a severe form of asphyxia, the infant is referred to an academic center with MRI scanning and hypothermia treatment facilities. If DBAT results in less severe asphyxia, the infant is admitted to the pediatric department of the regional hospital.
In an index cohort, we recruited all consecutive infants with DBAT who were admitted to the neonatal unit of the Gelre Regional Hospital Apeldoorn, the Netherlands, between January 1, 1999, and July 1, 2005.20 Infants were eligible for the index cohort if they were born at term (ie, birth after 36 completed weeks of gestation), if they were born in the hospital (referrals from midwife practices or outpatient hospital delivery), and if they fulfilled at least 2 of the following clinical criteria for DBAT: (1) abnormal cardiotocogram (ie, late decelerations, persistent bradycardia or persistent tachycardia), (2) Apgar score <7 at 5 minutes, (3) umbilical pH <7.20, and (4) umbilical base excess ≤10 mmol/L.3,6,21 Infants with severe NE and with major congenital malformations were not eligible. Eighty infants presented with DBAT to the neonatal unit. The pediatrician (S.B.), within the first 24 hours after delivery and on the basis of neurological parameters, determined the degree of NE according to the grading of Sarnat and Sarnat4 (eTab. 1). Seventeen infants were not included because parents declined participation, resulting in an index cohort of 63 infants (Fig. 1). Infants who did participate (n=63) and those who did not participate (n=17) were similar in terms of inclusion criteria and severity of NE.
Flow diagram: intake of study group with difficult birth at term and reference group.
In a reference cohort, we recruited healthy term infants at the Gelre Hospital and nearby midwife practices during the same period (1999–2005). Again, infants with major congenital anomalies were not eligible. We matched infants in the reference cohort with the index cohort for sex, gestational age, birth weight, and cesarean section. We recruited the healthy term infants: (1) at home or in an outpatient clinic under the guidance of a midwife (n=63) or (2) from infants born in the hospital after cesarean section (n=21). In the latter infants, cesarean section was applied either because the mother previously had had a cesarean section or because delivery was not progressing. If the latter was the case, it still had resulted in the birth of a healthy neonate without signs of DBAT. In total, the reference cohort consisted of 84 term infants (Fig. 1).
The parents of the participants gave signed informed consent, and the procedures were approved by the Medical Ethical Committee of University Medical Center Utrecht (project number: 04-163). Clinical assessments (ie, Apgar scores, cardiotocogram, umbilical pH and base excess) were performed in all infants with DBAT as part of standard clinical care.
Children from both cohorts were invited for follow-up at 6 years of age. One child with moderate NE in the index cohort had died, and 3 children in the reference cohort belonged to families who declined participation, either because of assessment burden (n=2) or for logistical reasons (n=1; Fig. 1). The assessment at 6 years consisted of a motor and neurological assessment and a behavioral and academic evaluation by means of parental and teachers' questionnaires. In addition, parents completed a questionnaire on the child's medical history, including information on the use of paramedical care (speech therapy, physical therapy, or occupational therapy).
We assessed mobility with the Movement Assessment Battery for Children (MABC, version 1).22 The MABC has been developed to identify and evaluate children with mild-to-moderate limitations in activities, covered by the chapter “Mobility” of the ICF-CY.22,23 The test consists of 4 age bands, each with 8 functional motor tasks representing: (1) manual dexterity (ICF-CY code d440: fine hand use); (2) ball skills (ICF-CY code d445: hand and arm use); and (3) static and dynamic balance skills (ICF-CY codes d410 and d455: changing basic body position and moving around, respectively).13,22 Quantitative performance of each test item is scored from 0 (best) to 5 (worst). Item scores are added up, producing 3 subscores (ie, manual abilities, ball skills, and static and dynamic balance) and a total score. Performance on the total MABC is typical if >15th percentile (P15), borderline if 5th percentile (P5) ≤ score ≤ P15, or definitely impaired if <P5.24 In the present study, we chose to dichotomize outcome on the total MABC into “typical” (>P15) and “limited” (≤P15). Performance in the 3 domains (manual abilities, ball skills, and balance) was considered typical if ≥P5 and limited if <P5.
The chosen cutoffs for the total score and the domain scores are recommended by the European Academy for Childhood Disability and the Dutch National Developmental Coordination Disorder Committee to use in the diagnosis of developmental coordination disorder (DCD).16 The MABC version 1 has good test-retest and interrater reliability, moderate concurrent validity lacking a suitable gold standard, and good construct validity.23–26 The validity of the subscale scores is satisfactory.24,27
In order to evaluate behavior, we asked the parents and teachers of all children to fill out Achenbach System of Empirically Based Assessment (ASEBA) questionnaires, which include the Child Behavior Checklist (CBCL; for parents) and the Teachers Report Form (TRF; for teachers).28,29 For both questionnaires, we dichotomized the resulting scale and total scores on the basis of the T-scores into “typical” (score <95th percentile [P95]) and “behavioral problems” (score ≥P95, including both borderline and clinical scores). The reliability of the CBCL and TRF is good.30 The concurrent validity of the CBCL and TRF based on correlations with outcome of related checklists and questionnaires also is good.30–33 The TRF also comprises open questions about academic achievement, school grades, extra educational assistance, repetition of class, and attendance of a special school. Attendance of a special school in the Netherlands is based on the presence of physical, cognitive, and behavioral impairment, often a combination of these impairments. On the basis of this information, we defined the presence of learning problems as the presence of special assistance or special education or being in an inappropriate grade for age.29,30
To assess neurological condition, we used the standardized, age-specific and criterion-referenced examination of the child with minor neurological dysfunction (MND).34 This examination assesses the presence of MND in 8 domains: (1) dysfunctional posture and muscle tone regulation, (2) dysfunctional reflex activity, (3) mild dyskinesia (eg, choreiform or athetotiform movements), (4) mild problems in coordination, (5) mild problems in fine manipulative ability, (6) excessive associated movements, (7) mild cranial nerve dysfunction, and (8) mild sensory dysfunction. Importantly, a single sign has no clinical significance. Signs obtain significance if they cluster in a domain; for each domain, the criteria for dysfunction have been determined.33 At school age, the assessment results in the following classification: (1) neurologically normal, implying the absence of dysfunctional domains or isolated dysfunction in the domain “reflexes”; (2) simple MND, denoting the presence of dysfunction in 1 or 2 domains; (3) complex MND, denoting the presence of dysfunction in at least 3 domains; and (4) neurologically abnormal, implying the presence of a clear neurological disorder, such as CP.34 The diagnosis of CP implies the presence of a classical configuration of neurological signs as specified by the Surveillance of Cerebral Palsy in Europe network.35 Simple MND is considered to reflect typical, but nonoptimal, brain function; complex MND is regarded as the clinically relevant form of MND, as it is clearly associated with motor, learning, and behavioral problems.34,36
All children were independently assessed by 2 authors. The first author (P.I.), who was aware of the clinical condition of the children, performed the initial neurological examination. The last author (M.H-A.), who is a neurodevelopmental expert and was masked to all details of the child, assessed neurological condition on the basis of a video recording of the assessment of the first author. In case of disagreement between the authors, the findings of the expert were used. The MND assessment has good intrarater, interrater, and test-retest reliability (κ=.71–.83).34,36–38 The construct validity, based on the relationship of MND with prenatal and perinatal adversities, is good.34,39,40 The predictive validity also is good: severity of MND at 9 years of age is related to the risk of MND at 12 and 14 years of age and that of learning and behavioral problems at 9 and 14 years of age.34,40–42
The primary outcome measure was limited mobility (MABC score ≤P15) at 6 years of age. The secondary outcome measure included presence of MND, whether the child had received physical therapy, and learning and behavioral problems assessed with the CBCL and TRF at 6 years of age.
Data Analysis
Power calculations based on the Dutch norms of the MABC (X̅=4.4, SD=4.3)22 demonstrated that for detection of a difference of at least 2.5 points in total MABC score with 95% power (α=.05), at least 65 children had to be included per group. The frequencies of primary and secondary outcomes were compared among index and reference cohorts with risk ratios (RRs) and 95% confidence intervals (95% CIs). To this end, we used Poisson regression. In one model (model A), we adjusted for those factors for which we initially matched the index and reference cohorts (ie, sex, gestational age, birth weight, and cesarean section). In a second model (model B), we adjusted for matching factors and those factors that changed the crude RRs by more than 5%. Finally, we did subgroup analyses according to severity of NE for motor, neurological, and behavioral outcomes. Outcomes are expressed in RRs with their 95% CIs. P values of less than .05 were considered statistically significant.
Results
In the index cohort, 3 children who had experienced DBAT with moderate NE had CP. We excluded them from the analyses because they were unable to perform the MABC. In total, 59 children in the index cohort and 81 children in the reference cohort were included in the analyses (Fig. 1). Cohorts were similar in terms of matching factors and social and anthropometric characteristics at 6 years of age (Tab. 1). Of the 59 children with DBAT, 9 had moderate NE, 16 had mild NE, and 34 showed no signs of NE (Tab. 1).
Characteristics of the Study Population at Baseline and at 6 Years of Agea
Results are presented as crude RRs and 95% CIs, as adjustment for matching factors or other potential confounders did not influence the RRs (eTab. 2). Children with DBAT more often had limited mobility (total MABC ≤P15) than children without DBAT (RR=2.44; 95% CI=1.16, 5.14; P=.019; Tab. 2), which was mainly explained by limited manual abilities (RR=4.12; 95% CI=1.40, 12.14; P=.010) and, to a lesser extent, by limited balance skills (RR=1.77; 95% CI=0.96, 3.26; P=.069; Tab. 2).
Crude RR Values for Limited Mobility at 6 Years of Age in Children With and Without DBAT by Mobility Domainsa
Table 3 shows the RRs for limited mobility (MABC ≤P15) and limited manual abilities, ball skills, and balance skills by severity of NE. For limited mobility and limited manual abilities, risk rose with severity of NE (Fig. 2); this trend was not present for limited balance and ball skills. Children with DBAT, but without NE, were not at increased risk for limited mobility (Tab. 3).
Crude RR Values for Limitations in Total MABC Score, Manual Abilities, Ball Skills, and Balance Skills at 6 Years of Age in Children With and Without DBAT by Sarnat Stagea
Rate of limited mobility (Movement Assessment Battery for Children [MABC] ≤15th percentile [P15]) at 6 years of age in children with and without difficult birth at term (DBAT) by severity of neonatal encephalopathy (NE).
Children with DBAT more often had complex MND (RR=1.94; 95% CI=1.01, 3.76; P=.048) and learning problems (RR=2.75; 95% CI=1.50, 5.03; P=.001) and received physical therapy more frequently (RR=2.86; 95% CI=1.57, 5.22; P=.001) than children without DBAT, but rates of simple MND and behavioral problems were similar in children with and without DBAT (Tab. 4). The risk for complex MND rose with the severity of NE; the association with learning problems and physical therapy guidance was independent of the degree of NE (eTabs. 3–6).
Crude RR Values for Secondary Outcomes at 6 Years of Age in Children With and Without DBATa
Discussion
Our study showed that children with DBAT diagnosed in a nonacademic setting more often had limitations in the activity of mobility at 6 years of age than children without DBAT. The association was dependent on severity of NE following DBAT and was mainly explained by limited manual skills. The association between severity of NE and limited mobility was supported by a similar association between severity of NE and complex MND. Finally, we found that, independent of severity of NE, children with DBAT were at risk for learning problems and more often received physical therapy.
Our finding of an increased risk for adverse neurodevelopmental outcome in children with moderate NE following DBAT is consistent with previous reviews addressing long-term neurodevelopmental outcomes in children with mild-to-moderate NE.3,6,7,10–12,21 In the current study, we demonstrated that the increased risk for adverse neurodevelopmental outcome was not restricted to children with moderate NE; children with mild NE after DBAT also were at increased risk for adverse neurodevelopmental outcomes (ie, for limited mobility, learning problems, and complex MND). This finding is at variance with most previous reviews,3,6,7,21 but in line with more recent work that looked at different neurodevelopmental domains separately.10–12 Moreover, in one of these studies, which focused on the pathology of the corpus callosum, it was shown that children with mild and moderate NE scored significantly worse on the MABC than controls.7 Our study focused on the outcome of limited mobility and was thereby able to show that the increased risk for limited mobility after DBAT was dependent on the presence and severity of NE and that children with DBAT, but without NE, are not at risk for limited mobility.
There are several possible explanations why we found an effect of mild NE on developmental outcome, whereas most other studies did not. First, due to the origin of our population (ie, children with DBAT recruited in a regional hospital), the rate of children with mild NE in our study was higher than in previous studies. Second, the present study focused on limited mobility assessed with a standardized tool, whereas other studies addressed other developmental domains. Finally, we assessed children at 6 years of age. In previous reviews, the length of follow-up differed substantially among studies, but it was generally shorter than in our study.3,6,21 As it takes time for specific motor and cognitive functions to develop, some deficits may not have had sufficient developmental time to manifest themselves (“growing into deficit” phenomenon).42
The finding that an increased risk for limited mobility in children with DBAT depends on the presence and severity of NE was supported by the data on neurological impairment. Also, the complex form of MND was dependent on the presence and severity of NE. Previously, it has been shown that the presence of complex MND is associated with a substantially increased risk for developmental coordination disorder.43 Children with DBAT, but without NE, were not at increased risk for limited mobility and neurological impairment. Interestingly, all children with DBAT, regardless of the presence and severity of NE, were at risk for learning problems (defined as the presence of special assistance or special education or being in an inappropriate grade for age) and the use of physical therapy. This finding suggests that the pathways underlying learning problems and the use of physical therapy differ from those of limited mobility and neurological impairment measured with standardized tests. Presumably, the limited mobility can be largely attributed to impaired neurological integrity due to perinatal adversities. For the learning problems and the use of physical therapy, 2 explanations may be offered. First, the use of educational and physical therapy guidance may indicate that the child's DBAT history generated parental concern over the child's development, which, in turn, resulted in a higher request for developmental guidance.44 Second, DBAT may reflect a generally reduced capacity to cope with heterogeneous conditions (ie, at birth, during motor development, and at school).
The strengths of our study were the focus on the effect of DBAT accompanied by milder forms of NE on limited mobility, the use of standardized tools for outcomes, and the minimal attrition during follow-up. These strengths of our study mean that our results may be generalized to similar settings. Also, by applying standardized tools, such as the MABC, we were able to measure more subtle components of mobility than most former studies did.
Our study had limitations. First, we suspect that, despite matching and multivariable analyses for known potential confounders, selection of participants in the reference cohort might have influenced outcome. Indeed, in our study, the rate of simple MND in the reference cohort was higher than expected,34 which may have underestimated the true effect of DBAT on neurodevelopmental outcomes. Second, we assessed learning problems—a secondary outcome—with the TRF.28,29 This tool provides a global estimation of learning problems, but it does not allow for a specification of underlying cognitive deficits. Third, subgroup analyses should be interpreted with caution. Nevertheless, the finding that the risk of limited mobility rose with increasing severity of NE strengthens our results.
The nonacademic setting of our study can be regarded as both a limitation and a strength of the cohort. Studying DBAT in a regional hospital meant that neonatal MRI findings were conspicuous by their absence. Magnetic resonance imaging has proven to be of additional value with regard to diagnosis and prognosis of DBAT resulting in moderate-to-severe NE.5 The size and the site of moderate-to-severe brain lesions predict developmental outcome well.7,45–48 However, the relationship between mild or nonlocalized brain lesions and limited mobility is less well understood.15 Apart from concerns regarding the usefulness of MRI in infants with milder variants of NE, MRI is not ubiquitously available for infants at high risk in nonacademic settings, including those in lower and middle income countries. In these settings, simple clinical parameters of DBAT and NE may help local staff to identify children with DBAT in need of continued monitoring.49
Another difficulty of our study was the inclusion of infants born both in and out of the hospital. Although imbalances between the index and reference cohorts potentially could have influenced our results, this mix was inherent to our aim to include milder forms of DBAT and the way Dutch health care is organized.18,19 Finally, it may be considered a limitation that our study evaluated perinatal care provided from 1999 through 2005. Perinatal care has changed since that time, including the introduction of hypothermia treatment. This treatment is applied in academic hospitals, especially in infants with severe NE, but also increasingly often in infants with moderate NE.50,51 It is conceivable that hypothermia treatment has an effect on long-term neurodevelopmental outcome. This possibility needs to be addressed in future studies.
Our findings have implications for clinical practice and future research. First, children with DBAT not resulting in NE are not at risk for limited mobility. Parents of these children may be reassured. Second, children with DBAT resulting in mild and moderate NE are at risk for limited mobility. We, therefore, recommend routine monitoring of neuromotor development of all children with DBAT resulting in NE, regardless of whether they do or do not receive hypothermia treatment. Early detection of impairments and limitations offers a means for the provision of early intervention, which may assist in the prevention of limitations in mobility in later life.52–54 The frequency of monitoring during infancy may be guided by the clinical signs of the infant; after infancy, a biannual assessment is recommended.
In conclusion, this study shows that children with mild or moderate NE following DBAT are at risk for limited mobility, in particular for limited manual abilities. The risk of limited mobility is dependent on the presence and severity of NE, whereby children with DBAT without NE are not at risk for limited mobility. Further studies in children with DBAT are warranted to confirm our findings. In the meantime, clinicians are encouraged to monitor development of all children with NE following DBAT, ensuring that children with limited mobility are detected in an early stage.
Footnotes
Dr van Iersel, Dr Bakker, Mr Jonker, and Professor Hadders-Algra provided concept/idea/research design. All authors provided writing. Dr van Iersel and Mr Jonker provided data collection and facilities/equipment. Dr van Iersel, Dr Algra, and Professor Hadders-Algra provided data analysis. Dr van Iersel provided project management. Dr van Iersel and Dr Bakker provided participants. Dr Bakker provided institutional liaisons. Dr Bakker and Mr Jonker provided consultation (including review of manuscript before submission). The authors thank Ale Algra (University Medical Center Utrecht) for his critical comments, Anneke Kracht (University Medical Center Groningen) for technical assistance, and Elisa Hamer and Nienke Devlin for critical remarks on a previous draft of the manuscript.
This study was approved by the Medical Ethical Committee of University Medical Center Utrecht.
- Received April 12, 2015.
- Accepted January 24, 2016.
- © 2016 American Physical Therapy Association