Early intervention and follow-up programs among children with cerebral palsy in Moldova: Do they make a difference?

Abstract Aim: To study whether early intervention services (EI) and a follow-up program (FU) influence outcomes of children with cerebral palsy (CP) in Moldova. Methods: Records from 351 children with CP in Moldova born during 2009 and 2010 were retrieved from hospital and orphanage archives between 1 July 2016 and 30 September 2017. We investigated the proportion enrolled in EI and FU at the Early Intervention Centre Voinicel and at the Institute of Mother and Child in 2009-2012. Logistic regression analyses were applied to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for outcomes in children enrolled and not enrolled. Results: Among all children with CP, 166 (47%) were enrolled in EI and FU. Of the 51 children born extremely preterm (gestational age ≤31 weeks), 46 (90%) were enrolled, compared to 97 (39%) of the 250 children born at term. Among 110 non-walking children with CP, 82 (74%) were enrolled into EI and FU, compared to 84 (35%) of 241 able to walk. There was no difference in outcomes of cognition, communication, vision and hearing impairments between those enrolled or not enrolled in EI and FU. However, the subgroup analyses showed that the risk of contractures was five times higher among those not enrolled, regardless of GMFCS level (OR = 5.474, 95% CI 3.306–9.063, p <0.000). Conclusion: In Moldova, EI and FU seem to be offered mostly to extremely preterm and non-walking children with CP. The results indicate a decreased risk for contractures in these children.

and epilepsy [1]. The brain lesion is non-progressive, but its consequences do change over time, and can be barriers to activity and participation in different life arenas [2].
In all children the most rapid maturation and development of both the musculoskeletal and central nervous systems occurs during preschool age, and this development forms the basis for future function [3]. Among clinicians in paediatric rehabilitation, a general consensus is that children with lesions of the central nervous system should receive rehabilitation interventions as soon as possible, due to the rapid brain development during early life [4].
Clinicians and researchers therefore share a common goal to enhance development of function and prevent known secondary complications in as many developmental areas as possible in children at risk of CP, or already diagnosed with CP. These services are called early intervention (EI). EI is differently defined across countries, and there is no consensus regarding age. The Early Intervention Handbook [5] defines it as "multidisciplinary services provided to children from birth to five years of age to promote child health and well-being, enhance emerging competencies, minimise developmental delays, remediate existing or emerging disabilities, prevent functional deterioration and promote adaptive parenting and overall family function". EI includes several rehabilitation services targeting five developmental areas (cognitive, physical, communication, adaptive and social-emotional). Early life is the period of the highest developmental potential due to the high plasticity of the immature brain [6]. A review by De Graaf-Peters and Hadders-Algra [6] suggested that intervention prior to 40-44 weeks post menstrual age (PMA) should be restricted to interventions aiming to mimic the intrauterine environment, such as the Newborn Individualized Developmental Care and Assessment Program (NIDCAP). However, after 40-44 weeks, the intervention should include active stimulation of the child's development. Recent research has documented that the period of dendritic outgrowth and active synapse formation is the best period for the repair of brain damage. This indicates that the period between 28 weeks PMA and 15 months postnatally would be best for EI [6].
However, a recent systematic review by Morgan et al. concluded that the evidence for early motor intervention is limited by the lack of high-quality trials [7]. The most promising intervention included child-initiated movement, task specificity and environmental modification [7]. This systematic review showed the importance of familycentred activities as well as specific environmental changes.
Guralnic [8] also described the positive effect on mother-child interaction of an EI program for both preterm and term-born children. Another study showed a positive effect of a Mother-Infant Transaction Program (MITP) on important qualities of social interaction between mothers of moderately and late preterm infants at 12 months. Being a first-time mother seems to be a mediator that enhances the effects of the intervention [9].
A recent Cochrane review by Spittle et al. [10] concluded that EI in infants born preterm (<37 gestational weeks) is associated with improved cognitive development during infancy and preschool age, and a minor positive effect on infant motor development.
Interestingly, the general positive effects of EI occur in the presence of a large variety of theoretical concepts and actual program content. Parent-infant relationships have a greater impact on cognitive outcomes at infancy and preschool age than intervention programs that focus on either infant development or parent support [10].
Fewer studies examine the effect of EI on children born at term with CP. The available results among children with CP born at term showed a large variation in intervention approaches, similar to EI in infants born preterm [10]. According to Novak, the preferable interventions are child-active approaches that induce maximal neuroplasticity [4].
Moreover, specific motor training programs, such as training locomotor movements on a treadmill and general developmental programs, targeting the child's exploration of active motor behaviour, showed a positive effect on motor development [11].
Early detection of children with CP or at high risk of developing CP is crucial to including them as soon as possible in EI programs. Predictive tools for CP are now available, such as the Hammersmith Infant Neurological Evaluation (HINE), the General Movement Assessment (PRECHTL GMA) tool, and cerebral MRI classifications [4].
High-quality evidence to support EI in improving neurodevelopmental outcomes is sparse.
The existing evidence for infants with CP or at high risk of CP recommends interventions based on motor learning principles, active involvement of the parents and enrichment of the environment [4,7,10].

Setting -the situation in Moldova
In 2003, the first Centre of Early Intervention (CEI) Services Voinicel was founded in Chisinau, Moldova, with the help of the Norwegian non-governmental organisation Ahead-Moldova. The need for family-based intervention was identified in order to address the high rate of abandoned children with disabilities in four orphanages, resulting from a lack of services for families with children at risk of developmental disorders, as well as those with identified disabilities.
The National Agency of Public Health has reported that neurological disability is the second most frequent paediatric disability in Moldova, and that 60% of those with a neurological disability are children with CP [12]. Therefore, some early-stage interventions had to be implemented as soon as possible.
In 2008, a study of the multidisciplinary model of EI services for children with disabilities in Moldova was performed, resulting in a permanent EI program [13].
Around the same time that CEI Voinicel began providing EI services, neonatal mortality and morbidity prevention strategies in Moldova were established in three national The primary aim of this study was to explore whether EI and FU programs influence function and associated impairment outcomes in children with CP, by comparing those enrolled and those not enrolled in EI and FU programs.

Design and study population
Eligible for inclusion in this comparative cross-sectional study were children with CP

Clinical characteristics -outcome measures
CP was diagnosed and classified according to theSurveillance of Cerebral Palsy in Europe (SCPE) protocol [2], into spastic, dyskinetic, ataxic and not classified subtypes. The spastic subtype was sub-classified into uni-and bilateral CP, spastic unilateral CP into right and left hemiplegia, and spastic bilateral CP into quadriplegia and diplegia, in accordance with the International Classification of Diseases 10 th revision (ICD 10) [15].

Gross motor function was classified according to the Gross Motor Function Classification
System (GMFCS) [16]. As the data were collected from descriptions in medical records of variable quality, the children's gross motor function was dichotomised into walking (GMFCS levels I, II and III), and non-walking (GMFCS levels IV and V) children, as proposed by Andersen et al. [17] and used in a previous study by Gincota et al. [18].

Fine motor function was classified according to the Bimanual Fine Motor Function (BFMF)
scale [19] and was described by speech therapists as free text in medical records, as the development of communication at an early stage is closely related to use of hands, and dichotomised into BFMF level I-III, and BFMF levels IV and V as proposed by Andersen et al. [17] and used in a previous study by Gincota et al. [18].
Contractures and deformities were described as present or absent by the neurologists or physical therapists, and represent a unique muscle adaptation where increased passive muscle stiffness causes reduced range of motion without active force production of the muscle [20].

Associated impairments
Associated impairments include seizures, cognition, communication, feeding, hearing, and visual disorders. Speech therapists described speech and feeding abilities in free text in the medical records. Speech was classified on a five-level scale from zero to four, where zero indicated normal speech, level I indicated indistinct speech, level II obviously indistinct speech, level III severely indistinct speech (difficult to understand) and level IV indicated children with no speech. Cognitive function was assessed using the Development Assessment of Young Children Evaluation tool (DAYC) and classified into intellectual disability (IQ score <70) and normal intellectual ability (IQ score ≥70) [21].

Statistical methods
Descriptive statistics were used to generate frequencies and central tendencies.
Comparisons between children with CP who were and were not enrolled in EI and/or FU services were performed using chi square tests.
Odds ratios (OR) and their associated 95% confidence intervals (CI) were calculated by means of logistic regression, with children enrolled in EI or FU serving as reference group.
To control for any confounding effect by gestational age (GA), children who were and were not enrolled in rehabilitation programs were initially assessed separately to identify whether the gestational age had a potential effect on the association between program enrolment and gross or fine motor function.
Data analyses were conducted using the Statistical Package for Social Sciences for Windows version 22.0 (SPSS Inc., Chicago, IL, USA). A significance level of 0.05 was chosen.

Ethics
Ethical approvals and collaboration agreements were obtained and formalised by all involved institutions Parents or primary caregivers of patients treated at this centre signed an informed consent form stating that medical data collected as part of the admission may be used for research purposes. The use of this regularly collected medical information in the present study was approved as described above and did not require a new individual consent form to be completed.

Results
Among all 351 children born in 2009-2010 diagnosed with CP, mean age at diagnosis 4.7 years, 166 (47%) had been enrolled in EI and/or FU programs. Of those 166 children, 112 (67%) were included in a FU program at the Institute of Mother and Child, 95 (85%) from rural areas. The remaining 54 children (33%) were included in EI at CEI Voinicel (Table 1).
Among the 166 children enrolled in EI and/or FU programs, 84 (35%) children were classified at GMFCS levels I-III, compared to 157 (65%) of the children who had no intervention. However, among those enrolled in EI and/or FU programs, 82 children (74%) were classified at GMFCS level IV-V, compared to 28 children (26%) who were not enrolled (Table 2).  Table 2). Both socially disadvantaged families and those who belonged to middle-and high-income families had equal access to the EI and/or FU programs, 49% versus 51%, respectively ( Table 2).
The results of the second step of the study did not show statistically significant differences between outcomes in any of the developmental areas (intellectual development, speech, feeding abilities, and gross or fine motor function) between the groups enrolled or not enrolled in the EI and/or FU programs (Table 2 and 3).
The logistic regression analyses showed that EI and/or FU program enrolment was a highly protective factor for development of contractures. Of all the children with CP, the risk of contractures was more than five times higher among those not enrolled in EI and/or FU programs, regardless of GMFCS level (OR = 5.474 (95% CI 3.306-9.063), p <0.000) ( Table   4).
When subgroup analyses of contractures in upper and lower extremities were performed among children who were enrolled in EI and/or FU programs, we found that there was an increased risk (OR = 1.677, 95% CI 1.426-1.972, p <0.000) for contractures among those not enrolled in EI and/or FU programs among walking children (GMFCS I-III) ( Table 4) compared to those enrolled.
Moreover, the present study showed a significant risk of developing contractures among children regardless of BFMF level who were not enrolled in an EI and/or FU program (OR = 4.570, 95% CI 2.728-7.658, p = 0.001) ( Table 4). .
Having these results, we decided to examine the ORs of developing contractures among children born at different GA (preterm and term-born children), enrolled or not in EI and/or FU programs, and we found that those born preterm had a more than 40% higher risk of developing contractures compared to children born at term (OR = 1.415, 95% CI 1.225-1.635, p = 0.001) ( Table 4).
The adjusted analyses with all three covariates showed that the only statistically significant covariate in development of contractures among children enrolled in EI and/or FU programs was the GMFCS level (OR = 28.550, 95% CI 5.801-140.510, p = 0.002) ( Table   4).

Discussion
In this study of EI and FU programs for children with CP in Moldova, we found that less than half of eligible children were enrolled in rehabilitation programs. These results are Given that Institute of Mother and Child is a Republican hospital, most of the children across the country with severe disabilities are referred to it, and we assume that the biggest group of children with CP will receive services at this hospital, while the CEI Voinicel and two other centres (Tony Hawks Rehabilitation Centre and Republican Centre for Child Rehabilitation) cover Chisinau municipality.
The proportion of children with unilateral, ataxic and non-classified CP referred to EI and FU programs was significantly lower than those with more severe impairments. This might be explained by the mild clinical symptoms in the early life stages, as well as an insufficient level of competence in diagnosing unilateral CP among health care professionals, as it is stated in several publications (4,7,10). The use of the SCPErecommended classification tree and inclusion and exclusion criteria could improve the number of children who would benefit from the EI or FU programs.
The significant difference between the GA groups referred and not referred to EI and/or FU programs (preterm and term birth) could be explained by the fact that the FU program is This may also be explained by the fact that children born after complicated deliveries (including severe prematurity) are referred from all over the country to the Institute of Mother and Child for diagnosis and treatment, so they were included in the FU program to prevent possible complications. However, only a very small proportion of children born at term, with neurological symptoms, were referred to the FU program. This is to our knowledge the first study showing the inclusion of children at risk to FU programs and its outcomes in time.
One positive finding of the present study is that accessibility of both the EI and FU services was equal to families regardless of social status, as well as place of residence (rural or urban). This is explained by the fact that the Institute of Mother and Child is a To be able to provide the right child the right intervention at the right time, correct subdiagnosis and classification of functional level is crucial. It is therefore important for the authorities to revise the National Clinical Protocol of CP. The process of identification, diagnosis and evaluation of children with CP is likely to improve referral to EI or FU programs during the first three years of their lives, which is crucial for the whole family of children with special needs.
This also involves the best evidence-based knowledge of CP for the health care professionals involved in diagnosis and treatment of children with CP in Moldova. Revising the curricula of continuous medical education provided by the State Medical and Pharmacy University, 'N, Testimitanu', would have a high impact.
The results of the present study should be treated with caution because of the inclusion bias, where only the most severe cases were referred to the EI and FU programs.

Conclusions
In Moldova, EI and FU programs seem to be offered mostly to extremely preterm children with CP, as well as to more severely impaired children, likely due to competence and capacity issues. Six centres are now providing early rehabilitation services in the central and northern parts of the country regions, compared to two at the time of the study.
However, since only half of eligible children were enrolled in EI or FU programs, there is still a need for more centres in all 36 counties of Moldova, in order to improve geographical access to these services.
Based on the results of the present study, we would also recommend paying more attention to enrolling all preterm and term-born children with neurological signs in EI programs, as those enrolled showed a significantly lower prevalence of contractures, which may enhance functional development.   I-III, IV-V  Level I,II,III  Level IV,V  Total  BFMF** categories I-II, III, IV-V  I-II  III  IV