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SYSTEMATIC REVIEW

Motor Developmental Delay After Cardiac Surgery in Children With a Critical Congenital Heart Defect: A Systematic Literature Review and Meta-analysis

Sprong, Maaike C. A. MSc; Broeders, Willem MSc; van der Net, Janjaap PhD; Breur, Johannes M. P. J. MD, PhD; de Vries, Linda S. MD, PhD; Slieker, Martijn G. MD, PhD; van Brussel, Marco PhD

Author Information
doi: 10.1097/PEP.0000000000000827

INTRODUCTION

Congenital heart defects (CHDs) are the most common congenital disorders in newborns1 and the leading causes of infant death from birth defects.2 CHD can be classified as mild, moderate, or severe. Infants with severe CHD are presenting severely ill in the newborn period or early infancy and show acyanotic lesions such as aortic stenosis and coarctation of aorta, or cyanotic lesions such as single-ventricle physiologies (SVPs), like hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and tetralogy of Fallot (TOF).3 Approximately 25% of CHDs are considered to be critical and require surgery within the first year of life.4 The mortality rate after neonatal cardiac surgery markedly declined over the past decades due to major advances in cardiac surgery and perioperative care.5

Several studies have reported a high prevalence of prenatal and postnatal preoperative and postoperative abnormal cerebral findings, such as delayed brain maturation and brain injury in newborns with a critical congenital heart defect (CCHD).6–11 As a result of brain injury and immaturity, children with a CCHD frequently demonstrate abnormal motor development,12–17 even after a solitary surgical intervention.18 Additionally, the literature describes person-specific parameters, usually innate and nonmodifiable, such as type and severity of heart defect, gender, environmental factors, and family factors, as well as procedure-specific parameters, such as number of operations, length of hospital stay, complications, cardiopulmonary bypass time, and deep hypothermic circulatory arrest (DHCA). These parameters can influence motor development independently, cumulatively, and synergistically. The underlying cause of developmental problems is often multifactorial, and not yet fully understood.19,20

Although motor developmental outcomes in CCHD can range from normal motor development to severe motor delays, children with CCHD are at higher risk for neurodevelopmental delays.12,21,22 This is worrisome in view of long-term outcomes because they are a potential risk for future limited physical and cognitive competences, reduced social interaction, and diminished quality of life.21,23–26 More specifically, gross motor delay can complicate participation in exercise and sports and result in a sedentary lifestyle and social isolation from peers. Fine motor delay can lead to educational problems, especially in combination with cognitive impairments. Therefore, awareness of the severity and prevalence of adverse neurodevelopmental outcomes in CCHD is crucial for identifying, and predicting motor delays to be able to intervene at an early stage and avert motor complications later in life. Early interventions positively influence postoperative recovery and motor development of children with CCHD.27,28

Most studies exploring motor development in children with CHD or CCHD have a retrospective or cross-sectional study design.29 Furthermore, these studies frequently involved children with CCHD, including underlying genetic anomalies.29 Through improved genetic technology, genetic causes of CHD can be identified in an increasing percentage of infants. Currently, an underlying genetic anomaly is found in up to 30% of children with CHD.30,31 Chromosomal aneuploidy conditions, such as 22q11 deletion syndrome, Down syndrome, Williams syndrome, Noonan syndrome, CHARGE syndrome, and the VACTERL association, account for 10% of the genetic anomalies in children with CCHD and are associated with worse neurodevelopmental outcomes. Furthermore, nonsyndromic CCHD infants with copy number variation show worse neurological outcomes; therefore, a genetic burden appears to influence the neurodevelopmental outcome, including the motor development, even in isolated CCHD.18,20,22,30,32,33

However, for children with CCHD but without underlying genetic anomalies, which is the case for most children with CCHD, an overview of the prevalence and severity of motor development delays per type of CCHD is lacking. As a result, vital clinical questions, such as what to expect with regard to the motor delay of children with a specific type of CCHD in different age ranges, remain unanswered. Therefore, the objective of this systematic review is to provide a comprehensive overview of the severity and prevalence of motor development delays in children with specific types of CCHD without an underlying genetic disorder.

METHODS

The literature was systematically reviewed according to the PRISMA statement for reporting systematic reviews.34 The electronic databases PubMed/MEDLINE, Embase, Web of Science, and CINAHL were searched for eligible articles from database inception up to October 2020. The search was conducted without any language or timespan restrictions. The following MESH terms, Emtree terms, and keywords were employed to identify the domain and outcome: congenital heart defect, congenital heart disease, aortic coarctation, hypoplastic left heart syndrome, Norwood procedures, right-heart bypass, tetralogy of Fallot, transposition of great vessels, arterial switch operation, motor skills, motor skills disorders, child development, neurodevelopment, and developmental disabilities. The complete search string is in Supplemental Digital Content 1 (available at: http://links.lww.com/PPT/A329). Articles were eligible for inclusion when (1) motor development in children with a CCHD was assessed with an objective measurement tool, and index or composite scores were reported, (2) children were within the age range of 0 to 12 years, and (3) surgery was performed within 6 months after birth and/or disease type was categorized as moderate or severe CHD according to the classification by Hoffman and Kaplan.3 Articles were excluded if (1) it concerned a study cohort born before 1990 because survival rates increased significantly since 1990 due to improved care, (2) children diagnosed with an additional genetic syndrome (eg, 22q11, trisomy 21, and Marfan) were included and their motor development outcomes were included in the group averages, (3) articles did not categorize the outcome by disease type, (4) articles were case reports, dissertations, systematic reviews, reports or opinions of experts, and clinical experiences of respected authorities, (5) the mean age of the study population was not clearly defined, or (6) full text was unavailable in English.

The selection of studies and data extraction were performed independently by 2 researchers, and disagreements were resolved by involving a third researcher until consensus was reached. Initially, articles were screened based on their title and abstract. When the title and abstract implied an article was potentially eligible for inclusion, the full paper of the report was obtained. Additionally, reference tracking was performed in all included articles. The reviewers extracted data using a standard extraction form. Data extracted from the included articles were: (1) first author, publication year, and study location, (2) study design, (3) participant characteristics, (4) methods for motor development assessment, and (5) study results. If data were missing or further information was required, attempts were made to contact the corresponding author to request the required information. The risk of bias of the included articles was assessed with 3 different instruments due to the different study designs.

We applied the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, the assessment tool for controlled intervention studies and before-after (pre-post) or the assessment tool for studies with no control group by the National Heart, Lung, and Blood Institute at the National Institutes of Health, the United States, to assess the risk of bias and methodological quality for all selected observational studies.35 Two reviewers independently conducted the quality assessment for each study to ensure an objective evaluation process. Supplemental Digital Content 2 (available at: http://links.lww.com/PPT/A330) provides the results of the methodological quality assessment. Studies were given a cumulative quality rating poor, fair, or good based on responses to the questions. A score of 5 or less was classified as poor, a score of 6 or more as fair, and a score of 10 or more was classified as good. Disagreements regarding methodological quality were resolved by discussion until consensus was reached.

For the majority of the motor development assessment instruments, a motor index or scale score of <−2 standard deviations (SD) indicates a significant motor delay or an abnormal motor development.36 Scores between −2 and −1 SD are often indicative of a risk for motor delay. To compare the results, reported outcomes were converted to z scores with the subsequent formula: reported sample mean score minus normative mean score/standard deviation. The z-score system expresses measured outcome values as several SDs below or above the test-specific reference's mean value. For clinical and practical usefulness, all motor developmental scores were categorized as “abnormal” when z scores were <−2 SD, “below average” when z scores were between –1 and –2 SD, and “average” when z scores were between −1 and +1 SD. Furthermore, we subdivided the results per diagnosis and in age ranges from 0 to 12 months, 12 to 24 months, 24 to 36 months, and 36 months and older for clinical application.

When reported, the prevalence of children with motor delays was extracted in addition to the group averages. Cut-off scores of 2 SD below the normative mean or scores below the fifth percentile were considered abnormal.37

Meta-analysis

We calculated the pooled mean of motor developmental scores if at least 3 studies were available for the same disease type at the same age and if they applied identical measurement tools. Mean age was not more than 0.5 month apart when motor developmental scores were grouped in the pooled analysis. A fixed-effects model was applied because we expected the study population, measurement tools, outcomes, and age of assessment to not vary among the studies.

RESULTS

Overall, 1394 records were identified, of which 206 articles were eligible (Figure 1). In total, 29 full-text articles, including 1369 children with a CCHD, met the inclusion criteria. Twenty-seven of these were cohort studies, 1 was a randomized controlled trial,38 and 1 was a feasibility study.39 Sixteen studies examined children with SVP exclusively.38,40–54 Because HLHS is one of the most severe types of SVP, 5 studies reported separate scores for HLHS and other types of SVP.45,50–52,55 Four studies exclusively examined HLHS.41,43,46,54 Four studies exclusively examined TGA55–59 and 5 studies examined SVP and TGA simultaneously.37,39,60–62 TOF was exclusively examined in 1 study,63 and 1 study examined both TOF and TGA.64 Interrupted aortic arch (IAA) was exclusively examined in 1 study.65 Twelve studies assessed motor development between 0 and 12 months,38,40,41,44,45,47,50,52,55,56,61,63 12 studies between 12 and 24 months,37,39,40,46,48,53,58–60,62,64,65 5 studies between 24 and 36 months,42,49,51,54,61 and 2 studies above 36 months.43,60 None of the included studies examined motor development in children 4.5 years and older. With regard to motor development assessment, different measuring instruments were used. Two studies distinguished between fine and gross motor skills.37,39 An overview of the measuring instruments is Table 1.

Fig. 1.
Fig. 1.:
PRISMA flow diagram. This figure is available in color online (www.pedpt.com).
TABLE 1 - Characteristics of the Included Studies
Author and Study Location Study Design Types of CHD Included in the Study Number of Participants (M/F)a Age (±SD)a at Measurement, Unless Otherwise Stated, mo Measurement Instrument Mean Motor Score (±SD) Unless Otherwise Stated Number of Patients <2 SD
Abeysekera et al,62 Canada Prospective cohort study HLHS, TGA HLHS: 36 (24/12)
TGA: 24 (12/12)
21.6 (±3.2) Bayley-III HLHS: 85.3 (±16.2)
TGA: 98.6 (±8.6)
NR
Acton et al,37 Canada Prospective cohort study SVP, TGA 68 21.3 (±3.9) Bayley-III SV (n = 22): 86.2 (±13.9)
TGA (n = 46): 99.8 (±10.5)
SV 1 (4.5%)
TGA 0 (0%)
Aly et al,40 the United States Prospective longitudinal cohort study SVP 40 (23/17) 6, 15, 21 Bayley-III At 6: 68 (±15)
At 15: 65 (±20)
At 21: 68 (±17)
NR
Cheatham et al,41 the United States Prospective nonrandomized longitudinal cohort study HLHS 11-14 2 (median: 62 d),
4 (median: 117 d),
6 (median: 170 d)
TIMP (2,4)
Bayley-III (6)
At 2 (n = 14): 63.9 (±18.1)
At 4 (n = 14): 108.3 (±14.9)
At 6 (n = 11): 78.9 (±16.4)
2 (18.2%)
Cheng et al,56 the United States Prospective cohort study TGA 37 12 BSID-II 89 (±14) NR
Freed et al,58 Canada Retrospective cohort study TGA 82 18-24 BSID-II 92 (±15) 5 (6.1%)
Goldberg et al,38 the United States RCT SVP 50 12b BSID-II 77.1 (±21.2) NR
Heye et al,42 Germany and Switzerland Retrospective cohort study SVP 44 26.7 (±3.9) Bayley-III 97b (88-107) 2 (4.5%)
Hoffman and Kaplan,3 the United States Prospective cohort study HLHS 13 4.5 (±0.7) y MSOCAM 42 (±10) 1 (8%)
Hoskoppal et al,44 the United States Prospective cohort study SVP 8 8.8 BSID-II
AIMS
75.8 (±14)
17 (74% <p5)
Ibuki et al,60 Japan Prospective longitudinal cohort study SVP, TGA SV: 23
TGA:10
15.4 (±6.2)
38.8 (±17.4)
BSID-II SV at 15.4: 75.9 (±18.5)
SV at 38.8: 79.3 (±20.9)
TGA at 15.4: 94.6 (±13.9)
TGA at 38.8: 97.3 (±13.4)
NR
Joynt et al,65 Canada Retrospective cohort study IAA 17 18-24 BSID-II 79.1 (±14.3) NR
Khalid and Harrison,55 the United States Retrospective
Cohort study
HLHS, SVP HLHS: 9
SV:15
12 Bayley-III HLHS: 85.7 (±12.1)
SV: 80 (±11.7)
1 (11%)
3 (20%)
Knirsch et al,45 Switzerland Prospective cohort study HLHS, SVP 20 12b (10-15) BSID-II 57b (49-99) 12 (60%)
Li et al,46 China Retrospective cohort study HLHS 26 18-24 Bayley-III 85.0 (±17.0) NR
Lim et al,59 Canada Prospective cohort study TGA 24 18 Bayley-III 104 (±12) NR
Medoff-Cooper et al,47 the United States Prospective cohort study SVP 72 6
12
BSID-II At 6: 76.58 (±14.77)
At 12: 73.94 (±15.78)
NR
Peyvandi et al,7 the United States Prospective cohort study SVP, TGA SV at 12: 20
SV at 30: 16
TGA at 12: 84
TGA at 30: 54
12
30
BSID-II SV at 12: 70.7 (±3.55)
SV at 30: 79.9 (±4.15)
TGA at 12: 83.2 (±2.05)
TGA at 30: 92.1 (±1.95)
NR
Ravishankar et al,48 the United States Prospective cohort study SVP 170 14 (±1) BSID-II 80.3 (±18.1) 48 (28%)
Reich et al,49 Germany and Switzerland Prospective cohort study SVP 48 26.3 (±3.4) Bayley-III 97b (88, 107) 3 (6.3%)
Reich et al,54 Germany Prospective cohort study HLHS 20 26.5 (±3.6) Bayley-III 98 (±11.7) 1 (5%)
Sarajuuri et al,50 Finland Prospective cohort study HLHS, SVP HLHS: 20
SV: 12
12.2b Griffiths, AIMS Griffiths HLHS: 91.6
Griffiths SV: 100.6
AIMS HLHS: 37.5 (±14.5)
AIMS SV: 43.5 (±13.1)
NR
Sarajuuri et al,51 Finland Prospective cohort study HLHS, SVP HLHS: 22
SV: 12
30.2b (29.1-32.5) BSID-II HLHS: 80.7 (±27.1)
SV: 94.5 (±10.8)
NR
Soul et al,64 the United States Prospective cohort study TGA, TOF TGA: 19
TOF: 20
TGA: 1.1 (±0.1) y
TOF: 1.2 (±0.2) y
BSID-II TGA: 84.8 (±14.9)
TOF: 86.5 (±19.7)
NR
Stieber et al,39 Canada Prospective pilot study SVP, TGA SV: 10 (7/3)
TGA: 10 (8/2)
SV: 18.0 (±4.3)
TGA: 18.1 (±3.9)
PDMS-2 SV TMQ: 79.56 (±8.095)
TGA TMQ: 98.78 (±6.515)
NR
Toet et al,57 the Netherlands Prospective cohort study TGA 15 30-36 BSID-II 101.0 (±18.34) 1 (6,7%)
Visconti et al,52 the United States Retrospective cohort study HLHS, SVP 29 (22/7) 12 BSID-II 75.2 (±14.5) NR
Williams et al,53 the United States Retrospective cohort study SVP 82 (48/34) 14.3 (±1.0) BSID-II 76.4 (±19.8) 51 (62%
< −1 SD)
Zeltser et al,63 the United States Retrospective cohort study TOF 49 12.24 (±0.6) BSID-II 85 (±15) 2 (4%)
Abbreviations: AIMS, Alberta Infant Motor Scales; BSID, Bayley Scales of Infant Development; CHD, congenital heart disease; F, female; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; IQR, interquartile range; M, male; MSOCAM, McCarthy Scale of Children's Abilities–Motor; NR, not reported; PMDS-2, Peabody Developmental Motor Scales, Second Edition; RCT, randomized controlled trial; SD, standard deviation; SVP, single-ventricle physiology; TIMP, Test of Infant Motor Performance; TGA, transposition of the great arteries; TMQ, total motor quotient; TOF, tetralogy of Fallot.
aIf available.
bMedian (IQR).

In summary, 13 studies had good methodological quality,38,40,43,46–48,51,52,56,59–62 8 studies had fair methodological quality,39,42,53–55,57,58,64 and 8 studies had poor methodological quality.37,41,44,45,49,50,63,65 The high risk of bias in the studies that scored poorly is attributed mostly to the lack of exposure. In these studies, the motor skills of children with a CCHD were compared with the general population without considering other factors. Also, no pre- and postmeasurement or difference measurement was collected. An overview of the methodological quality assessment is in Supplemental Digital Content 2 (available at: http://links.lww.com/PPT/A330).

Results of Individual Studies

A total of 49 motor developmental outcomes from various types of CCHD were reported. Six mean outcomes (12.2%) reported in 3 different studies indicated an abnormal (<−2 SD) motor development.40,45,50 Nineteen mean results (38.8%) reported in 14 studies indicated a below average (between −2 and −1 SD) motor development,38,39,41,44,47,48,51–53,55,60,61,64,65 and 24 mean outcomes (49.0%) reported in 20 different studies indicated an average motor development.37,39,41–43,46,49–51,54–64

Single-Ventricle Physiology

Twenty-two studies included children with SVP with a total of 34 different mean motor developmental outcomes.37–55,60–62 In total, 3 studies described 6 separate abnormal motor developmental scores.40,45,50 Twelve studies described 16 mean below average motor developmental scores,38,39,41,44,47,48,51,53,60,61,64 of which 2 studies reported mean scores for children with SVP and HLHS separately.51,55 Eleven studies37,41–43,46,49–51,54,55,62 described 12 mean average motor developmental scores (±1 SD) of which 3 studies reported separate scores for HLHS and SVP.50,51,54,55 Details and mean z scores are in Table 2.

TABLE 2 - Results of Individual Studies
Study Age Mean (±SD)a at Measurement, mo Measurement Instrument (n) Mean Z Score
SVP/HLHS
Cheatham et al41 2.0 TIMP (14) –1.62
4.0 TIMP (14) –0.73
6.0 BSID-III (11) –1.41
Aly et al40 6.0 Bayley-III (40) –2.13
Medoff-Cooper et al47 6.0 BSID-II (72) –1.56
Hoskoppal et al44 8.8 BSID-II (8) –1.61
Goldberg et al38 12.0 BSID-II (50) –1.52
Khalid and Harrison55 12.0 Bayley-III HLHS (9)
Bayley-III SV (15)
–0.96
–1.33
Knirsch et al45 12.0b (10.0-15.0) BSID-II (20) –2.86c
Medoff-Cooper et al47 12.0 BSID-II (72) –1.74
Peyvandi et al7 12.0 BSID-II (20) –1.95
Visconti et al52 12.0 BSID-II (29) –1.65
Sarajuuri et al50 12.2b Griffiths HLHS (20)
Griffiths SV (12)
AIMS HLHS (20)
AIMS SV (12)
–0.56
+0.04
–3.78
–2.46
Ravishankar et al48 14.0 (±1.0) BSID-II (170) –1.31
Williams et al53 14.3 (±1.0) BSID-II (82) –1.57
Aly et al40 15.0 Bayley-III (40) –2.33
Ibuki et al60 15.4 (±6.2) BSID-II (23) –1.61
Stieber et al39 18.0 (±4.3) PDMS-2 (10) –1.36
Aly et al40 21.0 Bayley-III (40) –2.13
Acton et al37 21.3 (±3.9) Bayley-III (22) –0.92
Abeysekera et al62 21.6 (±3.2) Bayley-III (36) –0.91
Reich et al49 26.3 (±3.4) Bayley-III (48) –0.2c
Reich et al54 26.5 (±3.6) Bayley-III (20) –0.13
Heye et al42 26.7 (±3.9) Bayley-III (44) –0.2c
Peyvandi et al7 30.0 BSID-II (16) –1.34
Sarajuuri et al51 30.2b (29.1-32.5) BSID-II HLHS (22)
BSID-II SV (12)
–1.29
–0.37
Ibuki et al60 38.8 (±17.4) BSID-II (23) –1.38
Hoffman and Kaplan3 54 (±8.4) MSOCAM (13) –0.8
TGA
Cheng et al56 12.0 BSID-II (37) –0.73
Peyvandi et al7 12.0 BSID-II (84) –1.12
Soul et al64 14.4 (±2.4) BSID-II (19) –1.01
Ibuki et al60 15.4 (±6.2) BSID-II (10) –0.36
Freed et al58 18.0-24.0 BSID-II (82) –0.53
Lim et al59 18.0 Bayley-III (24) +0.27
Stieber et al39 18.1 (±3.9) PDMS-2 (10) –0.08
Acton et al37 21.3 (±3.9) Bayley-III (46) –0.013
Abeysekera et al62 21.6 (±3.2) Bayley-III (24) –0.014
Peyvandi et al7 30.0 BSID-II (54) –0.53
Toet et al57 30.0-36.0 BSID-II (15) +0.07
Ibuki et al60 38.8 (±17.4) BSID-II (10) –0.18
TOF
Soul et al64 1.2 (±0.2) y BSID-II (20) –0.9
Zeltser et al63 12.24 (±0.6) BSID-II (49) –1.0
IAA
Joynt et al65 18.0-24.0 BSID-II (17) –1.39
Abbreviations: AIMS, Alberta Infant Motor Scales; BSID, Bayley Scales of Infant Development; IAA, interrupted aortic arch; MSOCAM, McCarthy Scale of Children's Abilities–Motor; PMDS-2, Peabody Developmental Motor Scales, Second Edition; SD, standard deviation; SVP/HLHS, single-ventricle physiology/hypoplastic left heart syndrome; TIMP, Test of Infant Motor Performance; TGA, transposition of the great arteries; TOF, tetralogy of Fallot.
aUnless otherwise stated.
bMedian.
cZ score derived from median.

Age 0 to 12 Months

Between 0 and 12 months of age, 17 different mean motor developmental outcomes were reported,38,40,41,44,45,47,50,52,55,60 of which 4 (23.5%) were classified as abnormal,40,44,50 9 outcomes (53%) were classified as below average,38,41,44,47,52,55,61 and 4 outcomes (23.5%) were classified as average.41,50,55 The studies of Sarajuuri et al50 and Khalid and Harrison55 reported separate scores for HLHS and SVP., Sarajuuri et al50 found that children with HLHS scored the lowest, while Khalid and Harrison55 reported lower outcomes in children with other types of SVP. The prevalence of abnormal motor development was described in 4 studies and was seen in 18.2% to 60% of the populations assessed at or below 12 months of age.41,44,55,66

Age 12 to 24 Months

Between 12 and 24 months of age, 9 mean outcomes were reported,37,39,40,46,48,53,60,62 of which 2 outcomes (22.2%) were classified as abnormal. Both results were reported in the same study, which assessed the children at 15 and 21 months.40 Four results (44.4%) were classified as below average motor scores,39,48,53,60 and 3 outcomes (33.3%) were classified as average.37,46,62 The prevalence of abnormal motor development was merely described in 2 studies and was seen in respectively 4.5% and 28% of populations assessed between 12 and 24 months.37,48 One study described the prevalence of below average in 62% of the study population in children between 12 and 24 months of age.53

Age 24 to 36 Months

Between 24 and 36 months, 6 mean outcomes were reported,49,51,54,61,67 of which 2 outcomes (33%) were classified as below average51,61 and 4 (67%) classified as average motor development.41,49,51,54 The study of Sarajuuri et al50 reported separate scores for HLHS and SVP. Children with SVP achieved a mean average score, whereas children with HLHS achieved a below average score. The prevalence of abnormal motor development was seen in 4.5% to 6.3% of the study populations.42,49,54

36 Months and Older

Above 36 months, 2 mean outcomes were described,43,60 of which 1 was classified below average60 and 1was classified as average.43 The prevalence of abnormal motor development was seen in 8% of the study population.43

Transposition of the Great Arteries

In 10 different studies, 12 mean motor development outcomes of children with TGA were reported,37,39,56–62,64 of which 2 studies reported outcomes at different ages (15.4 and 38.8 months, and 12.0 and 30.0 months, respectively).60,61 Of all reported outcomes, 2 studies (16.7%) described mean below average motor development,61,64 and 10 mean motor developmental scores (83.3%) were classified as average.37,39,56–62 No abnormal population means were reported in children with TGA. Detailed information and z scores are in Table 2.

Age 0 to 12 Months

Between 0 and 12 months, one out of 2 studies described an average motor developmental score in children with TGA.56 The other study reported a below average mean motor developmental score.61 No information regarding the prevalence was reported in these studies.

Age 12 to 24 Months

Between 12 and 24 months, 7 mean outcomes were reported,37,39,58–60,64,of which 1 outcome (14.4%) was classified as below average64 and 6 (85.6%) outcomes were classified as average motor development.37,39,58–60,62 Although none of the studies in children with TGA reported abnormal z scores (below −2 SD), 3 studies in children with TGA reported the number of outcomes defined abnormal, in addition to the population mean.37,57,58 The prevalence of abnormal motor development in the age range 12 to 24 months was seen in 0% to 6% of the study populations.37,58

24 Months and Older

All studies in children of 24 months and older reported average mean motor developmental scores,57,60,68 with a prevalence of 6.7% of an abnormal motor development.57

Tetralogy of Fallot

Two studies addressed motor development in children with TOF.63,64 Zeltser et al63 and Soul et al64 assessed motor development in children with TOF at 12.2 and 14.4 months and found mean average z scores of −1.0 and −0.9, respectively. Furthermore, Zeltser et al63 also reported the prevalence of abnormal motor development in 4% of the study population.

Interrupted Aortic Arch

The only study in children with IAA assessed motor development at 18 to 24 months and reported a mean below average z score of −1.4.65 No outcomes defined as abnormal were reported in this study.

Meta-analysis

Seven studies with 8 developmental outcomes were eligible for statistical pooling using meta-analysis.38,40,41,47,52,55,61 All studies examined motor development in children with SVP/HLHS using the Bayley Scales of Infant Development-II (BSID-II) or BSID-III. Meta-analysis was performed in 3 studies at 6 months and 5 studies at 12 months. At 6 and 12 months, mean differences in motor development of –26.02 (95% confidence interval [CI]: –29.77 to –22.27; P < .00001) and –24.75 (95% CI: –27.69 to –21.80; P < .00001), respectively, were found (Figure 2). Heterogeneity was high at 6 months (I2 = 58%) but low at 12 months (I2 = 25%).

Fig. 2.
Fig. 2.:
Meta-analysis motor development at 6 (A) and 12 (B) months in children with SVP/HLHS. CI, indicates confidence interval; HLHS, hypoplastic left heart syndrome; IV, inverse variance; SD, standard deviation; SVP, single-ventricle physiology. This figure is available in color online (www.pedpt.com).

DISCUSSION

The current systematic review indicates that more than half of all included studies in children with a CCHD reported below average mean motor developmental scores (<−1 SD). Twelve percent had abnormal mean motor developmental scores (<−2 SD). Within the reviewed pediatric CCHD populations, children with SVP (including HLHS) have the worst outcomes regarding early motor development. The majority (64.7%) of studies including children with SVP indicate below average motor developmental scores, of which 27.3% showed even abnormal motor developmental scores. Although meta-analysis could only be performed in 7 studies, these pooled data also indicate (significantly) lower motor developmental scores for children with SVP/HLHS at 6 and 12 months compared with healthy controls.

Brain Development and Brain Injury Related to Motor Outcome

The highest severity and prevalence levels of motor delay were in children with SVP (especially HLHS). This might be attributed to its severity level within the CCHD population because univentricular heart defects seem to affect the brain more than biventricular heart defects.5,6 Decreased cerebral perfusion in children with SVP could affect cerebral development as a result of reduced fetal cerebral oxygen consumption. Postpartum hemodynamic variability resulting in reduced oxygen delivery to the brain contributes to possible brain injury in the newborn at risk.7–9,14,16,17,70 Furthermore, smaller cortical volumes and lower gyrification indices are found in newborns with SVP. Although there is a significant increase in cortical volume and gyrification in infants with congenital heart disease from the pre- to postoperative period, the cortical volume remains reduced compared with healthy controls, even after surgery.10,71 The reported immaturity and smaller cortical volumes are associated with increased vulnerability to white matter injury around neonatal cardiac surgery.6,10,69 Infants with SVP more often have brain injury, both pre- and postoperatively, compared with the other diagnostic groups.61,68 Children with SVP more frequently experience DHCA with longer surgery and cardiopulmonary bypass time and are longer on postoperative mechanical ventilation. The latter, in combination with commonly low cardiac output syndrome and repeated open-heart surgery, may cause postoperative brain injury.72,73

Cardiac Diagnosis and Other Factors Related to Motor Outcome

Most included studies examining SVP did not analyze HLHS separately. Only 4 studies50,51,54,55 reported separate scores for children with HLHS, and reported lower developmental scores compared with other SVPs. These lower motor developmental scores in children with HLHS could be partly explained by hypoplasia of all left-sided cardiac structures. This hypoplasia is already present in utero, and results in decreased perfusion and oxygenation of the brain due to intracardiac mixing and retrograde flow in the aortic arch.74–77 In addition, prior studies in children with HLHS found lower gyrification indices and immature cortices in fetuses and infants before heart surgery, resulting in smaller head circumferences compared with other types of SVP.78,79

The cortex has a vital role in cognitive, behavioral, and motor functioning. A delay in cortical development in infants with CCHD can lead to alterations in these neurodevelopmental domains. Naef et al80 found a significantly associated interaction of head circumference at birth and motor development at 6 years of age. Children with CHD with larger head circumference at birth had more improvement in motor functions within the first 6 years of life. The difference in motor function between children with SVP (including HLHS) and other types of CCHD could therefore be attributed to the immaturity and vulnerability of the brain.10,11,81,82 In addition, factors that are known to be associated with motor developmental delays in children after early cardiac surgery are long-term DHCA, older age at surgery, a higher number of and longer hospital stays, immobilization after one or more open heart surgical procedures, a higher number of days in the intensive care unit, palliative procedures, lower pre- and postoperative neurological scores, presence of microcephaly, history of epileptic seizures, and oxygen saturation levels below 85%.39,48,50,51,55,83–87 Although the worst motor developmental scores were seen in children with SVP, studies including children with other CCHD diagnostic groups show relatively low motor scores as well. The study of Sun et al71 showed smaller brain volumes in children with SVP, TGA, TOF, and IAA compared with other CHD subgroups and healthy controls. In approximately 20% of the studies describing children with TGA, motor developmental scores were below average. Brain perfusion in children with TGA is generally normal and streaming results in well-oxygenated blood being directed to the pulmonary circulation. However, the blood supplied to the brain is derived largely from more deoxygenated blood returning from the caval veins, leading to a significant difference in brain volume.71,88 These smaller brain volumes are, as described, associated with increased vulnerability of the white matter injury around neonatal cardiac surgery and decrements in neurodevelopmental outcome at 2 years and could explain the below average motor scores.8 Infants with TGA often require a preoperative balloon atrioseptostomy (BAS). Infants requiring such preoperative BAS had significantly smaller cortical gray matter volumes and lower gyrification indices at postoperative scans and showed lower preoperative oxygen saturation values than infants who did not require this intervention.10 This is in line with literature describing higher levels of hypoxemia and hemodynamic instability in infants requiring BAS. As a result, they seem to be at higher risk for hypoxia and ischemia-associated brain injury.89

Prevalence of Abnormal Motor Development

While half of the included studies reported the actual number of participants scoring abnormal motor development, the current review specifies that the prevalence of children with an abnormal motor development is the highest between 0 and 12 months, varying from 4% to 74% of the children. It is expected, normatively, that scores below these cut-offs would occur in only 2.27% of the population.37 The prevalence seems to decrease between 12 and 24 months, varying from 4.5% to 28% and decreases further to 3.5% to 6.7 % of the children with CCHD aged 24 to 36 months. Even so, the prevalence of abnormal motor development between 24 and 36 months remains higher compared with the normal population.36,90 Strikingly, the prevalence of abnormal motor development or motor delay seems to rise again around school age,43 probably due to more complex motor challenges that partly rely on executive functioning.91,92 Executive functions are higher cognitive functions, such as shifting, inhibition, updating, planning, decision-making, problem-solving, visuospatial working memory, and response inhibition.93 At (pre-)school age, speed, task orientation, planning precision, and attention play a more important role in successfully performing the motor tasks during a motor test than at a younger age. There is growing evidence that children with CCHD have particular problems in executive function, leading to difficulties in daily life.94 Limitations in these higher cognitive functions can, therefore, negatively affect motor performance.91 Latal12 wrote a narrative article about neurodevelopment in children with CHD and reported problems in motor development in 30% to 60% of children with a CHD from birth to 12 years. When children attend school, more complex motor skills are vital in participating with peers during sports and games. Motor (developmental) delays can have an effect on a child's academic success, can limit recreational activities, and can affect social integration.95 Recently, Naef et al80 concluded that children with CHD have a mild improvement in cognitive and motor functions between 1 and 6 years of age. The results of these studies were based on a heterogeneous study group consisting of various heart defects, including genetic anomalies.

Importance of Differentiation Between Gross and Fine Motor Skills

Most of the included studies did not clearly differentiate between gross and fine motor skills but merely applied composed scores of motor development. However, this differentiation is of interest because, clinically, we frequently see a marked discrepancy favoring fine motor scores over gross motor scores in our population of children with a CCHD. Only 2 of the included studies37,39 differentiated between gross and fine motor domain and found lower gross motor scaled scores compared with fine motor scaled scores. Furthermore, both studies indicated significant differences in gross motor scaled scores between diagnostic groups to the detriment of children with SVP. Abnormal gross motor scores were also found by Sarajuuri et al.50 He reported separated scores for SVP and HLHS assessed with the Alberta Infant Motor Scale, which is a specific test for gross motor skills. Lower gross motor scores might be the result of the immobilization due to (multiple) surgical interventions.96 Uzark et al96 found that gross motor scores declined postoperatively in 64% of the children with different cardiac diagnoses who had cardiac surgery in the first months of life. Neurological findings, usually muscle hypo-/hypertonia, appear to correlate with magnetic resonance imaging findings.97 Multiple authors describe that muscle hypotonia partially explains the gross motor problems of children with severe CHD.12,98 Accordingly, only reporting motor composite scores is insufficient for describing motor development in children with CCHD.

Strengths and Limitations

Most previous studies regarding motor development in children with a CCHD provided general statements based on mean values of heterogeneous pediatric populations. These studies were, for example, heterogeneous in cardiac diagnosis, had no age differentiation, and included genetic anomalies. Recently, a systematic review regarding the general development of children with heterogeneous groups of children with CCHD was published by Huisenga et al.29 This review did not exclude studies with outcomes of children with an underlying genetic disorder. The current review tried to differentiate between subtypes of CCHD without genetic anomalies because most children with CCHD have no genetic anomalies and also to exclude the possible effects of chromosomal anomalies on motor developmental outcome. Our study is the first systematic review that describes, besides population means, the severity and prevalence of motor delays by age and for specific types of CCHD.

The current study has limitations. We excluded a large number of informative studies that did not report the motor outcomes of CHD subtypes. Although a large number of studies assessed the motor development of children with HLHS or SVP, only a limited number of studies reported the motor development of other subgroups of children with CCHDs, such as TGA, TOF, or IAA. Therefore, the overall conclusion of this review can be applied to a limited number of heart defects and, possibly, over- or underestimates the true prevalence of motor problems of these subgroups. Even though this review focused on motor development in children with a CCHD up to 12 years of age, all included studies examined motor development in children 4.5 years and younger. Therefore, it is still unclear to what extent school-aged children with specific types of CCHD show comparable (decreased) motor development as was observed in the first months and years of life. Naef et al21 recently concluded that the prevalence of children without a genetic disorder who had a poor motor performance (<10th percentile) ranged from 21.2% to 41.1% (P < .01 for all) at school age. This study included different types of heart defects. Furthermore, the most commonly applied assessment tool for motor development was the BSID-II, followed by the Bayley-III. We combined both versions in our meta-analysis. We are aware that these scores are not entirely comparable, partly because the study of Acton et al37 concludes that the Bayley-III may overestimate the motor abilities of children after early complex cardiac surgery. This could entail the risk of not identifying a developmental delay that wrongly prevents children from being offered early intervention. For this reason, the Bayley III should be interpreted with caution, especially when used for clinical purposes to discriminate between abnormal and normal motor skills. Comparing the included studies of the current review, we saw no indications that the application of the Bayley-III inevitably would lead to better results.

We are aware of the effect of intercultural differences, such as standardized motor developmental assessments having limited validity in cultures other than that in which the normative sample was established.99 In the current review, we did not focus on intercultural differences, as the majority of the included studies have been conducted in developed countries. Lastly, most of the included studies did not exclude premature infants or infants with very low birth weight. Because these infants are at increased risk of developmental disorders regardless of their (C)CHD, we cannot rule out any effect of prematurity and dysmaturity on the developmental results.

Recommendations

Based on the current review, we recommend differentiating between the types of CCHD and between fine and gross motor development, both for clinical and research purposes. To increase knowledge for each subgroup, the outcomes of children with a known underlying genetic anomaly, premature, or dysmature-born infants should preferably be excluded or reported separately. Based on the known risk factors, risk stratification should be applied to provide more personalized recommendations and predictions regarding motor development in discrete subtypes of CCHD. The latter can correspondingly be used to determine the need for early individualized interventions to reduce a delay in (gross) motor development based on all aspects of pediatric physical therapy. Although the understanding of the underlying mechanisms and possible risk factors has improved in recent years, the full interplay between these factors is still not clear, and there is a gap of knowledge regarding therapeutic options to improve motor development. In view of the high incidence of (gross) motor delays, systematic evaluation of motor skills during childhood and adolescence in children with CCHD is warranted. The need for therapeutic options is high and should be the focus of future research.

Lastly, the extent of motor problems at school age still remains unclear. Therefore, future (longitudinal) research into motor development of school-aged children and adolescents with CCHD would be of great value for health professionals. The latter data are indispensable in providing parents and participants with information about the possible trajectories of motor development in different types of CCHD and in establishing appropriate interventions when indicated.

ACKNOWLEDGMENTS

We would like to thank Ms Paulien Wiersma, the librarian at the University Library Utrecht, for her help in constructing the search string.

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Keywords:

cardiac surgery; children; complex congenital heart disease; hypoplastic left heart syndrome; motor development; single-ventricle physiology; tetralogy of Fallot; transposition of the great arteries

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