How to Cite this Article: Visootsak J, Mahle WT, Kirshbom P, Huddleston L, Caron-Besch M, Ransom A, Sherman SL. 2011. Neurodevelopmental outcomes in children with Down syndrome and congenital heart defects. Am J Med Genet Part A 155: 2688–2691.
Trisomy 21, the chromosomal condition responsible for Down syndrome (DS, OMIM #190685), is the most common identifiable genetic cause of intellectual disability and birth defects with an incidence of one in 691 live births [Parker et al., 2010]. This suggests that approximately 6,000 of the ∼4 million infants born each year in USA have DS. Although intellectual disability and hypotonia are present in virtually all individuals with DS, the expression of other DS-associated congenital and acquired medical complications is variable. For instance, 41–56% of all individuals with DS have congenital heart defects (CHD) [Freeman et al., 1998; Stoll et al., 1998; Torfs and Christianson, 1998; Freeman et al., 2008], 5% manifest various gastrointestinal defects, and 0.6% develop leukemia [Roizen, 2001]. In population-based studies of CHD subtypes in DS, atrioventricular septal defects (AVSD) occur in 31–61% of individuals with DS and CHD, ventricular septal defects from 11–44%, atrial septal defects from 11–42%, and tetralogy of Fallot from 3–7% [Ferencz et al., 1989; Wells et al., 1994; Freeman et al., 1998, 2008; Stoll et al., 1998; Torfs and Christianson, 1998; Roizen, 2001]. Thus, AVSD is the most common form of CHD in DS with a much higher prevalence than in the general population for whom AVSD is observed in only one in 10,000 live births [Loffredo et al., 2001]. This represents a dramatic 2,000-fold increase in risk for AVSD among newborns with DS compared to those without DS [Kerstann et al., 2004]. With approximately 61% of AVSD occurring in association with DS [Ferencz et al., 1989], this major CHD is of significant interest.
Typically developing children with CHD have been shown to have neurocognitive and psychomotor deficits [Malec et al., 1999; Mahle and Wernovsky, 2001; Kirshbom et al., 2005; Mahle et al., 2006]. For instance, school-aged children with hypoplastic left heart syndrome have a mean full-scale IQ of 86, which is below the population normative value, approximately one standard deviation [Mahle et al., 2006].
Likewise, significant impairment in fine motor function, visual-motor integration, and attention in school-aged survivors of total anomalous pulmonary venous connection repair was noted [Kirshbom et al., 2005]. Despite the improved survival rates in children with CHD who had surgical repairs, they have neurodevelopmental issues characterized by deficits in executive functioning, attention, and fine motor function.
No studies examining the neurodevelopmental challenges experienced by children with DS and CHD have been conducted. There is a need to determine how the inherent risks of CHD interact with the typical developmental phenotype of DS. As advances in surgical techniques have improved the survival rates in children with DS and CHD, it is important to understand the course of their early neurodevelopment.
MATERIALS AND METHODS
Participants were ascertained from the Down Syndrome Clinic at Emory University. Parents provided written consent for participation, as approved by the Emory University Institutional Review Board. A patient was eligible for participation if he/she had a confirmed trisomy 21 based on chromosomal karyotype, was delivered ≥34 weeks gestational age, had vision and hearing within normal limits, with or without corrections and parents spoke English as the primary language. Participants also did not have other medical complications (e.g., hypothyroidism, seizures) except for AVSD in those with CHDs. The hearing and vision tests were normal. For this study, we defined cases as children with DS and AVSD (DS + AVSD). Although this is not the only CHD to affect children with DS, we focused on this CHD to increase sample homogeneity with respect to cardiac status and surgical repair. That is, the operative techniques and timing of repair of other types of CHDs, such as ventricular septal defects and atrial septal defects, differ when compared to AVSDs. For these reasons, we only considered AVSDs in this study. Subjects with DS + AVSD were ascertained after AVSD repair. Controls were patients with DS who met the same eligibility criteria and structurally normal hearts (DS − CHD) as documented by echocardiograms. They were matched by age of the case group. The DS + AVSD cohort mean age was relatively the same as controls with DS − CHD, 14.5 ± 7.3 months compared with 14.1 ± 8.4 months, respectively.
Our Master's level psychometrician administered the Bayley Scales of Infant and Toddler Development III (Bayley-III) to 29 subjects (12 DS + AVSD and 17 DS − CHD) at the DS Clinic at Emory University. Our psychometrician was not aware of the child's cardiac status and the parents were instructed not to reveal the child's cardiac status during testing. The Bayley-III is one of the most commonly used instruments for assessing developmental function of infants and children between 1 month and 42 months of age and has well-documented construct validity [Bayley, 2006]. The composite scores on this assessment were derived from sums of the subtest scaled scores and were generated for the cognitive scale, language scale, and motor scale. The Bayley-III test results were expressed as cognitive, language, motor developmental indexes, with a mean of 100 and a standard deviation (SD) of 15. Composite scores (cognitive, language, and motor) between 70 and 84 (−2 to −1 SD) are considered abnormal and composite scores of less than 69 (<−2 SD) indicate severe developmental delay.
Because infants with DS had global developmental delay and were unable to perform tasks at their chronological age, we adjusted the Bayley-III testing by starting the test items that were usually appropriate for children younger than the chronological age of our subjects (1, 5, and 9 months instead of 3, 12, and 24 months).
Summary statistics were given as the mean ± SD. Descriptive analyses were conducted to examine the distributions of outcome measures. Based on the modest sample size and the fact that the outcome measures were not normally distributed, groupwise comparison was performed using the Mann–Whitney U two-sample test to compare the two groups. Statistical analysis was performed using SAS, version 9.1 (Cary, NC).
As seen in Table I, cases with DS + AVSD were tested at approximately the same age as controls with DS − CHD, 14.5 ± 7.3 months compared with 14.1 ± 8.4 months (P = 0.90), respectively. The ethnic/racial compositions were similar in both groups, and the parents of cases were slightly older than controls (P = 0.34 for maternal age and P = 0.36 for paternal age). Parental educational levels were similar; 58% of fathers in both groups and 66% (cases) and 70% (controls) of mothers had college degrees or higher. In terms of family income, 94% of controls reported family income above $50,000 compared to 70% of cases (P = 0.13).
Table I. Demographics of Subjects With DS + AVSD Compared to DS − CHD
DS + AVSD (n = 12)
DS − CHD (n = 17)
Groups (chronological age and parental age) were compared using t-test, and no statistically significant differences were observed.
Data are missing for three participants in the DS − CHD group.
Data are missing for one participant in the DS − CHD group.
Chronological age in months
14.5 ± 7.3 [5.1–33.5]
14.1 ± 8.4 [5.1–31.8]
Maternal age at delivery (years) [range]
34.8 ± 6.5 [21–43]
33.3 ± 3.6 [23–37]
Paternal age at delivery (years) [range]
35.7 ± 6.2 [23–49]
34.3 ± 5.8 [23–47]
Total family annual income < $50,000/> $50,000/Refuse to disclose
Paternal educationa < 4 years college/4 years college/>college degree
Maternal educationb < 4 years college/4 years college/>college degree
The composite scores in all domains for the DS + AVSD cases compared to the DS − CHD controls is described in Figure 1. Although the motor domain was the only domain that showed a statistically significant difference between groups (P < 0.05), both cognitive scores (P = 0.63) and language composite scores (P = 0.10) were lower in the DS + AVSD cases compared with the DS − CHD controls, although the differences were not statistically significant. The subscale scores for expressive and receptive language, and gross and fine motor did not differ significantly between the two groups.
Nearly half of all children with DS are born with a significant CHD, the most common of which is an AVSD. Although the long-term mortality rate after AVSD repair is low, there is growing recognition and concern that these individuals are at greater risk of adverse neurodevelopmental outcomes. This is the first study to examine a broad range of the very early developmental domains of children with DS + AVSD compared with individuals with DS and structurally normal hearts (DS − CHD). Our results from this preliminary study serve as an impetus for further longitudinal neurodevelopmental studies in this area.
Our preliminary cross-sectional data revealed that children with DS + AVSD had greater developmental deficits in the motor domain, compared to children with DS − CHD. The results were consistent with findings from previous neurodevelopmental outcome studies of children with CHD without DS [Mathew et al., 1990; Dunlop et al., 2004]. Given the high frequency of CHD in children with DS, it is important for clinicians to refer these children to early intervention program for a comprehensive assessment and ongoing therapies, including physical therapy beginning shortly after birth.
Although the language and cognitive standard scores are lower for DS + AVSD cases compared to DS − CHD, it is not statistically significant and may be limited by our small sample size. For children with DS + AVSD, it may be beneficial to receive language assessment and therapy after surgical repairs. There are no published reports assessing the language profiles of children with DS + AVSD. Such studies are important, because early intervention during the first 3 years of life is essential to foster prelinguistic and/or early linguistic skills and thereby reduce barriers to community inclusion and later independent living [Chapman and Hesketh, 2000]. Considering the relative strength in the receptive language skills compared to expressive language skills in children with DS, it is important to provide an early language-based communication goals utilizing total communication (signs, gestures, objects, pictures, and printed as well as spoken words).
In general, children with DS manifest delayed gross motor skills as a consequence of their hypotonia and ligamentous hyperlaxity. We noted in our sample that children with DS + AVSD scored lower than the DS − CHD group in the gross motor domain. There are several possible explanations, both perioperiative and post-operative for this delay. As a consequence of the CHD, fatigue and poor endurance may result. Early neurological outcomes in the postoperative period include a variety of abnormalities, including hypotonia, asymmetry of tone, and decreased level of alertness, resulting in gross motor deficits [Miller et al., 1995]. Lengthy hospital stays may result in limited developmental intervention during the early months. Thus, it is important to begin physical therapy shortly after birth, with emphasis on improving tone, strength, and coordination. Parents, physical therapists, and clinicians may find the book “Gross Motor Skills in Children with Down Syndrome: A Guide for Parents and Professionals” by Patricia C. Winders as a valuable resource in helping children with DS master the basic motor skills accurately.
Although our sample size remains a limitation of this study and may limit our statistical significance, our preliminary findings are relevant with regard to the delineation and interventional implications of distinct neurodevelopmental outcomes. We also recognize that our AVSD group may not be homogeneous in terms of the severity of defect, the timing of the surgery, or the nature of the surgery (e.g., length of sedation). The small sample makes it impossible to examine any of these factors. We did restrict our recruitment to those with complete AVSD and compared them to those with structurally normal hearts, all documented by echocardiograms.
Currently, there are no studies examining the neurodevelopmental outcomes of individuals (DS and non-DS) with AVSD; however, in previous studies of other CHD subtypes in typically developing children, perioperative management strategies have been identified as potential factors for impaired neurodevelopmental outcomes [Bellinger et al., 1999; Mahle and Wernovsky, 2001; Bellinger et al., 2003; Mahle et al., 2006]. Specific patient characteristics, such as fixed factors like race or gestational age, are also important determinants of neurodevelopmental outcomes after cardiac repair [Gaynor et al., 2003, 2007].
Our preliminary cross-sectional data have documented that there may be possible developmental differences in children with DS + AVSD compared to children with DS without CHDs. Of course, our results are preliminary in nature. Issues that remain largely unknown in children with DS + AVSD are (a) the magnitude of their cognitive, language, motor, social, and adaptive deficits; (b) the patient-related characteristics and perioperative factors that may influence their neurodevelopmental outcomes; and (c) the effect of home environmental variables on their development. These issues need to be investigated in a longitudinal clinical research study. In order to fully understand the neurodevelopmental outcomes of children with DS + AVSD, we hope that our preliminary cross-sectional data will spark further studies with a larger sample size to evaluate the neurodevelopmental outcomes in children with DS and CHD, and will consider age-related patterns by examining development profiles before and after surgical repairs. Additionally, focus on relative contributions of a variety of modifiable peri- and post-operative risk factors and specific fixed patient-related variables (e.g., ethnicity and parental education) on the developmental trajectories will be important.
The authors would like to thank the parents and children for their participation in this study. JV received a grant from NIH/NICHD (1K23HD058043-01A1) and SLS received a grant from NIH/NHLBI (HL083300).