PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1633-1639 (doi:10.1542/10.1542/peds.2006-1136)
ARTICLE |
Comorbidity, Hospitalization, and Medication Use and Their Influence on Mental and Motor Development of Young Infants With Down Syndrome
Departments of a Pediatric Endocrinology
b Pediatrics
c Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Young infants with Down syndrome have an increased occurrence of several well-known medical conditions such as congenital heart and gastrointestinal disease. The aim of this study was to establish consequences like hospitalization and medication use rates and to determine their possible influence on early neurodevelopment.
PATIENTS AND METHODS. This study compared 2 years of thyroxine treatment with placebo in 196 neonates with Down syndrome who were included in a previously reported randomized clinical trial. Parents were interviewed about comorbidity, hospitalization, and medication use at random assignment and regularly thereafter. Data were cross-checked with discharge letters when available. The influence of comorbidity on neurodevelopment at 2 years old (Bayley Scales of Infant Development II) was determined by stepwise multiple linear-regression analysis.
RESULTS. Before trial entry, 163 infants with Down syndrome had been admitted to hospital for an average of 14.01 days, whereas during the trial, 95 of 181 infants who completed the trial were hospitalized for an average 19.75 days. Main hospitalization reasons during the trial were lung/airway and congenital heart and gastrointestinal disease. The 48 infants operated on for heart or gastrointestinal disease accounted for 1401 of the total number of 1876 hospital admission days during the trial and for 33 of 62 admissions for lung/airway infection. During their second year of life, 
60% of the infants were prescribed drugs, mostly antibiotics and pulmonary. Regression analysis showed infantile spasms, "other" central nervous system disease, and gastrointestinal disease necessitating surgery to be associated with greater developmental age delays at 24 months old (mental: 6.87, 3.52, and 1.69 months; and motor: 3.59, 2.54, and 1.68 months, respectively).
CONCLUSIONS. Hospital admission and medication use rates in young infants with Down syndrome are still very high, mainly because of congenital heart and gastrointestinal disease and acquired respiratory disease. Central nervous system disease and gastrointestinal disease necessitating surgery were independently associated with a worse developmental outcome.
Key Words: Down syndrome • congenital heart disease • congenital gastrointestinal disease • infantile spasms • hospitalization • medication use • Bayley Scales of Infant Development
Abbreviations: DS—Down syndrome • BSID II—Bayley Scales of Infant Development II • CI—confidence interval • CNS—central nervous system
Down syndrome (DS) is often accompanied by congenital heart and gastrointestinal disease, almost always manifesting in early infancy and often necessitating surgery.1 In addition, infants with DS run increased risks of medical conditions and problems like celiac disease, feeding difficulties, severe constipation, and seizures.1,2 During the past 2 to 3 decades, the prevalence and clinical management of these disorders and problems have been well established.2 Yet, reports on their impact on hospital admission are scarce and on medication use are even lacking. Remarkably, the possible influence of the various types of comorbidity on early neurodevelopment has also not been investigated.
Recently, we conducted a randomized clinical trial in which 196 infants were treated with either thyroxine or placebo during their first 2 years of life with mental and motor development as primary outcome. Thyroxine treatment resulted in subtle improvements in motor development and somatic growth, confirming that young infants with DS have genuine mild congenital hypothyroidism.3 This trial provided us with a unique opportunity to study the impact of the aforementioned medical conditions on hospitalization and medication use rates in young infants with DS and to investigate their influence on neurodevelopment during the first 2 years of life.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The trial design has been reported previously, according to the Consolidated Standards of Reporting Trials guidelines.3,4 In short, between June 1999 and September 2003, we conducted a single-center, randomized, double-blind, 24-month trial with nationwide recruitment (enrollment until August 2001), comparing thyroxine administration with placebo. The primary outcome was mental and motor development at 24 months old, assessed with the Bayley Scales of Infant Development II (BSID II). Neonates, referred by pediatricians and the Dutch Down Syndrome Foundation, were allowed to participate in the trial when their congenital hypothyroidism screening result was normal, their gestational age
252 days, their 5-minute Apgar score 7, their postnatal age 
28 days, and 1 parent had sufficient command of the Dutch language. The study was conducted in the Emma Children's Hospital, Academic Medical Center, of the University of Amsterdam, after approval by its ethics committee. Written informed consent was obtained from all of the parents. Of the 196 neonates with DS enrolled in the trial, 99 neonates were randomly assigned to thyroxine treatment and 97 to placebo; 91 infants in the thyroxine group and 90 infants in the placebo group completed the trial. The primary outcome was available in 90 thyroxine- and 91 placebo-treated infants. The thyroxine-treated children had a 0.7-month smaller delay in motor developmental age (95% confidence interval [CI]: –1.4 to –0.02) corresponding with a difference of 7 motor developmental index points. The mental developmental age delay was also 0.7 month less in the thyroxine group (95% CI: –1.5 to 0.2), but this lacked statistical significance (intention-to-treat analysis). The thyroxine-treated infants who completed the trial had somewhat greater gains in length and weight. Comorbidity did not significantly differ between the 2 treatment groups, except that in the thyroxine group, 5 infants were diagnosed with "other" central nervous system (CNS) disease. There were no adverse events that could be related to thyroxine treatment.3
Assessments
Other than study visits at random assignment and 24 months old, obligatory visits to the Academic Medical Center were at ages 2, 6, 12, and 18 months. At all of these visits, parents were interviewed about the perinatal period (at random assignment, mean age: 0.8 months), their child's medical condition, hospital admission(s), medical checkups, diagnoses, procedures, and medication use in the preceding period (ages 2–24 months). Interviews were done by a pediatric endocrinologist or research nurse by means of a standardized questionnaire. Data were cross-checked with discharge letters that were available in 133 (67.9%) of 196 infants. With the exception of prescribing trial medication, the investigators did not interfere in the medical decision-making.
At 24 months old, development was assessed with the BSID-II. The BSID-II was adjusted by starting with items for children younger than the actual age at testing (9 months instead of 24 months). Developmental status was expressed as mental and motor developmental age delays (in months). All of the developmental tests were conducted by the same developmental psychologist, blinded for the treatment allocation.
Statistical Analysis
Developmental age delays were compared using the independent samples t test. Stepwise multiple linear-regression analysis was used to assess the association of mental and motor developmental age delays with comorbidity (the presence of infantile spasms, other CNS disease, heart or gastrointestinal disease necessitating surgery, or recurrent lung/airway disease) and thyroxine treatment. Means, SDs, medians, ranges, numbers, percentages, and statistical analyses were calculated with SPSS 11.0.1 for Windows (SPSS Inc, Chicago, IL).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Hospital Admission Before Entry Into the Trial
Before trial entry, 163 (83.2%) of 196 neonates with DS were admitted to hospital. In these 163 neonates, mean and median admission durations were 14.01 (SD: 10.85) and 11 (range: 2–53) days, respectively. A total of 146 admissions (89.6%) took place within the first 24 hours after birth, 16 (9.8%) between 2 and 7 days after birth, and 1 (0.6%) thereafter. Table 1 shows the admission reasons: cyanosis and/or low oxygen saturation, (mild) preterm birth or low birth weight, diagnosis of DS (suspicion), and feeding difficulties accounted for 78.5% of admissions. Only 14 admissions (8.6%) were on maternity wards.
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Hospitalization During the Trial
During the trial period, 95 (52.5%) of 181 infants with DS who completed the trial were hospitalized 197 times, with a total admission duration of 1876 days. A total of 86 infants were never admitted to the hospital between trial entry and 2 years old but were regularly seen in the outpatient clinic by local pediatricians. In these 95 infants, the mean and median numbers of admissions were 2.07 (SD: 1.55) and 2 (range: 1–8), whereas the mean and median number of admission days were 19.75 (SD: 22.68) and 14 (range: 1–139), respectively. Most hospital admissions (130 [66.0%]) were in the first year of life. Table 2 shows the hospitalization reasons. From trial entry to age 1 year, the numbers of infants admitted for lung/airway and heart disease were clearly higher than during the second trial year, whereas the numbers of infants admitted for gastrointestinal disease were about similar. The 48 infants operated on for heart and/or gastrointestinal disease accounted for 1401 (74.7%) of the total number of 1876 hospital admission days and for 33 of the 62 admissions for "respiratory syncytial virus infection" or "lung/airway infection not specified." This implies an
3 times higher risk of admission for respiratory infection in this subgroup.
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Medication Use During the Trial
During the trial, the percentage of infants with DS who used
1 physician-prescribed drugs (either as short course or as maintenance treatment) increased from 21.2% at trial entry to maximally 61.2% between ages 2 and 12 months (Table 3). At that age, the most frequently used drugs were antibiotics, inhaled ß2-adrenergic agonists and glucocorticoids, and laxative agents.
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Comorbidity: CNS, Heart, Gastrointestinal, and Pulmonary Disease
Of the 176 infants with DS who completed the trial and whose developmental testing results at 24 months old were available, 6 were diagnosed with infantile spasms at a median age of 7.7 months (range: 5.3–9.0). All of the infants were treated with oral anticonvulsants. Before trial entry, 2 more infants had suffered from neonatal convulsions, probably related to hypoxia and meningitis, respectively, and were also treated with oral anticonvulsants. During the trial 4 infants were diagnosed with other CNS disease (Dandy-Walker malformation, meningitis, postnatal cerebral infarction, and prenatal cerebral infarction; at ages 10.5, 7.6, 16.0, and 19.2 months, respectively) and 1 with probable CNS damage (severe hypoxia because of accidental extubation after cardiac surgery at age 1.4 months).
Thirty-five infants underwent heart surgery for congenital heart disease, at a median age of 3.9 months; 1 infant, operated on for ventricular septal defect, did not undergo BSID II testing at 24 months old and was not included in the regression analysis. During the trial, 2 infants with DS (1.0%) had died, one from heart failure caused by (inoperable) congenital heart disease (atrioventricular septal defect + tetralogy of Fallot) at the age of 4 months and the other probably from chylothorax (after heart surgery) worsened by pneumonia at the age of 11 months. Fifteen infants underwent surgery for congenital gastrointestinal disease, 8 of them before trial entry, at a median age of 0.1 month (range: 0.03–0.13 months). The other 7 infants had an operation later on at a median age of 11.7 months (range: 5.01–17.40 months). Table 4 shows the precise surgical diagnoses. Forty-two infants were hospitalized twice or more for pulmonary infection or used inhaled ß2-adrenergic agonist or glucocorticoids for 6 months.
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Comorbidity and Hospitalization and Their Relation to Mental and Motor Development at the Age of 24 Months
At the age of 24 months, the 6 infants with DS and infantile spasms had a substantially greater developmental age delay than the other 170 infants with DS, with mental developmental delay being greater than motor developmental delay (Table 4). In these 6 infants, a small and statistically significant difference in mental (but not in motor) delay was already present at 6 months old (0.65 months; 95% CI: 0.11 to 1.18; P = .019), 0.2 to 3.0 months before the diagnosis was made in 5 of them (Fig 1). At 24 months old, the 7 infants with CNS disease other than infantile spasms also had a greater developmental delay than infants without these problems. However, the differences in mental and motor delay were smaller than those of the infants with infantile spasms (Table 4).
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, n = 6) versus those without infantile spasms (
, n = 170). P values refer to the comparison of means by independent samples t test.In additional univariate analyses, infants with DS who were admitted to hospital >11 days before trial entry had a significantly greater mental developmental age delay than infants without this feature. Infants with DS who underwent gastrointestinal surgery during the first 2 years of life, had recurrent lung/airway disease, were admitted to hospital >11 days before trial entry, or were hospitalized >14 days during the trial had significantly greater motor developmental age delays (Table 4). The motor developmental age delays in the infants with DS who underwent gastrointestinal surgery before trial entry and during the trial were approximately similar.
Table 5 shows the result of stepwise multiple linear-regression analyses, assessing the relation between mental and motor developmental age delay at 24 months old and comorbidity. Only the presence of infantile spasms, other CNS disease, and gastrointestinal disease necessitating surgery were found to be independently associated with greater mental and motor developmental age delays at 24 months old. In the regression analysis, thyroxine treatment during the first 2 years of life was found to be positively and significantly associated with better motor development at 24 months old, confirming our previous findings.3
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Carrying out a national randomized clinical trial in young infants with DS with early neurodevelopment as the main outcome offered an ideal opportunity to systematically investigate comorbidity and its possible influence on this outcome. In addition, the (by definition) prospective character of the study and the high study adherence (as expected) promised a very complete set of data.
It is not a surprise that hospital admission and medication use rates of the infants with DS participating in our randomized clinical trial turned out to be much higher than in the general Dutch population. Between 1999 and 2003, the neonatal hospital admission rate in the general Dutch population was 30 in 100, and the admission rate in 1- to 5-year-old children was 11 in 100. In the same period, the medication use rate among 0- to 11-year-old Dutch children was, on average, 16.5%.5 This means that among the 0- to 2-year-old infants with DS, the admission rate in the neonatal period was 2.8 times higher and after the neonatal period, 2.2 times higher. The medication use rate at the age of 1 year was 4 times higher.
These findings not only complement but also update the apparently sole data on hospitalization in children with DS by Frid et al.6 These authors retrospectively studied the use of medical care in relation to congenital malformations in all 211 of the children with DS born between 1973 and 1980 in the northern part of Sweden and in the 90 children with DS born between 1995 and 1998 in the same region (neonatal hospital admissions only). Mean neonatal admission duration decreased from 24.9 to 10.7 days. The latter figure is approximately similar to the mean neonatal admission duration of the 196 infants with DS included in our study. The combined Swedish and Dutch figures suggest that the hospitalization duration beyond the neonatal period has also decreased from 8.3 days per year during the first 3 years of life in the 1970s in the Swedish study to 5.2 days per year during the first 2 years of life in our present study. So, although hospital admission rates in young infants with DS are still substantially higher than in the general infant population, admission durations have clearly decreased in recent decades. This decrease, in combination with the probably much lower current mortality rate in infants and children with DS (1.0 in 100 before the age of 2 years in our patient cohort vs 23.7 in 100 before the age of 10 years in the Swedish patients in the 1970s and 1980s), can only be explained by much improved medical care for patients with DS.
With regard to hospitalization reasons and medication use beyond the neonatal period, our data highlight lung/airway disease as a major cause of morbidity and hospitalization in young infants with DS, especially in those with congenital heart and gastrointestinal disease. A further decrease in early infancy hospitalization rates and duration might be achieved by developing and implementing strategies aimed at preventing severe respiratory disease because of (common viral) infections, for example, rigorous prophylactic antiviral and antibacterial treatments.
Our findings that congenital gastrointestinal disease, necessitating surgery during infancy, was independently associated with greater mental and motor developmental age delays at 24 months old and that most infants with infantile spasms had a greater mental developmental age delay already before this diagnosis was made are novel and quite intriguing. In general, 80% of cases of infantile spasms are classified as so-called "symptomatic" (ie, caused by an underlying brain abnormality) and 20% as "cryptogenic" (normal previous development, no known causative factors, and normal brain imaging).7 Children with symptomatic spasms are more at risk for impaired development than those with cryptogenic disease (94% vs 49%, respectively).7 Although infantile spasms in infants with DS are symptomatic by definition, there is some controversy about the consequences of the spasms on developmental outcome.8,9 Our findings, however, showing a clearly worse mental development in the infants with infantile spasms already demonstrable before the spasms become clinically manifest, suggest the consequences for mental and motor development to be quite severe. Further investigations may reveal whether infantile spasms in DS reflect the extreme end of the spectrum of brain abnormalities in DS.
The association between gastrointestinal disease necessitating surgery and worse mental and motor development at 24 months old is even more intriguing. Because congenital heart disease necessitating surgery did not negatively influence neurodevelopment, it is unlikely that this developmental delay is caused by the surgical procedure or the general anesthesia. Neither can hypoglycemia be held responsible. Also considering this facet of DS, the question arises whether there may be an "intrinsic link" between congenital gastrointestinal disease, for example, Hirschsprung disease, and worse neurodevelopment. In the last few years, 2 such links have been discovered, although not in DS. Wakamatsu et al10 reported that mutations in the ZFHX1B gene, located at 2q22 and encoding Smad-interacting protein 1, are responsible for several cases of Hirschsprung disease associated with microcephaly, mental retardation, epilepsy, and characteristic facial features and that Smad-interacting protein 1 seems to have crucial roles in normal embryonic neural and neural crest development. Recently, Brooks et al11 demonstrated that homozygous nonsense mutations in the KIAA1279 gene, located at 10q22.1, underlie a syndromic form of Hirschsprung disease and mental retardation associated with polymicrogyria, establishing the importance of this gene in both brain and gastrointestinal tract development. Of course, our observations in young infants with DS can not be explained by mutations in the aforementioned genes. However, if chromosome 21 harbors genes that encode transcription regulators of these or similarly involved genes, trisomy 21-related dosage imbalance of such regulating genes might explain the simultaneous occurrence of gastrointestinal and more severe brain abnormalities.12
This study had some limitations. First, our trial was not designed to study the influence of comorbidity on early neurodevelopment of young infants with DS, and the results of our subgroup analyses should be interpreted with this in mind. However, the percentages of infants with congenital heart and gastrointestinal disease necessitating surgery and of infants with infantile spasms in our trial correspond well with the previously reported prevalence of these conditions in DS,1 suggesting our cohort to be a valuable random sample. Second, neonates with DS born after a gestational age <252 days were not allowed to enter the trial. This may have resulted in underestimation of the true neonatal admission rate. On the other hand, a large proportion of trial participants were sent in by pediatricians. Because hospital admission might increase the chance of being informed about the trial and of referral, this may have resulted in overestimation of the neonatal admission rate.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Hospital admission and medication use rates in young infants with DS are still very high, mainly because of congenital heart and gastrointestinal disease and acquired respiratory disease. The presence of CNS disease and congenital gastrointestinal disease necessitating surgery was associated with a worse developmental outcome. Hypothetically, the association between gastrointestinal disease and worse neurodevelopment might be explained by dosage imbalance of chromosome 21 genes that regulate genes involved in both embryonic brain and gastrointestinal tract development.
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ACKNOWLEDGMENTS |
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This work was financially supported by Netherlands Organization for Health Research and Development (ZonMw) grant 2100.0025.
We thank Jeannette C.D. Ridder for collecting part of the data and Susanne L. Rutgers van Rozenburg-Marres for carrying out the developmental tests.
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FOOTNOTES |
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Accepted May 23, 2006.
Address correspondence to A.S. Paul van Trotsenburg, MD, Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, Netherlands. E-mail: a.s.vantrotsenburg{at}amc.uva.nl
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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- van Trotsenburg AS, Vulsma T, Rutgers van Rozenburg-Marres SL, et al. The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial.
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[Abstract/Free Full Text] - Revised recommendations for improving the quality of reports of parallel group randomized trials 2001. Available at: www.consort-statement.org. Accessed April 1, 2006
- Statistics Netherlands. Available at: http://statline.cbs.nl/StatWeb/Start.asp?lp=Search/Search&LA=EN&DM=SLEN. Accessed: April 1, 2006
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- Hrachovy RA, Frost JD Jr. Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/West syndrome). J Clin Neurophysiol. 2003;20 :408 –425[Web of Science][Medline]
- Stafstrom CE, Konkol RJ. Infantile spasms in children with Down syndrome. Dev Med Child Neurol. 1994;36 :576 –585[Web of Science][Medline]
- Goldberg-Stern H, Strawsburg RH, Patterson B, et al. Seizure frequency and characteristics in children with Down syndrome. Brain Dev. 2001;23 :375 –378[CrossRef][Web of Science][Medline]
- Wakamatsu N, Yamada Y, Yamada K, et al. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet. 2001;27 :369 –370[CrossRef][Web of Science][Medline]
- Brooks AS, Bertoli-Avella AM, Burzynski GM, et al. Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems. Am J Hum Genet. 2005;77 :120 –126[CrossRef][Web of Science][Medline]
- Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet. 2004;5 :725 –738[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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