PEDIATRICS Vol. 123 No. 1 January 2009, pp. 256-261 (doi:10.1542/peds.2007-2840)
ARTICLE |
Has Prenatal Screening Influenced the Prevalence of Comorbidities Associated With Down Syndrome and Subsequent Survival Rates?
a Murdoch Childrens Research Institute, Parkville, Victoria, Australia
b Victorian Birth Defects Register, Department of Human Services, Victoria, Australia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. With this study we aimed to compare survival rates for children with Down syndrome in 2 time periods, 1 before prenatal screening (1988–1990) and 1 contemporaneous with screening (1998–2000), and to examine the frequency of comorbidities and their influence on survival rates.
METHODS. Record-linkage was performed between the population-based Victorian Birth Defects Register and records of deaths in children up to 15 years of age collected under the auspice of the Consultative Council on Obstetric and Pediatric Mortality and Morbidity. Cases of Down syndrome were coded according to the presence or absence of comorbidities by using the International Classification of Diseases, Ninth Revision classification of birth defects. Kaplan-Meier survival functions and log rank tests for equality of survival distributions were performed.
RESULTS. Of infants liveborn with Down syndrome in 1998–2000, 90% survived to 5 years of age, compared with 86% in the earlier cohort. With fetal deaths excluded, the proportion of isolated Down syndrome cases in the earlier cohort was 48.7% compared with 46.1% in the most recent cohort. In 1988–1990 there was at least 1 cardiac defect in 41.1% of cases and in 45.4% in 1998–2000. There was significant variation in survival rates for the different comorbidity groupings in the 1988–1990 cohort, but this was not so evident in the1998–2000 cohort.
CONCLUSIONS. Survival of children with Down syndrome continues to improve, and there is an overall survival figure of 90% to at least 5 years of age. It is clear from this study that prenatal screening technologies are not differentially ascertaining fetuses with Down syndrome and additional defects, because there has been no proportional increase in births of isolated cases with Down syndrome.
Key Words: comorbidity • congenital abnormalities/anomalies • Down syndrome • prenatal • survival rate
Abbreviations: DS—Down syndrome • NT—nuchal translucency • VBDR—Victorian Birth Defects Registry • CCOPMM—Consultative Council of Obstetric and Pediatric Morbidity and Mortality • df—degrees of freedom
In Victoria, Australia, Down syndrome (DS) is a common birth defect with an estimated 1 in 364 fetuses affected in 2003–2004.1 Although the number of livebirths of children with DS has remained fairly stable in Victoria (with 45–60 a year since 1996) the overall prevalence, including both births and terminations of pregnancy, is increasing.2 This increase is attributable to 2 main factors. First, an increase in maternal age has occurred, with 22.4% of women giving birth in 2004 being 35 years or older, compared with 7.9% in 1985.3 Second, there is an increase because of ascertainment of fetuses with DS by prenatal screening in late first trimester or early second trimester. First-trimester screening began in 1999 using nuchal translucency (NT) screening, although second-trimester maternal serum screening was becoming widely used at that time, with 
24% of pregnant women having screening in 2000.4 The increased use of prenatal screening is well documented both locally4,5 and internationally.6 These screening tests detect fetuses with DS that would otherwise spontaneously abort,7,8 so that now previously undetected and unreported cases are being detected and entering the statistics.
DS is associated with specific birth defects, cardiac defects being the most common, reported as occurring in approximately 40% to 55% of patients.9–15 Atrioventricular septal defects, ventricular septal defects, and patent ductus arteriosus are the 3 main types. Cardiac defects in general have been the major cause of death in children with DS, with complete atrioventricular canal defects having the poorest prognosis.11,16–119
Gastrointestinal disorders are also reported in patients with DS, but fewer studies have examined their prevalence compared with cardiac defects. One very large registry study in France reports a frequency of 6%,12 whereas other publications suggest higher rates, with duodenal atresia reported as being present in 5%,15 12%20 or 10% to 15%21 of children with DS. Most recently, a hospital-based study looking at pooled data over 10 years, on livebirths only, had a particularly low frequency of all gastrointestinal defects of 2.8%,22 but such hospital discharge data often have poor ascertainment.
The probability of survival in a child born with DS with or without an associated defect has improved over the last 30 years, and at least 90% of cases are found in a number of studies to survive to 1 year of age and 85% to 10 years.23 There is also an increase in the mean longevity, having survived these early years.23 Not surprisingly, survival is strongly associated with the presence of multiple birth defects.24 The available unbiased studies have mainly focused on the survival rate of children with DS and cardiac defects11,17,18, finding it to be 85%, around 10% less than those without a cardiac defect.
The last 20 years or so have seen significant changes in the availability and uptake of prenatal screening for the identification of DS in many countries, all of which have influenced the prevalence of DS in a number of ways.24–28 Australian and New Zealand guidelines and other long-standing sets of recommendations from international bodies state how prenatal screening and diagnosis for DS should be implemented.29,30 Prenatal screening is available to pregnant women of all ages as distinct from prenatal diagnosis (chorion villous sampling and amniocentesis), which has historically been targeted to women of advanced maternal age. Prenatal screening includes maternal serum screening, often combined with NT screening in the first trimester, as well as other fetal ultrasound in the second trimester. In recent times, in many places, most pregnant women have at least 1 fetal anomaly scan during their pregnancy.31,32
We hypothesize that increasing use of prenatal screening, concomitant with improvements in ultrasound techniques, would result in increased prenatal diagnoses of structural defects associated with DS, followed by consequent termination of pregnancy. This would increase the proportion of infants liveborn with isolated DS. However, this hypothesis has not been tested, because most of the published studies on survival relate to a period before prenatal screening was widespread. This study also aims to compare survival rates for DS in 2 time periods, 1 before screening (1988–1990) and 1 contemporaneous with screening (1998–2000) and to determine the frequency of comorbidities and their influence on survival rates of children with DS.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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There were 2 databases used in this study: the Victorian Birth Defects Register (VBDR) and the Consultative Council of Obstetric and Pediatric Morbidity and Mortality (CCOPMM).
The Victorian Birth Defects Register
The VBDR contains information on all birth defects relating to livebirths and stillbirths at 20 weeks' gestation and later, occurring in the state of Victoria since January 1, 1982, irrespective of the age at diagnosis and up to 15 years of age. Data related to terminations of pregnancy for a birth defect occurring at any gestation (before or after 20 weeks' gestation) are also collected. Notifications to the VBDR are obtained from multiple sources including the following:
- The Perinatal Morbidity Statistics form. Completion of this form is mandatory (required by the State Health Act 1958), and this is usually done by midwives who attend each birth in the state of Victoria of at least 20 weeks' gestation
- Perinatal death certificates and autopsy reports
- Cytogenetic laboratory reports
- Inpatient and outpatient listings from major teaching pediatric hospitals
- Maternal and child health nurses, other health professionals, support organizations, and parents.
For each case, all diagnosed conditions are coded using the British Pediatric Association Classification of Diseases (compatible with the International Classification of Diseases, Ninth Revision (ICD-9). Up to 13 conditions can be coded per individual.
Completeness of VBDR Data on DS
There has been 100% ascertainment of all children born in Victoria with chromosomal anomalies admitted to the 2 major pediatric teaching hospitals in the state.33 There are 4 laboratories in Victoria doing cytogenetic testing, both prenatally and postnatally, and they all notify the VBDR of any chromosomal abnormalities. In addition, active follow-up of all abnormal prenatal diagnoses with trisomies 13, 18, and 21, is conducted annually by the VBDR to obtain outcome data (ie, spontaneous loss, termination, or birth) from the treating obstetricians.
The Consultative Council of Obstetric and Pediatric Morbidity and Mortality
All perinatal, infant, child, and maternal deaths occurring in the state of Victoria since 1961 are reported to CCOPMM as a requirement of the Health Act 1958. The CCOPMM database contains information on all perinatal deaths (stillbirth or neonatal death) occurring from 20 weeks' gestation or with a birth weight of 400 g or more and all infant and child deaths that occur up to, but not including, the age of 15 years. Case files are compiled from death certificates, autopsy reports, hospital medical charts, coronial services, specialist and general practitioners, midwives, and the Newborn Emergency Transfer Service to ensure data are as complete as possible.
The Department of Human Services Human Research Ethics Committee and the La Trobe University Faculty of Health Sciences Human Ethics Committee approved this research project.
Data Collected
Two cohorts with DS notified to the VBDR from the 4 cytogenetics laboratories in Victoria were identified for follow-up, those born from 1988 to 1990 and those born from 1998 to 2000.
Manual record-linkage of cases with DS selected from the VBDR with those in the CCOPMM database, from year of birth to 2005, was undertaken using different combinations of identifying factors: mother's surname, given name and date of birth; infant's date of birth; gender and postcode.
If a case did not have a match among the deaths, it was considered a survivor. Otherwise, for each linked case, the age at death up to 5 years of age was noted for survival analysis.
Categories of perinatal death were termination for a birth defect (all gestations), stillbirth (20 weeks' gestation or later), and neonatal death (up to 28 days from livebirth). Later infant and child deaths were grouped into 6 month and yearly intervals.
The livebirths with DS were coded according to presence or absence of comorbidities. The categories of comorbidities include the following: isolated cases of DS (not born with an associated defect), DS with a single or multiple cardiac defect within the code range: ICD-9 7450–7479 (eg, ventricular septal defect, endocardial cushion defect), DS with gastrointestinal defect within the code range ICD-9 7503–7519 (eg, duodenal atresia, Hirschsprung disease), DS with both system defects (ie, a cardiac defect as well as a gastrointestinal defect), and DS with other system anomalies (eg, encephalocele, brain abnormalities).
Data Analysis
2 tests were used to assess associations between birth period (1988–1990; 1998–2000) and categorical outcome variables. Fisher's exact tests (1-tailed) for association testing were used where expected frequencies were small. SPSS 15 (SPSS Inc, Chicago, IL) was used to generate Kaplan-Meier survival functions and perform log rank tests for equality of survival distributions between birth cohorts and for different comorbidities.
All terminations and stillbirths were excluded from the comorbidity descriptions and survival analyses because of suspected incomplete recording of comorbidities in many of these cases.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Overall Prevalence and Perinatal Outcome
The overall prevalence (including terminations of pregnancy) in 1988–1990 was 1 in 620 births (315 of 195177 births) and in 1998–2000 was 1 in 410 (461 of 188191 births). In the earlier cohort, there was a termination of pregnancy in 23% of cases (n = 71) compared with 63% (n = 289) in the more recent one (see Fig 1).
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Overall Survival
After linkage to the CCOPMM database, we examined the exact age at death of all cases. The numbers in each death category are shown in Fig 1 and are plotted in Fig 2.
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Ninety percent of infants with DS in 1998–2000 survived to at least 5 years of age, compared with 86% in the earlier cohort. The difference in the survival distribution for each cohort was not statistically significant (log rank Mantel Cox–
2: 1.17, degrees of freedom [df]: 1, P = .28).
Frequency of Comorbidities
With fetal deaths excluded, there was little difference in the proportion of isolated cases in the earlier cohort (48.7%) compared with the proportion of isolated cases in the most recent cohort (46.1%; 2: 0.37, P = .54; see Table 1).
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There were more single cardiac defects reported in the 1988–1990 cohort, but not as many multiple cardiac defects. Combining data on the 3 categories with at least 1 cardiac defect, in 1988–1990 there was at least 1 cardiac defect in 41.1% of cases and in 45.4% in 1998–2000 (
2: 0.75; P = .39).
Combining data from the gastrointestinal defect category and the cardiac defect and gastrointestinal defect category, there was an increase from 11% to 13.9% of cases with a gastrointestinal defect, noting that the majority of these had both a cardiac and a gastrointestinal defect (2: 0.77; P = .38).
Survival Rates in the Presence of Comorbidities
Survival rates for comorbidity groupings to 5 years of age in each cohort are shown in Table 2. Of the 25 deaths in the 1988–1990 cohort, 56% died within 1 year of birth, whereas in the latter cohort all but 1 of the 10 deaths occurred in the first year.
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There was significant variation in survival rates for the different comorbidity groupings in the 1988–1990 cohort (log rank Mantel Cox test:
2: 5; df: 26.5; P < .001), but this was not so evident in the 1998–2000 cohort (2: 10.92, df: 5; P = .05).
The lowest survival rate for children liveborn with DS, of 60%, occurred in cases with a gastrointestinal anomaly in the 1988–1990 cohort. There was weak evidence for an improvement in this group in 1998–2000 to 100% (Fisher's exact 1-tailed, P = .07). However, if the 2 categories with gastrointestinal defects are combined, there is strong evidence for an increase in survival from 69% (18 of 26) to 96% (22 of 23) (Fisher's exact, 1-tailed test, P = .019). None of the other slight improvements in survival rates, observed for individual comorbidities over the study period, were significant. Combining the 3 categories with cardiac defects did not demonstrate a significant increase in survival over time (2: 1.0, P = .32).
The deaths associated with DS and a gastrointestinal defect in the 1988–1990 cohort had all occurred by 6 months of age. Most of the other early deaths tended to be related to the structural defect (usually cardiac), or were classified as infections. Later deaths included 4 cases of leukemia and 2 accidents (1 drowning and 1 scalding). In the later cohort, 6 deaths were classified as infections and the others were directly related to the structural defect.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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More widespread prenatal screening, as well as increasing maternal age, has been responsible for an increase in the overall prevalence of DS. The concomitant increase in terminations does not reflect a difference in choice about continuation or not of a pregnancy in which the fetus has DS, but reflects the actual prenatal detection rate; of the pregnancies in which there was a fetus diagnosed with DS, over 90% were terminated in both cohorts.2
In 1998–2000, in Victoria, Australia, an infant born with DS had a 90% probability of surviving beyond 5 years compared with 86% for a child born in 1988–1990. Other studies on survival have presented pooled data collected over many years11 or for study periods that do not encompass a time when prenatal screening was widely used.34 In our study, the survival rate of infants notified to the VBDR with DS from the 2 birth cohorts was obtained through linkage to the CCOPMM database accessing detailed information on deaths of children up to at least 5 years of age. Given the wide range of notifiers to the VBDR, a strength of this study is the complete coverage of births associated with DS in Victoria. This is complemented by the high quality of the mandated collection of data held by CCOPMM. Through the linkage undertaken we were confident we traced outcomes of all births up to at least 5 years of age, unless the child died interstate. Australian census data show that the proportion of people moving out of the state is <2% in Victoria in both study periods,35 and this small migration is unlikely to impact on the comparison of survival rates.
Apart from examining overall survival rates for children with DS, the main point of our study was to compare results for 2 cohorts, with particular attention to the presence of comorbidities or not, 1 cohort born before widespread prenatal screening and the other during a period of increasing growth of screening. Because of the potentially poor quality of autopsy or postmortem information for terminations or stillbirths, with comorbidities being overlooked and therefore underrecorded, we examined the comorbidity and survival data in relation to livebirths only.
In the early cohort there were quite marked differences in survival of infants with DS, depending on the comorbidity grouping; however, these differences had decreased in all categories in the most recent cohort. Survival to 5 years was over 90% in all comorbidity groupings, and specifically was 99% among those with isolated DS.
The most important finding was that the proportion of infants with DS without comorbidities, ie, isolated cases, has decreased slightly in the most recent cohort (46% compared with 49%), rather than increased as might have been expected if the hypothesis that prenatal screening was selectively detecting those with comorbidities was correct. In particular, it is possible that prenatal screening would selectively detect fetuses with DS and cardiac defects,36 and result in a declining prevalence at birth of children with DS and cardiac defects. However, this does not seem to be happening, and in fact we saw a slight overall increase in diagnosis of DS with cardiac defects, from 41% in the earlier cohort to 45% in the later one. In particular, there was an increase in the proportion with multiple cardiac defects. This may be because of improved diagnosis of "minor" cardiac defects in children in the study period as has been reported elsewhere.37 Another study demonstrated a marked improvement in ascertainment of cardiac malformations in infants with DS between1968 and 1989, however most of this time span is well before our study period, and a continuation in improvement may not have been as great since then.38
Another consideration in this context is the actual ability to detect cardiac defects antenatally and, although increased NT seen by first-trimester ultrasound has been described as being associated with heart defects generally39,40, and specifically in fetuses with DS36,41, this has not led to a reduction in the prevalence of cardiac defects in livebirths with DS in our study population. This is probably because we report here on a period when first trimester NT scans were not widespread, and a potential effect of first trimester screening may not be evident as yet. There are no data available on the antenatal detection rate of cardiac defects specifically in fetuses found to have DS by prenatal screening. However, the later second-trimester fetal anomaly scan, performed more routinely in Victoria, has been shown in a recently published study to detect only 55% of chromosomally abnormal cardiac defect cases.32 Given the possibility of a substantial improvement in prenatal detection rate and an increase in use of first-trimester screening, it still remains possible that the hypothesized decrease in livebirth prevalence of infants with DS and cardiac defects will occur. This, however, may be counterbalanced by increasing ascertainment of "minor" heart defects in living children, as discussed earlier.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This population-based study shows that the survival of children born with DS continues to improve, and these latest data provide an overall survival figure of 90% to at least 5 years of age. In 1998–2000, children born with DS and multiple cardiac defects had a survival rate of 84%, whereas those with other comorbidities or a single cardiac defect did not have a reduced survival rate compared with children born with isolated DS. It is clear from this study that prenatal screening technologies up to the year 2000 were not differentially ascertaining fetuses with DS and additional defects, because there was no proportional increase in isolated cases of DS. This may change with increasing use of first-trimester screening and improved prenatal ascertainment of cardiac defects by ultrasound.
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ACKNOWLEDGMENTS |
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This work was undertaken with considerable input from staff at the Perinatal Data Collection Unit in the Victorian Government Department of Human Services. Their help along with the invaluable cooperation from those who notify the VBDR and CCOPMM of birth defects and deaths is much appreciated.
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FOOTNOTES |
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Accepted Apr 22, 2008.
Address correspondence to Jane Halliday, PhD, Murdoch Childrens Research Institute, Public Health Genetics, Parkville 3052, Australia. E-mail: jane.halliday{at}mcri.edu.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject The prevalence of children liveborn with DS has been influenced by prenatal screening. Many infants with DS have a comorbidity (eg, up to 50% have a cardiac defect). Survival rates have increased over time.
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| What This Study Adds Despite widespread use of prenatal screening, there has been no change in the prevalence of DS as an isolated condition (ie, prenatal screening does not selectively detect cases of DS with comorbidities such as cardiac defects).
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PEDIATRICS (ISSN 1098-4275). ©2009 by the American Academy of Pediatrics
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