Hum. Reprod. Advance Access originally published online on March 28, 2008
Human Reproduction 2008 23(6):1297-1305; doi:10.1093/humrep/den093
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Admission to hospital of singleton children born following assisted reproductive technology (ART)
1 Centre for Child Health Research, Telethon Institute for Child Health Research, The University of Western Australia, PO Box 855, West Perth, Western Australia 6872, Australia 2 The National Perinatal Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK
3 Correspondence address. Tel: +61-8-9489-7771; Fax: +61-8-9489-7700; E-mail: michele{at}ichr.uwa.edu.au
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Abstract |
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BACKGROUND: Adverse perinatal outcomes are more common in singletons born following assisted reproductive technology (ART) and this would predict an increase in hospitalization during infancy and early childhood.
METHODS: We investigated hospital admissions during the first 3 years of life for all singleton children born in Western Australia between 1994 and 2000 [1328 ART, 162 350 spontaneously conceived (SC)].
RESULTS: ART infants had a significantly longer birth admission and were four times more likely to be admitted to neonatal intensive care units (NICU) than SC infants. ART children had a 60% greater risk of one or more admissions in their first year and an equal risk of admission in their second and third years. Their length of stay in hospital was longer in each age period. Maternal, infant and socio-economic confounders accounted for most of the increased admission risk in the first year. However, after adjustment, a 20% increase in the risk of admission to NICU (P < 0.05) and admission to hospital during the first year (P < 0.05) remained.
CONCLUSIONS: Couples undertaking ART should be aware that ART infants are more likely to be admitted to a NICU, to be hospitalized in the first year of life and to stay in hospital longer than other children.
Key words: assisted reproductive technology/hospital admission/IVF/morbidity/epidemiology
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAuthor's RoleFundingAcknowledgementsReferences |
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Since babies born following assisted reproductive technologies (ART) now represent 1–4% of births in many developed countries (Andersen et al., 2005
; Wright et al., 2006), the health of these babies is not only of concern to their parents and clinicians but also to healthcare providers. Perinatal outcome following ART is well documented and shown in many studies to be poorer than for spontaneously conceived (SC) infants (Bergh et al., 1999; Schieve et al., 2002; Hansen et al., 2005). The higher perinatal mortality and morbidity rates in ART infants are in large part due to high rates of multiple birth (Wennerholm and Bergh, 2006). Nevertheless, although elective single embryo transfer minimizes the risk of adverse perinatal outcome (Pinborg et al., 2005), low birthweight and preterm birth persist in singletons born following ART compared with SC singletons (Schieve et al., 2004; Wang et al., 2005).
On the basis of the excess risk of prematurity, low birthweight and other complications of pregnancy, an increase in the incidence of admission to neonatal intensive care units (NICU) and hospitalization in infancy and early childhood would be anticipated. Although there is evidence of an increase in the likelihood of admission to NICU for ART singletons (Helmerhorst et al., 2004; Jackson et al., 2004; McDonald et al., 2005), there are few available and appropriately sized published studies with follow up of hospital admissions during infancy and early childhood. Recent large studies of the Swedish and Finnish populations using record linkage have shown an increase in the hospitalization of ART compared with SC singletons in this period (Ericson et al., 2002; Kallen et al., 2005; Klemetti et al., 2006). However, the authors of a recent review of the available evidence concluded that the contradictory results of studies in this field do not yet allow a definitive conclusion to be reached (Ludwig et al., 2006).
The aim of this study was to investigate the rate of in-patient hospital admission by 3 years of age for singletons born following ART (IVF, ICSI or GIFT) compared with their SC counterparts in Western Australia and so add to the accumulating evidence addressing this issue.
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Materials and Methods |
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This cohort study was conducted using record linkage methods to identify hospital admissions up to the age of 3 years for children born as singletons following either ART or spontaneous conception. Data relating to Aboriginal children (who account for 6% of all births) were excluded throughout, since Aboriginal women are much less likely to receive ART treatment than other women in the population and their children have high levels of hospitalization at all ages (Hansen et al., 2002
; Carville et al., 2007).
Creation of the linked data set
The Western Australian Reproductive Technology Register is a statutory database containing information about all procedures performed with ART in Western Australia since April 1993 (The Human Reproductive Technology Act 1991—Directions, 1997). The Midwives' Notification System (MNS) statutorily collects demographic and clinical information about all births from 20 weeks gestation onwards (or 400 g or greater birthweight) including stillbirths, regardless of the place of delivery in Western Australia. The MNS data are routinely linked to information on deaths collected by the Registrar General (Stanley et al., 1994, 1997).
For the purposes of this study, data from the Reproductive Technology Register were linked to the MNS and death data for infants born from October 1993 to October 2000 to enable identification of live births, stillbirths and later deaths following ART (1328 singletons) and those SC (162 350 singletons); linkage was 100% complete for ART births in Western Australia. This combined births and deaths data set was used in the analysis of birth outcomes.
The combined data set, with the exclusion of stillbirths, was then linked to the in-patient hospital admission data held in the Western Australian Hospital Morbidity Data System (HMDS) for admissions to the end of 2000. This data system contains clinical information about all in-patient hospital admissions in the State of Western Australia at both public and private hospitals. Diagnostic information during this period was coded using the 9th and 10th revisions of the International Classification of Diseases (ICD9 and ICD10) (National Coding Centre, 1996; National Centre for Classification in Health, 1999) and ICD10 codes were mapped back to ICD9 codes to enable comparisons over time. Only the principal diagnosis code, which is determined at discharge and represents the primary reason for admission, was used in the analysis. Hospital transfers were merged into a single admission to avoid double counting and we excluded all admissions for social reasons (ICD9 Chapter 18, V codes) since our primary interest was to assess the health of the children.
The combined data set was also linked to the Western Australian Birth Defects Registry (BDR) which collects information about birth defects diagnosed prenatally and up to the age of 6 years. Cases included in the BDR are ascertained from multiple statutory and voluntary sources with a high level of ascertainment and accuracy (Bower et al., 2001). The birth defects information was used as a covariate in the adjusted logistic regression analyses (see below) as it is known that infants born following ART are at an increased risk of birth defects (Hansen et al., 2002; Rimm et al., 2004; Hansen et al., 2005; McDonald et al., 2005). For information about birth defects as a reason for hospitalization, we used the principal diagnosis (ICD9 codes 740–759) derived from the hospital morbidity data.
All record linkage was carried out using the probabilistic matching software Automatch (AUTOMATCH generalized linkage system, 1996). For confidentiality and legal reasons, the record linkage was carried out by the Data Record Linkage Unit at the Western Australian Health Department and a de-identified data set was released to the authors for analysis. Data linkages were validated by comparing the date of birth, death and gender across records from the various linked data sets as well as ensuring admission and discharge dates fell within the birth and death dates for each child. Admission and discharge sequences were also validated.
Cohort analysis
We analysed hospital admissions up to 3 years of age. Infants born in the later years had not yet reached the age of 3 years when the data sets were linked, thus, to allow for the differential length of follow-up, we initially attempted to analyse the data using Cox proportional hazards modelling. However, the assumption of proportional hazards was violated. We therefore proceeded by dividing the duration of follow-up into three 1 year (first, second and third) age periods in which the children included in the analysis for each period were those children at risk of being admitted for the whole of that age period. Only children alive at the start of an age period were included in the denominator for that period. For these reasons, the denominator changes between periods. Where an admission spanned two time periods, the admission was allocated to the first period to avoid double counting. The length of stay (LOS) was calculated as the number of days from admission to discharge or death. If a child was admitted and discharged on the same day then a LOS of 0.5 days was assigned.
Admissions to a NICU were analysed separately from other first year admissions and the denominator for this analysis was all live births. All births in hospital, which account for 99% of all births, are counted as an admission in the Western Australian hospitalization data. Thus for the purposes of calculating admissions in the first year, we needed to separate ‘normal’ birth admissions from admissions in which the neonate was ‘sick’. Although we were able to identify admissions to NICUs, not all sick neonates are admitted to a NICU. Based upon the definition of a ‘newborn’ in the National Health Data Dictionary (Australian Institute of Health and Welfare, 2006), we defined a birth admission of 10 days or longer as a ‘morbid’ admission for inclusion in the first period analysis; 95.7% of all birth admissions were 9 days or less. Admissions in the first year were therefore defined as children in hospital on Day 10 or admitted after this day up to the child's first birthday. The denominator for this period was all children alive at age 10 days who were born on or before 31 December 1999, i.e. children with follow-up information available to their first birthday.
Analytical methods
The data analysis was carried out using SPSS statistical software (version 13.0) and SAS/STAT software (version 9.1). Means were derived for comparison, and medians were used for variables that were not normally distributed. Student's and Welch's t-test were used to compare means and non-parametric tests were used to compare medians. Logistic regression was used to derive odds ratios (ORs) and their 95% confidence intervals (95%CI) to compare the relative odds of birth outcomes and hospital admissions in ART children compared with SC children. The effects of covariates on the OR estimates were examined. These included maternal age, parity, child's year of birth (to adjust for cohort effects), preterm birth, low birthweight and the presence of major birth defects since these are all factors known to be associated with ART conception. We also adjusted for the effects of admission to a NICU, cigarette smoking, private health insurance status and SEIFA codes (a small area geographical-based score of social disadvantage) (Australian Bureau of Statistics, 2003).
Data access and ethics approval
Access to the data was approved by the Confidentially of Health Information Committee and the Western Australian Reproductive Technology Council on behalf of the Commissioner for Health. Ethics approval for the study was granted by the Princess Margaret Hospital and King Edward Memorial Hospital Ethics Committee.
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Results |
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During the period of analysis, 1328 (0.8%) children were born as singletons after ART conception and 162 350 (99.2%) after spontaneous conception (Table I). Of the ART children, 67% were born following IVF, 25% following ICSI and 8% following GIFT. Compared with the SC group, the ART children were more likely to be born to older, primiparous mothers (Table I). They were three times more likely to be born at or before 32 weeks gestation or weigh <1500 g and twice as likely to be born between 33 and 36 weeks gestation or weigh between 1500 and <2500 g. They were nearly twice as likely to have a major birth defect, 60% more likely to be stillborn and twice as likely to die before their first birthday (OR 1.8, 95% CI 1.1–2.7). Their mothers were five times more likely to be covered by private health insurance, twice as likely to live in an area of high social advantage and 60% less likely to smoke during pregnancy. Figure 1 illustrates the odds of a series of perinatal outcomes which are more common in the ART group compared with the SC group, having adjusted for maternal age, parity and infant's year of birth.
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Birth admission
The median LOS of the birth admission was 6 days for ART compared with 4 days for SC infants. Stratification showed that Caesarean section, preterm birth, low birthweight and major birth defects all increased the length of the birth admission. In each of these groups, the median LOS was also 2 days longer for ART than for SC infants (data not shown). Those with private health insurance had longer birth admissions than public patients; however, in both groups (private and public), the median LOS was still 1 day longer for ART than SC births.
Admission to NICU
Admission to NICU was recorded for 8.8% of ART infants compared with 2.3% of SC infants (OR 4.2, 95% CI 3.4–5.1). ICSI infants were marginally more likely to be admitted to NICU than IVF infants (OR 1.5, 95% CI 1.0–2.3). Only four GIFT infants were admitted to a NICU. Table II shows the results of adjusting for potential maternal, infant and socio-economic confounders. After adjusting for maternal age, parity and year of birth, ART infants were still twice as likely to be admitted to NICU as SC infants. The addition of preterm birth to the model had little material effect and adding low birthweight had no further effect. The ratio was further reduced by adjusting for private health insurance at birth (OR 1.3, 95% CI 1.0–1.6), but not influenced by adjusting for the effects of social disadvantage or maternal smoking during pregnancy (data not shown). The addition of major birth defect to the model resulted in a residual, and statistically significant, 20% increase in the risk of admission to NICU for ART compared with SC infants which could not be accounted for by the potential confounders adjusted for.
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Admissions to 3 years of age
Details of hospitalization for ART and SC children during their first 3 years of life (excluding birth admissions <10 days and social admissions) are shown in Table III. During the first year, 29% of ART and 20% of SC children were admitted to hospital at least once. In the second year, equal proportions (16%) were admitted at least once, whereas in the third year, the figures were 14% and 12%, respectively. Thus, ART singletons were 60% more likely to be admitted to hospital at least once before their first birthday compared with SC singletons, and having adjusted for all covariates a 20% excess risk of hospital admission remained (OR 1.2, 95%CI 1.0–1.4). In the second year, the ART children were at the same risk of admission as the SC children (adjusted OR 1.0, 95%CI 0.8–1.2), but were at a 20% increased risk, which was not statistically significant, in the third year (adjusted OR 1.2; 95% CI 0.9–1.6). IVF infants tended to have slightly higher odds of hospital admission than ICSI and GIFT infants during their first 3 years of life, but the differences were small and not statistically significant (data not shown). The proportion of children admitted more than twice was greater for ART than SC children in each year and the mean total LOS per child admitted was significantly longer for ART than SC children (Table III). The median total LOS was also longer for ART children (significant only in the first year).
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Admissions by principal diagnosis
We examined the principal diagnoses by the ICD9 chapters where more than five ART children were admitted in at least one of the considered age groups (Table IV). The odds of admission for diseases of the digestive system were increased in the first year (unadjusted OR 1.5, 95% CI 1.0–2.2; adjusted OR 1.3, 95% CI 0.8–2.0) but not for older children. There was around a 2-fold increase in the unadjusted odds of genitourinary diseases in the first and third years and adjustment increased the odds. Admission with a principal diagnosis of congenital malformations (Chapter 14) was twice as common for ART compared with SC children in all three age groups. The unadjusted odds of admission with a principal diagnosis of symptoms, signs and ill-defined conditions (Chapter 16) for the ART group was nearly twice that of the SC children in the first year; however, adjustment reduced the odds to only a 10% non-significant increase. All other categories in Table IV showed no significant difference between the two groups.
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Discussion |
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Our study, in agreement with numerous published reports and a recent review (Wennerholm and Bergh, 2006), confirms that adverse perinatal outcomes are more common in ART than SC singletons. These findings would predict an increase in hospitalization during infancy and early childhood for ART children and this is indeed confirmed by our findings. Our results show that in their first year of life, ART children had a longer birth admission; were more likely to be admitted to a NICU; and had a higher risk of at least one hospital admission in addition to the (normal <10 day) birth admission. Furthermore, when they were admitted to hospital during the first 3 years of their life, they also spent longer in hospital.
The 4-fold increase in risk of admission to a NICU for ART compared with SC singletons found in this study was mostly, although not completely, explained by known characteristics of ART infants and their mothers. Nevertheless, after adjustment for year of birth, maternal age, parity, length of gestation, birthweight, private health insurance, a measure of social disadvantage and major birth defects, a 20% increase in the risk of admission remained. Several meta-analyses of perinatal outcome in infants following ART have found similar increases in the risk of admission to a NICU for ART singletons. ORs ranging from 1.2 to 1.6 with varying adjustments for infant and maternal variables have been reported and our results are in line with these (Helmerhorst et al., 2004; Jackson et al., 2004; McDonald et al., 2005). There is however little information on the length of the birth admission for all ART compared with SC singletons. Our analyses show that the median LOS for all birth admissions including NICU was 6 days for ART singletons, 50% longer than that for SC singletons.
Analyses of early childhood hospital admissions after the birth admission are few and inconclusive (Ludwig et al., 2006). In this study, 29% of ART and 20% of SC singletons were admitted to hospital during their first year (excluding the normal birth admission). The 60% increase in risk of admission for ART singletons was largely, although not completely, accounted for by adjustment for maternal, infant and socio-economic confounders. During their second and third years, there was little difference in the likelihood of at least one hospital admission for ART and SC singletons, although in each of these periods the risk of more than two admissions and the total time spent in hospital was greater for ART children. Overall, these results are similar to those from large record linkage studies examining hospital admission in Swedish children up to the age of 6 years (Ericson et al., 2002; Kallen et al., 2005) and Finnish children to the age of 4 years (Klemetti et al., 2006). A smaller study from Finland which analysed hospital admission to 7 years of age also found that ART singletons were admitted more often and for longer periods than SC singletons (Koivurova et al., 2003, 2007).
A number of studies have assessed hospital admission by parental interview or questionnaire. Of these, a multi-centre cohort study of 5-year-old singleton children born after 32 weeks gestational age found that children conceived after IVF or ICSI were more likely to have been admitted to hospital than SC children and to have used medical therapies such as speech or physiotherapy (Bonduelle et al., 2005). In contrast, four smaller studies showed no significant difference in the levels of hospitalization between ART and SC children (Saunders et al., 1996; Bowen et al., 1998; Leslie et al., 1998; Belva et al., 2007).
Our study has a number of methodological advantages including a large population-based data source obtained from record linkage of existing databases, and independent analyses of each of the first 3 years of life so that children who had died before the beginning of each time period were not included in the denominators for that or subsequent periods. Validation studies have been undertaken to ensure the quality of routinely collected data in Western Australia's Hospital Morbidity Data System and Midwives' Notification of Birth System and these have found that data on primary diagnoses and procedures are accurately coded and seldom missing (Gee and Dawes, 1994; Holman et al., 1999). In the case of hospital morbidity data, there are 21 different quality checks built into the provision of data from hospitals and there are periodic audits of random selections of hospital-assigned codes. Although information on up to 20 co-morbidities is recorded, we specifically did not analyse this information as there is evidence that co-morbidities are both under-reported and differentially reported between public and private hospitals in Western Australia (Preen et al., 2004).
We were unable to investigate the use of healthcare services apart from hospital admissions and reports from other studies that have attempted to do this have been conflicting (Ludwig et al., 2006). In addition, the Western Australian Reproductive Technology Register does not record information about non-ART treatments such as intrauterine insemination or ovulation induction and births following these treatments will be included in our SC comparison group. It has been suggested that the use of these treatments is also associated with adverse perinatal outcomes (Kallen et al., 2002; Wang et al., 2002; Gaudoin et al., 2003) so that these children may be expected to have higher rates of hospital admission. If this is the case our results would be biased towards the null.
Comparisons of diagnoses reported in the literature are complicated by differences in the specific categories of diagnoses examined, by the groups of children included (all infants versus singletons only), and by different attitudes across countries towards different medical conditions (e.g. day treatment versus hospitalization for the same medical condition). Small numbers in each category also make interpretation difficult. The well documented increase in the risk of birth defects in ART compared with SC singletons (Rimm et al., 2004; Hansen et al., 2005; McDonald et al., 2005) is reflected in our result with a doubling of the risk of admission to hospital with birth defect as a principal diagnosis in all three periods. Our results also confirm earlier findings of increased admission rates for diseases of the genitourinary system (Bonduelle et al., 2005; Klemetti et al., 2006).
We could not confirm increases in admissions for infections, diseases of the nervous system or asthma (data not shown) reported in a large Swedish study that did not separate results by plurality (Ericson et al., 2002; Kallen et al., 2005), and the number of children with admissions for tumours in our study was too small to report meaningful results. Our results are more easily comparable, and similar, to the record linkage study of IVF children in Finland where analyses of singleton births are reported separately (Klemetti et al., 2006).
Our results add to the accumulating evidence that, in addition to the established increase in admission to a NICU required by ART compared with SC singletons, they are also more likely to have more and longer hospital admissions during infancy and early childhood, especially in their first year of life. Although most of the increase can be accounted for by known maternal and infant characteristics, there is still a residual risk. This may in part be due to underlying causes of parental infertility, to components of the ART procedure or to increased concern about children who are born following a long period of infertility (Kallen et al., 2005; Koivurova et al., 2007). These hypotheses merit further investigation. We are unable to explore this any further with the data available to us, although the increase in the risk of admissions with an indeterminate diagnosis may be a sign of increased parental concern.
We found little difference between hospital admission in ART and SC children in the second and third years of life. Klemetti et al. (2006) also found that the difference in hospital admission between ART and SC children was clearest during infancy. If the residual increased risk in admission seen for infants in our study (having adjusted for maternal age, year of birth, parity, preterm birth, low birthweight and other potential confounders) is related to greater parental concern for children conceived following ART, it is possible that this concern may diminish over time. Alternatively, increased admissions and longer hospital stays for ART infants in the first year may have a positive impact on their subsequent health reducing hospital admissions in later years.
The slight increase in NICU admission seen for ICSI versus IVF infants in this study has not been reported elsewhere and may be due to chance. Bonduelle et al. (2002, 2005) have found slight non-significant increases in IVF NICU admission compared with ICSI, whereas most other authors have presented results for ART as a whole. IVF infants in our study tended to have slightly higher hospital admission rates than did ICSI and GIFT infants in each of the first 3 years of life, although differences were small and did not reach statistical significance.
Healthcare providers need to take account of the disproportionate amount of healthcare resources used by ART singletons compared with their SC counterparts. Indeed, a number of recent studies have attempted to cost hospital admission data either during the birth admission or in the neonatal or post-neonatal periods (Koivurova et al., 2004, 2007; Chambers et al., 2007). Although the higher risk of one or more hospital admissions occurs mainly in the first year of life, the mean and median total LOS in hospital remain longer for IVF children in their second and third years. In terms of healthcare provision, the 4-fold risk of admission to a NICU; the 60% increased risk of hospitalization in addition to the normal birth admission up to 1 year of age; and the 
4 days extra spent in hospital each year during the first 3 years, all add to the indirect costs of ART.
Since the known characteristics of ART babies and their mothers account for most of their extra risk of admission to hospital, clinicians and parents can be reassured that their babies are probably not suffering from problems other than those we know about, including birth defects. However, in addition to being told of the increased likelihood of birth defects, perinatal mortality, preterm birth and low birthweight, couples undertaking ART should be informed of the increased risks of hospitalization of their child.
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Author's Role |
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M.H. and L.C. prepared the linked data files for analysis, conducted the analyses and collated the results. M.H., B.P., L.C. and J.K. drafted the paper. N.K. provided statistical advice. C.B. and J.K. contributed to the study design and data analysis. All authors contributed to the interpretation of the data and all were involved in the critical revision of the paper.
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Funding |
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National Health and Medical Research Council of Australia (Project Grant #211930 to M.H., Principal Research Fellowship #353628 to C.B.); Department of Health and National Health Service Research and Development, UK (National Public Health Career Scientist Award PHCS022 to J.J.K.).
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Acknowledgements |
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We are indebted to all the contributors to, and staff of, the Midwives' Notification of Birth System, the WA Reproductive Technology Register, the Hospital Morbidity Data System and the WA Birth Defects Registry. Special thanks to Ms Carol Garfield and Mr Peter Cosgrove for providing data linkage between registers.
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References |
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Submitted on December 13, 2007; resubmitted on February 20, 2008; accepted on March 3, 2008.
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