1 The Fertility Clinic, University of Copenhagen, Rigshospitalet, 3 National Board of Health, Health Statistics, Copenhagen, Denmark
2 To whom correspondence should be addressed: The Fertility Clinic, University of Copenhagen, Rigshopitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. Email: apinborg{at}rh.dk
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Abstract |
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Key words: epidemiology/hospital admission/hospital care resources/ICSI twins/IVF/surgical procedures
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Introduction |
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In a Swedish register study, the risk of hospital admissions was higher in a cohort of IVF children born between 1982 and 1995 than in naturally conceived children born during the same period. This was to a large extent due to the increased incidence of multiple births in IVF children (Ericson et al., 2002). Similar results were provided in a small Australian study on 95 IVF children (Leslie et al., 1998
). They found that apart from admissions to neonatal intensive care unit (NICU), IVF infants did not seem to over-utilize health care resources during the remainder of their first year of life.
Our questionnaire survey on (n=1740) 4 year old IVF/ICSI children born in 1997 showed similar frequency and length of hospitalizations in IVF/ICSI twins and singletons after exclusion of NICU admissions (Pinborg et al., 2003). Two register studies on the same Danish cohort of IVF/ICSI twins born between 1995 and 2000 revealed that IVF/ICSI twins were twice as likely to be admitted to NICU than IVF/ICSI singletons and also, to a less but still significant extent, more likely to be admitted to NICU than naturally conceived twins (Pinborg et al., 2004a
,b
). As data on other assisted reproductive procedures such as ovarian induction or intrauterine insemination until 2002 were not recorded in The Danish IVF Registry, a certain proportion of the control twins was not spontaneously conceived. Our previous national questionnaire survey on the 1997 twin birth cohort in Denmark demonstrated that 17.3% of the control twins were born after assisted reproduction treatment other than IVF/ICSI (Pinborg et al., 2003
).
To further emphasize on whether to keep our policy of dual embryo transfer or to implement eSET as our daily clinical practice, the aim of this study was to assess the risk of hospital admissions and surgical procedures in the same Danish National cohort of IVF/ICSI twins born between 1995 and 2000 aged 27 years compared with all IVF/ICSI singletons and all non-IVF/ICSI twins born during the same period.
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Material and methods |
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Records on fertilization method and obstetric outcome were drawn from the IVF Registry and MBR, respectively. Since January 1st, 1994 it has been compulsory to register each initiated IVF or ICSI cycle to the Danish IVF Registry in the National Board of Health (Nyboe Andersen et al., 1999). We enrolled all 3393 IVF/ICSI twins, 5130 IVF/ICSI singletons and 10 239 non-IVF/ICSI twins born in Denmark between 1995 and 2000. Data on neonatal outcome including neonatal admissions, the risk of neurological sequelae and mortality rates in the three cohorts have recently been published (Pinborg et al., 2004a
,b
,c
).
Outcome measures
By cross-reference with the National Patient Registry, we identified all children diagnosed or treated in a hospital setting between their delivery and December 31st, 2002. The National Patient Registry contains information on all hospitalizations in Denmark including diagnoses and operations performed, dates of entrance to and discharge from the hospital (Andersen et al., 1999). Diagnosis codes and surgical procedures in the National Patient Registry are classified according to the International Classification of Diseases, 10th edn (ICD-10).
We studied the proportion of infants in the three cohorts, who had been hospitalized at any age (up to a maximum of 7 years) and we calculated the frequency of hospitalizations and the mean number of days spent in hospital. The frequency of children, who underwent a surgical procedure and the average number of interventions were assessed. To ensure an appropriate age at diagnosis, all children were between 2 and 7 years of age at time of retrieval of diagnoses from the National Patient Registry with the average age in the study group being 4.2 years (Table I). Diagnosis codes, recorded between January 1st, 1995 and December 31st, 2002 in the National Patient Registry, were included in the study. International definitions were followed for term birth (delivery 37 completed weeks) and neonatal admission (children with day of entrance to hospital within the first 28 days of life).
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Analysis
Statistical analysis was performed using SPSS for Windows (Statistical Packages for Social Sciences) version 10.0. P<0.05 was considered statistically significant. Differences of means of continuous parametric data were analysed with the use of Student's t-test. Pearson 2-analyses were used to compare distributions between groups. The study group was compared separately with each of the two control groups. We calculated OR (OR) with 95% confidence intervals (CI) for hospitalization and surgical procedure with MantelHaenszel estimate after stratification for year of birth, maternal age (<25, 2530, 3035,
35 years) and parity (0 or
1 previous deliveries). To exclude the monozygotic twins, we performed separate analyses restricted to different sex twin pairs. OR in ICSI children versus conventional IVF children were also calculated with respect to hospital admissions and surgical procedures.
Infant was the unit of analysis, since each child in a twin pair was calculated with a separate record and not as a pair. To evaluate the co-dependency of twin variables, we made two separate analyses comparing IVF/ICSI singletons with only one IVF/ICSI twin of a pair. In each of the two analyses the IVF/ICSI twin of a pair was randomly selected. These analyses were performed for both admissions and operations and further restricted to term birth infants.
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Results |
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We calculated OR of being hospitalized with stratification for year of birth, maternal age and parity (Table III). Since the boy:girl ratio was equal in all three cohorts, we did not stratify for child sex. Similar adjusted OR of admissions in IVF/ICSI versus control twins were observed; however, a 2.5-fold increased risk in IVF/ICSI twins was seen, when compared with IVF/ICSI singletons (adjusted OR 0.42, 95% CI 0.38, 0.46). The ten most frequent discharge diagnoses listed in descending order were prematurity, low birthweight, fever convulsions, observation, pneumonia, asthma, virus, diarrhoea, bronchitis, and respiratory distress syndrome. Since most of these diagnoses are related to preterm birth, we calculated adjusted OR for term infants to eliminate the influence of prematurity (Table III). Even after exclusion of premature infants, IVF/ICSI twins had a 1.4-fold increased risk of hospital admission compared with IVF/ICSI singletons (adjusted OR 0.73, 95% CI 0.66, 0.82).
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ICSI
There was no significant difference in the proportion of twins in the IVF VS the ICSI group; 39.4% of the conventional IVF children and 39.8% of the ICSI children were twins. Data on twins and singletons were therefore pooled to estimate OR of being hospitalized and having a surgical intervention in ICSI versus conventional IVF children. Among IVF children (twins + singletons) 58.5% and among ICSI children 56.7% were admitted to hospital (P=0.2). The analyses demonstrated no increased risk of hospital admissions [OR 0.93 (0.84, 1.03)] and surgical procedures [OR 0.89 (0.75, 1.06)] in ICSI as compared with children born after conventional IVF.
Zygosity
To exclude the MZ twin pairs, analyses were restricted to different sex twins. Of the different sex IVF/ICSI and control twins 71.2 and 69.2% had been admitted to hospital respectively. The risk (adjusted OR) of admittance to hospital in different sex IVF/ICSI twins versus control twins was 0.97 (0.83, 1.13) and the adjusted OR calculated for term infants was 1.01 (0.84, 1.21). Risks were adjusted for year of birth, maternal age and parity.
In the different sex twins, 9.6% of the IVF/ICSI and 10.4% of the control twins underwent a surgical procedure. The adjusted OR of a surgical procedure in IVF/ICSI versus control twins was 1.02 (0.81, 1.28). The corresponding adjusted OR for term infants was 1.18 (0.84, 1.65).
Co-dependency of variables in twins
To evaluate the co-dependency of twin variables, we made two separate analyses comparing IVF/ICSI singletons with only one IVF/ICSI twin of a pair. In each of the two analyses the IVF/ICSI twin of a pair was randomly selected. These analyses were performed for both admissions and operations and further restricted to only term birth infants with adjustment for year of birth, maternal age and parity. Taken together, as expected, this resulted in a slight broadening of the CI, although the overall OR remained similar and the statistically significant results were not altered. For example, adjusted OR of admission in IVF/ICSI singletons versus one randomly selected IVF/ICSI twin of a pair was 0.41 (0.35, 0.48) and the year of birth, age and parity adjusted OR was 0.42 (0.36, 0.48). The remaining results from these analyses are not shown here.
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Discussion |
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The strength of this study is primarily the nationwide design, which makes it the largest study on the use of hospital care resources in IVF/ICSI twins with a relatively high child age of 4.2 years at retrieval of diagnoses. The unique CPR number system and the compulsory IVF registry enabled us to track the complete cohort of IVF/ICSI twins and IVF/ICSI singletons born during a 6 year period in Denmark. Since the Danish IVF Registry was initiated in 1994, only children born after January 1, 1995 were enrolled. To maintain a sufficient follow-up period, data on admissions and surgical interventions were drawn from the National Patient Registry from infant birth until December 31, 2002. Thus, all children in study and control groups were followed with admissions and surgical procedures until they were aged 2 years, with the oldest children aged 7 years and a mean age in the study group of 4.2 years at diagnoses retrieval. The sample size allowed us to adjust for relevant confounders (year of birth, maternal age and parity) and to perform sub-analyses on term birth infants, different sex twins and ICSI infants.
Another strength of this study was the essential linkage of a mother and her children. Further, the mandatory recording of all outpatient, discharge and operative diagnoses in the National Patient Registry enabled us to gain information on the use of all health care resources in a hospital setting. Data on non-hospital services such as help to disabled children were not available for any of the three cohorts. Since the main focus was to compare morbidity in IVF/ICSI twins with IVF/ICSI singletons to shed light on the controversy of dual versus single embryo transfer, we did not include a control group of spontaneously conceived singletons.
The Danish IVF Registry records all IVF cycles performed in Denmark; however, assisted reproduction treatments other than IVF cycles are currently not recorded, but will be implemented in the near future. Therefore a limitation of this study was the lack of data on the proportion of women in the control twin group, who conceived after assisted reproduction treatments other than IVF. Our recently published study with data originating from a questionnaire sent to the subpopulation of women in the three cohorts, who delivered in 1997, revealed that 17.3% of women in the control twin group conceived after other kinds of assisted reproduction treatments (Pinborg et al., 2003). However, a recent study has shown that infants conceived after hormonal induction or intrauterine insemination (IUI) have neonatal outcome similar to that of spontaneously conceived children (Basso and Baird, 2003
). Thus, it should not bias data on neonatal admissions in the present study. However, follow-up data with sufficient sample size on twins conceived by IUI do not exist.
Moreover, the questionnaire study showed no fundamental differences in terms of socio-economic position between women who conceived after IVF and women who conceived spontaneously. This is probably explained by the fact that the first three IVF/ICSI treatments are reimbursed in Denmark combined with a liberal access to this treatment, which is confirmed by Denmark having the highest number of IVF cycles performed per inhabitant in Europe. In addition, 65% of all cycles are performed in public clinics, making IVF/ICSI treatment available for all citizens.
This study confirms previously published observations that the main increased utilization of health care by IVF twins occurs during the first period of life (Leslie et al., 1998; Ericson et al., 2002
). Also in spontaneously conceived pregnancies preterm birth is a major predictor of how much an individual will cost hospital service providers during the first 5 years of life (Petrou et al., 2003
). However, after restriction of analyses to term infants, there was still an apparent increased OR of admission in IVF twins versus singletons, albeit considerably reduced from 2.4 to 1.4. The increased odds of surgical interventions disappeared after exclusion of preterm infants. Our previous studies showed that (56.3, 52.4 and 25.0%) of IVF/ICSI twins, control twins and IVF/ICSI singletons respectively were admitted to NICU (Pinborg et al., 2004a
,b
), whereas frequency of admissions in the present study with follow-up was (69.8, 69.6, 49.8%).
As observations on twins are not fully independent, there is a potential risk of estimating the CI as too narrow. As expected, the analyses performed to evaluate the role of co-dependency of twin data resulted in a slight broadening of the CI, but the overall OR remained similar and the statistically significant results were not altered. This suggests that the co-dependency in twin data was of less importance. Almost one out of ten children in each cohort underwent a surgical procedure. However, it is reassuring that more than half of the total number of surgical procedures was attributable to minor operations, e.g. ear surgery and diagnostic procedures such as endoscopies and lumbar punctures. To acknowledge that the majority of surgical procedures recorded in the National Patient Registry are minor and not our primary concern, specific surgical procedures with a prevalence of >5 in 1000 children have been listed in Appendix I.
In population-based studies on naturally conceived children, twins have a 4-fold higher risk of cerebral palsy than singletons (Scher et al., 2002). Among IVF children, only two nationwide studies with sufficient sample size have been published showing contradictory results. Strömberg et al. (2002)
revealed that IVF twins were more likely to develop cerebral palsy than IVF singletons, whereas in our Danish register study similar risks of neurological sequelae in IVF twins and IVF singletons were observed (Pinborg et al., 2004c
).
It is unclear to what extent outcome measures such as number of hospital admissions and average length of hospital stay serve as valid indicators of infant morbidity. The aim of this study was, however, to assess the use of hospital care resources. Data on morbidity and the prevalence of specific diseases in the same cohorts have previously been published (Pinborg et al., 2003, 2004c
). Though our previous study showed similar prevalence rates of neurological sequelae in the three cohorts, we observed increased use of hospital care resources in IVF/ICSI twins versus IVF/ICSI singletons in terms of admissions and surgical interventions in the present study. In addition, our questionnaire study revealed that IVF/ICSI twin mothers estimated the physical health and speech development of their children as poorer than IVF/ICSI singleton mothers and that IVF twins were more likely to have special needs than IVF singletons (Pinborg et al., 2003
). Taken together these results indicate that even after the neonatal high-risk period mainly related to prematurity, IVF twins at least until 7 years of age in general have an increased use of hospital care resources than IVF singletons, which is in accordance with previous controlled studies (Ericson et al., 2002
; Koivurova et al., 2003
). However, it must be stated that this over-use of hospital care in these Danish IVF/ICSI twins did not cover severe neurological disabilities, which certainly is reassuring (Pinborg et al., 2004c
).
Corresponding with previous studies, we showed no excess morbidity in ICSI children as compared with children conceived after conventional IVF (Sutcliffe et al., 2001). Despite previous studies showing higher morbidity in monozygotic twins (Loos et al., 1998
), we did not demonstrate differences between IVF and control twins, when data were restricted to different sex twins.
In conclusion, by implementing eSET, thereby reducing the IVF twin birth rate, a substantial saving of hospital cost could be achieved, most likely counterbalancing one or two extra embryo transfers to obtain pregnancy (Gerris et al., 2004). The increased use of hospital care resources in terms of admissions to hospital and surgical procedures in IVF/ICSI twins versus IVF/ICSI singletons suggested in this study, is another argument for implementing eSET as our standard clinical procedure.
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Appendix I. Total number of surgical interventions in IVF/ICSI twins, IVF/ICSI singletons and control twins sorted according to organ system |
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Submitted on April 30, 2004; resubmitted on June 21, 2004; accepted on July 23, 2004.