STAKES, National Research and Development Centre for Welfare and Health, Helsinki, Finland
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Abstract |
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Key words: epidemiology/IVF/Medical Birth Register/perinatal health/temporal trends
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Introduction |
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However, it is not clear whether these outcomes have improved over time. According to annual IVF statistics for New Zealand and Australia, the birthweight of IVF infants increased and proportions of preterm births declined from 1992 to 1997 (Lancaster et al., 1995; Hurst et al., 1999
). The main reason for perinatal health problems of IVF children is multiplicity. In Sweden the multiple birth rate in IVF pregnancies declined from 34% in 1991 to 24% in 1995 (Bergh et al., 1999
). In New Zealand and Australia the rates have been lower, but increased from 18% in 1992 to 21% in 1999 (Lancaster et al., 1995
; Hurst and Lancaster, 2001
).
In Finland, the perinatal outcomes of IVF were studied for the 19911993 period (hereafter called the first time-period). The results showed that IVF mothers used more health care services than did other mothers and that the outcomes of their infants were poorer on all indicators (Gissler et al., 1995). The purpose of this study was to repeat the same analysis for the 19981999 time-period (the second time-period) to study whether the perinatal health outcomes of IVF have improved in Finland, and, if so, what role has been played by antenatal and hospital care. Although data for such a comparison exist in the annual statistics of many countries, this study is the first register-based, specifically comparative study of perinatal outcomes of IVF in which the data have been adjusted for mothers' background characteristics.
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Materials and methods |
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The source of data for both time-periods was the Finnish Medical Birth Register (MBR). The MBR was started in 1987 and is run by the National Research and Development Centre for Welfare and Health. The register includes information on IVF, the mother's background, care during pregnancy and delivery, and the infant's health up to the age of 7 days. A question on assisted pregnancy was introduced in 1990 (in a question concerning risks associated with pregnancy: `Was the pregnancy an in-vitro fertilization pregnancy?'). In 1996, the MBR data collection form was changed, and the question on assisted pregnancy was divided into two questions, one on `in-vitro fertilization' and the other on `other assisted reproduction' (ovulation inductions and inseminations). This reformulation has not worked as intended, and it has been estimated that only 9% of the named `other assisted reproduction' is such and 91% actually refer to IVF (E.Hemminki, R.Klemetti, M.Rinta-Paavola and J.Martikainen, unpublished data). Thus, for the second time-period, IVF and other assisted reproduction were combined and called IVF. A sensitivity analysis with one perinatal health outcome (low birthweight) was done to estimate the effect of the differences in data collection in the two time-periods.
The use of health care services during pregnancy and after delivery and perinatal outcomes in the two time-periods was analysed using the same methods as the earlier study (Gissler et al., 1995). IVF pregnancies were compared with the pregnancies not reported to be assisted by IVF. Singleton and multiple births were analysed separately. First, the mothers' use of health care services (timing of the first visit and total number of visits in antenatal care; relative index; mother's hospitalization during pregnancy, 2 days before delivery and 7 days after delivery; rate of Caesarean sections; use of oxytocin and epidural analgesia during labour) and the infant outcomes [mean birthweight; low birthweight (i.e. <2500 g); prematurity (i.e. gestation length <37 weeks); 1 min Apgar score; treatment in special care; infant in hospital 7 days after birth; perinatal mortality] for IVF children born in the two time-periods were compared. The relative index refers to the intensity of the use of antenatal care; the actual number of visits was divided by the gestation-adjusted recommendation given by the Ministry of Health and Social Affairs (Hemminki and Gissler, 1993
). A score of 1.0 indicates the norm. Second, the use of services and outcomes of IVF children were compared with those of other children in the two time-periods to detect for general trends in perinatal outcomes over time. Third, three obstetric intervention variables (mother's hospitalization during pregnancy, hospitalization 7 days after delivery and Caesarean section) and five outcome variables (low birthweight, prematurity, 1 min Apgar score, infant in hospital 7 days after birth and perinatal mortality) were analysed by adjusting for mothers' background variables (nominal variables of county, marital status and smoking and continuous variables of age, previous pregnancies and previous deliveries) by logistic regression, separately for singletons and multiples and for the two time-periods, to exclude the effect of changes in maternal characteristics. Background variables were the same as in the original 19911993 study (Gissler et al., 1995
) and chosen for their impact on perinatal health outcomes and availability in the MBR. Social class was not available in the first time-period and could not be used. Fourth, the total outcomes of IVF children and the use of health care services in the first time-period were compared with those in the second time-period to obtain an estimation of the total outcomes of IVF treatments. Fifth, the main outcomes including and excluding triplets and quadruplets were compared with clarify the impact of higher order multiplicity in two time-periods. To specify how much of the improved outcomes of the multiples is explained by the higher order multiples, the following percentage was calculated for five perinatal outcomes. The proportion of IVF multiples in the second time-period was subtracted from the proportion of IVF multiples in the first time-period (`change in multiples'). The same was done for IVF twins (`change in twins'). The difference between `change in multiples' and `change in twins' was calculated as a percentage of change in multiples.
The statistical significance of differences between the two time-periods was investigated using tests for relative proportions and t-tests. Confidence intervals were calculated for adjusted odds ratios.
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Results |
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The age distribution of IVF mothers was the same in both time-periods (Table I), but other mothers were significantly older in the second time-period than in the first time-period. In the second time-period, IVF mothers were more often single and less frequently primipara and smokers than in the first period. In both time-periods, the obstetric history of IVF mothers differed from that of the other mothers. IVF mothers had fewer births and induced abortions than other mothers.
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The Caesarean section rate of IVF mothers with multiple pregnancies declined and that of IVF mothers with single pregnancies remained the same (Table II). The use of epidural analgesia during labour increased among IVF mothers both with single and multiple pregnancies. The use of oxytocin increased also, but the increase was statistically significant only for multiple IVF pregnancies.
The mean birthweight increased and perinatal mortality decreased among IVF singletons (Table III). There was also some decrease in preterm birth but this change was not statistically significant. Likewise, the outcomes of IVF multiples improved over time. Thus, in the second time-period some outcome variables for IVF multiples (weight <1500 g, low Apgar scores and need for special care) no longer differed from those for other multiples. The difference between the perinatal mortality rates was also statistically insignificant.
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After adjustment for the mothers' background characteristics, all health indicators in the two time-periods improved, with the exceptions of hospitalization up to seven days and the Caesarean section rate for single pregnancies (Table IV). A trend suggested that outcomes, especially that of multiples, had improved, but the 95% confidence intervals did not overlap only for preterm birth and birthweight of multiples.
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When restricting the comparison of plural births to twins (excluding higher order births), the outcomes of IVF twins improved over time, with the exception of low Apgar scores, somewhat more than that of other twins (Table V). As a result, the IVF twins were more like the other twins in the second than in the first time-period. Including triplets and quadruplets, the improvement in multiple IVF births from the first to the second time-period was much larger than for twins only. The reduced number of higher order births in the second time-period explained much of the improved outcomes of IVF multiples: 77% low birthweight infants, 46% of preterm births, 41% of low Apgar scores and 33% of newborns in hospital
7 days. However, it did not explain reduced perinatal mortality.
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Discussion |
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Another potential source of bias is the changed question formulation in the MBR data collection form. In the 19911993 period, only information on IVF pregnancies was requested. Even though the purpose of the 1996 modification was to obtain data on assisted reproduction besides IVF (as defined in this paper), it has turned out that most of the former is actually IVF (see Materials and methods). But an estimated 9% of IVF pregnancies in the second time-period were ovulation inductions (with or without insemination) rather than IVF. The small number of non-IVF pregnancies is unlikely to explain the improved perinatal outcomes of IVF infants.
Unlike among IVF multiples, the mean birthweight among other multiples did not increase and the proportion of low birthweight (<2500 g) infants did not decrease from the first to the second time-period. What could explain this? One explanation is the change in mothers' age: the proportion of older mothers decreased among IVF births and increased among other multiple births. Another reason could be ovulation induction pregnancies included among other pregnancies. Ovulation induction pregnancies are not monitored in Finland, but according to unpublished Finnish data the total multiple birth rate among these pregnancies was 6.4% and the twin birth rate was 5.9% (i.e. 11% of all other twins were ovulation induction twins) in 19961999 (R.Klemetti, M.Gissler and E.Hemminki, unpublished data). The inclusion of these ovulation induction twins among other twins could have worsened the perinatal outcomes, because outcomes for ovulation induction multiples (Addor et al., 1998; our unpublished data) are somewhat worse than those for other multiples. However, our unpublished data do not suggest that ovulation induction pregnancies had increased during the study period; the number of children resulting from ovulation induction pregnancies declined from 1997 to 1999.
The multiple birth rate in IVF pregnancies, especially the number of higher order pregnancies, decreased from the first to the second time-period. Our results suggest that the main reason for the improved outcomes, among multiples, was the smaller number of higher order pregnancies in the second compared with the first time-period.
Another explanation for improved outcomes may be the characteristics of IVF mothers. Because the number of treated women has increased, it is likely that a greater number of `easy cases' have been treated. With some of the new technology, such as ICSI, IVF treatment is given to women who do not have obstetric problems. So, in the second time-period, a larger number of healthy women might have undergone IVF than in the first time-period. We adjusted for some mothers' characteristics, but only very crude measures were available in the register, none of which measured health directly.
The third reason for the improved outcomes may be that with longer use of IVF technology the skill and experience of those performing IVF and selecting the women have improved. The fourth reason may be improved or more intensive maternity care for IVF mothers. In the study period, IVF mothers increased the number of their antenatal visits. The increase was larger among IVF mothers with multiple pregnancy and the outcomes of multiples improved most. IVF mothers made many more visits than recommended. IVF mothers themselves may have become more motivated to seek care during pregnancy, or the health care workers may recommend additional visits for IVF mothers, especially to specialist care in hospital.
Even with the improvements over time, in the 19981999 period IVF children still had worse outcomes than did the other children. But the finding that the outcomes of IVF may have improved during the 1990s is important for both the couples planning to use IVF and for all IVF specialists. Because the main reason for improvement apparently was a reduced number of higher order multiple pregnancies, our results should further motivate a limit on the number of transferred embryos. To confirm our finding, a study that includes all IVF births and also treatments not ending in birth is needed. Because such a study requires a large number of cases and the possibility to adjust for mothers' background characteristics, we encourage those who have the opportunity to study the development of the outcomes of IVF treatments over time to do so.
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Acknowledgements |
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Notes |
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References |
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Submitted on November 29, 2001; accepted on March 25, 2002.