1 Centre for the Study of Mothers' and Children's Health, La Trobe University, Carlton 3053, 2 Menzies Centre for Population Health Research, University of Tasmania, GPO Box 25223, Hobart 7001, Australia, 3 Stakes (the National Research and Development Centre for Welfare and Health), Helsinki 00531, Finland, 4 Department of Obstetrics and Gynaecology, Monash University, Clayton 3168 and 5 Monash IVF, Richmond 3121, Australia
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Abstract |
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Key words: complications of treatment/death/follow-up/IVF/maternal mortality
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Introduction |
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There have been attempts to establish the frequency of complications of IVF treatment. Bergh and Lundkvist surveyed 12 IVF clinics in Nordic countries (Bergh and Lundkvist, 1992). Based on 10125 treatment cycles commenced, OHSS needing hospital care occurred in 0.7% of cycles. Complications of follicle puncture involving bleeding occurred in 0.5% of cycles with embryo transfer, while post-operative infections requiring antibiotics or surgical management occurred in 0.3% of cycles. Similar findings came from a retrospective analysis of 2495 IVF cycles at a single Dutch clinic (Roest et al., 1996
). Hospital admission was required in 0.7% of cycles due to severe OHSS; adnexal torsion occurred in two patients, and both required ovariectomy; and post-operative infection requiring hospital admission occurred in 0.3% of cycles. Neither of these studies reported fatal complications of IVF treatment.
IVF pregnancies are at higher risk of serious complications because of the relatively high incidence of ectopic pregnancies, multiple pregnancies and advanced maternal age compared with normally conceived pregnancies in the general population. Unlike reports of IVF treatment complications, which have relied on voluntary reporting of adverse events in relatively small series of patients, data on IVF pregnancy complications have been collected systematically at a national level in Australia and elsewhere (de Mouzon and Lancaster, 1997). In the period 197997, there were 22 308 clinical IVF pregnancies in Australia and New Zealand, of which 4.0% were ectopic (Hurst et al., 1999
), 28.2% occurred in women aged 3539 and 6.2% in women aged
40 years. In the same time period, 19.5% of IVF pregnancies of at least 20 weeks gestation were multiple pregnancies; of these 10.6% were higher order multiples. By comparison, general population data from 1997 show 12.9% of confinements in women aged 3539, and 2.1% in women aged
40 years. Multiple pregnancies made up 1.5% of all Australian confinements, of which 3.0% were higher order multiples (Day et al., 1999
). Case reports of maternal deaths following IVF conception have appeared in the literature (Bewley and Wright, 1995
; Sucov et al., 1995
).
Although there have been estimates of the incidence of serious physical and mental complications of IVF treatment and pregnancy, there have been no systematic studies of the mortality rate in these patients. It is widely recognized that many patients experience psychological distress in the course of their infertility treatment, but it is not known whether they are at increased risk of suicide. Suicide rates provide a proxy measure for the most severe end of the spectrum of distress and have been used previously to examine associations with reproductive outcomes (Gissler et al., 1996).
We recently established a cohort of 29700 women who were referred for IVF treatment to at least one of 10 IVF clinics participating in our multicentre study. The cohort included women who received IVF treatment and others who were referred but not treated. The incidence of breast and gynaecological cancers in this cohort has been reported previously (Venn et al., 1999). Here, we present the results of record-linkage of patient names with the National Death Index (NDI), which allowed us to determine the mortality rate in this large and well-defined group of patients. Our aims were to compare the mortality rates of treated and untreated IVF patients with the mortality rate in the general female population, to determine the number of maternal deaths following IVF conception and to establish whether any deaths had occurred that could be related to complications of IVF procedures.
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Materials and methods |
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Ascertainment of deaths
Ascertainment of deaths from all causes was by record-linkage with the NDI for women residing in all Australian States and Territories except South Australia (n = 24 945). The NDI contains records on deaths that have occurred in Australia since 1980. Because of different privacy restrictions in South Australia, we were not able to link with the NDI for residents of this State (n = 4755). However, we were able to ascertain deaths from neoplasms in these patients by record-linkage with the State Cancer Registry. Record-linkage with the NDI and Cancer Registry was on name, date of birth, and State of residence. Cause of death was recorded by International Classification of Diseases codes, ninth revision (ICD-9) (World Health Organization, 1977).
When a death occurred within two years of an IVF treatment cycle, clinic records were checked to (i) verify the date of the last treatment cycle, (ii) find out whether the patient had conceived with treatment, and (iii) if the patient had conceived, to determine whether the death was classifiable as a maternal death. Maternal deaths were defined according to criteria used in previous reports on maternal deaths in Australia (NHMRC Maternal Mortality Working Party, 1998); that is, the death of a woman during pregnancy, childbirth or in the 42 days of the puerperium, irrespective of the duration and site of the pregnancy. This includes deaths from any cause related to or aggravated by the pregnancy or its management and deaths from incidental causes. This definition accords with World Health Organization (WHO) criteria used in the time period covered by this study, except in the inclusion of incidental deaths (World Health Organization, 1977
). Deaths occurring >42 days but <12 months after the end of an IVF pregnancy were termed late maternal deaths.
Where a death occurred within 12 months of IVF treatment in a woman who had not conceived with treatment, and of causes that could be related to IVF treatment, further information was sought from the death certificate and from the IVF clinic records to investigate whether there appeared to be a causal relationship. Deaths occurring >12 months after IVF treatment were not investigated further.
Statistical methods
Standardized mortality ratios (SMR) were calculated from the ratio of observed to expected number of deaths. The time-age-specific rates for the Australian population for all-cause mortality, all neoplasms, breast cancer, diseases of the circulatory system, injury and poisoning and suicide were used with age in 5 year periods and time in four calendar periods (19751985198619901991199519961997) to calculate the expected numbers of deaths. Population rates were provided by the NDI.
The person-years of follow-up for untreated women were defined as those between registration in an IVF programme and death or end of follow-up (31.12.1997), whichever was first. The untreated group also included the person-years at risk accumulated by women who spent time on an IVF programme waiting list before commencing treatment. Person-years of follow-up in the treated group were calculated from the date of first cycle of treatment to death or end of follow-up.
The person-years were calculated using the DATAB module of the EPICURE software package (Version 1.8w). This apportioned the appropriate person-years into those treated with IVF and those not, and calculated the observed and expected numbers of deaths using the cohort data and the mortality rate data. Since data on deaths from causes other than neoplasms were not available from South Australia, numbers and person-years of follow-up are less for these causes. SMRs and 95% confidence intervals (CI) were then calculated using standard formulae (Clayton and Hills, 1993).
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Results |
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Mortality compared with the general population
The observed and expected numbers of deaths in the IVF treated and untreated groups are given in Table III. Overall, mortality from all causes was significantly lower in IVF patients than in the general female population of the same age (72 deaths observed, 125 expected in the treated group; 51 deaths observed, 82 expected in the untreated group). The lower mortality rate in IVF patients, irrespective of treatment status, was apparent in the selected major cause of death groups and for suicide. There was little difference between the mortality rates in the treated and untreated groups for all-cause mortality, diseases of the circulatory system and injury and poisoning: the confidence intervals for the SMR estimates of the treated group overlapped the SMR point estimates in the untreated group. In the treated group, the number of breast cancer deaths was similar to the number expected from general population rates.
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Discussion |
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The most likely explanation for this finding of a low mortality rate, which could reflect a `healthy patient effect', is in the selection factors that make IVF patients differ from the general population. The concept of a `healthy patient effect' comes from the healthy worker effect, initially observed in epidemiological studies of occupational diseases, which describes the phenomenon whereby workers exhibit lower death rates than the general population because of the tendency for the severely ill and disabled to be excluded from employment. We suggest that a healthy patient effect may arise in IVF programmes if the unhealthiest women in the community are deterred from planning a pregnancy or accessing IVF services. The suggestion that women who are planning a pregnancy may be healthier than other women is supported by findings of low mortality rates in pregnant and recently pregnant women compared with the general female population of the same age (Gissler et al., 1997; NHMRC Maternal Mortality Working Party, 1998
; Ronsmans et al., 2001
).
Studies of health differentials in the general population of women aged 2564 years (Mathers, 1994) have shown that married women have lower mortality rates than single women; women in higher income families and those with higher education levels report better health; and socioeconomic advantage of area of residence is associated with lower mortality and better health. A relevant exception is the positive association between socioeconomic advantage of area of residence and mortality from breast cancer (Williams et al., 1991
). These factors may have contributed to the low mortality rate in this IVF cohort, since the majority of women in this study were married (a legislative requirement for access to IVF in the State where most patients resided) and most IVF patients have private health insurance, which suggests higher socioeconomic status in Australia.
A further possible explanation for the finding of a low mortality rate in IVF patients is that we failed to identify some deaths, either because they were not recorded in the NDI, or because women appeared in the NDI under a different name. We would have had to miss 60 deaths, giving a record-linkage sensitivity of 67%, for the SMR for all-cause mortality to be not significantly <1.0. Linkage with the NDI was found to have 95% sensitivity in a recent large cohort study of Australian women (Powers et al., 2000). Our analyses of deaths occurring within 12 months of an IVF pregnancy or treatment cycle are unlikely to have been affected by ascertainment problems due to women changing their names.
The two maternal deaths that occurred within 42 days of delivery in our study sample had been identified in routine reports of national IVF statistics (Hurst et al., 1999). These reports relied on passive reporting of maternal deaths and it was reassuring, therefore, to see that record-linkage with the NDI did not identify any previously unreported deaths in this category. We were unable to calculate the maternal mortality rate as a proportion of all IVF confinements because we did not have complete data on pregnancies and confinements that had occurred in the whole cohort. However, from national data based on passive reporting up to 1997, there have been six maternal deaths in Australian IVF patients among 23 321 IVF and gamete intra-Fallopian (GIFT) confinements (Hurst et al., 1999
), giving a maternal mortality rate of 25.7 per 100000 confinements. The overall maternal mortality rate in the Australian female population in the triennium 199193 was 10.9 per 100 000 confinements (NHMRC Maternal Mortality Working Party, 1998
), which included direct, indirect and incidental deaths within 42 days of the puerperium. Advanced maternal age, a high proportion of multiple births and a high Caesarean section rate would be expected to contribute to an increased risk of maternal mortality rate in IVF pregnancies.
Among 17112 women in this study who had 59681 IVF treatment cycles, there appeared to be no deaths due to complications of OHSS. The finding provides some reassurance that appropriate clinical management of severe OHSS prevented patient deaths. IVF treatment may have contributed to the death caused by pulmonary embolism in a young woman 32 days after embryo transfer, though this could not be confirmed from available records. Venous thromboembolism and pulmonary embolus are the leading non-surgical causes of post-operative death (Laros, 1994). The reported incidence, 0.010.29% before and during pregnancy and 0.11.0% postpartum, varies widely and accurate diagnosis remains difficult. Pelvic surgery, even transvaginal oocyte retrieval, venous stasis and leg elevation are all known risk factors for deep venous thrombophlebitis and pulmonary embolism.
In conclusion, we found that IVF patients in this follow-up study had a low mortality rate compared with that in the general female population of the same age. The maternal mortality rate in IVF pregnancies appears to be higher than in the general population, probably due to increased maternal risk factors and the higher incidence of multiple births. Complications of OHSS were not directly related to any of the deaths observed. Treatment may have played a role in one death due to pulmonary embolism 32 days after embryo transfer. As well as providing some reassurance about the safety of IVF treatment, these findings indicate that selection processes are occurring whereby the unhealthiest women in the population are deterred from pregnancy and infertility treatment.
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Acknowledgements |
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Notes |
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References |
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Submitted on February 2, 2001; accepted on August 31, 2001.