1 Perinatal Data Collection Unit, Department of Human Services, Victoria 3001, 2 Centre for the Study of Mothers' & Children's Health, La Trobe University, Victoria 3053, 3 Prince Henry's Institute of Medical Research, Victoria 3168 and 4 Monash IVF, Victoria 3121, Australia
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Abstract |
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Key words: birth defects/donor insemination/follow-up/pregnancy outcomes
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Introduction |
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Only a few studies have compared the perinatal or obstetric outcomes of DI with a control group. The outcomes of 470 DI pregnancies have been compared with a series of hospital controls matched for parity and maternal age and with national births survey data (Grefenstette et al., 1990). Higher rates of multiple pregnancy, preterm birth and delivery by Caesarean section were found after DI. Data on the outcomes of an increasingly large series of DI pregnancies have been collected prospectively by the French CECOS Federation for >10 years (Mattei and Le Marec, 1983
; Thepot et al., 1996
; Lansac et al., 1997
). In the most recent publication (Lansac et al., 1997
), 21132 DI pregnancies with known outcomes were reported. A sub-sample of 8943 single pregnancies were compared with data from a sample of 13631 births from a French national register. The authors concluded that DI singleton births were no more likely to be low birthweight, preterm or stillborn than births in the general population. The high multiple birth rate of 8.0% reflected the use of ovulation induction in the treatment of 77.4% of those women who became pregnant with DI. The selection criteria for the sub-sample of DI births were not described. It is not clear how representative the French national registry data were of all births in the regions covered or whether adverse pregnancy outcomes, including congenital abnormalities, were ascertained equally in the DI and control populations.
Studies describing the prevalence of birth defects after DI have given variable results (Dixon and Buttram, 1976; Mattei and Le Marec, 1983
; Virro and Shewchuk, 1984
; Forse et al., 1985
; Amuzu et al., 1990
). The problems of small study populations, the lack of appropriate comparison groups and, in some instances, a failure to adjust for maternal age have made interpretation of these findings on relatively rare outcomes particularly difficult. The CECOS group has accrued data on the largest number of DI pregnancies with good follow-up. The prevalence of congenital abnormalities was 1.7% in 18 128 children at birth and 90 pregnancies terminated because of the presence of an abnormality (Lansac et al., 1997
). The authors concluded that the prevalence was no different from that in the general population. The main difficulty in interpreting these findings comes from the comparison with regional birth registries where the quality of data and ascertainment of birth defects for the general population was likely to have been poorer than for the DI births (Thepot et al., 1996
).
Two studies have described a higher than expected incidence of pre-eclampsia in pregnancies conceived by donor insemination. In a large study of 584 Australian DI pregnancies (Need et al., 1983), pre-eclampsia was found to be more common than expected from general population estimates, especially in multiparous women. Differences in the way pre-eclampsia was defined and measured in the DI group compared with the general population made the size of the effect difficult to assess. Pre-eclampsia was significantly more common in a small group of 37 DI patients than in 44 patients who had artificial insemination with partner spermatozoa (Smith et al., 1997
). The findings from these studies were interpreted as consistent with an immunological basis of pre-eclampsia: the idea that repeated exposure to sperm antigens prior to a pregnancy with that partner offers protection against pre-eclampsia.
Our study was prompted by an apparent increase in the incidence of perinatal death in the DI pregnancies conceived at two clinics in Victoria, Australia. Prior to this study, the clinics relied on women to report their pregnancy outcomes or data were collected by clinic staff who contacted women after the expected delivery date. Follow-up was known to be incomplete for women who were hard to trace and adverse perinatal outcomes were not usually verified with medical records. This study aimed to provide a more complete follow-up of DI pregnancies using data from the State's population-based births register and to compare DI outcomes with an appropriate comparison group selected from the same register.
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Materials and methods |
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Five normally conceived controls were randomly selected for each DI birth from the PDCU database and matched on year of birth of the infant. Multiple births were identified and all babies of twin and triplet pregnancies were included in the controls, as they were for the DI births. DI births that appeared in the random selection of controls were identified and excluded. The ratio of one DI to five control births was maintained after these inclusions and exclusions.
Data sources
The Health Act in Victoria mandates that all births must be reported to the PDCU. The PDCU was established in 1982 to collect, analyse and monitor the information contained in these reports. The information collected is maintained in two databases, the first contains data reported by the midwife attending the birth and includes a large number of variables relating to the mother and the obstetric and perinatal outcomes. The second database is the Congenital Malformations Register (CMR), which contains reports of congenital malformations apparent at birth or later in childhood from a voluntary network of laboratories and health professionals and is continually updated. Validation studies have shown that ascertainment of chromosomal anomalies was very high in the period covered by this study: >90% in 19821985 (Lumley et al., 1988) and 100% in 19891992 (Kilkenny et al., 1995
). Ascertainment of other groups of birth defects was less complete but was not expected to differ between the DI and control groups.
Record linkage
Record linkage of DI pregnancies with the PDCU was carried out manually. A successful match was based on a match of three or more of the following data items: surname and first name of the mother, maternal date of birth, infant date of birth, sex of infant and expected date of delivery (with matched gestation). Additional data items could be used to confirm a match when one of these variables was missing, including birthweight, gestation, hospital of birth or residential postcode. For each successful match, data were abstracted from the birth notification data and the CMR. All data were de-identified following record linkage.
Statistical analysis
Power calculations using EpiInfo 6.0 indicated that the sample size available gave the study 80% power (with 0.05 level of significance) to detect the following increases in relative risk (RR): low birthweight RR = 1.4, preterm birth RR = 1.4, total birth defects RR = 1.5, perinatal mortality RR = 2.0, and Caesarean section RR = 1.2.
Analyses were performed using the statistical package SPSS for Windows (version 6.1, 1994, SPSS Inc., Chicago, Illinois). Where univariate analyses showed a difference between DI births and controls, logistic regression was used to derive an adjusted odds ratio (OR) and 95% confidence interval (95% CI) to account for the contribution of relevant independent variables that were probable predictors of the outcome.
Calculations for perinatal outcomes included all infants, while those for obstetric factors and demographic information included records for all singleton births and the first born infant in multiple births.
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Results |
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Perinatal outcomes
There was no significant difference in the sex ratio between DI and control births, nor did the overall prevalence of multiple births differ significantly between the two groups. DI births did not differ from controls in their incidence of preterm birth, low birthweight and perinatal deaths.
The overall prevalence of birth defects did not differ significantly between the DI and control births (Table III). The observation of a higher number of chromosomal abnormalities in the group of DI births, however, prompted further analysis of this sub-group of birth defects. The chromosomal abnormalities identified in each group are listed in Table IV
. For the DI births, all the chromosomal abnormalities were aneuploidies (additional or deleted chromosomes). Two were sex chromosome aneuploidies, not usually detected at birth or in early childhood, that had been detected by prenatal diagnosis. For the controls, 11 were chromosomal aneuploidies and three were other chromosomal abnormalities with no additional genetic material. The odds ratio for the autosomal trisomies, which can be ascertained at birth quite readily, was 2.7 (95% CI 0.98.2), adjusted for maternal age. All other observed differences were not statistically significant.
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Discussion |
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The method of record-linkage with the State's population-based births register gave more complete outcomes data than the clinics had been able to obtain by making contact with patients and care providers directly. However, there were discrepancies between clinic records and PDCU data in the recording of perinatal deaths that showed that the clinic had more complete information. Six perinatal deaths at 2022 weeks gestation were notified to the clinic but did not appear in the PDCU database. Although it is a legal requirement for all births in Victoria of at least 20 weeks gestation or 400 g birthweight to be registered, the inclusion of births into the PDCU database is known to be incomplete for births at 2022 weeks during some of the study period, and we would expect similarly incomplete data for both the control group and the DI group.
Women who conceived as a result of DI were significantly older than women in the control group. This was to be expected, because women tend not to commence treatment until after diagnosis of infertility following unsuccessful attempts to become pregnant. During the 1980s there was also a waiting list for treatment of up to 12 months duration. Women in the DI group were also significantly more likely to be married than the controls, a reflection of the legal requirement in Victoria for couples undergoing DI to be married.
The study showed that DI was not associated with any significant difference in the incidence of preterm birth, low birthweight and perinatal mortality compared with the general population. These findings are reassuring. The sex ratio of DI births did not differ significantly from the controls. Reports (Alfredson, 1984; Amuzu et al., 1990
) that DI is associated with a reduced proportion of male infants were not supported in this study. Multiple pregnancy was more common in the DI group than in the controls, though not significantly so, and reflected the restricted use of ovulation induction only for the treatment of women who had irregular cycles.
There were no significant differences between the DI and control groups in the overall prevalence of birth defects. The study does not, however, include malformation data from pregnancies lost prior to 20 weeks gestation for DI births or controls. Although the overall prevalence of birth defects was no different between the two groups, the higher prevalence of chromosomal aneuploidies in the DI group warrants further investigation and needs confirmation in other large studies. Validation of the CMR has shown that the reporting rate of chromosomal anomalies is very high. Differences in the reporting of birth defects between the DI and control groups is therefore unlikely to account for the increased prevalence of chromosomal aneuploidies in the DI births. This finding has to be interpreted cautiously, however, because of the very small number of affected pregnancies and the possibility that a greater use of prenatal testing in the DI group might explain the finding, since the sex chromosome aneuploidies found in the DI group were detected through prenatal testing. The importance of using the same definitions of birth defects and the same methods of ascertainment when comparing pregnancy outcomes after assisted conception with a control group have been highlighted recently in the controversy about the incidence of abnormalities in children conceived by intracytoplasmic sperm injection (Bonduelle et al., 1997; Kurinczuk and Bower, 1997
).
This study found significant differences between the amount of obstetric intervention in both labour and delivery for DI births. Adjusted odds ratios demonstrated this for Caesarean section, forceps delivery and induced labour. An increase in the proportion of deliveries by Caesarean section has been reported previously (Grefenstette et al., 1990). The reasons for these differences are unclear. A possible explanation is the difference between obstetric practice in the private and public sector but data on health insurance status are not collected by the PDCU. It is also possible that pregnancies conceived following assisted conception are perceived to be more `precious'. This may result in the belief by some women and/or their obstetricians that a lower threshold for intervention is appropriate. We do not know in what percentage of cases did the obstetrician know that the conception was following DI. Several studies (Tan et al., 1992
; Venn and Lumley, 1993
; Reubinoff et al., 1997
) have shown that Caesarean section is significantly more common in pregnancies following a period of infertility or IVF treatment. The increased rate has not been readily explained by maternal characteristics or obstetric complications. Women's views of the method of delivery, and those of their caregivers, have not yet been explored in studies of pregnancy outcomes after assisted conception.
The amount of obstetric intervention may, in part, reflect the increased incidence of pre-eclampsia found in the DI pregnancies. Misclassification of pre-eclampsia and eclampsia reported to the PDCU has been described (Riley and Halliday, 1998) but is likely to have occurred to a similar extent in the DI and control pregnancies.
Pre-eclampsia is a common and serious complication of pregnancy that has been shown to be more common in first than in subsequent pregnancies. Subsequent pregnancies with a change in paternity, however, have a similar risk to first pregnancies. The duration of exposure to sperm antigens has been associated with the risk of pre-eclampsia in some studies (Clark, 1994; Robillard et al., 1994
); repeated exposure having a protective effect. Protection appears to be reduced when barrier methods of contraception are used. This immunological model of the relationship between exposure to sperm antigens and the risk of pre-eclampsia predicts that DI patients would be at an increased risk. Further studies of pre-eclampsia in pregnancies conceived by DI or oocyte donation may contribute to our understanding of the mechanisms underlying this condition.
The results of this study will be reassuring to the many couples considering DI as an option for their infertility, to the clinics offering DI and to those who provide antenatal care to women who have conceived as a result of DI. Thorough follow-up of the outcomes of pregnancies conceived by reproductive technologies is an ongoing responsibility of those offering infertility treatment. To obtain meaningful outcomes data, studies should be mindful of the importance of size of the study population, completeness of follow-up, comparison with appropriate control groups and appropriate statistical analyses to account for differences in maternal characteristics.
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Acknowledgments |
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Notes |
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References |
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Submitted on December 1, 1998; accepted on April 9, 1998.