Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort.

BACKGROUND: Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS: We identified a nationwide historic cohort of 19,146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997-1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS: After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16-2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62-6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25-14.33 and 2.14; 95% CI = 1.07-4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS: Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

[Ten years of results of in-vitro fertilisation in the Netherlands 1996-2005]. / Tien jaar resultaten van in-vitrofertilisatie in Nederland, 1996-2005.

OBJECTIVE: To present the numbers and results of Dutch IVF treatment from 1996-2005 and to describe trends and differences between centres. DESIGN: Retrospective data-collection, description and analysis. METHOD: The annual statistics from all Dutch IVF centres covering the years 1996-2005 were collected, described and analysed. RESULTS: During this period 138,217 IVF or intracytoplasmic sperm injection (ICSI) cycles were started and 14,881 transfers of frozen-thawed embryos (cryo transfers) were performed. The number of ICSI treatments, in particular, increased to more than 6000 cycles during this period. These treatments resulted in 30,488 ongoing pregnancies (22.1% per cycle started; 19.1% for IVF and 23.4% for ICSI). The ongoing pregnancy rate per cycle increased from 17.6% in 1996 to 24.4% in 2005. The increase after cryo transfers was remarkable (from 9.4% to 17.6%). It is estimated that during this period, about 1 in 52 newborns in the Netherlands was an IVF or ICSI child (1996: 1 in 77, 2005: 1 in 43). There were differences between the individual centres regarding the ongoing pregnancy rate per cycle (range: 15.0-26.4%), the percentage of ICSI (range 20-58%), the percentage of cryo transfers per cycle (range: 4-22%) and the multiple pregnancy rate (range 5-27% in 2005). CONCLUSIONS: In the Netherlands the pregnancy rate has increased over the last 10 years as has the number of IVF treatments. Cryo transfers have become increasingly important and the multiple pregnancy rate has decreased. Although thanks to the collaboration of all centres, the current registry produces important data and works well, there are a number of limitations e.g. the retrospective nature with no validation, which must be tackled over the coming years.

[Methods and results of in-vitro fertilisation in the Netherlands in the years 1983-1994]. / Methoden en resultaten van in-vitrofertilisatie in Nederland in de jaren 1983-1994.

OBJECTIVE: To describe methods and results of in-vitro fertilisation (IVF) treatment during the first 12 years after the introduction of IVF treatment in the Netherlands. Design. Retrospective cohort study. METHOD: A nationwide study was conducted among women who had had their first IVF cycle stimulated with gonadotrophins in 12 IVF centres in the Netherlands in the period 1 January 1983 to 31 December 1994 (n = 8, 184). RESULTS: The subfertility diagnosis related to tubal factors decreased from 70% in 1987 to 25% in 1994. The subfertility diagnosis related to a male factor increased from 8.7% in 1987 to 35.5% in 1994. The mean age at first IVF treatment remained roughly constant. During the introduction of GnRH agonists there was an increase in gonadotrophin dosages, the number of retrieved oocytes, the number of high responders and/or women who experienced an ovarian hyperstimulation syndrome (OHSS). The percentage of deliveries with at least one baby born alive after the first IVF cycle increased from 6% in 1984 to 18% in 1994. The number of live births per 100 transferred embryos increased from 2.5 in 1985 to 12 in 1994. Furthermore, the mean numbers of embryos transferred after the first IVF cycle decreased from 3.2 in 1987 to 2.2 in 1994. The overall success rate - defined as the proportion of women who had at least one child born alive after one or more IVF cycles - for women who had their first IVF treatment between 1983 and 1994 was 37.1%. The percentage of triplets or quadruplets decreased from 8.7 in 1989 to 1.2 in 1994. The percentage of twin deliveries remained about 25. CONCLUSION: The introduction of GnRH agonists and the higher dosages of gonadotrophins led to a higher oocyte harvest. During the first years of IVF treatment there was an increase in the success rate after the first treatment cycle. The overall success rate remained constant after 1991. The risk of developing an OHSS increased whereas the rate of twin deliveries remained constant.

[Results of in vitro fertilization in the Netherlands, 1996-2000]. / Resultaten van in-vitrofertilisatie in Nederland, 1996-2000.

OBJECTIVE: To describe the annual results in all 13 Dutch in vitro fertilisation (IVF) centres in the period 1996-2000, and to look for possible differences between individual centres and years. DESIGN: Retrospective data collection, description and analysis. METHOD: The results collected on the website of the Dutch Society of Obstetrics and Gynaecology (Dutch acronym: NVOG; www.nvog.nl) in the period 1996-2000 were integrated and described, with special attention to possible differences between centres and years. RESULTS: In 1996-2000 (5 years), 63,414 IVF or ICSI treatment cycles were started in the Netherlands, and 5,884 transfers of cryopreserved embryos were performed. The number of treatment cycles increased over the years, particularly the number of ICSI cycles. The total number of ongoing pregnancies was 12,991 (20.5% per started cycle; 22.5% for ICSI and 18.3% for IVF). Particularly during the first 3 years, there was an increase in these percentages (IVF: from 16.4% (1996) to 19.2% (1998); ICSI: from 18.3% (1996) to 23.9% (1998)). There were differences between the centres in both the percentage of ongoing pregnancies per started IVF/ICSI cycle (range 13.7-25.1%) and the percentage ICSI (14-61%) and cryo-transfers per total number of treatment cycles (0-26%). It was estimated that, during this 5-year period, 1 out of every 61 Dutch neonates resulted from IVF or ICSI. CONCLUSION: The pregnancy-rates after IVF and ICSI increased during the study period, and were comparable with the rates in other European countries. Some important data are still missing from the inventory, for example regarding the number of embryos per transfer, multiple pregnancies, live births, congenital malformations and complications.

Effects of subfertility cause, smoking and body weight on the success rate of IVF.

BACKGROUND: We investigated the separate and combined effects of smoking and body mass index (BMI) on the success rate of IVF for couples with different causes of subfertility. METHODS: The success rate of IVF was examined in 8457 women. Detailed information on reproduction and lifestyle factors was combined with medical record data on IVF treatment. All IVF clinics in The Netherlands participated in this study. The main outcome measures were live birth rate per first cycle of IVF differentiated for the major predictive factors. RESULTS: For male subfertility the delivery rate per cycle was significantly lower than unexplained subfertility, OR of 0.70 (95% CI 0.57-0.86); for tubal pathology, the delivery rate was slightly lower, OR = 0.86 (95% CI 0.70-1.01). Smoking was associated with a significantly lower delivery rate was slightly lower; for OR = 0.72 (95% CI 0.61-0.84) and a significantly higher abortion rate compared to non-smoking delivery rates of 21.4% and 16.4%, respectively (P=0.02). Women with a BMI of > or = 27 kg/m2 had a significantly lower delivery rate, with an OR of 0.67 (95% CI 0.48-0.94), compared with normal weight women (BMI > or = 20 and <27 kg/m2). CONCLUSIONS: Both smoking and overweight unfavourably affect the live birth rate after IVF. The devastating impact of smoking on the live birth rate in IVF treatment is comparable with an increase in female age of >10 years from age 20 to 30 years. Subfertile couples may improve the outcome of IVF treatment by lifestyle changes.

Prion transmission in blood and urine: what are the implications for recombinant and urinary-derived gonadotrophins?

Evidence is emerging that suggests that the protease-resistant isoform (PrP(sc)) of the normal cellular prion protein (PrP(c)) can be detected in the blood and urine of animals and humans with transmissible spongiform encephalopathies (TSEs). The production of the human menopausal and recombinant gonadotrophin preparations for use in ovarian stimulation protocols in fertility treatment is one area where the pharmaceutical industry needs to be vigilant and take appropriate steps to ensure that the safety of such drugs remains as high as ever. The recombinant preparations utilize fetal calf serum or other animal sera or proteins as part of a culture medium during production. Human urinary-derived menotrophin preparations are exposed to the theoretical risk of infection from menopausal donors of urine. Nevertheless, the failure to demonstrate irrefutably infectivity following intracerebral inoculation with urine from TSE-infected hosts suggests that the risk associated with products derived from urine is merely theoretical. Despite the paucity of evidence to date and its relevance to the infectious spread of TSEs, it is important that robust measures are implemented to either remove or inactivate PrP(sc) in order to minimize contamination. Validation of each production process is required to assess the likelihood of contamination.