Abstract
Is there a reduced live-birth rate (LBR) after IVF/ICSI treatment in women with a previous unilateral oophorectomy (UO)?
A significantly reduced LBR after IVF/ICSI was found in women with previous UO when compared with women with intact ovaries in this large multicentre cohort, both crudely and after adjustment for age, BMI, fertility centre and calendar period and regardless of whether the analysis was based on transfer of embryos in the fresh cycle only or on cumulative results including transfers using frozen-thawed embryos.
Similar pregnancy rates after IVF/ICSI have been previously reported in case-control studies and small cohort studies of women with previous UO versus women without ovarian surgery. In all previous studies multiple embryos were transferred. No study has previously evaluated LBR in a large cohort of women with a history of UO.
This research was a multicentre cohort study, including five reproductive medicine centres in Sweden: Carl von Linné Clinic (A), Karolinska University Hospital (B), Uppsala University Hospital (C), Linköping University Hospital (D) and Örebro University Hospital (E). The women underwent IVF/ICSI between January 1999 and November 2015. Single embryo transfer (SET) was performed in approximately 70% of all treatments, without any significant difference between UO exposed women versus controls (68% versus 71%), respectively (P = 0.32), and a maximum of two embryos were transferred in the remaining cases. The dataset included all consecutive treatments and fresh and frozen-thawed cycles.
The exposed cohort included 154 women with UO who underwent 301 IVF/ICSI cycles and the unexposed control cohort consisted of 22 693 women who underwent 41 545 IVF/ICSI cycles. Overall, at the five centres (A–E), the exposed cohort underwent 151, 34, 35, 41 and 40 treatments, respectively, and they were compared with controls of the same centre (18 484, 8371, 5575, 4670 and 4445, respectively).
The primary outcome was LBR, which was analysed per started cycle, per ovum pick-up (OPU) and per embryo transfer (ET). Secondary outcomes included the numbers of oocytes retrieved and supernumerary embryos obtained, the Ovarian Sensitivity Index (OSI), embryo quality scores and cumulative pregnancy rates. We used a Generalized Estimating Equation (GEE) model for statistical analysis in order to account for repeated treatments.
The exposed (UO) and control women's groups were comparable with regard to age and performance of IVF or ICSI. Significant differences in LBR, both crude and age-adjusted, were observed between the UO and control groups: LBR per started cycle (18.6% versus 25.4%, P = 0.007 and P = 0.014, respectively), LBR/OPU (20.3% versus 27.1%, P = 0.012 and P = 0.015, respectively) and LBR/ET (23.0% versus 29.7%, P = 0.022 and P = 0.025, respectively). The differences in LBR remained significant after inclusion of both fresh and frozen-thawed transfers (both crude and age-adjusted data): LBR/OPU (26.1% versus 34.4%, P = 0.005 and P = 0.006, respectively) and LBR/ET (28.3% versus 37.1%, P = 0.006 and P = 0.006, respectively). The crude cancellation rate was significantly higher among women with a history of UO than in controls (18.9% versus 14.5%, P = 0.034 and age-adjusted, P = 0.178). In a multivariate GEE model, the cumulative odds ratios for LBR (fresh and frozen-thawed)/OPU (OR 0.70, 95% CI 0.52–0.94, P = 0.016) and LBR (fresh and frozen-thawed)/ET (OR 0.68, 95% CI 0.51–0.92, P = 0.012) were approximately 30% lower in the group of women with UO when adjusted for age, BMI, reproductive centre, calendar period and number of embryos transferred when appropriate. The OSI was significantly lower in women with a history of UO than in controls (3.6 versus 6.0) and the difference was significant for both crude and age-adjusted data (P = <0.001 for both). Significantly fewer oocytes were retrieved in treatments of women with UO than in controls (7.2 versus 9.9, P = <0.001, respectively).
Due to the nature of the topic, this is a retrospective analysis, with all its inherent limitations. Furthermore, the cause for UO was not possible to obtain in all cases. A diagnosis of endometriosis was also more common in the UO group, i.e. a selection bias in terms of poorer patient characteristics in the UO group cannot be completely ruled out. However, adjustment for all known confounders did not affect the general results.
To date, this is the largest cohort investigated and the first study indicating an association of achieving reduced live birth after IVF/ICSI in women with previous UO. These findings are novel and contradict the earlier notion that IVF/ICSI treatment is not affected, or is only marginally affected by previous UO.
None.
Not applicable.
Introduction
Current guidelines recommend a conservative attitude with regard to ovarian surgery in young women and girls (ACOG, 2007; RCOG, 2011; Brun et al., 2014). Sweden has witnessed a reduction in the number of unilateral oophorectomies (UOs) performed in women of reproductive age in recent decades, and the current annual incidence is approximately 41 per 100 000 women, in contrast to 57/100 000 in 1998 (National Board of Health and Welfare, 2016).
The ovarian reserve represents the reproductive potential and is defined as ‘a function of the number and quality of remaining oocytes’ (Practice Committee of Society for Assisted Reproductive and Practice Committee of American Society for Reproductive, 2012). The ovarian reserve should theoretically be reduced by half after a UO. However, there are no published data available supporting the assertion that a woman's fertility could be reduced by half as a result of UO. Nevertheless, women may vary in their ovarian reserve, and the effect of removing half of it may be more critical in women of advanced reproductive age or in those with a low ovarian reserve before surgery. In these women, UO may cause irreversible infertility (Lass, 1999). The results of previous cohort studies indicate that women who undergo UO may experience an earlier onset of menopause (about 1 year earlier) (Yasui et al., 2012; Bjelland et al., 2014).
Several studies on fertility in women with UO have found pregnancy rates similar to those in controls (Lass et al., 1997; Al-Hasani et al., 2003; Levi et al., 2003; Hendricks et al., 2010). In a recent study including 51 women with UO and 1:2 age-matched controls, a significantly lower pregnancy rate was found in women with UO, but there were no differences in the live-birth rate (LBR) after IVF/ICSI treatment (Khan et al., 2014). The authors discussed the possibility of increased compensatory follicular recruitment in the remaining ovaries of women with a history of UO (Khan et al., 2014).
In line with the findings of Khan et al., we previously reported approximately 30% lower pregnancy rates in young women with UO when compared to women without previous ovarian surgery (Lind. et al., 2015). In most studies, women with UO have had fewer oocytes retrieved at ovum pick-up, and they have required higher doses of gonadotrophins for ovarian stimulation compared with controls (Boutteville et al., 1987; Lam et al., 1987; Khalifa et al., 1992; Lass et al., 1997; Al-Hasani et al., 2003; Levi et al., 2003; Hendricks et al., 2010; Khan et al., 2014). In all previous reports, only fresh cycles have been investigated, and in most studies, multiple embryos (up to three) have been transferred. Up-to-date no study has reported on LBR in women with a history of UO.
Our study was primarily carried out to investigate if women with a history of UO treated by IVF/ICSI have a reduced LBR compared with women with intact ovaries. The study cohort was collected at five large Swedish reproductive medicine centres with a policy of performing mostly single embryo transfer (SET) over the years. We hypothesized that women with a history of UO would have lower LBRs per started cycle, per ovum pick-up (OPU) and per embryo transfer (ET), and a lower cumulative LBR. Secondary aims included analysis of the effects of UO on the clinical pregnancy rate (fresh cycles and cumulative), numbers of oocytes retrieved, numbers of supernumerary embryos obtained per treatment cycle, and embryo scores. We included all fresh and frozen-thawed cycles and investigated the Ovarian Sensitivity Index (OSI), which is the ratio between oocyte yield and the dose of gonadotrophin administered. The OSI has proven to have superior predictive value as regards LBR in comparison with oocyte yield, as both stimulus and effect are taken into account (Huber et al., 2013; Li et al., 2014).
Materials and Methods
Participants
A population of 22 847 patients (154 UO cases and 22 693 controls) who underwent IVF/ICSI treatments from 1 January 1999 until 24 November 2015 were included in the study. The cases and controls were collected from five large reproductive medicine units, including one private (Carl von Linné Clinic, from 1 January 1999 until 16 November 2015 (A)) and four academic units at university hospitals (Reproductive Medicine, Karolinska University Hospital, 8 June 1999 until 6 November 2015 (B), Reproductive Centre, Uppsala University Hospital, 5 March 1999 until 4 November 2015 (C), Reproductive Medicine, Linköping University Hospital, 16 May 2002 until 24 November 2015 (D) and Fertility Unit, Örebro University Hospital, 8 January 2003 until 29 September 2015 (E)). The cohort of 154 women with a history of UO underwent 301 IVF/ICSI treatment cycles. The 22 693 control women with intact ovaries underwent 41 545 IVF/ICSI treatment cycles. During the study period, all five clinics used the same clinical chart registry for documentation of IVF/ICSI treatments. All treatment-related data was collected from the respective clinics version of an electronic registry database (Linnefiler, Fertsoft AB, Uppsala, Sweden).
Treatment protocols
Ovarian stimulation was performed by using either a long GnRH agonist protocol (Nafarelin Synarela; Pfizer, 400 μg twice daily or Buserelin Suprecur; Sanofi Aventis, 0.3 mg nasally three times a day) or an antagonist protocol (Cetrorelix Cetrotide; Merck Serono or Ganirelix Orgalutran, Organon, starting injections on Day 5 or 6 of stimulation). The gonadotrophins used included rFSH, such as follitropin alfa (Gonal F; Merck Serono), follitropin beta (Puregon; Organon) or hMG (Menopur, Ferring). In these treatments, the gonadotrophin dose was individualized according to the woman's age, ovarian reserve and antral follicle count. Final oocyte maturation was achieved by using 10 000 IU hCG (Pregnyl) or 250 μg recombinant hCG (Ovitrelle, Merck Serono) when at least three follicles of ≥17 mm were visible in ultrasonography. Oocyte retrieval was carried out by transvaginal ultrasound-guided ovarian puncture 36–37 h after hCG administration. Luteal-phase support with vaginal micronized progesterone suppositories (Progesteron MIC, APL) or vaginal progesterone gel (Crinone, Merck Serono) or vaginal progesterone tablets (Lutinus, Ferring) was given to all patients (Bergh et al., 2012). Embryos were transferred at cleavage stage Day 2 or Day 3 in the majority of cases (94%) and at blastocyst stage on Day 5 in the remaining cases (6%). All patients underwent evaluation of a viable intrauterine pregnancy by transvaginal ultrasonography at gestational Weeks 7–8 at their respective centres. Women with on-going pregnancies were requested to report delivery data to the centres. In cases of missing data, information on delivery was completed by way of direct patient contact via telephone.
Embryos were scored on Day 2 according to the integrated morphology cleavage embryo score (IMC) on a 10° scale (Holte et al., 2007) at clinics A and B. The remaining centres used a different embryo morphological classification.
Regulations issued by the National Board of Health and Welfare legalizes all assisted reproduction treatments in Sweden. Since January 2003, the board has recommended transferring only one embryo at the time of treatment, unless the risk of twin pregnancy is considered low (Sweden. National Board of Health and Welfare, 2009). Subsequent frozen-embryo transfer was performed either in a natural cycle or in an artificial cycle with the administration of oestradiol (Progynon, Bayer) and vaginal micronized progesterone suppositories (Progesteron MIC, APL) or vaginal progesterone gel (Crinone, Merck Serono) or vaginal progesterone tablets (Lutinus, Ferring).
Outcome measures
The primary outcome was the LBR (including all fresh and frozen-thawed cycles), which was analysed per started cycle, per OPU and per ET. Secondary outcomes included the clinical pregnancy rate (fresh cycles and cumulative), numbers of oocytes retrieved, numbers of supernumerary embryos obtained per treatment cycle, embryo quality scores and the OSI, calculated by the number of oocytes recovered/total FSH dose. Clinical pregnancy was defined as a viable intrauterine pregnancy confirmed by transvaginal ultrasonography at gestational Weeks 7–8.
Statistical analysis
Over half of the women (57%, n = 13 057) had more than one treatment, including both fresh and frozen-thawed cycles, and therefore we used Generalized Estimating Equation (GEE) models for the analysis (Zeger and Liang, 1986). These models take into account the dependence between repeated treatments for each woman. The GEE models were used for continuous as well as for dichotomous outcome variables. Effect measures included mean differences and odds ratios with 95% confidence intervals for continuous and dichotomous variables, respectively. Differences were considered statistically significant if P-values were <0.05 in two-sided tests. We assessed effects in univariate and multivariate models after adjustment for women's age as a continuous variable, BMI, fertility centre, calendar period and number of retrieved oocytes. In analyses of embryo transfers we adjusted for single and multiple embryo transfers. Data (means and 95% confidence intervals) presented were based on normal approximation. Interaction test was performed between all variables, oophorectomy and LBR. A generalized additive model (GAM) analysis was done to illustrate the association between oocyte yields (number) and the outcome variables LBR/OPU. We used an OSI nomogram (Ovarian sensitivity index, OSI; which is the ratio between oocyte yield and the dose of gonadotrophin administered) (Huber et al., 2013) to categorize the women into three groups: poor, normal and high-level responders. Outcome LBR in women with versus without endometriosis was analysed with a generalized estimating equation (GEE) model that fully accounts for the dependence between treatments for the same woman and adjusted for age. Statistical analyses were undertaken with the statistical program package SAS 9.4 (SAS Institute).
Ethics approval
The study was approved by the Regional Ethics Review Board in Stockholm, Sweden (d-nr 2011/1758-31/2 and 2014/1360-32).
Results
ART characteristics per clinical centre
Of the total of 22 693 patients included, 154 had a history of UO. A higher proportion of women with UO presented with a history of endometriosis (24.6%) when compared with controls (5.6%) (P < 0.0001). Table I shows demographic data including age, BMI, infertility diagnosis, previous IVF/ICSI treatments and previous pregnancies and live births. Most women were nulliparous at time of treatment (88.0% of cases versus 90.7% of controls). The prevalence of UO in women differed between the five clinics (Table I). At clinic A, women were slightly older (mean age 34.9 y) than the women at the four academic centres, B (33.3 y), C (32.6 y), D (32.1 y) and E (33.1 y) (P < 0.0001 when comparing centre A with C/D). The gonadotrophin dose required for stimulation was also higher at clinic A compared with the other four clinics, B, C, D and E (2510 IU versus 2294 IU, 1972 IU, 1853 IU and 2239 IU) (P < 0.0001). The proportion of cycles treated by IVF was 55%, 52%, 65%, 55% and 50% at centres A, B, C, D and E, respectively.
Description of demographics, previous pregnancies and IVF/ICSI cycles and treatment cycles characteristics by clinical centre. Data are n (%) unless stated otherwise.
| Variable | Whole study cohort | Centre | ||||
|---|---|---|---|---|---|---|
| A | B | C | D | E | ||
| Carl von Linné Clinic | Karolinska University Hospital | Uppsala University Hospital | Linköping University Hospital | Örebro University Hospital | ||
| Treatments cycles (n) | 41 545 | 18 484 | 8371 | 5575 | 4670 | 4445 |
| Treatments cycles UO (n) | 301 | 151 | 34 | 35 | 41 | 40 |
| Age at OPU (y) Mean (SD) | 33.7 (4.4) | 34.8 (4.5) | 33.4 (4.0) | 32.6 (4.2) | 32.1 (4.0) | 33.1 (4.7) |
| BMI (kg/m2) Mean (SD) | 23.8 (3.8) | 23.5 (3.7) | 24.1 (4.1) | 24.1 (3.9) | 23.7 (3.2) | 24.8 (4.3) |
| Infertility diagnosis | ||||||
| Controls | ||||||
| Female factor | 11 418 (27.5) | 5649 (30.6) | 1926 (23) | 1369 (24.6) | 1663 (35.6) | 811 (18.2) |
| Tubal | 3852 (9.3) | 2422 (13.1) | 499 (6.0) | 360 (6.5) | 368 (7.9) | 203 (4.6) |
| Anovulation/PCO | 3676 (8.9) | 1311 (7.1) | 797 (9.5) | 605 (10.9) | 662 (14.2) | 301 (6.8) |
| Endometriosis | 2328 (5.6) | 946 (5.1) | 419 (5.0) | 345 (6.2) | 459 (9.8) | 159 (3.6) |
| Ovarian | 1494 (3.6) | 954 (5.2) | 201 (2.4) | 54 (1.0) | 169 (3.6) | 116 (2.6) |
| Uterine/cervical | 68 (0.2) | 16 (0.0) | 10 (0.0) | 5 (0.0) | 5 (0.0) | 32 (0.7) |
| Male factor | 9076 (21.8) | 4666 (25.2) | 1842 (22.0) | 1469 (26.3) | 1070 (22.9) | 29 (0.7) |
| Combined female and male factor | 274 (0.7) | 0 | 202 (2.4) | 30 (0.5) | 29 (0.6) | 13 (0.2) |
| Infertility, unspecified diagnosis | 7158 (17.2) | 769 (4.2) | 1893 (22. 6) | 765 (13.8) | 404 (8.7) | 3327 (74.9) |
| Unexplained | 13 619 (32.8) | 7400 (40.0) | 2508 (30.0) | 1942 (34.8) | 1504 (32.2) | 265 (6.0) |
| Infertility diagnosis | ||||||
| Cases | ||||||
| Female factor | 172 (57.1) | 99 (65.6) | 12 (35.3) | 21 (60.0) | 21 (51.2) | 19 (47.5) |
| Endometriosis | 74 (24.6) | 25 (16.6) | 6 (17.6) | 16 (45.7) | 13 (31.7) | 14 (34.1) |
| Tubal | 73 (24.3) | 59 (39.1) | 0 | 3 (8.6) | 7 (17.1) | 4 (9.8) |
| Ovarian | 22 (7.3) | 13 (8.6) | 6 (17.6) | 2 (5.7) | 1 (2.4) | 0 |
| Anovulation/PCO | 3 (1.0) | 2 (1.3) | 0 | 0 | 0 | 1 (2.4) |
| Male factor | 49 (16.3) | 25 (16.6) | 4 (11.8) | 6 (17.1) | 14 (34.1) | 0 |
| Combined female and male factor | 10 (3.3) | 0 | 3 (8.8) | 0 | 0 | 7 (17.5) |
| Infertility, unspecified diagnosis | 34 (11.3) | 6 (4.0) | 9 (26.5) | 4 (11.4) | 1 (2.4) | 14 (35.0) |
| Unexplained | 36 (12.0) | 21 (13.9) | 6 (17.6) | 4 (11.4) | 5 (12.2) | 0 |
| Previous IVF/ICSI treatment cycles | ||||||
| Controls | ||||||
| 0 | 21 413 (51.5) | 8715 (47.1) | 4723 (56.4) | 3243 (58.2) | 2823 (60.4) | 1909 (42.9) |
| 1 | 11 176 (26.9) | 4879 (26.4) | 2279 (27.2) | 1452 (26.0) | 1248 (26.7) | 1318 (29.7) |
| ≥2 | 3648 (8.9) | 2349 (12.7) | 365 (4.4) | 292 (5.2) | 173 (3.7) | 469 (10.6) |
| Number not specified in database | 5308 (12.8) | 2541 (13.7) | 1004 (12.0) | 588 (10.5) | 426 (9.1) | 749 (16.9) |
| Previous IVF/ICSI treatment cycles | ||||||
| Cases | ||||||
| 0 | 141 (46.9) | 62 (41.1) | 19 (55.9) | 19 (54.3) | 22 (53.7) | 19 (47.5) |
| 1 | 82 (27.2) | 43 (28.5) | 11 (32.4) | 6 (17.1) | 11 (26.8) | 11 (27.5) |
| ≥2 | 36 (12.0) | 21 (13.9) | 0 | 7 (20.0) | 3 (7.3) | 5 (12.5) |
| Number not specified in database | 44 (14.6) | 25 (16.6) | 4 (11.8) | 3 (8.6) | 5 (12.2) | 5 (12.5) |
| Previous pregnancies | ||||||
| Controls (n) (%) | ||||||
| 0 | 28 854 (69.4) | 11 343 (61.3) | 6303 (75.3) | 4154 (74.5) | 3321 (71.1) | 3733 (84.0) |
| 1 | 9284 (22.3) | 4964 (26.9) | 1584 (18.9) | 1116 (20.0) | 1077 (23.1) | 543 (12.2) |
| ≥2 | 3407 (8.2) | 2177 (11.8) | 484 (5.8) | 305 (5.5) | 272 (5.8) | 169 (3.8) |
| Previous pregnancies | ||||||
| Cases | ||||||
| 0 | 201 (69.8) | 91 (60.3) | 30 (88.2) | 24 (68.6) | 28 (68.3) | 37 (92.5) |
| 1 | 65 (21.6) | 38 (25.2) | 2 (5.9) | 10 (28.6) | 13 (31.7) | 2 (5.0) |
| ≥2 | 26 (8.6) | 22 (14.6) | 2 (5.9) | 1 (2.9) | 0 | 1 (2.5) |
| Previous children | ||||||
| Controls | ||||||
| 0 | 38 019 (91.5) | 15 717 (85.0) | 8288 (99.0) | 5348 (95.9) | 4427 (94.2) | 4239 (95.4) |
| 1 | 3529 (8.5) | 2752 (14.9) | 80 (1.0) | 225 (4.0) | 266 (5.7) | 206 (4.6) |
| ≥2 | 22 (0.0) | 15 (0.1) | 3 (0.0) | 1 (0.0) | 3 (0.1) | 0 |
| Previous children | ||||||
| Cases | ||||||
| 0 | 267 (88.7) | 125 (82.8) | 34 (100) | 31 (88.6) | 40 (97.6) | 37 (92.5) |
| 1 | 34 (11.3) | 26 (17.2) | 0 | 4 (11.4) | 1 (2.4) | 3 (7.5) |
| ≥2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Total FSH dose (iu) Mean (SD) | 2302 (1264) | 2510 (1331) | 2294 (1309) | 1972 (1049) | 1853 (857) | 2239 (1147) |
| OPU oocytes Mean (SD) | 9.3 (5.8) | 9.7 (5.1) | 10.1 (6.0) | 9.7 (5.5) | 10.6 (5.7) | 9.6 (5.5) |
| OSIa Mean (SD) | 6.0 (4.9) | 5.5 (4.5) | 6.2 (5.2) | 6.5 (5.2) | 7.1 (5.1) | 5.7 (4.6) |
| IVF | 21 460 (55.3) | 9551 (55.1) | 3973 (52.1) | 3391 (64.8) | 2448 (54.9) | 2097 (50.2) |
| ICSI | 17 372 (44.7) | 7795 (44.9) | 3648 (47.9) | 1839 (35.2) | 2009 (45.1) | 2081 (49.8) |
| Embryos transferred at fresh + thawed cycles | ||||||
| Mean (SD) | 1.2 (0.4) | 1.3 (0.5) | 1.2 (0.4) | 1.1 (0.3) | 1.2 (0.4) | 1.1 (0.3) |
| Treatments with single embryo transfer, fresh + thawed cycles | 40 273 (76.7) | 14 865 (66.9) | 8962 (81.4) | 7367 (90.9) | 4323 (79.8) | 4756 (82.4) |
| Variable | Whole study cohort | Centre | ||||
|---|---|---|---|---|---|---|
| A | B | C | D | E | ||
| Carl von Linné Clinic | Karolinska University Hospital | Uppsala University Hospital | Linköping University Hospital | Örebro University Hospital | ||
| Treatments cycles (n) | 41 545 | 18 484 | 8371 | 5575 | 4670 | 4445 |
| Treatments cycles UO (n) | 301 | 151 | 34 | 35 | 41 | 40 |
| Age at OPU (y) Mean (SD) | 33.7 (4.4) | 34.8 (4.5) | 33.4 (4.0) | 32.6 (4.2) | 32.1 (4.0) | 33.1 (4.7) |
| BMI (kg/m2) Mean (SD) | 23.8 (3.8) | 23.5 (3.7) | 24.1 (4.1) | 24.1 (3.9) | 23.7 (3.2) | 24.8 (4.3) |
| Infertility diagnosis | ||||||
| Controls | ||||||
| Female factor | 11 418 (27.5) | 5649 (30.6) | 1926 (23) | 1369 (24.6) | 1663 (35.6) | 811 (18.2) |
| Tubal | 3852 (9.3) | 2422 (13.1) | 499 (6.0) | 360 (6.5) | 368 (7.9) | 203 (4.6) |
| Anovulation/PCO | 3676 (8.9) | 1311 (7.1) | 797 (9.5) | 605 (10.9) | 662 (14.2) | 301 (6.8) |
| Endometriosis | 2328 (5.6) | 946 (5.1) | 419 (5.0) | 345 (6.2) | 459 (9.8) | 159 (3.6) |
| Ovarian | 1494 (3.6) | 954 (5.2) | 201 (2.4) | 54 (1.0) | 169 (3.6) | 116 (2.6) |
| Uterine/cervical | 68 (0.2) | 16 (0.0) | 10 (0.0) | 5 (0.0) | 5 (0.0) | 32 (0.7) |
| Male factor | 9076 (21.8) | 4666 (25.2) | 1842 (22.0) | 1469 (26.3) | 1070 (22.9) | 29 (0.7) |
| Combined female and male factor | 274 (0.7) | 0 | 202 (2.4) | 30 (0.5) | 29 (0.6) | 13 (0.2) |
| Infertility, unspecified diagnosis | 7158 (17.2) | 769 (4.2) | 1893 (22. 6) | 765 (13.8) | 404 (8.7) | 3327 (74.9) |
| Unexplained | 13 619 (32.8) | 7400 (40.0) | 2508 (30.0) | 1942 (34.8) | 1504 (32.2) | 265 (6.0) |
| Infertility diagnosis | ||||||
| Cases | ||||||
| Female factor | 172 (57.1) | 99 (65.6) | 12 (35.3) | 21 (60.0) | 21 (51.2) | 19 (47.5) |
| Endometriosis | 74 (24.6) | 25 (16.6) | 6 (17.6) | 16 (45.7) | 13 (31.7) | 14 (34.1) |
| Tubal | 73 (24.3) | 59 (39.1) | 0 | 3 (8.6) | 7 (17.1) | 4 (9.8) |
| Ovarian | 22 (7.3) | 13 (8.6) | 6 (17.6) | 2 (5.7) | 1 (2.4) | 0 |
| Anovulation/PCO | 3 (1.0) | 2 (1.3) | 0 | 0 | 0 | 1 (2.4) |
| Male factor | 49 (16.3) | 25 (16.6) | 4 (11.8) | 6 (17.1) | 14 (34.1) | 0 |
| Combined female and male factor | 10 (3.3) | 0 | 3 (8.8) | 0 | 0 | 7 (17.5) |
| Infertility, unspecified diagnosis | 34 (11.3) | 6 (4.0) | 9 (26.5) | 4 (11.4) | 1 (2.4) | 14 (35.0) |
| Unexplained | 36 (12.0) | 21 (13.9) | 6 (17.6) | 4 (11.4) | 5 (12.2) | 0 |
| Previous IVF/ICSI treatment cycles | ||||||
| Controls | ||||||
| 0 | 21 413 (51.5) | 8715 (47.1) | 4723 (56.4) | 3243 (58.2) | 2823 (60.4) | 1909 (42.9) |
| 1 | 11 176 (26.9) | 4879 (26.4) | 2279 (27.2) | 1452 (26.0) | 1248 (26.7) | 1318 (29.7) |
| ≥2 | 3648 (8.9) | 2349 (12.7) | 365 (4.4) | 292 (5.2) | 173 (3.7) | 469 (10.6) |
| Number not specified in database | 5308 (12.8) | 2541 (13.7) | 1004 (12.0) | 588 (10.5) | 426 (9.1) | 749 (16.9) |
| Previous IVF/ICSI treatment cycles | ||||||
| Cases | ||||||
| 0 | 141 (46.9) | 62 (41.1) | 19 (55.9) | 19 (54.3) | 22 (53.7) | 19 (47.5) |
| 1 | 82 (27.2) | 43 (28.5) | 11 (32.4) | 6 (17.1) | 11 (26.8) | 11 (27.5) |
| ≥2 | 36 (12.0) | 21 (13.9) | 0 | 7 (20.0) | 3 (7.3) | 5 (12.5) |
| Number not specified in database | 44 (14.6) | 25 (16.6) | 4 (11.8) | 3 (8.6) | 5 (12.2) | 5 (12.5) |
| Previous pregnancies | ||||||
| Controls (n) (%) | ||||||
| 0 | 28 854 (69.4) | 11 343 (61.3) | 6303 (75.3) | 4154 (74.5) | 3321 (71.1) | 3733 (84.0) |
| 1 | 9284 (22.3) | 4964 (26.9) | 1584 (18.9) | 1116 (20.0) | 1077 (23.1) | 543 (12.2) |
| ≥2 | 3407 (8.2) | 2177 (11.8) | 484 (5.8) | 305 (5.5) | 272 (5.8) | 169 (3.8) |
| Previous pregnancies | ||||||
| Cases | ||||||
| 0 | 201 (69.8) | 91 (60.3) | 30 (88.2) | 24 (68.6) | 28 (68.3) | 37 (92.5) |
| 1 | 65 (21.6) | 38 (25.2) | 2 (5.9) | 10 (28.6) | 13 (31.7) | 2 (5.0) |
| ≥2 | 26 (8.6) | 22 (14.6) | 2 (5.9) | 1 (2.9) | 0 | 1 (2.5) |
| Previous children | ||||||
| Controls | ||||||
| 0 | 38 019 (91.5) | 15 717 (85.0) | 8288 (99.0) | 5348 (95.9) | 4427 (94.2) | 4239 (95.4) |
| 1 | 3529 (8.5) | 2752 (14.9) | 80 (1.0) | 225 (4.0) | 266 (5.7) | 206 (4.6) |
| ≥2 | 22 (0.0) | 15 (0.1) | 3 (0.0) | 1 (0.0) | 3 (0.1) | 0 |
| Previous children | ||||||
| Cases | ||||||
| 0 | 267 (88.7) | 125 (82.8) | 34 (100) | 31 (88.6) | 40 (97.6) | 37 (92.5) |
| 1 | 34 (11.3) | 26 (17.2) | 0 | 4 (11.4) | 1 (2.4) | 3 (7.5) |
| ≥2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Total FSH dose (iu) Mean (SD) | 2302 (1264) | 2510 (1331) | 2294 (1309) | 1972 (1049) | 1853 (857) | 2239 (1147) |
| OPU oocytes Mean (SD) | 9.3 (5.8) | 9.7 (5.1) | 10.1 (6.0) | 9.7 (5.5) | 10.6 (5.7) | 9.6 (5.5) |
| OSIa Mean (SD) | 6.0 (4.9) | 5.5 (4.5) | 6.2 (5.2) | 6.5 (5.2) | 7.1 (5.1) | 5.7 (4.6) |
| IVF | 21 460 (55.3) | 9551 (55.1) | 3973 (52.1) | 3391 (64.8) | 2448 (54.9) | 2097 (50.2) |
| ICSI | 17 372 (44.7) | 7795 (44.9) | 3648 (47.9) | 1839 (35.2) | 2009 (45.1) | 2081 (49.8) |
| Embryos transferred at fresh + thawed cycles | ||||||
| Mean (SD) | 1.2 (0.4) | 1.3 (0.5) | 1.2 (0.4) | 1.1 (0.3) | 1.2 (0.4) | 1.1 (0.3) |
| Treatments with single embryo transfer, fresh + thawed cycles | 40 273 (76.7) | 14 865 (66.9) | 8962 (81.4) | 7367 (90.9) | 4323 (79.8) | 4756 (82.4) |
UO, unilateral oophorectomy; OPU, oocyte pick-up; PCO, polycystic ovaries.
aOSI is the ratio between oocyte yield and the dose (iu) of FSH administrated *1000.
Description of demographics, previous pregnancies and IVF/ICSI cycles and treatment cycles characteristics by clinical centre. Data are n (%) unless stated otherwise.
| Variable | Whole study cohort | Centre | ||||
|---|---|---|---|---|---|---|
| A | B | C | D | E | ||
| Carl von Linné Clinic | Karolinska University Hospital | Uppsala University Hospital | Linköping University Hospital | Örebro University Hospital | ||
| Treatments cycles (n) | 41 545 | 18 484 | 8371 | 5575 | 4670 | 4445 |
| Treatments cycles UO (n) | 301 | 151 | 34 | 35 | 41 | 40 |
| Age at OPU (y) Mean (SD) | 33.7 (4.4) | 34.8 (4.5) | 33.4 (4.0) | 32.6 (4.2) | 32.1 (4.0) | 33.1 (4.7) |
| BMI (kg/m2) Mean (SD) | 23.8 (3.8) | 23.5 (3.7) | 24.1 (4.1) | 24.1 (3.9) | 23.7 (3.2) | 24.8 (4.3) |
| Infertility diagnosis | ||||||
| Controls | ||||||
| Female factor | 11 418 (27.5) | 5649 (30.6) | 1926 (23) | 1369 (24.6) | 1663 (35.6) | 811 (18.2) |
| Tubal | 3852 (9.3) | 2422 (13.1) | 499 (6.0) | 360 (6.5) | 368 (7.9) | 203 (4.6) |
| Anovulation/PCO | 3676 (8.9) | 1311 (7.1) | 797 (9.5) | 605 (10.9) | 662 (14.2) | 301 (6.8) |
| Endometriosis | 2328 (5.6) | 946 (5.1) | 419 (5.0) | 345 (6.2) | 459 (9.8) | 159 (3.6) |
| Ovarian | 1494 (3.6) | 954 (5.2) | 201 (2.4) | 54 (1.0) | 169 (3.6) | 116 (2.6) |
| Uterine/cervical | 68 (0.2) | 16 (0.0) | 10 (0.0) | 5 (0.0) | 5 (0.0) | 32 (0.7) |
| Male factor | 9076 (21.8) | 4666 (25.2) | 1842 (22.0) | 1469 (26.3) | 1070 (22.9) | 29 (0.7) |
| Combined female and male factor | 274 (0.7) | 0 | 202 (2.4) | 30 (0.5) | 29 (0.6) | 13 (0.2) |
| Infertility, unspecified diagnosis | 7158 (17.2) | 769 (4.2) | 1893 (22. 6) | 765 (13.8) | 404 (8.7) | 3327 (74.9) |
| Unexplained | 13 619 (32.8) | 7400 (40.0) | 2508 (30.0) | 1942 (34.8) | 1504 (32.2) | 265 (6.0) |
| Infertility diagnosis | ||||||
| Cases | ||||||
| Female factor | 172 (57.1) | 99 (65.6) | 12 (35.3) | 21 (60.0) | 21 (51.2) | 19 (47.5) |
| Endometriosis | 74 (24.6) | 25 (16.6) | 6 (17.6) | 16 (45.7) | 13 (31.7) | 14 (34.1) |
| Tubal | 73 (24.3) | 59 (39.1) | 0 | 3 (8.6) | 7 (17.1) | 4 (9.8) |
| Ovarian | 22 (7.3) | 13 (8.6) | 6 (17.6) | 2 (5.7) | 1 (2.4) | 0 |
| Anovulation/PCO | 3 (1.0) | 2 (1.3) | 0 | 0 | 0 | 1 (2.4) |
| Male factor | 49 (16.3) | 25 (16.6) | 4 (11.8) | 6 (17.1) | 14 (34.1) | 0 |
| Combined female and male factor | 10 (3.3) | 0 | 3 (8.8) | 0 | 0 | 7 (17.5) |
| Infertility, unspecified diagnosis | 34 (11.3) | 6 (4.0) | 9 (26.5) | 4 (11.4) | 1 (2.4) | 14 (35.0) |
| Unexplained | 36 (12.0) | 21 (13.9) | 6 (17.6) | 4 (11.4) | 5 (12.2) | 0 |
| Previous IVF/ICSI treatment cycles | ||||||
| Controls | ||||||
| 0 | 21 413 (51.5) | 8715 (47.1) | 4723 (56.4) | 3243 (58.2) | 2823 (60.4) | 1909 (42.9) |
| 1 | 11 176 (26.9) | 4879 (26.4) | 2279 (27.2) | 1452 (26.0) | 1248 (26.7) | 1318 (29.7) |
| ≥2 | 3648 (8.9) | 2349 (12.7) | 365 (4.4) | 292 (5.2) | 173 (3.7) | 469 (10.6) |
| Number not specified in database | 5308 (12.8) | 2541 (13.7) | 1004 (12.0) | 588 (10.5) | 426 (9.1) | 749 (16.9) |
| Previous IVF/ICSI treatment cycles | ||||||
| Cases | ||||||
| 0 | 141 (46.9) | 62 (41.1) | 19 (55.9) | 19 (54.3) | 22 (53.7) | 19 (47.5) |
| 1 | 82 (27.2) | 43 (28.5) | 11 (32.4) | 6 (17.1) | 11 (26.8) | 11 (27.5) |
| ≥2 | 36 (12.0) | 21 (13.9) | 0 | 7 (20.0) | 3 (7.3) | 5 (12.5) |
| Number not specified in database | 44 (14.6) | 25 (16.6) | 4 (11.8) | 3 (8.6) | 5 (12.2) | 5 (12.5) |
| Previous pregnancies | ||||||
| Controls (n) (%) | ||||||
| 0 | 28 854 (69.4) | 11 343 (61.3) | 6303 (75.3) | 4154 (74.5) | 3321 (71.1) | 3733 (84.0) |
| 1 | 9284 (22.3) | 4964 (26.9) | 1584 (18.9) | 1116 (20.0) | 1077 (23.1) | 543 (12.2) |
| ≥2 | 3407 (8.2) | 2177 (11.8) | 484 (5.8) | 305 (5.5) | 272 (5.8) | 169 (3.8) |
| Previous pregnancies | ||||||
| Cases | ||||||
| 0 | 201 (69.8) | 91 (60.3) | 30 (88.2) | 24 (68.6) | 28 (68.3) | 37 (92.5) |
| 1 | 65 (21.6) | 38 (25.2) | 2 (5.9) | 10 (28.6) | 13 (31.7) | 2 (5.0) |
| ≥2 | 26 (8.6) | 22 (14.6) | 2 (5.9) | 1 (2.9) | 0 | 1 (2.5) |
| Previous children | ||||||
| Controls | ||||||
| 0 | 38 019 (91.5) | 15 717 (85.0) | 8288 (99.0) | 5348 (95.9) | 4427 (94.2) | 4239 (95.4) |
| 1 | 3529 (8.5) | 2752 (14.9) | 80 (1.0) | 225 (4.0) | 266 (5.7) | 206 (4.6) |
| ≥2 | 22 (0.0) | 15 (0.1) | 3 (0.0) | 1 (0.0) | 3 (0.1) | 0 |
| Previous children | ||||||
| Cases | ||||||
| 0 | 267 (88.7) | 125 (82.8) | 34 (100) | 31 (88.6) | 40 (97.6) | 37 (92.5) |
| 1 | 34 (11.3) | 26 (17.2) | 0 | 4 (11.4) | 1 (2.4) | 3 (7.5) |
| ≥2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Total FSH dose (iu) Mean (SD) | 2302 (1264) | 2510 (1331) | 2294 (1309) | 1972 (1049) | 1853 (857) | 2239 (1147) |
| OPU oocytes Mean (SD) | 9.3 (5.8) | 9.7 (5.1) | 10.1 (6.0) | 9.7 (5.5) | 10.6 (5.7) | 9.6 (5.5) |
| OSIa Mean (SD) | 6.0 (4.9) | 5.5 (4.5) | 6.2 (5.2) | 6.5 (5.2) | 7.1 (5.1) | 5.7 (4.6) |
| IVF | 21 460 (55.3) | 9551 (55.1) | 3973 (52.1) | 3391 (64.8) | 2448 (54.9) | 2097 (50.2) |
| ICSI | 17 372 (44.7) | 7795 (44.9) | 3648 (47.9) | 1839 (35.2) | 2009 (45.1) | 2081 (49.8) |
| Embryos transferred at fresh + thawed cycles | ||||||
| Mean (SD) | 1.2 (0.4) | 1.3 (0.5) | 1.2 (0.4) | 1.1 (0.3) | 1.2 (0.4) | 1.1 (0.3) |
| Treatments with single embryo transfer, fresh + thawed cycles | 40 273 (76.7) | 14 865 (66.9) | 8962 (81.4) | 7367 (90.9) | 4323 (79.8) | 4756 (82.4) |
| Variable | Whole study cohort | Centre | ||||
|---|---|---|---|---|---|---|
| A | B | C | D | E | ||
| Carl von Linné Clinic | Karolinska University Hospital | Uppsala University Hospital | Linköping University Hospital | Örebro University Hospital | ||
| Treatments cycles (n) | 41 545 | 18 484 | 8371 | 5575 | 4670 | 4445 |
| Treatments cycles UO (n) | 301 | 151 | 34 | 35 | 41 | 40 |
| Age at OPU (y) Mean (SD) | 33.7 (4.4) | 34.8 (4.5) | 33.4 (4.0) | 32.6 (4.2) | 32.1 (4.0) | 33.1 (4.7) |
| BMI (kg/m2) Mean (SD) | 23.8 (3.8) | 23.5 (3.7) | 24.1 (4.1) | 24.1 (3.9) | 23.7 (3.2) | 24.8 (4.3) |
| Infertility diagnosis | ||||||
| Controls | ||||||
| Female factor | 11 418 (27.5) | 5649 (30.6) | 1926 (23) | 1369 (24.6) | 1663 (35.6) | 811 (18.2) |
| Tubal | 3852 (9.3) | 2422 (13.1) | 499 (6.0) | 360 (6.5) | 368 (7.9) | 203 (4.6) |
| Anovulation/PCO | 3676 (8.9) | 1311 (7.1) | 797 (9.5) | 605 (10.9) | 662 (14.2) | 301 (6.8) |
| Endometriosis | 2328 (5.6) | 946 (5.1) | 419 (5.0) | 345 (6.2) | 459 (9.8) | 159 (3.6) |
| Ovarian | 1494 (3.6) | 954 (5.2) | 201 (2.4) | 54 (1.0) | 169 (3.6) | 116 (2.6) |
| Uterine/cervical | 68 (0.2) | 16 (0.0) | 10 (0.0) | 5 (0.0) | 5 (0.0) | 32 (0.7) |
| Male factor | 9076 (21.8) | 4666 (25.2) | 1842 (22.0) | 1469 (26.3) | 1070 (22.9) | 29 (0.7) |
| Combined female and male factor | 274 (0.7) | 0 | 202 (2.4) | 30 (0.5) | 29 (0.6) | 13 (0.2) |
| Infertility, unspecified diagnosis | 7158 (17.2) | 769 (4.2) | 1893 (22. 6) | 765 (13.8) | 404 (8.7) | 3327 (74.9) |
| Unexplained | 13 619 (32.8) | 7400 (40.0) | 2508 (30.0) | 1942 (34.8) | 1504 (32.2) | 265 (6.0) |
| Infertility diagnosis | ||||||
| Cases | ||||||
| Female factor | 172 (57.1) | 99 (65.6) | 12 (35.3) | 21 (60.0) | 21 (51.2) | 19 (47.5) |
| Endometriosis | 74 (24.6) | 25 (16.6) | 6 (17.6) | 16 (45.7) | 13 (31.7) | 14 (34.1) |
| Tubal | 73 (24.3) | 59 (39.1) | 0 | 3 (8.6) | 7 (17.1) | 4 (9.8) |
| Ovarian | 22 (7.3) | 13 (8.6) | 6 (17.6) | 2 (5.7) | 1 (2.4) | 0 |
| Anovulation/PCO | 3 (1.0) | 2 (1.3) | 0 | 0 | 0 | 1 (2.4) |
| Male factor | 49 (16.3) | 25 (16.6) | 4 (11.8) | 6 (17.1) | 14 (34.1) | 0 |
| Combined female and male factor | 10 (3.3) | 0 | 3 (8.8) | 0 | 0 | 7 (17.5) |
| Infertility, unspecified diagnosis | 34 (11.3) | 6 (4.0) | 9 (26.5) | 4 (11.4) | 1 (2.4) | 14 (35.0) |
| Unexplained | 36 (12.0) | 21 (13.9) | 6 (17.6) | 4 (11.4) | 5 (12.2) | 0 |
| Previous IVF/ICSI treatment cycles | ||||||
| Controls | ||||||
| 0 | 21 413 (51.5) | 8715 (47.1) | 4723 (56.4) | 3243 (58.2) | 2823 (60.4) | 1909 (42.9) |
| 1 | 11 176 (26.9) | 4879 (26.4) | 2279 (27.2) | 1452 (26.0) | 1248 (26.7) | 1318 (29.7) |
| ≥2 | 3648 (8.9) | 2349 (12.7) | 365 (4.4) | 292 (5.2) | 173 (3.7) | 469 (10.6) |
| Number not specified in database | 5308 (12.8) | 2541 (13.7) | 1004 (12.0) | 588 (10.5) | 426 (9.1) | 749 (16.9) |
| Previous IVF/ICSI treatment cycles | ||||||
| Cases | ||||||
| 0 | 141 (46.9) | 62 (41.1) | 19 (55.9) | 19 (54.3) | 22 (53.7) | 19 (47.5) |
| 1 | 82 (27.2) | 43 (28.5) | 11 (32.4) | 6 (17.1) | 11 (26.8) | 11 (27.5) |
| ≥2 | 36 (12.0) | 21 (13.9) | 0 | 7 (20.0) | 3 (7.3) | 5 (12.5) |
| Number not specified in database | 44 (14.6) | 25 (16.6) | 4 (11.8) | 3 (8.6) | 5 (12.2) | 5 (12.5) |
| Previous pregnancies | ||||||
| Controls (n) (%) | ||||||
| 0 | 28 854 (69.4) | 11 343 (61.3) | 6303 (75.3) | 4154 (74.5) | 3321 (71.1) | 3733 (84.0) |
| 1 | 9284 (22.3) | 4964 (26.9) | 1584 (18.9) | 1116 (20.0) | 1077 (23.1) | 543 (12.2) |
| ≥2 | 3407 (8.2) | 2177 (11.8) | 484 (5.8) | 305 (5.5) | 272 (5.8) | 169 (3.8) |
| Previous pregnancies | ||||||
| Cases | ||||||
| 0 | 201 (69.8) | 91 (60.3) | 30 (88.2) | 24 (68.6) | 28 (68.3) | 37 (92.5) |
| 1 | 65 (21.6) | 38 (25.2) | 2 (5.9) | 10 (28.6) | 13 (31.7) | 2 (5.0) |
| ≥2 | 26 (8.6) | 22 (14.6) | 2 (5.9) | 1 (2.9) | 0 | 1 (2.5) |
| Previous children | ||||||
| Controls | ||||||
| 0 | 38 019 (91.5) | 15 717 (85.0) | 8288 (99.0) | 5348 (95.9) | 4427 (94.2) | 4239 (95.4) |
| 1 | 3529 (8.5) | 2752 (14.9) | 80 (1.0) | 225 (4.0) | 266 (5.7) | 206 (4.6) |
| ≥2 | 22 (0.0) | 15 (0.1) | 3 (0.0) | 1 (0.0) | 3 (0.1) | 0 |
| Previous children | ||||||
| Cases | ||||||
| 0 | 267 (88.7) | 125 (82.8) | 34 (100) | 31 (88.6) | 40 (97.6) | 37 (92.5) |
| 1 | 34 (11.3) | 26 (17.2) | 0 | 4 (11.4) | 1 (2.4) | 3 (7.5) |
| ≥2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Total FSH dose (iu) Mean (SD) | 2302 (1264) | 2510 (1331) | 2294 (1309) | 1972 (1049) | 1853 (857) | 2239 (1147) |
| OPU oocytes Mean (SD) | 9.3 (5.8) | 9.7 (5.1) | 10.1 (6.0) | 9.7 (5.5) | 10.6 (5.7) | 9.6 (5.5) |
| OSIa Mean (SD) | 6.0 (4.9) | 5.5 (4.5) | 6.2 (5.2) | 6.5 (5.2) | 7.1 (5.1) | 5.7 (4.6) |
| IVF | 21 460 (55.3) | 9551 (55.1) | 3973 (52.1) | 3391 (64.8) | 2448 (54.9) | 2097 (50.2) |
| ICSI | 17 372 (44.7) | 7795 (44.9) | 3648 (47.9) | 1839 (35.2) | 2009 (45.1) | 2081 (49.8) |
| Embryos transferred at fresh + thawed cycles | ||||||
| Mean (SD) | 1.2 (0.4) | 1.3 (0.5) | 1.2 (0.4) | 1.1 (0.3) | 1.2 (0.4) | 1.1 (0.3) |
| Treatments with single embryo transfer, fresh + thawed cycles | 40 273 (76.7) | 14 865 (66.9) | 8962 (81.4) | 7367 (90.9) | 4323 (79.8) | 4756 (82.4) |
UO, unilateral oophorectomy; OPU, oocyte pick-up; PCO, polycystic ovaries.
aOSI is the ratio between oocyte yield and the dose (iu) of FSH administrated *1000.
Outcome of IVF/ICSI treatments
Women in the UO group underwent only one fresh IVF/ICSI treatment in 49% of cases, similar to women in the control group (52%). The remaining women in the UO group underwent repeated treatments (51%, 2–8 treatments), similar to controls (48%, 2–12 treatments). The crude cancellation rate was significantly higher among women with a history of UO than in controls (18.9% versus 14.5%). Miscarriage rates, crude and age-adjusted, did not differ significantly between the UO and control groups (Table II).
Comparison of patient characteristics and IVF/ICSI treatment cycle outcomes between women with a history of UO versus controls (women with intact ovaries). Data are mean or percent (95% CI).
| Variable | Controls (41 545) | UO (301) | ||||
|---|---|---|---|---|---|---|
| Number of observations | Data | Number of observations | Data | P-value | Age-adjusted P-value | |
| Age at OPUa (years) | 38 930 | 33.7 (33.7–33.8) | 275 | 33.9 (33.3–34.4) | 0.7704 | |
| BMI (kg/m2) | 36 996 | 23.8 (23.8–23.9) | 285 | 25.4(24.9–25.9) | 0.0004 | 0.0001 |
| Antral follicle counts (AFC) | 13 938 | 18.5 (18.3–18.7) | 101 | 9.6 (8.3–10.9) | <0.0001 | <0.0001 |
| FSH, hMG total dose (IU)/OPU | 38 874 | 2285 (2273–2298) | 275 | 2826 (2667–2985) | <0.0001 | <0.0001 |
| Days of gonadotropin stimulation | 36 909 | 10.9 (10.8–10.9) | 274 | 11.2 (10.9–11.4) | 0.0387 | 0.0514 |
| Oocytes (total number retrieved at OPU) | 38 928 | 9.9 (9.8–10.0) | 276 | 7.2 (6.7–7.7) | <0.0001 | <0.0001 |
| Ovarian sensitivity indexb | 38 856 | 6.0 (5.9–6.0) | 275 | 3.6 (3.2–4.0) | <0.0001 | <0.0001 |
| IMC Embryoscorec (1–10) | 18 240 | 9.1 (9.1–9.2) | 138 | 8.6 (8.2–8.9) | 0.0072 | 0.0085 |
| Embryos obtained/OPU | 38 604 | 4.9 (4.8–4.9) | 275 | 3.8 (3.4–4.2) | <0.0001 | <0.0001 |
| Supernumerary embryos to freeze | 23 876 | 2.6 (2.6–2.6) | 152 | 2.1 (1.7–2.4) | 0.0050 | 0.0051 |
| Embryos to ETd (fresh) | 35 420 | 1.3 (1.3–1.3) | 243 | 1.3 (1.3–1.4) | 0.3349 | 0.3742 |
| Embryos to ET (thaw)e | 16 752 | 1.1 (1.1–1.1) | 105 | 1.1 (1.0–1.1) | 0.0030 | 0.0052 |
| Total embryos to ET (fresh and thaw) | 52 172 | 1.2 (1.2–1.2) | 348 | 1.2 (1.2–1.3) | 0.7956 | 0.8583 |
| SET (%) | 35 420 | 71.5 (71.0–71.9) | 243 | 67.9 (62.0–73.8) | 0.3197 | 0.3812 |
| Cancelled cycles (no OPU) (%) | 41 545 | 6.3 (6.1–6.5) | 301 | 8.3 (5.2–11.4) | 0.1620 | 0.3493 |
| Cancelled (No OPU or No ET) (%) | 41 545 | 14.5 (14.2–14.9) | 301 | 18.9 (14.5–23.4) | 0.0344 | 0.1782 |
| Clinical pregnancyf/Stimulation start (%) | 41 545 | 31.7 (31.2–32.1) | 301 | 22.9 (18.2–27.7) | 0.0014 | 0.0028 |
| Clinical pregnancyf/OPU (%) | 38 928 | 33.8 (33.4–34.3) | 276 | 25.0 (19.9–30.1) | 0.0024 | 0.0031 |
| Clinical pregnancyf/ET (%) | 35 514 | 37.1 (36.6–37.6) | 244 | 28.3 (22.6–34.0) | 0.0051 | 0.0057 |
| Clinical pregnancyf/ET Thaws (%) | 16 931 | 29.5 (28.8–30.2) | 106 | 23.6 (15.4–31.8) | 0.1874 | 0.1807 |
| Cumulative pregnancyg/OPU (including thaws) (%) | 38 928 | 41.5(41.0–42.0) | 276 | 31.2 (25.7–36.7) | 0.0009 | 0.0013 |
| Cumulative pregnancyg/ET (including thaws) (%) | 35 514 | 44.8 (44.3–45.4) | 244 | 33.6 (27.6–39.6) | 0.0009 | 0.0009 |
| Miscarriages (%) | 13 164 | 19.9 (19.2–20.6) | 69 | 18.8 (9.4–28.3) | 0.8190 | 0.7663 |
| Live-birth rates (LBRs)/Stimulation start (%) | 41 545 | 25.4 (25.0–25.8) | 301 | 18.6 (14.2–23.0) | 0.0074 | 0.0143 |
| LBRs/OPU (%) | 38 928 | 27.1 (26.6–27.5) | 276 | 20.3 (15.5–25.1) | 0.0119 | 0.0152 |
| LBRs/ET (%) | 35 514 | 29.7(29.2–30.2) | 244 | 23.0 (17.6–28.3) | 0.0217 | 0.0252 |
| LBRs/ET Thaws (%) | 16 931 | 24.0(23.4–24.7) | 106 | 17.0 (9.7–24.3) | 0.0894 | 0.0823 |
| Cumulative LBRs/OPU (fresh and frozen ET) (%) | 38 928 | 34.4 (33.9–34.8) | 276 | 26.1 (20.9–31.3) | 0.0049 | 0.0064 |
| Cumulative LBRs/ET (fresh and frozen ET) (%) | 35 514 | 37.1 (36.1–37.6) | 244 | 28.3 (22.6–34.0) | 0.0059 | 0.0063 |
| Total Frozen-Thawed treatments/OPU | 38 928 | 0.6 (0.6–0.6) | 276 | 0.5 (0.4–0.6) | 0.1852 | 0.2059 |
| Variable | Controls (41 545) | UO (301) | ||||
|---|---|---|---|---|---|---|
| Number of observations | Data | Number of observations | Data | P-value | Age-adjusted P-value | |
| Age at OPUa (years) | 38 930 | 33.7 (33.7–33.8) | 275 | 33.9 (33.3–34.4) | 0.7704 | |
| BMI (kg/m2) | 36 996 | 23.8 (23.8–23.9) | 285 | 25.4(24.9–25.9) | 0.0004 | 0.0001 |
| Antral follicle counts (AFC) | 13 938 | 18.5 (18.3–18.7) | 101 | 9.6 (8.3–10.9) | <0.0001 | <0.0001 |
| FSH, hMG total dose (IU)/OPU | 38 874 | 2285 (2273–2298) | 275 | 2826 (2667–2985) | <0.0001 | <0.0001 |
| Days of gonadotropin stimulation | 36 909 | 10.9 (10.8–10.9) | 274 | 11.2 (10.9–11.4) | 0.0387 | 0.0514 |
| Oocytes (total number retrieved at OPU) | 38 928 | 9.9 (9.8–10.0) | 276 | 7.2 (6.7–7.7) | <0.0001 | <0.0001 |
| Ovarian sensitivity indexb | 38 856 | 6.0 (5.9–6.0) | 275 | 3.6 (3.2–4.0) | <0.0001 | <0.0001 |
| IMC Embryoscorec (1–10) | 18 240 | 9.1 (9.1–9.2) | 138 | 8.6 (8.2–8.9) | 0.0072 | 0.0085 |
| Embryos obtained/OPU | 38 604 | 4.9 (4.8–4.9) | 275 | 3.8 (3.4–4.2) | <0.0001 | <0.0001 |
| Supernumerary embryos to freeze | 23 876 | 2.6 (2.6–2.6) | 152 | 2.1 (1.7–2.4) | 0.0050 | 0.0051 |
| Embryos to ETd (fresh) | 35 420 | 1.3 (1.3–1.3) | 243 | 1.3 (1.3–1.4) | 0.3349 | 0.3742 |
| Embryos to ET (thaw)e | 16 752 | 1.1 (1.1–1.1) | 105 | 1.1 (1.0–1.1) | 0.0030 | 0.0052 |
| Total embryos to ET (fresh and thaw) | 52 172 | 1.2 (1.2–1.2) | 348 | 1.2 (1.2–1.3) | 0.7956 | 0.8583 |
| SET (%) | 35 420 | 71.5 (71.0–71.9) | 243 | 67.9 (62.0–73.8) | 0.3197 | 0.3812 |
| Cancelled cycles (no OPU) (%) | 41 545 | 6.3 (6.1–6.5) | 301 | 8.3 (5.2–11.4) | 0.1620 | 0.3493 |
| Cancelled (No OPU or No ET) (%) | 41 545 | 14.5 (14.2–14.9) | 301 | 18.9 (14.5–23.4) | 0.0344 | 0.1782 |
| Clinical pregnancyf/Stimulation start (%) | 41 545 | 31.7 (31.2–32.1) | 301 | 22.9 (18.2–27.7) | 0.0014 | 0.0028 |
| Clinical pregnancyf/OPU (%) | 38 928 | 33.8 (33.4–34.3) | 276 | 25.0 (19.9–30.1) | 0.0024 | 0.0031 |
| Clinical pregnancyf/ET (%) | 35 514 | 37.1 (36.6–37.6) | 244 | 28.3 (22.6–34.0) | 0.0051 | 0.0057 |
| Clinical pregnancyf/ET Thaws (%) | 16 931 | 29.5 (28.8–30.2) | 106 | 23.6 (15.4–31.8) | 0.1874 | 0.1807 |
| Cumulative pregnancyg/OPU (including thaws) (%) | 38 928 | 41.5(41.0–42.0) | 276 | 31.2 (25.7–36.7) | 0.0009 | 0.0013 |
| Cumulative pregnancyg/ET (including thaws) (%) | 35 514 | 44.8 (44.3–45.4) | 244 | 33.6 (27.6–39.6) | 0.0009 | 0.0009 |
| Miscarriages (%) | 13 164 | 19.9 (19.2–20.6) | 69 | 18.8 (9.4–28.3) | 0.8190 | 0.7663 |
| Live-birth rates (LBRs)/Stimulation start (%) | 41 545 | 25.4 (25.0–25.8) | 301 | 18.6 (14.2–23.0) | 0.0074 | 0.0143 |
| LBRs/OPU (%) | 38 928 | 27.1 (26.6–27.5) | 276 | 20.3 (15.5–25.1) | 0.0119 | 0.0152 |
| LBRs/ET (%) | 35 514 | 29.7(29.2–30.2) | 244 | 23.0 (17.6–28.3) | 0.0217 | 0.0252 |
| LBRs/ET Thaws (%) | 16 931 | 24.0(23.4–24.7) | 106 | 17.0 (9.7–24.3) | 0.0894 | 0.0823 |
| Cumulative LBRs/OPU (fresh and frozen ET) (%) | 38 928 | 34.4 (33.9–34.8) | 276 | 26.1 (20.9–31.3) | 0.0049 | 0.0064 |
| Cumulative LBRs/ET (fresh and frozen ET) (%) | 35 514 | 37.1 (36.1–37.6) | 244 | 28.3 (22.6–34.0) | 0.0059 | 0.0063 |
| Total Frozen-Thawed treatments/OPU | 38 928 | 0.6 (0.6–0.6) | 276 | 0.5 (0.4–0.6) | 0.1852 | 0.2059 |
aOPU, oocyte pick-up.
bOvarian sensitivity index, OSI; which is the ratio between oocyte yield and the dose of gonadotrophin administered.
cEmbryo score includes the variable Blastomere (BL), Nucleus (NU), Fragmentation (FR), Equality (EQ) and Symmetry(SY).
dET, embryo transfer.
eMean value in controls are in exact numbers 1.12 and in the UO group 1.05.
fClinical pregnancy indicates a viable intrauterine pregnancy confirmed by transvaginal ultrasonography at gestational Weeks 7–8.
gOnly clinical pregnancies included.
Comparison of patient characteristics and IVF/ICSI treatment cycle outcomes between women with a history of UO versus controls (women with intact ovaries). Data are mean or percent (95% CI).
| Variable | Controls (41 545) | UO (301) | ||||
|---|---|---|---|---|---|---|
| Number of observations | Data | Number of observations | Data | P-value | Age-adjusted P-value | |
| Age at OPUa (years) | 38 930 | 33.7 (33.7–33.8) | 275 | 33.9 (33.3–34.4) | 0.7704 | |
| BMI (kg/m2) | 36 996 | 23.8 (23.8–23.9) | 285 | 25.4(24.9–25.9) | 0.0004 | 0.0001 |
| Antral follicle counts (AFC) | 13 938 | 18.5 (18.3–18.7) | 101 | 9.6 (8.3–10.9) | <0.0001 | <0.0001 |
| FSH, hMG total dose (IU)/OPU | 38 874 | 2285 (2273–2298) | 275 | 2826 (2667–2985) | <0.0001 | <0.0001 |
| Days of gonadotropin stimulation | 36 909 | 10.9 (10.8–10.9) | 274 | 11.2 (10.9–11.4) | 0.0387 | 0.0514 |
| Oocytes (total number retrieved at OPU) | 38 928 | 9.9 (9.8–10.0) | 276 | 7.2 (6.7–7.7) | <0.0001 | <0.0001 |
| Ovarian sensitivity indexb | 38 856 | 6.0 (5.9–6.0) | 275 | 3.6 (3.2–4.0) | <0.0001 | <0.0001 |
| IMC Embryoscorec (1–10) | 18 240 | 9.1 (9.1–9.2) | 138 | 8.6 (8.2–8.9) | 0.0072 | 0.0085 |
| Embryos obtained/OPU | 38 604 | 4.9 (4.8–4.9) | 275 | 3.8 (3.4–4.2) | <0.0001 | <0.0001 |
| Supernumerary embryos to freeze | 23 876 | 2.6 (2.6–2.6) | 152 | 2.1 (1.7–2.4) | 0.0050 | 0.0051 |
| Embryos to ETd (fresh) | 35 420 | 1.3 (1.3–1.3) | 243 | 1.3 (1.3–1.4) | 0.3349 | 0.3742 |
| Embryos to ET (thaw)e | 16 752 | 1.1 (1.1–1.1) | 105 | 1.1 (1.0–1.1) | 0.0030 | 0.0052 |
| Total embryos to ET (fresh and thaw) | 52 172 | 1.2 (1.2–1.2) | 348 | 1.2 (1.2–1.3) | 0.7956 | 0.8583 |
| SET (%) | 35 420 | 71.5 (71.0–71.9) | 243 | 67.9 (62.0–73.8) | 0.3197 | 0.3812 |
| Cancelled cycles (no OPU) (%) | 41 545 | 6.3 (6.1–6.5) | 301 | 8.3 (5.2–11.4) | 0.1620 | 0.3493 |
| Cancelled (No OPU or No ET) (%) | 41 545 | 14.5 (14.2–14.9) | 301 | 18.9 (14.5–23.4) | 0.0344 | 0.1782 |
| Clinical pregnancyf/Stimulation start (%) | 41 545 | 31.7 (31.2–32.1) | 301 | 22.9 (18.2–27.7) | 0.0014 | 0.0028 |
| Clinical pregnancyf/OPU (%) | 38 928 | 33.8 (33.4–34.3) | 276 | 25.0 (19.9–30.1) | 0.0024 | 0.0031 |
| Clinical pregnancyf/ET (%) | 35 514 | 37.1 (36.6–37.6) | 244 | 28.3 (22.6–34.0) | 0.0051 | 0.0057 |
| Clinical pregnancyf/ET Thaws (%) | 16 931 | 29.5 (28.8–30.2) | 106 | 23.6 (15.4–31.8) | 0.1874 | 0.1807 |
| Cumulative pregnancyg/OPU (including thaws) (%) | 38 928 | 41.5(41.0–42.0) | 276 | 31.2 (25.7–36.7) | 0.0009 | 0.0013 |
| Cumulative pregnancyg/ET (including thaws) (%) | 35 514 | 44.8 (44.3–45.4) | 244 | 33.6 (27.6–39.6) | 0.0009 | 0.0009 |
| Miscarriages (%) | 13 164 | 19.9 (19.2–20.6) | 69 | 18.8 (9.4–28.3) | 0.8190 | 0.7663 |
| Live-birth rates (LBRs)/Stimulation start (%) | 41 545 | 25.4 (25.0–25.8) | 301 | 18.6 (14.2–23.0) | 0.0074 | 0.0143 |
| LBRs/OPU (%) | 38 928 | 27.1 (26.6–27.5) | 276 | 20.3 (15.5–25.1) | 0.0119 | 0.0152 |
| LBRs/ET (%) | 35 514 | 29.7(29.2–30.2) | 244 | 23.0 (17.6–28.3) | 0.0217 | 0.0252 |
| LBRs/ET Thaws (%) | 16 931 | 24.0(23.4–24.7) | 106 | 17.0 (9.7–24.3) | 0.0894 | 0.0823 |
| Cumulative LBRs/OPU (fresh and frozen ET) (%) | 38 928 | 34.4 (33.9–34.8) | 276 | 26.1 (20.9–31.3) | 0.0049 | 0.0064 |
| Cumulative LBRs/ET (fresh and frozen ET) (%) | 35 514 | 37.1 (36.1–37.6) | 244 | 28.3 (22.6–34.0) | 0.0059 | 0.0063 |
| Total Frozen-Thawed treatments/OPU | 38 928 | 0.6 (0.6–0.6) | 276 | 0.5 (0.4–0.6) | 0.1852 | 0.2059 |
| Variable | Controls (41 545) | UO (301) | ||||
|---|---|---|---|---|---|---|
| Number of observations | Data | Number of observations | Data | P-value | Age-adjusted P-value | |
| Age at OPUa (years) | 38 930 | 33.7 (33.7–33.8) | 275 | 33.9 (33.3–34.4) | 0.7704 | |
| BMI (kg/m2) | 36 996 | 23.8 (23.8–23.9) | 285 | 25.4(24.9–25.9) | 0.0004 | 0.0001 |
| Antral follicle counts (AFC) | 13 938 | 18.5 (18.3–18.7) | 101 | 9.6 (8.3–10.9) | <0.0001 | <0.0001 |
| FSH, hMG total dose (IU)/OPU | 38 874 | 2285 (2273–2298) | 275 | 2826 (2667–2985) | <0.0001 | <0.0001 |
| Days of gonadotropin stimulation | 36 909 | 10.9 (10.8–10.9) | 274 | 11.2 (10.9–11.4) | 0.0387 | 0.0514 |
| Oocytes (total number retrieved at OPU) | 38 928 | 9.9 (9.8–10.0) | 276 | 7.2 (6.7–7.7) | <0.0001 | <0.0001 |
| Ovarian sensitivity indexb | 38 856 | 6.0 (5.9–6.0) | 275 | 3.6 (3.2–4.0) | <0.0001 | <0.0001 |
| IMC Embryoscorec (1–10) | 18 240 | 9.1 (9.1–9.2) | 138 | 8.6 (8.2–8.9) | 0.0072 | 0.0085 |
| Embryos obtained/OPU | 38 604 | 4.9 (4.8–4.9) | 275 | 3.8 (3.4–4.2) | <0.0001 | <0.0001 |
| Supernumerary embryos to freeze | 23 876 | 2.6 (2.6–2.6) | 152 | 2.1 (1.7–2.4) | 0.0050 | 0.0051 |
| Embryos to ETd (fresh) | 35 420 | 1.3 (1.3–1.3) | 243 | 1.3 (1.3–1.4) | 0.3349 | 0.3742 |
| Embryos to ET (thaw)e | 16 752 | 1.1 (1.1–1.1) | 105 | 1.1 (1.0–1.1) | 0.0030 | 0.0052 |
| Total embryos to ET (fresh and thaw) | 52 172 | 1.2 (1.2–1.2) | 348 | 1.2 (1.2–1.3) | 0.7956 | 0.8583 |
| SET (%) | 35 420 | 71.5 (71.0–71.9) | 243 | 67.9 (62.0–73.8) | 0.3197 | 0.3812 |
| Cancelled cycles (no OPU) (%) | 41 545 | 6.3 (6.1–6.5) | 301 | 8.3 (5.2–11.4) | 0.1620 | 0.3493 |
| Cancelled (No OPU or No ET) (%) | 41 545 | 14.5 (14.2–14.9) | 301 | 18.9 (14.5–23.4) | 0.0344 | 0.1782 |
| Clinical pregnancyf/Stimulation start (%) | 41 545 | 31.7 (31.2–32.1) | 301 | 22.9 (18.2–27.7) | 0.0014 | 0.0028 |
| Clinical pregnancyf/OPU (%) | 38 928 | 33.8 (33.4–34.3) | 276 | 25.0 (19.9–30.1) | 0.0024 | 0.0031 |
| Clinical pregnancyf/ET (%) | 35 514 | 37.1 (36.6–37.6) | 244 | 28.3 (22.6–34.0) | 0.0051 | 0.0057 |
| Clinical pregnancyf/ET Thaws (%) | 16 931 | 29.5 (28.8–30.2) | 106 | 23.6 (15.4–31.8) | 0.1874 | 0.1807 |
| Cumulative pregnancyg/OPU (including thaws) (%) | 38 928 | 41.5(41.0–42.0) | 276 | 31.2 (25.7–36.7) | 0.0009 | 0.0013 |
| Cumulative pregnancyg/ET (including thaws) (%) | 35 514 | 44.8 (44.3–45.4) | 244 | 33.6 (27.6–39.6) | 0.0009 | 0.0009 |
| Miscarriages (%) | 13 164 | 19.9 (19.2–20.6) | 69 | 18.8 (9.4–28.3) | 0.8190 | 0.7663 |
| Live-birth rates (LBRs)/Stimulation start (%) | 41 545 | 25.4 (25.0–25.8) | 301 | 18.6 (14.2–23.0) | 0.0074 | 0.0143 |
| LBRs/OPU (%) | 38 928 | 27.1 (26.6–27.5) | 276 | 20.3 (15.5–25.1) | 0.0119 | 0.0152 |
| LBRs/ET (%) | 35 514 | 29.7(29.2–30.2) | 244 | 23.0 (17.6–28.3) | 0.0217 | 0.0252 |
| LBRs/ET Thaws (%) | 16 931 | 24.0(23.4–24.7) | 106 | 17.0 (9.7–24.3) | 0.0894 | 0.0823 |
| Cumulative LBRs/OPU (fresh and frozen ET) (%) | 38 928 | 34.4 (33.9–34.8) | 276 | 26.1 (20.9–31.3) | 0.0049 | 0.0064 |
| Cumulative LBRs/ET (fresh and frozen ET) (%) | 35 514 | 37.1 (36.1–37.6) | 244 | 28.3 (22.6–34.0) | 0.0059 | 0.0063 |
| Total Frozen-Thawed treatments/OPU | 38 928 | 0.6 (0.6–0.6) | 276 | 0.5 (0.4–0.6) | 0.1852 | 0.2059 |
aOPU, oocyte pick-up.
bOvarian sensitivity index, OSI; which is the ratio between oocyte yield and the dose of gonadotrophin administered.
cEmbryo score includes the variable Blastomere (BL), Nucleus (NU), Fragmentation (FR), Equality (EQ) and Symmetry(SY).
dET, embryo transfer.
eMean value in controls are in exact numbers 1.12 and in the UO group 1.05.
fClinical pregnancy indicates a viable intrauterine pregnancy confirmed by transvaginal ultrasonography at gestational Weeks 7–8.
gOnly clinical pregnancies included.
The mean Antral Follicle Count (AFC) was significantly smaller in the women with UO. Although the mean total gonadotrophin dose administered was significantly higher in this group, the number of oocytes retrieved in the treatments was also significantly lower in the UO group (Table II). Hence, the OSI was significantly lower in women with a history of UO.
Analysis of embryo scoring data from the two centres that used a similar scoring system was performed in about half of the patients (controls, 44% versus 46%, women with UO). The scores were significantly lower in women with UO versus controls (8.6 versus 9.1, P = 0.009). No significant differences were found between the groups in terms of the numbers of embryos transferred in fresh or frozen-thawed cycles.
LBRs and clinical pregnancy rates
LBRs were significantly lower in women with UO compared with control women (both crude and age-adjusted data): LBR per started cycle, 18.6% versus 25.4%, P = 0.007 and P = 0.014, respectively, LBR/OPU, 20.3% versus 27.1%, P = 0.012 and P = 0.015, respectively, and LBR/ET, 23.0% versus 29.7%, P = 0.022 and P = 0.025, respectively. The difference in LBR remained significant after inclusion of both fresh and frozen-thawed transfers (Table II).
Clinical pregnancy rates (crude and age-adjusted data) per started cycle, per OPU and per ET were also significantly lower for both fresh cycles only and cumulative cycles. The difference in CPR remained significant after inclusion of both fresh and frozen-thawed transfers (Table II).
With regard to the fresh cycles, the Odds Ratio (OR) for LBR/OPU in a multivariate GEE model adjusted for age, BMI, reproductive centre and calendar period was reduced (0.70, 95% CI 0.51–0.95, P = 0.024) among women with UO compared with controls. Similarly, a reduced OR for LBR/OPU was found as regards both fresh and frozen/thawed embryos (OR 0.70, 95% CI 0.52–0.94, P = 0.016). This reduction was also apparent when analysed per embryo transfer (Table III). In a subgroup analysis of women who received SET only, using GEE modelling, a significantly decreased LBR was found in the UO group (LBR/ET OR; 0.71 CI: 0.43–0.97, P = 0.036), similar to the entire dataset encompassing both double embryo transfers (DET) and SET. This finding implies that women with UO had 30% reduced odds of achieving a LBR comparable to that in women of similar age with intact ovaries. Significantly fewer oocytes were retrieved in women with a history of UO (both crude and age-adjusted data) (7.2 versus 9.9, P < 0.001); therefore, a GEE model including the number oocytes was analysed. The ORs for clinical pregnancy rates remained significant (both fresh and frozen-thawed embryos) even after the numbers of retrieved oocytes were included in the model: CPR/OPU (OR 0.75, 95% CI 0.57–0.99, P = 0.04) and CPR/ET (OR 0.72, 95% CI 0.54–0.95, P = 0.021). However, the difference in LBR between women with and without UO disappeared after including numbers of retrieved oocytes in the model (Table III). Figure 1 illustrates the association between oocyte yield and LBR.
Odds Ratios (95% CI) comparing LBR in women with UO versus women with intact ovaries (reference for all comparisons).
| Model 1: Crude | Model 2: Age-adjusted | Model 3: Further adjusted for BMI, reproductive centre and time period | Model 4: As three further adjusted for number of oocytes retrieved | |
|---|---|---|---|---|
| Per stimulation start | ||||
| Fresh cycle | 0.67 (0.50–0.90) P = 0.007 | 0.69 (0.51–0.93) P = 0.014 | 0.71 (0.52–0.96) P = 0.028 | 0.80 (0.59–1.1) P = 0.141 |
| Fresh and thawed cycles | 0.66 (0.51–0.87) P = 0.003 | 0.68 (0.52–0.90) P = 0.006 | 0.71 (0.53–0.95) P = 0.020 | 0.86 (0.65–1.14) P = 0.287 |
| Per OPU | ||||
| Fresh cycle | 0.69 (0.51–0.92) P = 0.012 | 0.69 (0.51–0.93) P = 0.015 | 0.70 (0.51–0.95) P = 0.024 | 0.75 (0.56–1.02) P = 0.069 |
| Fresh and thawed cycles | 0.67 (0.51–0.89) P = 0.005 | 0.68 (0.51–0.90) P = 0.006 | 0.70 (0.52–0.94) P = 0.016 | 0.81 (0.61–1.10) P = 0.157 |
| Per embryo transfer | ||||
| Fresh cycle | 0.71 (0.52–0.95) P = 0.022 | 0.71 (0.52–0.96) P = 0.025 | 0.70a (0.51–0.96) P = 0.027 | 0.74a (0.54–1.02) P = 0.064 |
| Fresh + thawed cycles | 0.67 (0.50–0.89) P = 0.006 | 0.67 (0.50–0.89) P = 0.006 | 0.68a (0.51–0.92) P = 0.012 | 0.78a (0.58–1.04) P = 0.085 |
| Model 1: Crude | Model 2: Age-adjusted | Model 3: Further adjusted for BMI, reproductive centre and time period | Model 4: As three further adjusted for number of oocytes retrieved | |
|---|---|---|---|---|
| Per stimulation start | ||||
| Fresh cycle | 0.67 (0.50–0.90) P = 0.007 | 0.69 (0.51–0.93) P = 0.014 | 0.71 (0.52–0.96) P = 0.028 | 0.80 (0.59–1.1) P = 0.141 |
| Fresh and thawed cycles | 0.66 (0.51–0.87) P = 0.003 | 0.68 (0.52–0.90) P = 0.006 | 0.71 (0.53–0.95) P = 0.020 | 0.86 (0.65–1.14) P = 0.287 |
| Per OPU | ||||
| Fresh cycle | 0.69 (0.51–0.92) P = 0.012 | 0.69 (0.51–0.93) P = 0.015 | 0.70 (0.51–0.95) P = 0.024 | 0.75 (0.56–1.02) P = 0.069 |
| Fresh and thawed cycles | 0.67 (0.51–0.89) P = 0.005 | 0.68 (0.51–0.90) P = 0.006 | 0.70 (0.52–0.94) P = 0.016 | 0.81 (0.61–1.10) P = 0.157 |
| Per embryo transfer | ||||
| Fresh cycle | 0.71 (0.52–0.95) P = 0.022 | 0.71 (0.52–0.96) P = 0.025 | 0.70a (0.51–0.96) P = 0.027 | 0.74a (0.54–1.02) P = 0.064 |
| Fresh + thawed cycles | 0.67 (0.50–0.89) P = 0.006 | 0.67 (0.50–0.89) P = 0.006 | 0.68a (0.51–0.92) P = 0.012 | 0.78a (0.58–1.04) P = 0.085 |
aFurther adjusted for number of embryos transferred.
Odds Ratios (95% CI) comparing LBR in women with UO versus women with intact ovaries (reference for all comparisons).
| Model 1: Crude | Model 2: Age-adjusted | Model 3: Further adjusted for BMI, reproductive centre and time period | Model 4: As three further adjusted for number of oocytes retrieved | |
|---|---|---|---|---|
| Per stimulation start | ||||
| Fresh cycle | 0.67 (0.50–0.90) P = 0.007 | 0.69 (0.51–0.93) P = 0.014 | 0.71 (0.52–0.96) P = 0.028 | 0.80 (0.59–1.1) P = 0.141 |
| Fresh and thawed cycles | 0.66 (0.51–0.87) P = 0.003 | 0.68 (0.52–0.90) P = 0.006 | 0.71 (0.53–0.95) P = 0.020 | 0.86 (0.65–1.14) P = 0.287 |
| Per OPU | ||||
| Fresh cycle | 0.69 (0.51–0.92) P = 0.012 | 0.69 (0.51–0.93) P = 0.015 | 0.70 (0.51–0.95) P = 0.024 | 0.75 (0.56–1.02) P = 0.069 |
| Fresh and thawed cycles | 0.67 (0.51–0.89) P = 0.005 | 0.68 (0.51–0.90) P = 0.006 | 0.70 (0.52–0.94) P = 0.016 | 0.81 (0.61–1.10) P = 0.157 |
| Per embryo transfer | ||||
| Fresh cycle | 0.71 (0.52–0.95) P = 0.022 | 0.71 (0.52–0.96) P = 0.025 | 0.70a (0.51–0.96) P = 0.027 | 0.74a (0.54–1.02) P = 0.064 |
| Fresh + thawed cycles | 0.67 (0.50–0.89) P = 0.006 | 0.67 (0.50–0.89) P = 0.006 | 0.68a (0.51–0.92) P = 0.012 | 0.78a (0.58–1.04) P = 0.085 |
| Model 1: Crude | Model 2: Age-adjusted | Model 3: Further adjusted for BMI, reproductive centre and time period | Model 4: As three further adjusted for number of oocytes retrieved | |
|---|---|---|---|---|
| Per stimulation start | ||||
| Fresh cycle | 0.67 (0.50–0.90) P = 0.007 | 0.69 (0.51–0.93) P = 0.014 | 0.71 (0.52–0.96) P = 0.028 | 0.80 (0.59–1.1) P = 0.141 |
| Fresh and thawed cycles | 0.66 (0.51–0.87) P = 0.003 | 0.68 (0.52–0.90) P = 0.006 | 0.71 (0.53–0.95) P = 0.020 | 0.86 (0.65–1.14) P = 0.287 |
| Per OPU | ||||
| Fresh cycle | 0.69 (0.51–0.92) P = 0.012 | 0.69 (0.51–0.93) P = 0.015 | 0.70 (0.51–0.95) P = 0.024 | 0.75 (0.56–1.02) P = 0.069 |
| Fresh and thawed cycles | 0.67 (0.51–0.89) P = 0.005 | 0.68 (0.51–0.90) P = 0.006 | 0.70 (0.52–0.94) P = 0.016 | 0.81 (0.61–1.10) P = 0.157 |
| Per embryo transfer | ||||
| Fresh cycle | 0.71 (0.52–0.95) P = 0.022 | 0.71 (0.52–0.96) P = 0.025 | 0.70a (0.51–0.96) P = 0.027 | 0.74a (0.54–1.02) P = 0.064 |
| Fresh + thawed cycles | 0.67 (0.50–0.89) P = 0.006 | 0.67 (0.50–0.89) P = 0.006 | 0.68a (0.51–0.92) P = 0.012 | 0.78a (0.58–1.04) P = 0.085 |
aFurther adjusted for number of embryos transferred.
A generalized additive model (GAM) figure of number of oocytes and percentage live-birth rate/oocyte pick-up (LBR/OPU). Solid line represents fitted generalized additive model (GAM) smooth function. Dashed line represents distribution of the data for treatments in each group. Number of oocytes retrieved at OPU = Number of oocytes retrieved by transvaginal ovarian puncture (oocyte pick-up).
Interaction tests did not show any significant interaction between GnRH agonist/antagonist cycles, gonadotropin dose, SET, endometriosis, oophorectomy and our outcome variables LBR (live-birth rate/OPU), cumulative LBR/OPU (fresh and thaws) or LBR/ET.
The LBR in women with oophorectomy was similar and did not differ significantly between the women with endometriosis and those without endometriosis (20.7% versus 19.4%, P = 0.83). Similarly, we did not find any significant differences in LBR between women with versus without endometriosis in the control group.
Differences in OSI between the groups
After categorizing IVF/ICSI treatments into three groups in an OSI nomogram (i.e. poor, normal or high-level responders), we found an overall significant difference in OSI categories between women with UO and controls (P < 0.0001) (Fig. 2). A significantly higher frequency of poor responders was found in the women with UO than in the women with intact ovaries: 39% versus 22%, P < 0.0001. There was also a significantly lower frequency of high-level responders in women with UO: 5% versus 16%, P < 0.0001. We found no significant differences between women with UO and women with intact ovaries as regards associations between OSI categories and clinical pregnancy rates.
Ovarian Sensitivity Index (OSI) in women with unilateral oophorectomy (UO) and controls undergoing IVF/ICSI treatments. Nomogram of poor, normal and high-level responders. Number of oocytes retrieved at OPU = Number of oocytes retrieved by transvaginal ovarian puncture (oocyte pick-up); FSH total dose in IU; OSI: the ratio between oocyte yield and the dose of gonadotrophin administered (Huber et al., 2013; Li et al., 2014).
Discussion
This multicentre cohort study is the largest and the first to report that a previous UO is associated with a significant reduction in the LBR after IVF/ICSI treatment. In our study cohort we achieved a relatively large sample size of women with UO by collecting data from five large Swedish ART centres, where single embryo transfer has been the preferred method.
The LBRs (fresh cycles and cumulative) observed in women with UO were significantly lower per started cycle, per OPU and per ET than those found in women with intact ovaries treated during the same study period. These data indicate that women with UO may expect a reduction of approximately 30% in the odds of achieving live birth after IVF/ICSI. In the only previous study in which delivery rate was reported after IVF among women with UO (n = 51), no difference was detected versus controls (Khan et al., 2014). Previous data have also been conflicting as regards pregnancy rates; only two out of 14 earlier reports demonstrated a reduced pregnancy rate in women with UO compared with women with intact ovaries (Khan et al., 2014). These studies included only fresh cycles. In the study by Nargund and Bromhan (Nargund and Bromhan, 1995), a smaller number of embryos were transferred in the women with UO (mean of 1.9 in women with a history of UO versus 2.5 in women with intact ovaries), which might partly explain the reduced pregnancy rate in the UO group. In the study carried out by Khan and colleagues, the number of embryos transferred was not reported. In addition, two other retrospective studies of women with UO are currently available. Included were 162 treatment cycles each of patients with UO, compared with 788 and 1110 treatment cycles, respectively, in controls (Boutteville et al., 1987; Khalifa et al., 1992). Both studies showed significantly fewer oocytes retrieved. As opposed to the present study, multiple embryos were transferred both in women with UO and controls, 2.3 versus 3 (Boutteville et al., 1987) and 2.4 versus 3 (Khalifa et al., 1992). In these settings, no differences in pregnancy rates were observed between the groups (23.9% versus 24.4% and 13% versus 18%, respectively) (Boutteville et al., 1987; Khalifa et al., 1992).
The strengths of our study include the large cohort of women with UO (n = 154) who underwent several consecutive IVF/ICSI treatments (n = 301). In addition, we were able to analyse single treatments and the cumulative results of the treatments. Moreover, the present data included a sizeable group of control women, all with their ovaries intact. Thirdly, single embryo transfer was performed in most cases.
Our data confirm both the requirement for higher gonadotrophin doses and the retrieval of fewer oocytes at OPU in women with only one remaining ovary, trends that have been previously described in women with UO (Boutteville et al., 1987; Khalifa et al., 1992; Al-Hasani et al., 2003; Levi et al., 2003; Hendricks et al., 2010). The resulting ratio between oocyte yield and FSH dose, the OSI, was thus reduced in the UO group (Fig. 1). Importantly, this ratio is more closely related to outcome than oocyte yield per se, as it also takes into account the degree of stimulation and thus reflects ovarian sensitivity and ovarian reserve (Huber et al., 2013; Li et al., 2014). In our study, a risk of reduced clinical pregnancy rates and LBRs was observed in women with UO compared with controls with intact ovaries, with odds ratios of about 0.7. However, this risk disappeared as regards the LBR after including the number of retrieved oocytes in the regression model. Previously, Drakopoulos et al. among others demonstrated that the number of oocytes affects the cumulative LBR in IVF/ICSI treatment (Sunkara et al., 2011; Drakopoulos et al., 2016), which is in agreement with our results. In the present cohort, not only was the number of oocytes retrieved greater in women with two ovaries but also the proportion of oocytes fertilized/OPU and the number of supernumerary embryos that could be frozen—both greater in women with two ovaries. After adjusting for number of oocytes recovered, the differences in LBR between the groups were non-significant, suggesting that the lower oocyte yield in the UO group could at least partly explain their reduced chances to LBR after IVF/ICSI.
In about half of the IVF/ICSI cycles the embryo score could be determined. The proportion of embryos with good-quality morphological scores was significantly lower in women in the UO group. This may suggest that, in addition to the mere effect of a reduced number of available oocytes, also compromised oocyte quality may contribute to the lower LBR after UO.
Our study is not without limitations, as indications for the previous UO were not known for all cases. In our study cohort, all causes of infertility were present, but a high proportion of the women with UO had a history of endometriosis. This is expected, as surgical intervention in this group of patients is common, and for years this has been the case also for single endometriomas in Sweden (National Board of Health and Welfare, 2016). Although endometriosis is associated with a lower fecundity overall, recent large studies have shown similar LBRs, or even higher, in women with a diagnosis of endometriosis compared to women presenting with other infertility diagnoses undergoing ART (Senapati et al., 2016; Vaegter et al., 2017). Furthermore, women presenting with endometriomas at the time of OPU had reported similar LBR as control women with tubal infertility, and those with previous surgical treatment of endometriomas presented with signs of reduced ovarian reserve and reduced LBR (Bongioanni et al., 2011). A recent report from US national data showed that only when endometriosis was associated with concomitant diagnoses, as tubal factor or diminished ovarian reserve, reductions in LBR were observed (Senapati et al., 2016). When taken together, these data suggest that infertility associated endometriosis, including visible ovarian endometriosis, does not negatively affect IVF outcome. The reduced LBR reported for a more advanced disease may, at least partly, be the result of reduction of ovarian reserve after surgery, given the high frequency of surgical interventions in this group of patients. Our data show a similar LBR in women with UO regardless if they had endometriosis or not, similarly to what was observed in control. Thus, it seems unlikely that the cause of the lower LBRs in women with UO in the present study is solely explained by the higher incidence of endometriosis per se in this group. Conversely, it is suggested that an overly ambitious surgical approach to removal of, often symptomless, endometriomas is not an infrequent cause of iatrogenic reduction of ovarian reserve and hence compromised ART outcome. Although the women with UO in our study presented with reduced AFC values, biochemical markers of ovarian reserve such as the Anti-Mullerian Hormone (AMH) could not be analysed in the study. One main reason was the extended period of time that involved the data treatments of the study and the only late introduction of systematically AMH estimation in the clinics during recent years, also by using different analytical methods and reference values at the centres.
Although the inclusion of treatments from several centres might give rise to bias, we attempted to reduce this risk by including controls from each centre. At each centre, the two groups of women were similar regarding previous ART treatments, pregnancies and previous children. In Sweden, IVF/ICSI treatments are relatively homogeneous and all clinics follow the same protocols and offer similar treatments to infertile couples. To guarantee this consistency, they all report to the National Quality Registry. Additionally, the policy of single embryo transfer is well established, as recommended by the National Board of Health and Welfare (National Board of Helath and Welfare, 2013), (Karlstrom and Bergh, 2007). Sweden reports the highest rate of SET worldwide; in 2010, the figure was 69.8% in fresh cycles (Maheshwari et al., 2011).
The risk of bias was minimized, as all five clinics used the same data software, reporting the outcome variables of pregnancy and LBRs to the National Board of Health and Welfare, which reports yearly statistics (National Board of Helath and Welfare, 2013). Our results reflect a larger group of unselected women/couples with infertility problems; hence, external validity is high.
Clinical significance and future research
These results indicate that women with UO undergoing IVF/ICSI treatments may expect a reduced LBR compared with women with intact ovaries and the study outcome opens new questions and discussion on the role of previous UO and its impact on future fertility treatment. Patients should be informed of this possible negative effect of UO when consulted prior to surgery.
Additional research is needed to clarify the impact of age at the time of UO, and also at what level of ovarian reserve an oophorectomy might be less harmful, both factors that could not be accounted for in this study.
Authors’ roles
K.R.W. conceived the study and K.R.W, T.L., J.H., N.H. and L.B. participated in the planning and design of the study. T.L., J.H., J.I.O., J.G., E.N, M.L. and K.R.W. collected the data. T.L., J.H., J.I.O., N.H., L.B. and K.R.W. performed data analysis and interpretation. T.L., J.H., J.I.O., J.G., E.N., M.L., N.H., L.B. and K.R.W. participated in the writing of the manuscript and approved the final submitted version.
Funding
This study was supported by research grants from the Swedish Research Council, the Swedish Society of Medicine, and Stockholm County Council (to K.R.W.).
Conflict of interest
None declared.
Acknowledgements
The authors thank P.O. Karlström, Lena Hyberg and Martin Björkman for administrative support.
