Probability of live birth after IVF/ICSI treatments in female early onset cancer survivors: a Finnish population-based registry study

STUDY QUESTION Does the probability of a live birth after fresh IVF/ICSI cycles with autologous oocytes differ in early onset female cancer survivors compared to their siblings? SUMMARY ANSWER The probability of a live birth was similar in female cancer survivors and siblings after four fresh IVF/ICSI cycles. WHAT IS KNOWN ALREADY Fertility preservation strategies are rapidly being developed to help female cancer patients who wish to have children later. However, there are only a few studies available on fertility treatments and following live births in female cancer survivors before fertility preservation strategies became available. In one of them, the probability of a live birth was reduced after assisted reproductive technology with autologous oocytes in cancer survivors compared to siblings. STUDY DESIGN, SIZE, DURATION In this retrospective, register-based study, data from Finnish registers on cancer, birth and prescribed medications were merged to identify 8944 female cancer survivors (diagnosed with cancer between 1953 and 2012 at the age of 0–40 years) and 9848 female siblings of survivors eligible for IVF/ICSI treatments between January 1993 and December 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Fresh IVF/ICSI cycles and following live birth rates (LBRs) within 22–48 weeks in cancer survivors and siblings at the age of 20–41 years were identified. A binomial regression model with log-link function was used to calculate risk ratio (RR) for live births after fresh IVF/ICSI cycles in survivors compared to siblings, adjusting for attained age and calendar time. A Poisson regression model was used to estimate incidence rate ratios (IRRs) for an IVF/ICSI treatment, as well as overall live births, including both pregnancies after fertility treatments and spontaneous pregnancies, in survivors compared to siblings. MAIN RESULTS AND THE ROLE OF CHANCE We observed an overall decreased LBR, irrespective of IVF/ICSI treatments, in cancer survivors compared to siblings (IRR 0.68, 95% CI 0.64–0.71). All in all, 179 (2.0%) survivors and 230 (2.3%) siblings were prescribed fertility drugs for IVF/ICSI treatments (IRR 0.72, 95% CI 0.62–0.84). For the first fresh IVF/ICSI cycle, the LBR was 17.2% among survivors and 15.7% among siblings (RR 1.13, 95% CI 0.72–1.87). The mean LBR after four fresh IVF/ICSI cycles was not statistically different in survivors compared to siblings. LIMITATIONS, REASONS FOR CAUTION In this study, only IVF/ICSI treatments with autologous oocytes were included. The probability of a live birth after a frozen embryo transfer or oocyte donation could not be evaluated in this study. Information on miscarriages, extrauterine pregnancies or termination of pregnancies was not available. WIDER IMPLICATIONS OF THE FINDINGS For those early onset cancer survivors, who received IVF/ICSI treatments, the probability of live birth was not different from siblings who received IVF/ICSI treatments. However, an overall decreased LBR, irrespective of IVF/ICSI treatments, was observed in cancer survivors compared to siblings, indicating that cancer survivors receiving IVF/ICSI treatments in our study consisted of a selected group with at least a moderate ovarian reserve. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a grant from the Cancer Foundation (Finland) (grant number 130079) and by a grant from LähiTapiola. The authors have no potential conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

O-210 Sperm DNA fragmentation (SDF) is not associated with adverse maternal and neonatal outcomes in IVF-ICSI cycles with autologous oocytes

Study question Does an elevated SDF (>15%) increase the odds of adverse maternal and neonatal outcomes in autologous oocyte IVF-ICSI cycles from unselected couples? Summary answer No adverse effects of high SDF on obstetric and neonatal outcomes have been found in couples with sperm fragmentation undergoing IVF-ICSI cycles with own eggs. What is known already Sperm chromatin integrity assessment has been implemented as an additional tool in the clinical evaluation of sperm quality in infertile patients undergoing an assisted reproduction treatment. All of the published reports to date appraise its effect on clinical outcomes, and how it impacts embryo quality and the pregnancy chances after IVF and ICSI cycles. Sperm DNA integrity has also been hypothesized to affect offspring health but not many studies have reported in humans if an elevated SDF raises the risks of obstetric, delivery and neonatal outcomes. Study design, size, duration Multicentric retrospective cohort study of all IVF-ICSI cycles using autologous oocytes between January 2000-March 2019 at Spain IVIRMA clinics of couples with a SDF test on their ejaculated semen. The sperm fragmentation index was measured in all men with TUNEL assay. The database included 228 couples which had a delivery with at least a newborn. Subjects were divided into two study groups according to their level of SDF: ≤15% (low SDF) or > 15% (high SDF). Participants/materials, setting, methods Patients with missed information on maternal and neonatal outcomes were not counted for the analysis. The obstetric outcomes were gestational age, gestational diabetes, preeclampsia (hypertension with proteinuria after 20 weeks of gestation) and type of delivery. Neonatal outcomes were sex, birth weight, length, head circumference, Apgar score at 1, 5, 10 minutes, and neonatal intensive care unit (NICU) admission. Student’s t-test and Fisher’s test were used for statistical analysis. A p-value<0.05 was considered statistically significant. Main results and the role of chance Maternal age mean was 37.4 years (95%CI 36.9-38.0) in ≤ 15%SDF group and 37.2 years (95%CI 36.1-38.4) in > 15%SDF group (p = 0.8). Similar gestational age was found, 41.8 weeks (95%CI 41.3-42.2) in ≤ 15%SDF and 41.3 weeks (95%CI 40.4-42.3) in > 15%SDF. Gestational diabetes incidence was higher in > 15%SDF compared to ≤ 15%SDF group (3.5% versus 1.7% (OR = 2.0 (95%CI 0.03-39.8), p = 0.5). Equally, the incidence of preeclampsia was 3.6% in patients with high SDF versus 1.7% in couples with low SDF, OR = 2.1 (95%CI 0.03-41.3), p = 0.5. Type of delivery frequency was in the ≤15%SDF group 61.9% vaginal and 38.1% cesarean, while in the >15%SDF group 62.1% vaginal and 37.9% cesarean (OR = 1.0 (95%CI 0.4-2.6), p = 1.0). The overall proportion of singleton pregnancies was 87.2% (95%CI 82.4-91.2) and twins 12.8% (95%CI 8.8-17.6). There were no statistically differences between groups in the rate of delivery of twins and in the sex ratio of the newborns. When comparing the newborns of ≤ 15%SDF with >15%SDF group, the average of weight was 3011.7g (95%CI 2912.2-3111.2) versus 2986.4g (95%CI 2753.1-3219.7), of length was 49.2cm (95%CI 48.3-50.0) versus 49.5cm (95%CI 49.2-49.9), of head circumference was 34.9cm (95%CI 34.6-35.2) versus 34.3cm (95%CI 33.4-35.2). No statistically differences were observed for Apgar punctuation and for NICU admission. Limitations, reasons for caution Due to the retrospective nature of the study we have missing data from the lack of follow-up of many patients after the confirmation of the ongoing pregnancy. Although pregnancies of couples with elevated SDF have a higher incidence of gestational diabetes and preeclampsia, the sample size evaluated is a limitation. Wider implications of the findings This is one of the first reports to evaluate the relationship between paternal DNA damage and obstetric risks and neonatal health in couples with high SDF who underwent IVF-ICSI in our centers. Despite SDF did not jeopardize the maternal and neonatal outcomes, more studies are needed to confirm this conclusion. Trial registration number NA

P–005 Magnetic-activated cell sorting in couples undergoing preimplantation genetic testing for aneuploidies (PGT-A) using autologous oocytes shows slightly lower aneuploidy rates compared to standard semen processing

Study question Does the selection of non-apoptotic sperm via magnetic-activated cell sorting (MACS) reduce the aneuploidy rate of embryos from couples undergoing ICSI cycles with PGT-A using the patients’ own oocytes? Summary answer It does. The aneuploidy rate in the MACS group was 4.34% lower than the one obtained using semen samples processed according to standard clinical practice. What is known already MACS is a successful tool in eliminating proapoptotic sperm from a semen sample. However, the true effect of this technique on reproductive outcomes and the quality of the resulting embryos are a matter of controversy. Some studies report that its use improves the percentage of good quality blastocysts in women older than 30 years old compared to standard ICSI. Randomized clinical trials that compare MACS to a control sample consider parameters of embryo quality such as morphology at day 3 or day 5, symmetry of the blastomeres, blastocysts’ stage of expansion, but they do not consider embryo ploidy. Study design, size, duration Retrospective, multicentre, observational cohort study. 14,145 patients and 18,710 cycles were evaluated in the reference group. In the MACS group, 615 patients and 974 cycles were considered. Data were exported from cycles performed in Spanish IVIRMA clinics between January 2008 and February 2020. Participants/materials, setting, methods Unselected males in couples undergoing PGT-A cycles, then subdivided into male factor (MF) - total progressive motile sperm count lower than 5 million - and non-male factor (NMF) infertility. Statistical analysis performed using R v.4.0.0. Means were calculated and compared using two-tailed paired t-test, while proportions were compared using Fisher’s exact test and the chi-squared test and the appropriate correction for multiple comparisons. The aneuploidy rates for each group were compared using Fisher’s exact test. Main results and the role of chance In the control group 73,228 biopsied embryos, from which 71,439 were informative in the PGT-A. In the MACS group 3,919 biopsied embryos, from which 3,843 were informative. The aneuploidy rate, computed per informative embryo, was 68.87% (68.40%, 69.34%) in the reference group and 64.53% (62.43%, 66.64%) in the MACS group. Both comparisons were statistically significant (p-value ˂0.00001). According to these results, an embryo in the PGT-A programme using non-apoptotic sperm selected through MACS and autologous oocytes had a 5% less chance of being aneuploid than those embryos fertilised with standardly selected sperm (relative risk of 0.95 (0.91–0.98) p = 0.006769). Embryos conceived from NMF patients whose semen had been processed using MACS had a 4.27% lower aneuploidy rate than the reference (65.52% (63.16%, 67.88%) vs 69.79% (69.20%, 70.37%) respectively). This difference was statistically significant. Those embryos conceived using semen from patients with MF using MACS also showed a lower aneuploidy rate than the reference with MF (0.28% (55.48%, 65.08%) vs (64.94% (63.35%, 66.23%) respectively), although this difference was not statistically significant. Thus, the decrease in aneuploidy rate observed when comparing MACS and reference groups undergoing PGT-A cycles using autologous oocytes remained approximately the same in both MF and NMF semen samples. Limitations, reasons for caution The retrospective nature of the study subjects the data to biases or inaccuracies in their annotation in the clinics’ informatic platform from which they were exported. However, the statistical analysis aimed at controlling these biases as much as possible. Wider implications of the findings: The vast amount of data compiled for this study confirms that the selection of non-apoptotic sperm through MACS slightly decreases the aneuploidy rate of embryos compared to semen samples processed according to the clinics’ standards. This would be interesting for patients who are considering undergoing PGT-A cycles in the future. Trial registration number Not applicable

P–762 Preeclampsia in pregnancies resulting from oocyte donation, IVF or natural conception. A systematic review and meta-analysis

Study question What is the prevalence of preeclampsia (PE) in pregnancies after oocyte donation (OD) compared to natural conception (NC) and to IVF with autologous oocytes? Summary answer PE prevalence in singleton pregnancies after OD was five times higher than in NC and almost three times higher than after IVF with autologous oocytes. What is known already: The indication for OD is expanding to lesbian women requesting shared lesbian motherhood. Previous reviews showed that the risk of PE is higher in pregnancies after OD than after IVF with autologous oocytes and natural conception. Classification on severity of PE is lacking as is the relationship with known risk factors such as maternal age and multiple gestations. Furthermore the actual prevalence of PE following in pregnancies resulting from OD is not known. Study design, size, duration Systematic review and meta-analysis. A literature search was performed using the following databases: PubMed, EMBASE and CINAHL, OpenGrey and Greynet from January 1980 through July 2020. Participants/materials, setting, methods We included retrospective and prospective cohort studies. The study population consisted of pregnancies after OD and NC or IVF and data had to be available about prevalence of PE. We compared the risk of (severe) PE in OD versus NC and IVF pregnancies, subgrouped by parity and maternal age. We calculated individual and pooled odds ratios (OR) and prevalence estimates with 95% CI using a random effect model, while heterogeneity was assessed by the I2. Main results and the role of chance We included 28 studies comprising of 7131 OD pregnancies, 1.139.540 NC pregnancies and 72.763 IVF pregnancies were available for analysis. The risk of PE and severe PE was increased in OD pregnancies compared to NC pregnancies (pooled OR of all subgroups: 5.09, 95% CI: 4.29 – 6.04; I2 = 19% and OR: 7.42 (95% CI: 4.64–11.88; I2 = 49%). The pooled adjusted OR for PE was 3.24 (95% 2.74 – 3.83) for OD versus natural pregnancies.The risk of PE and severe PE was increased in OD pregnancies compared to IVF pregnancies (pooled OR of all subgroups: 2.96, 95% CI: 2.49 – 3.51; I2 = 51% and OR: 2.97, 95% CI: 2.15 – 4.11; I2 = 0%). The pooled adjusted OR for PE was 2.67 (95% 2.28 – 3.13) for OD versus IVF.The pooled prevalence of PE in singleton pregnancies after OD was 10.7% (95% CI 6.6 – 15.5) compared to 4.1% (95% CI 2.7 – 5.6) after IVF and 2% (95% CI 1.0 – 3.1) after NC. The prevalence in multiple pregnancies was 27.8% (95% CI 23.6 –32.2) after OD, 9.7% (95% CI 6.2 – 13.9) after IVF and 7.5% (95% CI 7.2 – 7.8) after NC. Limitations, reasons for caution The precise definition of PE is still a matter of debate. The different criteria could have affected the prevalence estimate. Wider implications of the findings: Nearly one in six women will suffer PE after OD. Women who can conceive naturally i.e. shared lesbian motherhood, should be discouraged to turn to OD. In women with premature ovarian failure factors that increase risk of PE should be avoided. We suggest therefore single embryo transfer. Trial registration number Not applicable

Turning a Turner to a twin mother

Women with Turner syndrome (TS) are subfertile due to premature ovarian insufficiency. Most women require hormone replacement therapy for attaining menarche and assisted reproductive technology (ART) using donor oocytes, autologous oocytes or in-vitro fertilisation for conception. Irrespective of the karyotype, monosomy X (45, X) or mosaic pattern, women with TS hold a very high risk for pregnancy due to high mortality rate secondary to aortic dissection and severe pre-eclampsia. Such high-risk pregnancies mandate extensive prepregnancy counselling, the need for multidisciplinary teams, close surveillance and follow-up to attain a successful outcome. In this article, we report one such case of pregnancy in a woman with TS carrying a twin gestation following ART with donor oocyte.

Sperm Selection by Magnetic-Activated Cell Sorting Before Microinjection of Autologous Oocytes Increases Cumulative Live Birth Rates with Limited Clinical Impact: A Retrospective Study in Unselected Males

The application of MACS non-apoptotic sperm selection in infertility clinics is controversial since the published literature does not agree on its effect on reproductive outcomes. Therefore, it is not part of the routine clinical practice. Classical measures of reproductive success (pregnancy or live birth rates per ovarian stimulation) introduce a bias in the evaluation of a technique’s effect, since only the best embryo is transferred. This retrospective, multicenter, observational study evaluated the impact of MACS on reproductive outcomes, measuring results in classical parameters and cumulative live birth rates (CLBR). Data from ICSI cycles using autologous oocyte in Spanish IVIRMA fertility clinics from January 2008 to February 2020 were divided into two groups according to their semen processing: standard practice (reference: 46,807 patients) versus an added MACS sperm selection (1779 patients). Only when measured as CLBR per embryo transferred and per MII oocyte used was the difference between groups statistically significant. There were no significant differences between MACS and reference groups on pregnancy and live birth rates. In conclusion, results suggest that non-apoptotic sperm selection by MACS on unselected males prior to ICSI with autologous oocytes has limited clinical impact, showing a subtle increase in CLBR per embryo transferred.

Fertilization by ICSI generates a higher number of live births than IVF in a pioneer facility applying >90% single blastocyst-stage embryo transfers

Following earlier studies introducing an IVF-ICSI Split model on couples with unexplained infertility to avoid the scenario of unexplained failed or poor fertilization, PIVET has adopted a high ICSI rate approaching 90%, whereas the general rate among Australian facilities is around 60%. This observational study with retrospective data analysis reports on the IVF±ICSI procedures conducted over the period 2011 to 2019 with follow-up of ensuing pregnancies through 2020. Using autologous oocytes, 2343 women had 3434 IVF±ICSI cycles where 84.5% of women had 88.9% of initiated treatment cycles using ICSI and only 5.3% of women had 4.0% of cycles by IVF. The remaining 10.1% of women utilized the IVF-ICSI Split model for the remaining 7.2% of cycles. It was shown that oocyte fertilization rates were significantly higher for ICSI (p<0.0001), but not significant for women >40 years. The utilization rates of the ensuing embryos were ~45% across all ages with no significant differences across the ages, except for those small numbers of women ≥45 years who had a higher rate from IVF-generated embryos (p<0.0002). Pregnancy outcome were higher from ICSI-generated embryos across the age groups, being especially marked among the younger women <40 years (p<0.0001). Miscarriage rates were lowest for the IVF-generated pregnancies (overall 6.7% vs 22.8%, p<0.0001) but nevertheless the final live birth productivity rates per initiated treatment cycle remained higher from the ICSI-generated pregnancies (56.5% vs 46.3%; p<0.0001). Although this study does not meet the highest standards for EBM, it emanates from a pioneer facility with >40 years of published activity and which practices 90% blastocyst transfers in >90% SET cycles. The study supports a high ICSI rate of almost 90% and an IVF-ICSI Split rate of 10%.