Freeze-all Policy Research Articles

Reproductive outcomes in women with advanced endometriosis in fresh versus frozen embryo transfer cycles

BackgroundART in women with endometriosis is associated with poor quality of the retrieved oocytes and lower fertilization and pregnancy rates, reflecting that endometriosis may influence fertility by altering the quality of both the oocyte and embryo quality and also by impairing the endometrial receptivity. On comparing endometriosis-affected patients to healthy counterparts, many differences were demonstrated at the endometrial level. Thus, choosing the appropriate method of embryo transfer is of utmost importance, particularly for patients with advanced endometriosis.ObjectiveThe aim of the present study was to compare the reproductive outcomes between fresh and frozen embryo transfer cycles in women with advanced endometriosis.Material and methodsA retrospective cohort study was conducted in the period from January 2018 until December 2021 for patients recruited from two IVF centers, Alexandria, Egypt. Careful review of paper and electronic medical records of infertile women (primary, relative, or secondary infertility) aged 18–37 years who were diagnosed with advanced endometriosis by means of laparoscopy and were scheduled for ICSI followed by either fresh embryo transfer (group I) or freeze-all embryos and deferred embryo transfer (group II) of day 5 embryo(s) was included in the study.ResultsTwo-hundred and eleven women were eligible and included in the study. Women in each study group were matched regarding baseline characteristics. Clinical pregnancy, implantation, and ongoing pregnancy rates were statistically significantly higher in the group of frozen embryo transfer (p < 0.001). Miscarriage rate was found to be higher in the group of fresh transfer compared to FET group but without a statistical significance (20.9% vs 9.2%, p = 0.072).ConclusionIn women with advanced endometriosis, freeze-all policy seems to be associated with better implantation, ongoing pregnancy rates.

P-613 Natural cycles monitoring for frozen embryo transfers: is it beneficial to start immediately after ovarian stimulation?

Abstract Study question Are there more advantages in performing frozen embryo transfer (FET) immediately after ovarian stimulation or in delaying it by at least one menstruation? Summary answer In natural cycles, timing of frozen embryo transfer does not affect clinical pregnancy rates, but immediate transfer is associated with higher rates of cycle cancellation. What is known already In order to achieve a reduced time to pregnancy and avoid additional stress for the couple, some Centers initiate FETs immediately, i.e. on the first menstrual cycle after ovarian stimulation. However, the detrimental effect of hormonal stimulation on ovarian function and endometrial receptivity may persist in the following cycle and immediate FETs may increase the possibility of cycle cancellation and reduce pregnancy rate. Available evidence on this subject, mainly focused on endometrial preparation with hormonal replacement therapy (HRT), showed contrasting results. Moreover, studies on FETs performed on natural cycles are lacking. Study design, size, duration This is a retrospective study conducted at the Infertility Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, Italy. A large amount of single FETs, performed between 2014 and 2021, was considered and was then divided in two groups according to their timing (immediate or delayed). The primary outcome was to assess the clinical pregnancy rate (CPR); secondary outcomes were live birth rate (LBR) and the cycle cancellation rate. Participants/materials, setting, methods True natural cycles (T-NC) and modified cycles with the use of triggered ovulation (M-NC) protocols for endometrial preparation were pursued in women with regular menses; otherwise, HRT was used. Immediate FET was defined when performed on the first menstruation following ovarian stimulation (i.e. withdrawal bleeding occurring after ovarian stimulation or after a failed fresh embryo transfer). Delayed FETs included those performed after at least two menstruations. Only the first transfer after ovarian stimulation was considered. Main results and the role of chance A total of 5,765 FET cycles were included in the study. FET cycles were achieved through T-NC in 4,477 cases (78% of all FETs), of which 364 were immediate and 4,113 were delayed. M-NC cycles accounted for 1% of the total amount of FETs and HRT protocols were pursued in 11% of cases. The analysis showed no impact of FET timing on CPR both in the whole cohort and in the subgroups based on different endometrial preparation protocols. Focusing on T-NC cycles, the CPR in the immediate group was comparable to that of the postponed group (29 vs. 32% respectively, OR 0.90 [95% CI 0.71 - 1.14]). On the other hand, LBR in T-NC cycles was significantly lower in the immediate group than in the delayed group (20% vs. 25% respectively, OR 0.74 [95% CI 0.56 - 0.96]). Consequently, immediate FETs resulted to be associated with a significantly higher rate of pregnancy loss (31% vs. 21% respectively, p = 0.03). Furthermore, cycle cancellation occurred more frequently in the immediate T-NC group, compared with the delayed group (18% vs. 12% respectively, p = 0.003). Similar results were observed in HRT cycles (15% in immediate FETs vs. 7% in delayed FETs, p = 0.08). Limitations, reasons for caution The retrospective nature of this study involves a risk of selection bias. Moreover, the reason for cycle cancellation was not always available; thus, these data were not included in the analysis. Lastly, these outcomes are only applicable to a similar cohort, that is Centers following a non-elective freeze-all policy. Wider implications of the findings This is the largest investigation on T-NC FETs and is among the very few studies providing separate results on different endometrial preparation protocols. Evidence from this study is in line with some previous retrospective analyses and in contrast with others. Thus, randomized controlled trials are needed to confirm these results. Trial registration number not applicable

Can serum progesterone concentration direct a fresh or freeze-all transfer strategy in the first in vitro fertilisation cycle?

PurposeTo examine the interaction between serum progesterone concentration on the trigger day and choice of freeze-all and fresh transfer strategies on live birth in an unselected population as well as in patients over 35 years old.MethodsWe performed a retrospective cohort study of 26,661 patients commencing their first IVF cycle in a large fertility centre between 2015 and 2019, including 4687 patients over 35 years old. We performed a multivariable fractional polynomial interaction analysis within a logistic regression model to investigate the interaction between serum progesterone concentration and the choice of freeze-all or fresh transfer strategy following the first transfer.Results15,539 patients underwent a fresh embryo transfer and 11,122 underwent a freeze-all strategy in their first IVF cycle. The freeze-all group had a higher live birth rate compared to the fresh group (43.9% vs 40.3%). After adjusting for confounding factors, there was a positive interaction between serum progesterone concentrations and the choice of a freeze-all versus fresh embryo transfer on live birth (p for interaction 0.0001), with a larger magnitude of effect when progesterone concentration was higher. Such an interaction was also observed in patients over 35 years old (p for interaction 0.01), but the treatment effect curve over progesterone concentrations was almost flat.ConclusionsIn an unselected population, frozen transfer is associated with greater chances of live birth, especially in patients with higher serum progesterone concentration. In patients over 35 years old, the benefit of a freeze-all policy appears small across all serum progesterone concentrations.

Higher pre-pregnancy body mass index was associated with adverse pregnancy and perinatal outcomes in women with polycystic ovary syndrome after a freeze-all strategy: Ahistorical cohort study.

Previous studies have demonstrated that abnormal body mass index (BMI) is associated with adverse pregnancy outcomes in frozen-thawed embryo transfer cycles. However, the relationship between BMI and pregnancy and perinatal outcomes in patients with polycystic ovary syndrome (PCOS) remains unclear. Furthermore, whether a diagnosis of PCOS could result in adverse pregnancy and perinatal outcomes in women with different BMIs remains unknown. A historical cohort study included 1667 women with PCOS and 12 256 women without PCOS after a freeze-all policy between January 2016 and December 2020. The outcomes encompassed both pregnancy and perinatal outcomes. Multivariate logistic regression analysis and restricted cubic spline models were performed to eliminate confounding factors when investigating the relationship between BMI and different outcomes. After controlling for covariates, pregnancy outcomes were comparable between underweight women with PCOS and normal weight women with PCOS. However, overweight patients had a lower clinical pregnancy rate and an overall live birth rate. Furthermore, patients with obesity had a lower rate of multiple pregnancies but a higher rate of biochemical pregnancy than in the normal BMI group. Additionally, the restricted cubic spline models showed that as maternal BMI increased to 32 kg/m2, the clinical pregnancy rate and live birth rate after blastocyst transfer decreased, but the risks of preterm birth, gestational diabetes mellitus, macrosomia, large-for-gestational age (LGA) and very LGA increased in patients with PCOS after a freeze-all strategy. Moreover, a diagnosis of PCOS resulted in a higher clinical pregnancy rate and live birth rate and a higher risk of small-for-gestational age in the normal weight group. However, women with PCOS in the overweight group exhibited higher risks of very preterm birth and gestational diabetes mellitus compared with women without PCOS. This study showed that a higher BMI had a detrimental impact on the pregnancy and perinatal outcomes of PCOS patients undergoing a freeze-all strategy. However, it was only statistically significant in the overweight group. A diagnosis of PCOS had a higher clinical pregnancy rate and live birth rate in normal weight women but higher risks of perinatal complications in normal weight and overweight women.

#381 : Can Serum Progesterone Concentration Direct a Fresh or Freeze-All Transfer Strategy in the First In Vitro Fertilisation Cycle?

Background and Aims: The role of progesterone in preparing the endometrium for implantation and sustaining early pregnancy is well established in ART, however the role of serum progesterone measurement within cycles in determining the outcome of embryo transfer (ET) is not defined. This study aimed to examine the interaction between serum progesterone concentration on the day of HCG trigger and choice of freeze-all and fresh transfer strategies on live birth. Method: We retrospectively studied 26661 women (Chengdu Xinan Hospital) commencing their first IVF cycle using autologous gametes between January 2015 and September 2019. We excluded cycles where oocyte retrieval was cancelled or no embryos were available for transfer, cycles where fresh or frozen transfer was determined by patient preference, and when serum progesterone on day of HCG was [Formula: see text] 2.0 or [Formula: see text] 20 oocytes were collected. The primary outcome of interest was live birth after 28 weeks gestation following first ET and expressed as an odds ratio (OR). Results: The predicted odds of live birth were greater in the frozen ET group at all progesterone concentrations. The effect was more pronounced with progressive increase in progesterone concentration (Figure 1) and maintained in both unadjusted and adjusted models. For women &gt;35 years (n=4687), a positive interaction between progesterone and treatment effect was present although the treatment effect curve was flattened (p for interaction = 0.01). Conclusion: In an unselected population undergoing IVF/ICSI, there is an increased chance of pregnancy with a freeze all ET strategy at different progesterone concentrations on HCG trigger day. The effect appears to be dose related with increasing magnitude of effect with rising progesterone concentration. This interaction was also observed in subsets of women with single ET and women &gt; 35 years old, however the benefit of a freeze-all policy appears low in these women.

The adenomyosis/endometriosis IVF patient – call for clinical focus

Endometriosis and adenomyosis are distinct clinical conditions that carry the same pathophysiological features. In recent years the clinical focus on assisted reproductive technology patients with either condition (E/A) has increased, in the recognition that this subgroup of patients might need special attention to obtain reproductive success. Endometriosis and adenomyosis are characterized by a disruption of progesterone and oestrogen signalling pathways, resulting in local oestrogen dominance and progesterone resistance at the receptor level. Recent scientific evidence suggests that the endometrial progesterone receptor resistance encountered in E/A patients can be overcome by a freeze-all policy, followed by down-regulating circulating oestradiol concentrations prior to frozen embryo transfer (FET), in combination with an increase in exogenous luteal phase progesterone supplementation in hormonal replacement therapy (HRT) FET cycles. Specifically, for adenomyosis patients who do not respond to gonadotrophin-releasing hormone agonist down-regulation in terms of a decrease in circulating oestradiol concentrations, a small case series has suggested that the addition of an aromatase inhibitor for 21 days prior to HRT–FET is a valid option. Endometriosis and adenomyosis are hormonally active diseases, which need to be treated by controlling local hyperoestrogenism and progesterone resistance. Based on physiology and recent preliminary clinical data, the authors of this opinion paper wish to stimulate discussion and spark interest in research in E/A patients.

Aspiration with Diosmin Intake in Endometrial Cavity Fluid Accumulation in ART Cycles: A Randomized Controlled Trial.

This was a prospective randomized controlled trial in 200 cases presented with endometrial cavity fluid at the day of oocyte retrieval at a private fertility center from 2013 to 2021. The cases were randomized at day of ovum pickup into 2 groups: Group 1 (control group) (n = 100): conventional management with follow-up and reassessment by transvaginal ultrasound on day 5. Group 2 (interventional group) (n = 100): aspiration of the fluid was done and cases were given diosmin 500mg 3 times per day till reassessment at embryo transfer day. In both groups, we proceeded with fresh embryo transfer if no fluid is present on day 5 or freeze-all policy if persistent fluid was detected. Endometrial fluid on the 5th day was significantly higher in the control group (28.0%) than in the interventional group (6.0%) (P < 0.001). Regarding pregnancy rate, although being higher in the interventional group (54.3% vs 50.0%), the difference was not statistically significant (P = 0.5). It was found that the intervention was associated with risk reduction of endometrial fluid (OR = 0.168, 95% CI = 0.065-0.429, P < 0.001. Aspiration of endometrial cavity fluid with diosmin intake increased the likelihood of fresh embryo transfer and with a slightly better pregnancy rate compared to conservative management.Clinical trial number: NCT02158000, Date of registration: 6/6/2014, Date of initial enrollment (first patient recruiting): 1/11/2014, URL: https://clinicaltrials.gov/ct2/show/NCT02158000.

Freeze-all embryos during treatment with assisted reproduction: Health economic aspects.

Assisted reproductive technologies are evolving, with the most recent example being the introduction of the freeze-all policy during which a fresh embryo transfer does not take place and all embryos of good quality are cryopreserved to be used in future frozen embryo transfers. As the freeze-all policy is becoming more prevalent, it is important to review the economic aspects of this approach, along with considerations of efficacy and safety, and the role of emerging freeze-all-specific ovarian stimulation strategies. Based on the available evidence, the freeze-all policy presents distinct clinical advantages, particularly for high responders. Available health economic evaluations are limited. Two good-quality cost-effectiveness analyses based on randomized controlled trials suggest that the freeze-all strategy is unlikely to be cost-effective in non-polycystic ovarian syndrome (non-PCOS), normally responding patients. However, the cost-effectiveness of the freeze-all strategy in different populations of patients and in different settings has not been evaluated, nor has the clinical and economic efficacy of modern freeze-all-specific ovarian stimulation protocols that are likely to simplify treatment and make it more affordable for patients. Economic evaluations that incorporate good practice health technology assessment (HTA) methods are needed to compare freeze-all with conventional embryo transfer strategies. Furthermore, future research should address the unique limitation of traditional HTA methods in valuing a life conceived through fertility treatment.

A drop in serum progesterone from oocyte pick-up +3 days to +5 days in fresh blastocyst transfer, using hCG-trigger and standard luteal support, is associated with lower ongoing pregnancy rates.

A drop in serum progesterone from oocyte pick-up +3 days to +5 days in fresh blastocyst transfer, using hCG-trigger and standard luteal support, is associated with lower ongoing pregnancy rates.

Live birth rate and neonatal outcomes following interventional embolization of hydrosalpinx

BackgroundHydrosalpinx has a negative effect on the pregnancy outcomes of in vitro fertilization and embryo transfer (IVF-ET), and the pretreatment for hydrosalpinx play an important role in improving the outcomes of IVF-ET. This study aimed to investigate the impacts of interventional embolization of hydrosalpinx on the live birth rate and neonatal outcome after in-vitro fertilization.MethodIn the present retrospective study, 3351 women receiving the first frozen embryo transfer (FET) after freeze-all policy were reviewed. Patients who received interventional embolization of hydrosalpinx (n = 1268) were included in the study group and those with hydrosalpinx-free bilateral fallopian tube obstruction (n = 2083) in the control group. The primary outcome was live birth (LB) rate; the secondary endpoints included rates of implantation, clinical pregnancy (CP), multiple pregnancy, and pregnancy loss.ResultsThe LB rate was similar between embolization group (39.91%) and control group (43.21%) (P > 0.05). The rate of implantation (35.81% vs. 32.24%), CP (50.84% vs. 47%) and multiple pregnancy rate (28.71% vs. 24.16%) in the control group were significantly higher than in the embolization group (P < 0.05). The miscarriage rate (39.91%, vs 43.21%, P > 0.05), ectopic gestation rate (2.35% vs 2.83%, P > 0.05), and ongoing pregnancy rate (41.56% vs 44.89%, P > 0.05) were comparable between two groups. After adjustment for confounding factors, interventional embolization of hydrosalpinx was found to have no influence on the LB rate. The thicker endometrium, more embryos transferred, and transfer of blastocyst stage embryos significantly increased the LB rate and CP rate.ConclusionThe interventional embolization of hydrosalpinx can achieve the LB rate similar to that of hydrosalpinx-free obstruction patients with less risk, less pain and reduced medical cost. Thus, embolization of hydrosalpinx is one of the preferable clinical treatments for patients with hydrosalpinx.

Association of infertility cause with perinatal outcomes in a freeze-all policy: an analysis including 10,151 singleton newborns

In vitro fertilization-conceived babies, even singletons, are at a higher risk of poor birth outcomes such as low birthweight and preterm birth than naturally conceived counterparts. It remains unclear as to what extent these adverse outcomes are attributed to the underlying causes of infertility. Evidence on this topic is scarce and has mainly focused on fresh embryo transfer cycles. This study aimed to investigate the effect of infertility cause on perinatal outcomes when a freeze-all strategy is applied. We conducted a retrospective cohort study involving singleton live births born to women who had undergone frozen-thawed embryo transfer during the period from January 2014 to December 2019 at a single center. Subjects were categorized into 7 groups as follows according to the sole cause of infertility: tubal disorder, polycystic ovary syndrome, diminished ovarian reserve, uterine factor infertility, endometriosis, male factor, and unexplained infertility. The perinatal outcomes evaluated were as follows: birthweight, newborn gender, gestational age, preterm birth, low birthweight, small for gestational age, large for gestational age, and macrosomia. Multivariable regression analyses were introduced to control for several important confounders, with unexplained infertility as a reference group. A total of 10,151 women were included for the final analysis. The most common maternal infertility diagnosis of the entire cohort was tubal disorder (42.5%), followed by diminished ovarian reserve (9.5%), endometriosis (9.4%), polycystic ovary syndrome (5.7%), and uterine factor infertility (1.6%). Male factor infertility was present in 19.8% of cycles, and infertility was diagnosed as unexplained in 11.4% of cycles. In the unadjusted analyses, the prevalence of low birthweight (odds ratio, 2.05; 95% confidence interval, 1.24-3.38) and preterm birth (odds ratio, 1.97; 95% confidence interval, 1.33-2.92) was higher among singletons in the polycystic ovary syndrome group than in those from the unexplained infertility group. However, these differences were no longer significant after correction for parental characteristics, treatment variables, and pregnancy complications (adjusted odds ratio, 1.50; 95% confidence interval, 0.98-2.28 for preterm birth; adjusted odds ratio, 1.70; 95% confidence interval, 0.99-2.91 for low birthweight). The risks of preterm birth (adjusted odds ratio, 2.66; 95% confidence interval, 1.53-4.63) and low birthweight (adjusted odds ratio, 3.51; 95% confidence interval, 1.79-6.90) with uterine factor infertility were significantly increased vs the reference group in both unadjusted and adjusted analyses. In addition, the perinatal outcomes in women with other infertility causes were comparable with unexplained infertility in terms of the rates of preterm birth, low birthweight, small for gestational age, large for gestational age, and macrosomia. With the exception of uterine factor infertility, other infertility causes do not seem to compromise perinatal outcomes when compared with unexplained infertility in a freeze-all approach. With the ever-increasing use of frozen-thawed embryo transfer globally, our data hold relevant clinical implications, as they can guide physicians in patient counseling.

It is not worth postponing frozen embryo transfers after oocyte pickup: A retrospective cohort study based on propensity score matching.

This study was to explore whether postponing frozen embryo transfers (FET) after oocyte pickup (OPU) improves clinical and neonatal outcomes. From May 2018 to Dec 2020, a total of 1109 patients underwent their first OPU cycles adopting a non-selective freeze-all policy were included in this retrospective cohort study. In the immediate group (n=219), patients underwent FET in the first menstrual cycle after OPU, and patients in the postponed group (n=890) waited for more than 1 menstrual cycle after OPU to perform FET. A propensity score matching (PSM) model was used to evaluate the clinical outcomes and neonatal outcomes between the two groups. There were 209 patients in the immediate group and 499 patients in the postponed one after PSM. Patients waited for a significantly shorter period for FET in the immediate group (30.74 ± 3.85 days) compared with the postponed group (80.39 ± 26.25 days, P<0.01). The clinical pregnancy rate (CPR) and live birth rate (LBR) in the immediate group were 58.4% and 48.3%, respectively, which were comparable to those of the postponed one (58.1%, 49.7%, P > 0.05). No statistical significance was found in the average birth weight (3088.82 ± 565.35 g vs 3038.64 ± 625.78 g, P > 0.05) and height (49.08 ± 1.87 cm vs 49.30 ± 2.52 cm) of neonates between the two groups. The gender ratio, the incidence of macrosomia and low birth weight did not differ significantly between the two groups. In conclusion, postponing FET does not improve clinical and neonatal outcomes. If patients have no contraindications, FETs should be carried out immediately after OPU.

The impact of a previous tubal ectopic pregnancy on live birth and perinatal outcomes in vitrified-warmed cycles

Research questionDoes a previous history of naturally conceived tubal ectopic pregnancy (TEP) affect subsequent pregnancy and perinatal outcomes when a freeze-all policy is applied? DesignA large retrospective study was performed involving women who had undergone their first frozen-thawed embryo transfer (FET) cycles, using vitrified-warmed embryos, from January 2013 to April 2018 at a tertiary care centre. Participants were divided into two groups: a study group consisting of women with a history of TEP preceding IVF, and a control group consisting of women without an initial TEP. The live birth rate (LBR) and perinatal outcomes were evaluated via a propensity score matching method. ResultsA total of 23,270 women were included for potential analysis and finally 2168 pairs of women were generated for comparison after propensity score matching. The LBR in the study group was similar to that in the control group (45.7% versus 44.0%, P = 0.259). No differences were noted regarding rates of ectopic pregnancy (5.4% versus 4.1%, P = 0.122), miscarriage (11.5% versus 13.5%, P = 0.158) or intrauterine implantation (35.8% versus 35.8%, P = 0.974) between the groups. Regarding birth outcomes, the mean gestational age and birthweight and the incidences of preterm birth and low birthweight were comparable between the groups for both singletons and twins. ConclusionsThe present study demonstrated that a prior history of TEP was not associated with adverse reproductive and perinatal outcomes in subsequent FET cycles. With the increasing utilization of FET globally, these results are important as they can help guide physicians during patient counselling.

Freeze-all policy versus luteal phase support with low dose of human chorionic gonadotrophin for high-responder patients undergoing intracytoplasmic sperm injection on pregnancy outcomes: a retrospective cohort observational study

BackgroundThe literature has always controversies on the use of freeze-all policy in high-responder women performing intracytoplasmic sperm injection. In this article, we discuss the benefits of freeze-all policy on the incidence of pregnancy outcomes and the complications.The main body of abstractFreeze-all policy is applied to the intracytoplasmic sperm injection program by freezing of all embryos and delaying embryo transfer to another subsequent ovarian cycle, to decrease the incidence of ovarian hyperstimulation syndrome, especially in high-responder women. Unfortunately, freeze-all policy is correlated with an increase in the economic costs and more ICSI laboratory effort. Delayed embryo transfer (ET) is correlated with more anxiety among the patients. An alternative strategy is to perform fresh embryo transfer with more intensive luteal phase support to compensate for the negative effect of the GnRH agonist on the endometrial receptivity and luteal phase support.Short conclusionThe freeze-all policy had better pregnancy rates with less incidence of moderate to severe hyperstimulation syndrome compared with original fresh embryo transfer in high-responder women performing intracytoplasmic sperm injection.

O-273 Risk of hypertensive disorders in pregnancy after fresh and frozen embryo transfer in assisted reproduction: A population-based cohort study with within sibship analysis

Abstract Study question Is the risk of hypertensive disorders in pregnancy (HDP) increased following assisted reproductive technology (ART) with fresh or frozen cycles compared to conception without ART? Summary answer Pregnancies after frozen embryo transfer (FET) had a substantially higher risk of HDP, also after accounting for constant parental factors in within sibship comparisons. What is known already FET in assisted reproductive technology (ART) is increasingly common because of improved cryopreservation methods, blastocyst culture, and freeze-all practice. Conventional observational studies have raised concerns about treatment safety due to higher risk of HDP after FET compared to both non-ART and fresh embryo transfer (fresh-ET). Whether this is attributable to parental factors or treatment is unknown. Within sibship comparisons can provide unique insight by controlling for confounding from unmeasured, constant parental factors, like genetics, preconception lifestyle and health, as well as socioeconomic status. Study design, size, duration Population-based cohort study with within sibship comparison using health registry data from three Nordic countries. In total, 4,523,028 singleton pregnancies resulting in delivery between 1988 and 2015 were included, of which 78,300 were after fresh-ET, and 18,037 were after FET. We identified 33,209 sibships that were conceived using two or three different conception methods (fresh-ET, FET, and non-ART). Participants/materials, setting, methods Data were collected from several national health registries in Denmark, Norway, and Sweden, including ART, medical birth, and patient registries, and linked using the residents’ unique identification numbers. Adjusted odds ratios (aOR) of HDP with 95% confidence intervals (CI) were estimated using multilevel logistic regression, where random effects provided conventional population estimates, and fixed effects gave within sibship estimates. Main models included adjustment for maternal age, parity, birth year and country. Main results and the role of chance Risk of HDP was higher after FET compared to non-ART conception, both at the population level (7.4% vs 4.3%, aOR 1.74, 95% CI 1.61 to 1.89) and within sibships (aOR 2.02, 95% CI 1.72 to 2.39). For fresh-ET, the risk was similar to non-ART, both at the population level (5.9% vs 4.3%, aOR 1.02, 95% CI 0.98 to 1.07) and within sibships (aOR 0.99, 95% CI 0.89 to 1.09). Sensitivity analyses with adjustment for body mass index (BMI) and smoking, restriction to full siblings (same mother and father) and siblings born within a three-year interval, were all consistent with our main findings. Furthermore, the results were not driven by order of conception method or other ART procedures (intracytoplasmic sperm injection, culture duration or number of embryos transferred). Limitations, reasons for caution Despite the extra control for shared confounders provided by the within sibship analyses, we cannot exclude residual confounding from non-shared confounders, such as smoking and BMI, where confounder control was limited by a large proportion of missingness, and causes of infertility, which were largely unknown. Wider implications of the findings Our findings are important for the ongoing discussion about the freeze-all policy, and further investigation of which treatment factors might be involved is warranted. Trial registration number Not applicable

P-333 The influence of hormonal stimulation on uterine peristalsis measured by ultrasound speckle tracking in women with IVF/ICSI treatment compared to normal ovulating women

Abstract Study question To investigate possible effects of ovarian stimulation during IVF/ICSI on uterine peristalsis features using ultrasound speckle tracking compared to normal ovulating women. Summary answer Patients with a normal uterus treated with exogenous hormones during IVF/ICSI treatment show significantly increased contraction amplitude and power parameters compared to normal ovulating women. What is known already Uterine peristalsis plays a role in procreation. Subjective visual inspection of uterine peristalsis is extensively researched throughout the menstrual cycle. Studies on uterine peristalsis in IVF/ICSI patients show higher frequency of uterine contractions during the periovulatory phase. Recently, a new automated quantitative method was validated to objectively analyse uterine strain using speckle tracking. Besides objective insight in frequency, also information on amplitude, power and coordination of motion is available. The effect of exogenous hormones on uterine contraction features has not objectively been studied using this new method. Study design, size, duration This multicentre prospective observational cohort study was performed between 2020 and 2022 in the Catharina Hospital in Eindhoven, the Netherlands, Embryolab Fertility Centre in Thessaloniki, Greece and University of Naples, Federico II in Naples, Italy. 30 normal ovulating patients served as controls. The primary outcomes were the contraction features frequency, amplitude, direction, velocity, power and coordination in women undergoing IVF/ICSI on the day of follicle aspiration compared to controls on cycle day 9 – 14. Participants/materials, setting, methods 19 women undergoing IVF/ICSI were included regardless of the treatment cycle number and stimulation protocol. Indication for IVF/ICSI treatment was male subfertility (n = 8), idiopathic subfertility (n = 5), tubal factor (n = 2), primary ovarian insufficiency (n = 2) or combined (n = 2), all women had normal uteri on transvaginal ultrasound. The control group consisted of 30 healthy pre-menopausal women with normal uteri on ultrasound and spontaneous regular cycles. Main results and the role of chance Each patient underwent a 2.5 – 4 minute transvaginal ultrasound of the uterus in mid-sagittal plane. The various contraction features were extracted using a quantitative dedicated speckle tracking algorithm analysis studying motion of the subendometrial junctional zone. Mean age of IVF/ICSI patients was 32.7 years and mean BMI was 25.6. Mean age of healthy controls was 33.8 years, BMI was 23.4, and cycle length was 27.44 days. Characteristics of IVF/ICSI patients and healthy volunteers showed no statistically significant differences. Both groups predominantly consisted of nulliparous women. In IVF/ICSI patients the contraction amplitude was significantly higher compared to controls (0.062 vs 0.040; p &amp;lt; 0.001). The contraction power (combination of amplitude and frequency) appeared to be significantly higher in IVF/ICSI patients compared to controls (1528.18 vs 683.44; p &amp;lt; 0.001). No significant differences were found in contraction frequency and coordination. Even though the mean coordination did not show statistically significant differences, the values were less scattered in IVF/ICSI patients, with a much smaller range of coordination values (1.04 – 3.06) compared to healthy volunteers (1.02 – 50.33). Limitations, reasons for caution The reported difference between IVF/ICSI patients and controls in contraction amplitude and power may not solely be attributed to the administration of exogenous hormones. The difference may also be due to an underlying cause for infertility in these patients. Another limitation of this study is the small sample size. Wider implications of the findings Future research should explore which uterine contraction profile is associated with viable pregnancy: during the natural menstrual cycle, or when treated with hormones. The question arises whether it is preferred to transfer the embryo in the stimulated cycle or implement a freeze-all policy and transfer during the natural menstrual cycle. Trial registration number NCT02310802

P-634 Safety of ART cycles with extremely high estradiol levels - A retrospective cohort study

Abstract Study question Are IVF treatments with extremely high peak estradiol levels during ovarian hyperstimulation associated with higher complication rates? Summary answer Extremely high estradiol levels were not associated with higher major complication rates, but patients were more likely to seek medical care following retrieval. What is known already The freeze-all policy and the increasing popularity of social oocyte freezing, have led to an increase in gonadotropin doses and number of oocytes retrieved and, as a direct effect, higher estradiol levels. Studies reporting major ART complications (OHSS, bleeding, infection, torsion, thromboembolic events) are based on heterogeneous patient populations without stratification by oocyte number or estradiol levels, except for a single study reporting an association between peak estradiol levels and the risk of ovarian torsion. Extreme estradiol levels, are associated with larger ovaries, repeated ovarian punctures, and possibly a thrombogenic effect. Therefore, higher complication rates can be expected. Study design, size, duration A retrospective cohort study including patients from two large medical centers treated between 2019-2021. Participants/materials, setting, methods A study group (239 patients) with extremely high peak estradiol levels (&amp;gt;20,000 pmol/L on the day of ovulation induction, or &amp;gt; 15,000 pmol/L on the previous day) and a control group (208 patients) with normal range estradiol levels (3000-12000pmol/L), treated at two large units were included. Patients were surveyed about complaints and medical care related to ovum pick up (OPU), and medical files were reviewed. Complication rates and the need for medical assistance were compared. Main results and the role of chance Several differences between the study and control group were observed as a consequence of the study design: Mean age was 33.01±5.14 vs. 34.57±4.52 (p = 0.01), Mean peak estradiol levels was 26645.34±8592.56 vs.7229.750±2329.20 (p &amp;lt; 0.001), mean number of oocytes were 27.55±13.46 vs. 11.63±5.77 (p &amp;lt; 0.001) for the study and control group respectivly. More patients in the control group underwent fertility preservation. Mean FSH levels and total gonadotropin dosage were higher in the control group. Major complications [3 (1.25%) in the study group vs. 1 (0.96%) in the control group] were similar between groups (p = 0.62). In the study group Two patients were diagnosed with ovarian torsion (0.83%), and one (0.41%) with early severe OHSS as a result of a positive BhCG related to an undiagnosed pregnancy prior to OPU. All three were admitted (1.25%). In the control group one patient was diagnosed with PID requiring inpatient IV antibiotic treatment (0.48%). One more patient was admitted with severe abdominal pain following OPU, for a total of 2 admissions (0.96%) (p = 1). 33 patients (13.8%) in the study group and 10 (4.8%) in the control group sought medical care after OPU, mostly due to abdominal pain, without further workup or hospitalization (p = 0.001). Limitations, reasons for caution A retrospective study with possible recall bias. Major adverse events are rare in IVF and may not be fully captured in the study population. Wider implications of the findings Based on our results, extremely high estradiol levels during ovarian hyperstimulation were not associated with thromboembolic events, higher major complication or hospitalization rates, thus may be considered safe. Nevertheless, patients may be informed of possible higher rates of discomfort, mostly abdominal pain. Larger studies are warranted to confirm our results. Trial registration number 0090-21-ASF

Differences in Ectopic Pregnancy Rates between Fresh and Frozen Embryo Transfer after In Vitro Fertilization: A Large Retrospective Study.

Ectopic pregnancy (EP) is increasingly found in women treated with in vitro fertilization and embryo transfer (IVF–ET). With the development of the freeze-all policy in reproductive medicine, it is controversial whether frozen embryo transfer (FET) could reduce the rate of EP. In this single-center, large-sample retrospective study, we analyzed 16,048 human chorionic gonadotrophin (hCG)-positive patients who underwent fresh embryo transfer (ET) or FET cycles between January 2013 and March 2022. Throughout the study, the total EP rate was 2.09% (336/16,048), 2.16% (82/3803) in the ET group, and 2.07% (254/12,245) in the FET group. After adjustment for age, infertility causes, and other confounding factors, logistic regression results showed no statistical difference in EP rates between FET and ET groups (odds ratio (OR) 0.93 (0.71–1.22), p > 0.05). However, among the 3808 patients who underwent fresh ET cycles, the OR for EP was significantly lower in the long agonist protocol group than in the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol group (OR 0.45 (0.22–0.93), p < 0.05). Through a large retrospective study, we demonstrated a slightly lower EP rate in FET cycles than in fresh ET cycles, but there was no significant difference. The long agonist protocol in ET cycles had a significantly lower risk of EP than the GnRH-ant protocol.

Pro: Fresh versus frozen embryo transfer. Is frozen embryo transfer the future?

Embryo cryopreservation has been an integral part of ART for close to 40 years and vitrification has boosted overall ART efficacy and safety. Recently, there has been a vivid scientific discussion on whether elective cryopreservation of all embryos (freeze-all) should be pursued for most patients, with a fresh embryo transfer taking place only in selected cases. In terms of efficacy, the available evidence suggests that the freeze-all strategy leads to higher live birth rates after the first embryo transfer compared to the conventional strategy in high responders, while there is no difference in normal responders. There is no evidence to suggest that the freeze-all strategy is inferior to the conventional strategy of fresh transfer when comparing cumulative live birth rates using data from all available randomized controlled trials. The incidence of ovarian hyperstimulation syndrome is significantly reduced in the freeze-all policy. However, regarding obstetric complications and neonatal outcomes, the evidence suggests that each strategy is associated with certain risks and, therefore, there is no approach that could be unequivocally accepted as safer. Similarly, limited evidence does not support the notion that patients would be universally against freeze-all owing to the inevitable delay in pregnancy achievement. Finally, the cost-effectiveness of freeze-all is likely to vary in different settings and there have been studies supporting that this policy can be, under certain conditions, cost-effective. Adoption of the freeze-all policy can also allow for more flexible treatment strategies that have the potential to increase efficacy, reduce cost and make treatment easier for patients and clinics. Importantly, freeze-all does not require the use of any experimental technologies, further training of personnel or the costly acquisition of new equipment. For these reasons, transitioning to the freeze-all policy for most patients appears to be the next logical step in ART.

Algorithm-based individualization methodology of the starting gonadotropin dose in IVF/ICSI and the freeze-all strategy prevent OHSS equally in normal responders: a systematic review and network meta-analysis of the evidence.

Ovarian hyperstimulation syndrome (OHSS) represents a rare but dangerous condition associated with controlled ovarian stimulation (COS) in IVF/ICSI. Over the last decades, many strategies have been introduced into clinical practice with the objective of preventing this potentially life-threatening condition. Among these, the freeze-all policy has gained great popularity, thanks to improvements in vitrification. Nevertheless, not all clinics have adequate skills in vitrification procedures and patients may be dissatisfied with a longer time to pregnancy. This study is a systematic review and network meta-analysis of randomized controlled trials comparing different strategies of ovarian stimulation in IVF/ICSI cycles (freeze-all policy, algorithm-based individualization of the starting dose, experience-based individualization of the starting dose, standard dose) in terms of reduction of OHSS, in normal responders. The results indicate that only the algorithm-based individualization of the starting gonadotropin dose reduces OHSS similarly to the freeze-all strategy. Albeit in the era of the freeze-all policy, the personalization of the starting gonadotropin dose obtained by the use of algorithms should be pursued as a valid and safe option for IVF.