Study question Does gonadotropin stimulation in conventional IVF (cIVF) affect the implantation, miscarriage and live birth rates? Summary answer Gonadotropin stimulation negatively affects the implantation and live birth but not the miscarriage rate in IVF treatments. What is known already Literature hypothesizes that embryos derived from unstimulated, natural cycle IVF (NC-IVF) have a higher implantation potential compared to embryos from cIVF. In NC-IVF, recruitment of the leading follicle is based on natural selection. Hormonal stimulation might not only affect the embryo but also endometrial function. It’s possible to compare outcomes of NC-IVF and cIVF if cIVF is performed without embryo selection, in other words, if only those zygotes, which will be transferred 1–2 days later, are left in culture and all other zygotes are cryopreserved. To test this hypothesis, we compared success rates in NC-IVF and in cIVF. Study design, size, duration We performed a cohort study from 2011–2016 including data on IVF cycles with transfer of fresh embryos on day 2–3 at a University based infertility center. Our sample consisted of 640 women with 1482 embryos transferred in 996 cycles. We defined implantation rate as the number of sonograhically detected amniotic sacs per transferred embryos. Data originated from the Swiss ART registry “FIVNAT” and the Bern IVF Cohort and was completed using medical and delivery records. Participants/materials, setting, methods We defined NC-IVF as IVF without stimulation of follicular growth and cIVF as IVF with gonadotropin stimulation ≥75 IE/d and >3 retrieved oocytes. We performed zygote, but not embryo selection and transferred embryos on day 2–3. We calculated implantation and live birth per transferred embryo as binary outcomes using bi- and multivariable multilevel logistic regression models accounting for two clusters; the women and the cycle; and adjusting for maternal and infertility characteristics using STATA. Main results and the role of chance Age of women (p = 0.531), parity (p = 0.194) and type of infertility (primary vs secondary) (p = 0.463) did not differ between women undergoing NC-IVF or cIVF. In NC-IVF, 468 (31.6%) embryos were transferred, 450 as single, 18 as double transfers. In cIVF, 1014 (68.4%) embryos were transferred, 91 as single, 830 as double and 93 as triple transfers. Implantation rate was higher in NC-IVF. In NC-IVF 80 (17.1%) and in cIVF 132 (13.0%) embryos developed into an amniotic sac (OR 1.58; 95% CI 1.01–2.46; p = 0.042). After adjustment for maternal age (p < 0.001), parity (p < 0.001), type of infertility (p = 0.037), duration of subfertility and indication for IVF, aOR for implantation per transferred embryo increased to 1.87 (95% CI 1.21–2.91; p = 0.005). Miscarriage rate was similar. In NC-IVF and cIVF 25% (n = 20; n = 33) miscarried and 75% (n = 60; n = 99) ended in a live birth, respectively (OR 0.91; 95% CI 0.32–2.60; p = 0.855; aOR 1.0; 95% CI 0.42–2.36; p = 1.000). Live birth rate per transferred embryo was increased in NC-IVF; 60 of 468 (12.8%) embryos in NC-IVF compared to 99 of 1041 (9.8%) embryos in cIVF resulted in a live birth (OR 1.51; 95% CI 0.92–2.49; p = 0.106); and became significantly higher after adjustment (aOR 1.85; 95% CI 1.16–2.95; p = 0.010). Limitations, reasons for caution This study analyses observational data from a clinic offering NC-IVF and cIVF treatment as equivalent options. NC-IVF is a model for natural fertility and allows us to study the impact of gonadotropins. However, it is not a randomised study and therefore prone to selection bias. Wider implications of the findings: The study suggests that gonadotropin stimulation might reduce the implantation potential and subsequently live birth rates, by possibly affecting embryo and endometrium quality. Clinicians should consider lower gonadotropin doses for stimulation. Trial registration number Not applicable

Research question Does antioestrogen effect of clomiphene citrate (CC) on the endometrium reduce implantation and thereby decrease pregnancy and live birth rate per transferred embryo? Methods In this cohort, unstimulated IVF cycles modified with clomiphene citrate (CC-NC-IVF) and unstimulated, natural IVF cycles (NC-IVF) conducted between 2011 and 2016 were included. CC was applied in a dosage of 25mcg per day, starting on cycle day 7 until ovulation trigger day. Primary outcomes were clinical pregnancy rate, defined as amniotic sac visible in ultrasound, and live birth rate per transferred embryo. Miscarriage rate calculated as amniotic sac not ending in a live birth was secondary outcome. A modified mixed-effect Poisson regression model was applied, and adjustments were made for female age, parity, type and cause of infertility. Additionally, stratification by parity and age was performed. Results Four hundred and ninety-nine couples underwent a total of 1042 IVF cycles, 453 being NC-IVF and 589 being CC-NC-IVF cycles. Baseline characteristics of both groups did not differ. Addition of CC did neither decrease clinical pregnancy rate (aRR 0.86; 95% CI 0.67–1.12) nor live birth rate per transferred embryo (aRR 0.84; 95% CI 0.62–1.13) in comparison with NC-IVF. Miscarriage rate did not differ between CC-NC-IVF and NC-IVF (aRR 0.95; 95% CI 0.57–1.57). Conclusion Low-dose CC does not reduce pregnancy or live birth rate per transferred embryo. It can be used in infertility treatment without negatively affecting the endometrium and implantation.

Research suggests that gonadotropin stimulation in in vitro fertilization (IVF) treatment affects embryo quality and the endometrium that might influence embryo implantation, placentation and establishment of a viable pregnancy. We assessed the impact of gonadotropin stimulation on implantation, live birth and miscarriage rates per transferred embryo by comparing stimulated and unstimulated IVF treatment. In a cohort of 728 couples, 1310 IVF cycles with successful embryo transfer were analysed; 857 cycles were stimulated with gonadotropins > 75 IU/day (333 poor responder < 4 oocytes; 524 normal responders), and 453 were unstimulated. In total, 1913 fresh cleavage-stage embryos were transferred. Zygote but no embryo selection was performed, and supernumerous zygotes were vitrified. The implantation rate was defined as number of sonographically detected amniotic sacs; live birth rate as number of children born per transferred embryo. Modified mixed effect Poisson regression was used to account for the dependency of cycles and embryos within the same women and the same transfer cycle. Adjustments were made for maternal age, parity, primary or secondary infertility and indication for IVF. Per transferred embryo, implantation rates (rate ratio (RR) 1.37; 95% CI 1.04–1.81; p = 0.028; aRR 1.42; 95% CI 1.10–1.84; p = 0.008) and live birth rates (RR 1.33; 95% CI 0.95–1.86; p = 0.093; aRR 1.38; 95% CI 1.01–1.88; p = 0.044) were higher in NC-IVF compared to cIVF normal responders. Miscarriage did not differ (RR 0.99; 95% CI 0.59–1.65; p = 0.965; aRR 0.90; 95% CI 0.52–1.53 p = 0.698). Similar results were obtained in poor responders. The study suggests an impact of gonadotropin stimulation on the implantation potential of embryos.