BACKGROUND: GnRH-a is commonly used in the luteal phase for pituitary down-regulation during in-vitro fertilization (IVF). There is an ineluctable risk of spontaneous pregnancy for infertile couples who lack the use of contraception during the luteal phase down-regulation before IVF treatment. However, it is unclear whether exposure to GnRH-a affects clinical pregnancy outcomes. METHODS: A single-center retrospective cohort study based on propensity score matching was used to analyze the clinical data of a total of 6602 infertile women who were about to undergo assisted reproduction with IVF or intracytoplasmic microsperm injection with spermatozoa (ICSI) and with confirmed clinical pregnancies outcomes in the Reproductive Center of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China, from January 2011 to December 2022. Participants were divided into the NP group (Natural pregnancy with the use of GnRH-a) and the CT group (Conceived through IVF/ICSI-ET). Baseline characteristics and pregnancy outcomes of the groups were compared by correlation analysis, analysis of variance, and generalized estimating equations. The correlation between pregnancy outcomes and GnRH-a exposure was analyzed based on logistic regression modeling. The primary outcome of the study is the ectopic pregnancy rate. The secondary outcomes included spontaneous abortion rate, clinical pregnancy rate, live birth rate and adverse neonatal outcomes rate. RESULTS: Our study demonstrates statistically significant differences in spontaneous abortion rate (29.5% vs. 13.6%, P <
0.05), ectopic pregnancy rate (14.3% vs. 3.1%, P <
0.05), live birth rate ((56.2% vs. 83.3%, P <
0.05)) between NP group and CT group. Logistic analysis showed that exposure to GnRH-a was a risk factor for adverse pregnancy outcomes and was associated with spontaneous abortion(odds ratio[ OR], 95% confidence interval [95% CI] {2.66,1.61-4.40}, P <
0.05) and ectopic pregnancy(odds ratio [OR], 95%confidence interval [95% CI] {5.21,2.39-11.32}, P <
0.05). CONCLUSION: Exposure to GnRH-a during the luteal phase of down-regulation can adversely affect pregnancy outcomes. Therefore, we recommend contraception during the IVF/ICSI down-regulation. A higher dose of progesterone during early pregnancy is needed for infertile women who conceive spontaneously after exposure to GnRH-a.