JBRA Assisted Reproduction 2025;29(Suppl.2 SBRA 2025):231
Poster Presentation
29^th Annual Congress of the SBRA. São Paulo/SP - Brazil, 2025
doi: 10.5935/1518-0557.20263850

P-219. The adverse effects of ovarian stimulation in women with infertility: a narrative review

Endjeli Vogler Reche¹, Sabrina de Aquino¹, Julia Castelo Branco Vilar Silva¹, Maria Monica Pereira¹

¹ Centro Universitário São Camilo - São Paulo – SP - Brasil

Objective: To investigate whether ovarian stimulation with hormonal medications in women with infertility is associated with an increased risk of adverse effects.
Methods: A literature review was conducted following the PRISMA-P protocol, based on studies indexed in the Medline (via PubMed) and LILACS (via BVS) databases, including articles published between 2020 and 2025, using terms related to infertility and ovulation induction, resulting in 89 studies. Eligible studies evaluated adult women diagnosed with infertility of any cause, undergoing ovarian stimulation with any hormonal protocol, with the aim of comparing the occurrence of adverse events between treatments. A double-blind peer selection was performed by two independent reviewers on the Rayyan platform, with conflicts resolved by a third reviewer. Data extraction was carried out using a Microsoft Excel spreadsheet. The information collected included: study type, population characteristics, sample size, type and duration of interventions, and frequency and nature of adverse events. After applying the inclusion criteria, six studies were selected for analysis in this review.
Results: Six studies were included after the selection process: five clinical trials and one prospective clinical study. The mean sample size was 92 participants and the mean age was 30,55 years. Regarding adverse effects, most studies reported a low frequency of severe events and a predominance of mild and transient symptoms. The combination of letrozole with human menopausal gonadotropin (HMG), compared to letrozole alone, showed similar mild adverse effects in both groups, with only one mild case of ovarian hyperstimulation syndrome (OHSS) in each group. The most common symptoms were headache, hot flashes, abdominal pain and fatigue. Few cases of ectopic pregnancy and fetal anomalies were reported, with no statistically significant differences between groups. Letrozole showed a safety profile similar to that of clomiphene citrate, with a slight advantage: lower frequency of nausea, dizziness and blurred vision, although not statistically significant (p>0.05). Additionally, fasting glucose levels were higher in the clomiphene group (p<0.001), suggesting greater metabolic impact. The use of clomiphene combined with vaginal sildenafil increased the risk of adverse events (RD=20%; p=0.034) compared to its combination with placebo, with headache and flushing being the most common events. A study evaluating ovarian stimulation with biosimilar recombinant follicle-stimulating hormone (r-hFSH) (Folitime^®) compared to the original r-hFSH (Gonal-f^®) observed a slight increase in systemic and local adverse event rates in the biosimilar group, although not statistically significant, and one severe case of late OHSS with jugular vein thrombosis, which resolved favorably after hospitalization. Ovarian stimulation before intrauterine insemination (IUI) with the combination of letrozole, r-FSH, and intramuscular hCG showed no significant difference in the rate of adverse events, such as congenital anomalies and miscarriages, when 500IU of hCG was administered directly into the uterus (intrauterine hCG) before IUI. In a prospective study comparing a combined protocol of follitropin delta + HP-hMG with historical data from follitropin delta monotherapy, a higher number of viable blastocysts was observed without an increase in severe adverse effects in the combined protocol. Only mild cases of OHSS were reported, with no need for hospitalization.
Conclusion: Ovarian stimulation in women with infertility demonstrates a favorable safety profile, with a predominance of mild and self-limiting adverse effects such as headache, nausea, and abdominal pain. These findings reinforce the importance of individualizing protocols and careful monitoring, especially in patients with risk factors such as age over 35 years. Further high-quality studies are needed to clarify the long-term thrombotic risk.