Effects of assisted reproductive techniques on offspring gonadal function: a systematic review and meta-analysis

Objective: To evaluate whether the use of assisted reproductive techniques (ARTs) affected the gonadal function of the offspring. Numerous concerns have emerged over the years about the use of ARTs and their effects on the health of the offspring. Evidence Review: Data were extracted through extensive searches in the PubMed and Scopus databases from their establishment until August 2022. Meta-analysis was performed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. All eligible studies were selected according to the Population, Exposure, Comparison/Comparator, Outcomes, Study design model. All studies that analyzed pubertal development and testicular and ovarian function of offspring conceived using ARTs were included. The quality of the studies was assessed using the Cambridge Quality Checklists. For the different outcomes, the standardized mean difference (SMD), the mean difference, and the odds ratio were evaluated. Cochran-Q and I-2 statistics were used to evaluate statistical heterogeneity. Differences in pubertal development, hormone levels, and sperm function in ART-conceived subjects compared with spontaneously conceived (SC) control subjects. Results: Children conceived using ART do not appear to have impaired pubertal development or achievement of pubertal milestones. From an endocrine point of view, ART-conceived males showed lower sex hormone-binding globulin levels than the control group (SMD = -0.25 [-0.44, -0.05]; I-2 = 29%) and a tendency to lower testosterone levels (SMD = -0.16 [-0.32, 0.01]; I-2 = 0). Lower levels of inhibin B, on the other hand, were present only in intracytoplasmic sperm injection-born males compared with the control group (SMD = -0.24 [-0.44, -0.04]; I-2 = 0). In females, higher luteinizing hormone levels were found in the ART group than in the control group (SMD = 0.33 [0.06, 0.59]; I-2 = 17%). In contrast, lower levels of 17 ss-estradiol were observed only in the intracytoplasmic sperm injection group compared with girls with SC (SMD = -0.39 [-0.74, -0.03]; I-2 = 0). However, no definitive conclusions can be drawn considering the heterogeneity of hormonal assessments in females. Finally, young adults born from ART had a reduced sperm concentration (SMD = -0.34 [-0.57, -0.11]; I-2 = 0), total sperm count (SMD = -0.28 [-0.51, -0.05]; I-2 = 0), and normal sperm morphology (SMD = -0.35 [-0.58, -0.13]; I-2 = 0) compared with those SC. Conclusion: A slight alteration in the function of the male germinal epithelium appears to be associated with the use of ART, as shown by the reduced levels of inhibin B and the altered sperm parameters.