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Gender dysphoria (GD) is defined as significant distress or impairment caused by the discrepancy between an individual’s experienced gender and the sex assigned at birth. This work explores the etiology, treatment safety, and outcomes of GD through four studies.

Study I utilizes a population-based approach to analyze the prevalence of GD in twins, using data from a Swedish population-based cohort from 2001 to 2016. The objective is to assess the influence of genetic and environmental factors on the development of GD by comparing its prevalence in different-sex twins, same-sex twins, and non-twin siblings. The results indicate a higher prevalence of GD in different-sex twins (37%) compared to same-sex twins (0%) and non-twin siblings (0.16%), suggesting a potential influence of intrauterine factors in the development of GD.

Study II focuses on evaluating the occurrence of IIH in individuals undergoing treatment with GnRHa for GD in Sweden between 2006 and 2016. The study did not observe any cases of IIH within the cohort of 410 individuals with GD who received GnRHa treatment. While better-powered studies are needed to clarify any potential association between GnRHa and IIH, the study results do not present substantial evidence to support an association.

Study III examines associations between perinatal factors and GD using a matched case-control design with 7,432 individuals with GD and 72,136 individuals without GD. Very preterm birth, low birth weight, small head circumference, and being small for gestational age were associated with increased odds of GD. ASD was present in 31% of individuals with GD versus 3.5% of controls. Mediation analysis revealed that ASD fully mediated the associations between several perinatal factors (Apgar score at 5 minutes, birth length, head circumference, small for gestational age, and fetal growth restriction percentile) and GD, suggesting that perinatal risk factors may influence GD development primarily through pathways involving ASD.

Study IV examines pregnancy and childbirth outcomes among TGD individuals in Sweden using national registry data from 2001-2023. The study included 198 TGD individuals with 303 deliveries, categorized into three cohorts: deliveries before GD diagnosis (n=186), after diagnosis without testosterone treatment (n=86), and after diagnosis with testosterone treatment history (n=31), compared to 1,187 cisgender individuals with 2,289 deliveries. The pre-diagnosis cohort showed higher socioeconomic vulnerability, including higher rates of teenage pregnancy, lower income and education levels, and higher smoking rates, along with higher preterm birth rates (15% vs 5.8% in cisgender controls) and low birth weight (7.5% vs 3.8%). Post-diagnosis cohorts showed outcomes generally comparable to controls, though all TGD cohorts had elevated rates of elective cesarean sections (16-28% vs 9.3% in cisgender). No adverse effects of having received testosterone treatment on birth outcomes were observed in the small sample studied.