Table 2.

Infertility outcome subgroups in men with epilepsy or bipolar disorder exposed and unexposed to valproate

Outcome	Cohort	Patient count before matching	Patient count after matching	Patients excluded because they had the outcome prior to follow-up	Remaining patient denominator analysed	Patients with outcome	Risk	Hazard ratio (95% CI)	Log-Rank p-value
Male infertility	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	137	78,834	216	0.3%	1.057 (0.864– 1.295)	0.589
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	136	78,835	167	0.2%
	Epilepsy exposed to valproate	60,860	50,102	58	50,044	112	0.2%	1.099 (0.826– 1.462)	0.517
	Epilepsy not exposed to valproate	399,984	50,102	76	50,026	82	0.2%
	Bipolar disorder exposed to valproate	33,450	22,826	60	22,766	57	0.3%	0.721 (0.510– 1.019)	0.062
	Bipolar disorder not exposed to valproate	123,881	22,826	58	22,768	74	0.3%
Testicular hypofunction	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	460	78,511	715	0.9%	0.916 (0.824–1.019)	0.107
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	510	78,461	651	0.8%
	Epilepsy exposed to valproate	60,860	50,102	207	49,895	355	0.7%	0.922 (0.792–1.073)	0.294
	Epilepsy not exposed to valproate	399,984	50,102	244	49,858	314	0.6%
	Bipolar disorder exposed to valproate	33,450	22,826	229	22,597	258	1.1%	0.943 (0.793– 1.121)	0.503
	Bipolar disorder not exposed to valproate	123,881	22,826	217	22,609	257	1.1%
Testicular atrophy	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	32	78,939	59	0.1%	1.000 (0.682–1.465)	0.998
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	39	78,932	48	0.1%
	Epilepsy exposed to valproate	60,860	50,102	16	50,086	35	0.1%	0.985 (0.601–1.613)	0.951
	Epilepsy not exposed to valproate	399,984	50,102	26	50,076	29	0.1%
	Bipolar disorder exposed to valproate	33,450	22,826	13	22,813	≤10^	0.0%	0.703 (0.296– 1.669)	0.422
	Bipolar disorder not exposed to valproate	123,881	22,826	12	22,814	12	0.1%
Low sperm concentration, motility, vitality, normal forms, or semen volume	Epilepsy or bipolar disorder exposed to valproate	91,917	78,971	45	78,926	70	0.1%	0.856 (0.613– 1.196)	0.362
	Epilepsy or bipolar disorder not exposed to valproate	535,803	78,971	59	78,912	68	0.1%
	Epilepsy exposed to valproate	60,860	50,102	19	50,083	23	0.0%	0.633 (0.366–1.096)	0.099
	Epilepsy not exposed to valproate	399,984	50,102	19	50,083	29	0.1%
	Bipolar disorder exposed to valproate	33,450	22,826	14	22,812	18	0.1%	0.948 (0.493– 1.823)	0.250
	Bipolar disorder not exposed to valproate	123,881	22,826	20	22,806	18	0.1%

Legend: low sperm concentration ( < 16 × 10⁶/ml semen semen), low sperm motility ( < 42% total motility), low sperm vitality ( < 54% viable), low normal forms ( < 4% of sperm have a normal morphology), or low semen volume ( < 1.4 mL); CI (Confidence interval); ^ = In order to protect patient anonymity, TriNetX shield figures to a value of ≤10 per outcome when there are 10 or fewer participants for the outcome.

N.B.: Statistics = Survival analysis using Cox-proportional hazard models with 95% CIs and two-sided Log-Rank p-values with a 0.05 level of significance. An expected mismatch is noted between the total number of patients with epilepsy and/or bipolar disorder and the sum of the number of patients in each subgroup. Since cohorts were not designed to be mutually exclusive, this mismatch is due to the ability for patients to have a record of one or both diagnoses (epilepsy and bipolar disorder) in their electronic health record.