Table 4.

Infertility outcomes in men with epilepsy and or bipolar disorder exposed and unexposed to valproate with key modifiable risk factors excluded

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
Overall infertility measure (composite outcome): -male infertilitya -testicular hypofunctionb or atrophyc -low sperm concentration, motility, vitality, normal forms, or semen volumed	Epilepsy or bipolar disorder exposed to valproate	32,885	27,946	50	27,896	96	0.3%	0.910 (0.680–1.218)	0.526
	Epilepsy or bipolar disorder not exposed to valproate	261,112	27,946	63	27,883	86	0.3%
Male infertility	Epilepsy or bipolar disorder exposed to valproate	32,885	27,946	14	27,932	36	0.1%	1.042 (0.636–1.709)	0.869
	Epilepsy or bipolar disorder not exposed to valproate	261,112	27,946	15	27,931	28	0.1%
Testicular hypofunction	Epilepsy or bipolar disorder exposed to valproate	32,885	27,946	31	27,915	50	0.2%	0.775 (0.527–1.142)	0.196
	Epilepsy or bipolar disorder not exposed to valproate	261,112	27,946	42	27,904	53	0.2%
Testicular atrophy	Epilepsy or bipolar disorder exposed to valproate	32,885	27,946	10	27,944	≤ 10^	0.04%	0.906 (0.304–2.698)	0.859
	Epilepsy or bipolar disorder not exposed to valproate	261,112	27,946	10	27,941	≤ 10^	0.04%
Low sperm concentration, motility, vitality, normal forms, or semen volume	Epilepsy or bipolar disorder exposed to valproate	32,885	27,946	10	27,940	≤ 10^	0.04%	3.717 (0.802– 17.221)	0.072
	Epilepsy or bipolar disorder not exposed to valproate	261,112	27,946	10	27,938	≤ 10^	0.04%

^a Male infertility (as defined by the World Health Organisation (WHO) through the International Classification of Diseases 10^th Revision Clinical Modification (ICD-10-CM) code N46—which includes N46.0 (Azoospermia), N46.1 (Oligospermia), N46.8 (Other male infertility—capturing where male infertility has been identified but the cause does not fit into any of the other specified (coded) aetiological categories), N46.9 (Male infertility, unspecified—capturing where male infertility that has been identified but the cause is unclear)⁵⁵, and 606 (Infertility, male—which is the ICD-9-CM code equivalent of N46, allowing healthcare systems using older coding to still be represented).

^b Testicular hypofunction (ICD-10-CM code E29.1)—which includes defective biosynthesis of testicular androgen, 5-delta-reductase deficiency (with male pseudohermaphroditism), and testicular hypogonadism.

^c Testicular atrophy (ICD-10-CM code N50.0)—a code which clinicians have the discretion to use when finding evidence of a pathological reduction in size of the testicles, e.g., using an orchidometer or ultrasound).

^d 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 shields 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.