Psychiatric comorbidities, sexual health and neurodevelopmental outcomes of offspring in men with epilepsy

Abstract

Background:

There is a paucity of data in the literature specific to men with epilepsy on anti-seizure medication (ASM). The current study investigated the time to conception as well as the gestational and the neurodevelopmental outcomes of offspring of men with epilepsy on ASM compared to controls. Additionally, the prevalence of psychiatric comorbidities, and measures of sexual performance in males with and without epilepsy were analyzed.

Methods:

A total of 450 male patients with and without epilepsy at one hospital were provided questionnaires to determine demographic characteristics, epilepsy history, type of ASM at the time of conception, comorbidities and sexual health. Time to conception, fertility methods and offspring birth and developmental history born to males with and without epilepsy was recorded. Survey data was evaluated using Student’s t-test for continuous variables and Fisher’s exact test for categorical variables. Odds ratio (OR) were calculated to determine associations between the measured data.

Results:

After matching for age, we analyzed a total of 110 males with epilepsy and 110 without epilepsy. In the epilepsy group there was a higher rate of psychiatric comorbidities such as major depressive disorder, general anxiety disorder, bipolar disorder, and suicidal ideation when compared to the control group (N = 110; OR 3.39; 95% IC: 1.87–6.13, p < 0.001). Males with epilepsy also had a higher frequency of low erection scores when compared to males without epilepsy (N = 70 with epilepsy, N = 76 without epilepsy; OR 3.67; 95% IC: 1.44–9.39, p = 0.005). Of the 110 men with a diagnosis of epilepsy, 17 conceived children while using ASMs (38 total children). A total of 18.42% of children born to fathers on ASMs experienced developmental delays compared to 2.63% of controls, however this result was not statistically significant (p = 0.056). In addition, we did not find that offspring had significantly different birth weights or gestational ages in men on ASM compared to controls (p > 0.05).

Conclusions:

The present study suggests that men with epilepsy have an increased incidence of psychiatric comorbidities, and altered sexual performance, specifically erectile dysfunction, when compared with men without epilepsy. There was no statistically significant difference in the rates of developmental disorders and birth characteristics among those men with epilepsy on ASM at the time of conception and controls.

1. Introduction

Epilepsy is the second most common neurological disorder and has a higher prevalence in men than in women [1–3]. Side effects of antiseizure medication (ASM) in women, particularly teratogenicity and offspring neurodevelopmental disorders, have been documented extensively in the literature [4–6]. However, such reproductive side effects of ASM may not be limited to women. In men, particular ASMs have been shown to alter sexual function, alter reproductive hormone levels, and alter sperm motility, morphology, and count when compared to controls [7–11]. Despite this, few extensive studies exist which evaluate the effects of ASMs on men and the offspring of men who use ASMs during conception [12]. This is important as men, particularly those of reproductive age, using ASMs frequently express concerns about these medications and potential negative effects on their future offspring. However, unlike for women, no registries exist with relevant data in this population. The existing evidence relates mostly to spermatic function and is limited to only a few ASMs, namely valproate, phenytoin, levetiracetam, and carbamazepine [10,13,14]. Additionally, mood disorders have been independently shown to negatively impact sexual and reproductive health [15,16]. Furthermore, it is known that epilepsy is associated with an increased prevalence of mental health disorders and a greater likelihood of anxiety disorders or suicidal thoughts [17].

Accordingly, the current study aimed to determine if men with epilepsy on ASM have increased psychiatric comorbidities, sexual dysfunction, and difficulty conceiving children compared to controls. Additionally, the neurodevelopmental outcomes of the offspring conceived to men on ASM are analyzed and compared to outcomes of children conceived by matched controls.

2. Materials and methods

2.1. Design

The present study included male patients with and without epilepsy at one academic hospital. All included patients were male and older than 18 years, irrespective of epilepsy diagnosis or ASM use. The study was approved by the Institutional Review Board. The study was conducted in an outpatient clinic from December 2015 to December 2018. After providing the participants with written consent, three consecutive questionnaires were given; the first regarding demographic characteristics, comorbidities, psychiatric history, epilepsy history, and history of ASMs; the second offspring demographics and developmental history; the third sexual performance. Seizure type was categorized into three groups: focal onset, generalized onset, or unknown according to the International League Against Epilepsy guidelines [18].

A total of 450 patients were provided questionnaires and agreed to participate in the study. A total of 88 patients were excluded from the study as the questionnaires were incomplete or incorrectly filled out. The total sample included 122 male patients with epilepsy and 240 male patients without epilepsy. After matching for age, we obtained a final sample of 110 patients in each group.

2.2. Questionnaires

2.2.1. ASM questionnaire

The first questionnaire inquired if the participant had epilepsy, epilepsy type, ASMs (including dates of administration), psychiatric history, and other medical/social history including cigarette, alcohol, and recreational drug use (Supplementary File 1). The questionnaire had a table with all the available ASM both generic and brand names as a visual aid for the participant. Psychiatric history included: bipolar disorder, major depressive disorder, general anxiety disorder, and suicidal thoughts.

2.2.2. Childhood development and paternal exposure to ASM

The second questionnaire inquired if the participant had children (Supplementary File 2). If so, the participant was asked to give the following information: time for conception (defined as the time between when the patient and their partner began attempting conception and when conception actually occurred), methods for conception (i.e. in-vitro fertilization), labor/delivery history (newborn weight, prematurity, complications during delivery, birth defects), chromosomal abnormalities at time of birth, and developmental history of the children, specifically the presence of developmental disorders defined as developmental delay, autism spectrum disorders, or learning disabilities.

2.2.3. Effect of ASM on sexual health in men

The third questionnaire analyzed sexual function (Supplementary File 3). Participants were asked to rate various aspects pertaining to sexual performance and libido over the past 4 weeks by assessing the following characteristics: erection characteristics (frequency, quality, and time), sexual intercourse satisfaction, and frequency. Participants were also asked about the frequency of ejaculation and quantification of sexual desire. Finally, participants were asked to characterize their erection using the erection hardness score; a scale previously used to assess erectile dysfunction [19].

2.3. Statistical analysis

Survey data were evaluated using descriptive statistical analysis such as Student’s t-test for continuous variables and Fisher’s exact test for categorical variable. Odds ratio (OR) were calculated as well to determine associations between the measured data. All analyses were performed using MATLAB version 2019a (Math-Works, Natick, MA). Results were taken to be statistically significant only if a p-value of less than 0.05 was calculated. A generalized linear model was constructed to determine whether ASM use predicted developmental delay in the resultant offspring. This model used parental age as a continuous variable predictor and whether the parent was on ASMs, parental diabetes history, hypertension history, sleep apnea history, migraine history, stroke, psychiatric history, parental developmental delay, smoking, alcohol use, and drug use as categorical variable predictors. The distribution was set to binomial and the linking function was logit.

2.4. Data availability

All research data are available upon direct request to the authors.

3. Results

3.1. Demographic characteristics

Participant characteristics are shown in Table 1. Both groups were matched for age. Significant differences between experimental and control groups were seen in relation to past history of migraine (40 vs. 25; p = 0.04), history of participant developmental delay (24 vs. 8; p = 0.005), history of alcohol use (12 vs. 39; p < 0.001), and rate of illicit drug use (47 vs. 24; p = 0.001). Additionally, there was a higher rate of psychiatric comorbidities such as major depressive disorder, general anxiety disorder, bipolar disorder, and suicidal ideation in participants with epilepsy when compared to the control group (p < 0.001; OR 3.39; 95% CI:1.87–6.13). Migraine was the most common medical comorbidity in patients with epilepsy and hypertension was the most common in the control group. The use of alcohol was lower in the epilepsy group than in the control group, whereas the use of drugs was higher in the control group (p < 0.001 and p = 0.001, respectively). The most common seizure type reported was generalized-onset seizures (45; 40.91%). In the epilepsy cohort, levetiracetam was the most commonly used ASM (52; 47.27%), followed by lamotrigine (24; 21.82%), and phenytoin (14; 12.73%).

Table 1.

Demographic characteristics for initial age match (N = 110 in each group).

	Male patients with epilepsy (%) N = 110	Male patients without epilepsy (%) N = 110	p value
Age	50.25	50.26	0.99
Past medical history
Diabetes	15 (13.64)	8 (7.27)	0.19
Hypertension	34 (30.91)	32 (29.09)	0.88
Hyperlipidemia	21 (19.9)	32 (29.09)	0.11
Cardiomyopathy	7 (6.36)	9 (8.18)	0.80
Sleep apnea	20 (18.18)	12 (10.91)	0.18
Migraine	40 (36.36)	25 (22.73)	0.04*
Stroke	11 (10)	14 (12.73)	0.67
Developmental delay (in the participant)	24 (21.82)	8 (7.27)	0.005*
Psychiatric Comorbiditiesa	52 (47.27)	23 (20.91)	<0.001*
Past social history
Tobacco	47 (42.73)	36 (32.73)	0.16
Alcohol	12 (10.91)	39 (35.45)	<0.001*
Drugs	47 (42.73)	24 (21.82)	0.001*
Primary seizure type
Focal onset	21 (19.09)
Generalized onset	45 (40.91)
Other	44 (40)
Current primary ASM
Levetiracetam	52 (47.27)
Lamotrigine	24 (21.82)
Phenytoin	14 (12.73)
Valproate	12 (10.91)
Lacosamide	11 (10.0)
Clobazam	8 (7.27)
Oxcarbamazepine	8 (7.27)
Zonisamide	6 (5.45)
Carbamazepine	4 (3.64)

^{* =}Statistical significance;

^{a =}major depression, general anxiety disorder, bipolar disorder and suicidal thoughts.

3.2. Parental conception and childhood development

Of the 110 men participating in the study with a diagnosis of epilepsy, 17 men conceived children while using ASMs (38 total children). Therefore, to evaluate the effect of ASM use on parental conception and child development, we performed a second age-match between men on ASMs during offspring conception and men not on ASMs during offspring conception. This resulted in an experimental group containing 17 men and 38 children and a control group containing 17 men and 38 children, matched for age. Table 2 gives basic demographic information for the 17 age-matched fathers who had children while on ASMs and the 17 controls.

Table 2.

Demographic characteristics for fathers on ASM during conception (N = 17) as compared to controls.

	Men on ASM at time of conception (%) N = 17	Men not on ASM at time of conception (%) N = 17	p value
Age	43.9	44.2	0.95
Past medical history
Diabetes	2 (11.8)	0 (0)	0.160
Hypertension	1 (5.9)	1 (5.9)	1
Hyperlipidemia	4 (23.5)	2 (11.8)	0.380
Sleep apnea	3 (17.6)	1 (5.9)	0.300
Migraine	4 (23.5)	4 (23.5)	1
Stroke	0 (0)	1 (5.9)	1
Developmental delay	3 (17.6)	1 (5.9)	0.300
Past social history
Tobacco	5 (29.4)	7 (41.2)	0.490
Alcohol	3 (17.6)	7 (41.2)	0.140
Rec. drug use	5 (29.4)	4 (23.5)	0.710
All seizure types
Focal Onset	3	NA	NA
Generalized Onset	14	NA	NA
Other	2	NA	NA
ASMs used during conception*
Levetiracetam	14	NA	NA
Phenytoin	5	NA	NA
Phenobarbital	5	NA	NA
Topiramate	5	NA	NA
Primidone	4	NA	NA
Clobazam	2	NA	NA
Valproate	2	NA	NA
Carbamazepine	1	NA	NA
Lamotrigine	1	NA	NA
Oxcarbazepine	1	NA	NA
Pregabalin	1	NA	NA
Lacosamide	1	NA	NA

^*Note that total number is greater than 38 as some fathers were on multiple ASMs at time of conception.

The differences between children born to men on ASM at the time of conception and controls is shown in Table 3. There was no difference in newborn weight, time for conception, the rate of premature offspring, or the incidence of birth defects (all p > 0.05). A total of 18.42% of children born to fathers on ASMs experienced developmental delays compared to 2.63% of controls. Of the 18.42% of children experiencing developmental delays, all were born to separate fathers (7 fathers) and only one father had a personal history of delayed milestones. By Fisher’s exact test, statistical significance was not achieved between paternal ASM exposure and developmental delay in the resultant offspring (p = 0.056). However, given the trend towards significances we performed multiple linear regression using parental age, parental ASM use, and parental comorbidities (DM, HTN, smoking, drug use, etc.) as predictors. The logistic regression also did not show a significant association with parental ASM use and child developmental delay (individual beta = 3.886, p = 0.069). (See Supplementary Table 1).

Table 3.

Parental conception and childhood development.

Category	Experimental N = 38	Control N = 38	p-value
Weight of the first child (lbs.)			0.69
Mean	7.01 ± 1.44	7.34 ± 2.61
Time for conception < 1 yeara			0.77
Number (%)	16 (64)	13 (59.1)
Premature babies			0.22
Number (%)	9 (23.68)	4 (10.52)
Offspring with developmental disordersb			0.056
Number (%)	7 (18.42)	1 (2.63)
Offspring with birth defectsc
Number (%)	1 (2.6)	0 (0.0)	1

^{a =}Only included were planned offspring (25 planned offspring in experimental, 22 planned offspring in control); defined as the time between when the patient and their partner began attempting conception and when conception actually occurred.

^{b =}developmental milestone delay, autism spectrum disorders, or learning disabilities.

^{c =}The one birth defect reported in this study was a case of cerebral palsy.

3.3. Sexual health

We evaluated sexual health in the initial 110 patient/control age-matched groups regarding erection quality, intercourse frequency, and sexual desire (Table 4). Note that the number of respondents for each question pertaining to sexual health does not equal 110 in all cases due to participant comfort levels sharing sensitive information. The data indicated no difference in the characteristics of the erection between both groups (p > 0.05). Additionally, there was no difference in the rate or frequency in sexual desire between the participants (p > 0.05). However, patients with epilepsy were observed to have a higher frequency of low erection scores when compared to patients without epilepsy (p = 0.005; OR 3.67; 95% CI: 1.44–9.39).

Table 4.

Sexual characteristics.

Category	Male patients with epilepsy (%)	Male patients without epilepsy (%)	p-value	ORc (95% CI)
Erection Quality	N = 88	N = 80	0.11
No. with very low-to-moderate	20 (22.72)	10 (12.5)
Erection Satisfaction	N = 71	N = 75	0.30
No. with very low-to-moderate	17 (23.94)	12 (16.0)
Erection frequency	N = 72	N = 76	0.14
No. with never-to-sometimes	24 (33.33)	17 (22.37)
Rate sexual desire	N = 86	N = 77	0.21
No. with very low-to-moderate	44 (51.16)	31 (40.26)
Frequency of sexual desire	N = 79	N = 74	0.31
No. with never-to-sometimes	30 (37.97)	22 (29.73)
Erection score	N = 70	N = 76	0.005	3.67(1.44–9.39)
No. with low score	19 (27.14)	7 (11.84)

4. Discussion

The present study sought to evaluate the effects of ASM use in males with epilepsy. To our knowledge, this is the first study to address the effect of male ASM use during conception.

Prior studies of ASM usage in males have suggested a reduced fertility rate [20,21]. Levetiracetam, a medication which increases levels of testosterone and induces spermatozoid abnormalities, was the most commonly used ASM in our sample, both in general and during the time of conception [10,22]. Lamotrigine, the second most common ASM used in our study overall, has failed to show altered testosterone levels or sexual dysfunction in adults, though phenytoin has been linked to reduced testosterone levels, sexual dysfunction, and altered sperm motility [7,23]. Our data suggests these previously published differences are not related to erection confidence, erection satisfaction, erection frequency, or sexual desire. However, observed changes in erection score were seen, which may be due to alterations in testosterone level and may ultimately contribute to the previously reported reduced fertility.

There was no difference in the rate of premature offspring, or offspring birthweight, between both groups. This finding differs with prior studies in females with epilepsy which demonstrated increased rates of premature offspring for females using ASMs during pregnancy [24]. We were unable to find prior studies evaluating men with epilepsy and subsequent rates of offspring prematurity. Given how a male’s biochemical involvement in pregnancy is limited to the conception event, this is not unexpected. In our study the control group was older than the epilepsy group, but this potential bias was controlled by age matching. Age matching was critical for our analysis as increased parental age is associated with adverse birth outcomes [25]. Our study found no statistically significant differences in rates of offspring prematurity, birth weight, and time for conception. The small sample size may preclude this finding from being re-assuring to men with epilepsy interested in having children.

There was a trend that was not statistically significant between rates of offspring developmental delays between fathers using ASMs and controls, analyzed either using the matched sample or multiple linear regression to control for paternal characteristics. This trend toward significance is worth further exploration given the prevalence of ASM use. This trend does not appear to be based on one father having multiple children with developmental delays, as the seven children who experienced developmental delays all came from separate fathers. Additionally, only one of these seven fathers had a personal history of delayed milestones, suggesting that paternal history of developmental delay did not drive this trend. However, there are a few main limitations to this analysis. First, limited maternal data are available for these offspring. Second, this analysis relied solely on parental reporting and therefore we were unable to diagnose and/or confirm any potential offspring developmental disorders. Finally, there was a surprisingly small sample size of men at our institution who conceived children while on ASMs, ultimately limiting the power of this study. As such, the significance of this trend remains unclear. Considering the widespread prevalence of ASMs and the frequent concerns of men on these medications regarding potential adverse implications for their offspring, we find the major utility of this study to be that of a platform calling for a prospective registry of men with epilepsy of reproductive age, similar to the prospective registries used for woman. Ideally, a follow-up study would be a large, multicenter collaboration and/or registry able to recruit a larger patient population, with inclusion of more extensive maternal data.

There is extensive literature proving an association between epilepsy and mood disorders [26,27]. Similarly, suicide rates are increased in patients with epilepsy secondary to depression [28,29]. Thus, we were interested in evaluating psychiatric comorbidities exclusively in our male epilepsy patient population. As expected, males with epilepsy had a substantially higher prevalence of psychiatric comorbidities when compared to males without epilepsy, which aligns well with results attained from population-based studies [30,31].

We demonstrated that males with epilepsy have three times more likelihood to have a low erection score when compared to patients without epilepsy. Prior studies have linked epilepsy with sexual dysfunction disorders such as loss of sexual desire and erectile dysfunction [32,33]. Interestingly, men with epilepsy tend to have lower numbers of children secondary to sexual problems [34]. Sexual dysfunction is a complex disease that involves multiple psychological and physiological factors. Although there was a trend in all the sexual characteristics evaluated in our study, we hypothesize we could not reach statistical significance given the limitations of a questionnaire to evaluate erectile dysfunction and the relatively small numbers in our study [35]. These data highlight the need for open discussion regarding sexual function with men with epilepsy as well as further research.

The present study has some limitations in addition to those previously discussed. First, the retrospective nature of the study limits the results because of recall bias. Second, without DNA testing one cannot be completely certain of a child’s paternity. Third, although we controlled for age, there were differences in the rates of migraine and substance abuse among both groups, which could account for differences in the rate of prematurity seen in our study. Additionally, the number of male patients on ASMs at the time of conception was small and results may vary depending upon the type of ASM as it does in the female population. Finally, the inability of this study to confirm pediatric diagnoses and the limited maternal data available are further limitations, as previously discussed. The strengths of this study include the similarity in the demographic characteristics, age, and cardiovascular risk factors between both groups and the fact that this study is one of the first studies to evaluate the fecundity, neurodevelopmental outcomes, and psychiatric adverse effects of ASMs exclusively in males. Our hope is that this study brings attention to this population and may be grounds for a registry, similar to its female counterpart.

5. Conclusions

The present study suggests men with epilepsy on ASM have an increased incidence of psychiatric comorbidities and changes in sexual performance, specifically erectile dysfunction when compared with men without epilepsy. There was no difference in difficulties with conception, prematurity, or birth defect. We did find a trend toward an increase in developmental delay in the children of fathers on ASMs, that was not statistically significant. Although the study has limitations, it is the first study that aims to determine effects of ASM use exclusively in the offspring of males. We hope that this study brings attention to the effects of ASM in the health of men and their progeny for future studies with large populations and prospective methodology.

Abbreviations:

ASM

antiseizure medication

OR

odds ratio