Counseling Reproductive-Age Youth with Epilepsy: Literature Review and Expert Opinion from the Epilepsy in the Child-Bearing Ages through Menopause Consortium (ECAM)

Abstract

Epilepsy in the Child-Bearing Ages through Menopause (ECAM) is an international consortium of clinicians dedicated to improving the health of women with epilepsy across the lifespan. ECAM’s Adolescent and Young Adult Committee addresses quality of care for female youth with epilepsy. The Committee developed a literature review and expert opinion guidance for child neurologists on performing optimal counseling about epilepsy and reproductive health for female youth with epilepsy. To do so, we identified and voted on key topics essential for this counseling, then conducted comprehensive literature reviews for each topic, iteratively developed key statements about counseling content and style for each topic and voted on final content for inclusion. The included topics were: teratogenesis, folic acid supplementation, pregnancy and fertility, contraception, heritability of epilepsy, menstrual and hormonal disorders, catamenial epilepsy, and taking a sexual history. This review provides a clear, novel framework for pediatric neurologists to counsel adolescent and young adult women with epilepsy about their reproductive health, supporting improvement in practices recommended by professional organization such as the American Academy of Neurology and Child Neurology Foundation.

Introduction

Pediatric neurologists must counsel female youth with epilepsy about reproductive health. We refer to this population as “reproductive-aged youth with epilepsy (RAYE),” ages 12-to-24 years-old. The American Academy of Neurology and Child Neurology Foundation recommend that pediatric neurologists discuss reproductive health with RAYE at least annually, addressing teratogenic risks of antiseizure medications (ASMs), folic acid supplementation, drug interactions between ASMs and contraceptives, and other pertinent anticipatory guidance [1–2]. This counseling is particularly important for RAYE given high rates of unintended pregnancy among youth compared with older adults and higher rates of teratogenic ASM prescriptions to RAYE compared with adult women with epilepsy [3, 4]. Yet, multiple studies have shown that pediatric neurologists omit this counseling or perform it poorly due to limited knowledge or comfort, limited time, and lack of guidelines specific to RAYE [5–10].

To support pediatric neurologists in counseling RAYE about reproductive health and epilepsy, the Adolescent and Young Adult Committee of the Epilepsy in the Child-Bearing Ages through Menopause Consortium (ECAM) has prepared a review of the literature and expert guidance on counseling strategies. ECAM, founded in January 2023, is a collaborative of multidisciplinary health professionals aiming to improve quality of care for women with epilepsy. ECAM has over 130 members in North America, Europe, Australia, and Asia. The Adolescent and Young Adult Committee of ECAM focuses specifically on RAYE.

Methods

The ECAM Adolescent and Young Adult Committee, comprised of 38 individuals, proposed and voted on the most important topics for counseling RAYE about reproductive health. Topics receiving multiple votes were approved for inclusion. The Committee divided into small groups, consisting of 2–4 individuals, each tasked with a literature review on one topic. Each small group presented a narrative review with supporting references and proposed key content statements to the full Committee, which were refined through Committee discussion and approved by Committee vote. The following content reflects this development process.

Teratogenicity

Most women with epilepsy have healthy pregnancies and healthy children [11–14].. However, in utero exposure to specific antiseizure medications (ASMs) carries increased risk of major congenital malformations (MCMs) and adverse neurocognitive outcomes [11–14]. Pediatric neurologists should be prepared to provide careful ASM selection and risk assessment in RAYE. Though we summarize evidence related to MCMs and neurocognitive outcomes below, we also direct readers to a 2024 American Academy of Neurology Guideline for a systematic review [15].

MCMs

In utero exposure to levetiracetam, lamotrigine, or oxcarbazepine monotherapy does not appear to increase the risk of MCMs over baseline population MCM rates [11–13, 16]. Valproate is associated with the highest-known risk of MCMs among ASMs, especially neural tube defects (NTDs) and renal and urogenital malformations. These effects are dose-dependent [11–13, 16]. Phenobarbital and phenytoin represent next highest-risk ASMs. Phenobarbital is associated with a moderate-to-high risk of cardiac malformations and cleft lip and palate [16]. In utero exposure to carbamazepine and topiramate is associated with moderately-increased risk of MCMs [11, 16]. Topiramate is associated with cleft lip and palate and small-for-gestational-age infants [11]. ASM polytherapy increases risk for MCMs more than monotherapy [12]. Emerging evidence suggests a probable low risk of MCMs for zonisamide and gabapentin [17]. There is limited data from the Kerala Registry of Epilepsy and Pregnancy suggesting a high rate of MCMs with clobazam [12]. Further investigation is needed in a larger sample. Evidence is limited for many other ASMs [18, 19]. Data about MCM risk is summarized in Table 1 and Figure 1.

Table 1.

Prevalence of MCMs with ASMs in the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) and the North American Antiepileptic Drug Pregnancy Registry [11, 19].

ASM	MCM Prevalence (EURAP) with 95% CI	MCM Prevalence (North American) with 95% CI
Levetiracetam	2.5 (1.8–3.5)	1.94 (1.3–2.88)
Lamotrigine	3.1 (2.5–3.7)	2.07 (1.56–2.72)
Oxcarbazepine	2.9 (1.7–5.0)	1.5 (0.55–3.66)
Carbamazepine	5.4 (4.5–6.4)	2.82 (1.97–4)
Topiramate	4.9 (2.7–8.8)	5.26 (3.56–7.66)
Phenytoin	6.3 (3.4–11.6)	2.84 (1.54–5.04)
Phenobarbital	6.2 (4.1–9.3)	6 (3.28–10.5)
Valproic acid	9.9 (8.5–11.5)	9.2 (6.43–12.93)
Zonisamide	Not available	1.24 (0.32–3.89)
Gabapentin	Not available	1.42 (0.46–3.85)

The prevalence of MCMs in the general population is about 3% of live births [30, 31].

Figure 1. ASMs and Risks of Major Congenital Malformations.

Neurocognitive Outcomes

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study reported that children exposed to valproate in utero have lower full-scale IQ and reduced verbal abilities compared with children exposed to several other ASMs [14]. There is also an increased risk of autistic traits in children exposed to valproate in utero compared with other ASMs [20]. There is mixed evidence about whether topiramate may be associated with an increased risk of autistic traits [21–23]. Children exposed to levetiracetam, lamotrigine or both in utero do not appear to have worse neurocognitive outcomes compared to unexposed peers [21–27]. In the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, in 6-year-old children exposed in utero, neither lamotrigine nor levetiracetam was associated with an increased risk of intellectual disability or autism [28]. Limited studies show reassuring outcomes with oxcarbazepine [21] and concerning outcomes with clonazepam [29]. There is limited data for other ASMs.

Conversations About Teratogenicity

Pediatric neurologists should routinely counsel RAYE and caregivers about the risks of in utero ASM exposure, particularly when starting or changing ASMs. Risk discussions should be honest, direct, and tailored to the individual RAYE, their epilepsy severity, and their ASMs. Reassurance may be provided regarding ASMs that are relatively safer in pregnancy. For ASMs with known risks, statistics and examples of specific associated malformations may be helpful.

Counseling should be free from medical jargon, particularly uncommon words like “teratogenic” and “congenital malformation.” Pediatric neurologists should be clear that patients taking teratogens can become pregnant and deliver, but that the child may be affected by MCMs (i.e. “birth defects”) or adverse neurodevelopment (i.e. “lower IQ” or “increased risk of autism”). This distinction is important given reports of miscommunication between pediatric neurologists and RAYE, in which some patients have mistakenly believed that teratogens cause infertility or prevent pregnancy [6, 7]. Such clinician-patient miscommunications may further amplify adverse reproductive outcomes among RAYE.

Folic Acid

Neurologists have long been encouraged to recommend daily folic acid supplementation for women with epilepsy, including RAYE [32]. Initially, folic acid supplementation was recommended to women with epilepsy to reduce NTD risk based on general population data [33–35]. The American College of Obstetricians and Gynecologists (ACOG) recommends that every reproductive-age female should take at least 0.4 milligrams of folic acid daily [36]. Individuals should start supplementation at least one month prior to conception given that neural tube development begins at 3–4 weeks of pregnancy (before many people are aware of pregnancy) and concludes by 6 weeks of pregnancy [36]. The ACOG recommendations concur with AAN guidelines specific to epilepsy [15]. However, folic acid supplementation has not specifically been shown to reduce NTD risk in children of women with epilepsy [11, 12, 16].

More recently, folic acid supplementation has been demonstrated to improve neurodevelopment of children of women with epilepsy [37–40]. In the MONEAD study, use of folic acid supplementation through at least the first trimester was associated with more favorable neurodevelopmental outcomes in children at 6 years of life [28].

There is insufficient data regarding appropriate folic acid dose for people with epilepsy. Many neurologists within the U.S. recommend 0.4 to one milligram of folic acid daily, though prescribers in several other countries use doses as high as five milligrams. Limited data suggest possible safety concerns with high-dose folic acid supplementation [41]. An observational study showed an increased risk of cancer in children of people with epilepsy exposed in utero to high-dose folic acid (defined as at least one milligram daily) [41]. This association was not seen in children of people without epilepsy exposed to similar doses and has neither been replicated nor explained mechanistically [42]. A subgroup analysis of children of people with epilepsy did not show significant increased risk with supplementation of one-to-three milligrams per day [41]. The same investigators raised concern that high-dose folic acid supplementation (of at least one milligram per day) may be associated with higher rates of cancer in women [43]. This association was not present in women with epilepsy. It is reasonable to exercise caution with doses above one milligram until further research establishes the most appropriate dosing. Given the preliminary and unreplicated nature of findings related to cancer risk in women and children, and also given our approach in recommending no more than one milligram of folic acid per day, we do not generally provide routine anticipatory guidance about cancer risks to every patient.

For RAYE who are not actively planning pregnancy, we recommend (at this time, pending further research) 0.4 to one milligram daily of folic acid supplementation.

Conversations About Folic Acid

Counseling in the child neurology context can increase the use of folic acid supplementation among RAYE [44]. Pediatric neurologists should inform RAYE and caregivers about the benefits of daily folic acid supplementation. They should explain that folic acid is a vitamin with minimal side effects at low doses, such as minor gastrointestinal upset. We advise explaining that the body does not generate folic acid and the amount obtained through food may be insufficient. We recommend counseling about the perinatal benefits, as well as the individual health benefits of folic acid, which include prevention of anemia, cardiovascular disease, and skin disease [45–47].

We advise explaining that folic acid supplements can be taken once daily and concretely recommending how to integrate supplements into a daily routine such as using a pill organizer or phone reminders about taking medications. We also advise emphasizing patient autonomy - to strongly recommend folic acid but reinforce that RAYE can decide whether they want to take it. When folic acid supplements are covered by insurance, prescribing supplements rather than recommending over-the-counter purchase can be helpful to families.

We generally recommend initiation of folic acid supplementation at menarche. For children with precocious puberty and very early onset of menses, we recommend shared decision-making approaches with RAYE and families about initiation of folic acid supplementation, though recommend starting no later than age 12 years old.

Pregnancy and Fertility

Unplanned pregnancy is equally common or more common among people with epilepsy than the general population [48, 49]. Among people with epilepsy, planned compared with unplanned pregnancies are associated with better seizure control in pregnancy and lower rates of preterm birth and MCMs [50]. Pre-pregnancy anticipatory guidance is essential for women with epilepsy, even those not imminently planning pregnancy (such as many RAYE). Counseling should address, where appropriate, that most women with epilepsy who become pregnant will have healthy pregnancies and children, particularly if they plan their pregnancies and obtain consistent preconception, prenatal, and postpartum care from neurologists and prenatal care providers. While we advise discussing pregnancy planning, it is important that neurologists not stigmatize unplanned pregnancy, which is a common experience [1]. RAYE should be advised to inform their neurologist about any pregnancies or plans to conceive as soon as possible to ensure initiation of appropriate care, ASM changes if needed, and therapeutic drug monitoring.

Pediatric neurologists should inform RAYE and caregivers that people with epilepsy are capable of becoming pregnant. For many years, the literature speculated that people with epilepsy have lower fertility than the general population. However, a rigorous prospective study demonstrated equivalency in median time-to-pregnancy, live births, and miscarriages between women with and without epilepsy who were trying to conceive [51]. Of note, people with baseline diagnoses of infertility were excluded, and most patients with epilepsy in the study were taking levetiracetam or lamotrigine. This study suggests that RAYE likely do not have reduced fertility compared to the general population, though further research is needed, particularly among women prescribed ASMs other than levetiracetam or lamotrigine [51]. More research is also needed on whether reproductive endocrine conditions linked to infertility such as Polycystic Ovary Syndrome (PCOS) or hyperandrogenism occur at different rates between women with and without epilepsy, as well as whether timing of menopause differs between these populations.

Conversations About Pregnancy and Fertility

Pediatric neurologists should confidentially ask RAYE if they ever envision themselves having children, and if so, at what life-stage. RAYE considering pregnancy in the next one-to-two years should establish care with a neurologist experienced in managing epilepsy during pregnancy and also with a prenatal care provider. Pediatric neurologists who do not manage pregnancy should establish rapid referral pathways to neurologists (either adult or pediatric) with this expertise. Pediatric and adult neurologists should be able to refer to obstetrician-gynecologists or maternal-fetal medicine specialists who are comfortable managing pregnancy in people with epilepsy.

RAYE imminently considering pregnancy should begin folic acid supplementation if they have not already done so. The neurologist and RAYE should together plan to optimize the ASM regimen for teratogenic and seizure risks. Optimizing seizure control is important in pregnancy, especially for patients with generalized and focal-to-bilateral tonic-clonic seizures. Patients who are seizure-free prior to pregnancy are likely to remain seizure-free during pregnancy on the same ASM regimen with appropriate therapeutic drug monitoring [52–54]. We recommend establishing baseline pre-pregnancy ASM serum concentrations to guide therapeutic drug monitoring during pregnancy given changes in physiology and drug metabolism [54].

RAYE interested in pregnancy, but not imminently, can be provided with general anticipatory guidance about planning pregnancy and fertility. They can be counseled about using contraception until ready to conceive, including (if desired) referral to adolescent medicine specialists, obstetrician-gynecologists, or complex family planning specialists for contraception.

RAYE who would never like to become pregnant can be asked how much information they would like about pregnancy (including if they have questions/concerns), should at minimum be told that they can become pregnant (if appropriate), and should be offered contraceptive counseling. Figure 2 displays recommendations for RAYE with different pregnancy goals.

Figure 2.

Counseling RAYE with different pregnancy goals about pregnancy and fertility.

Following confidential discussions of reproductive goals and pregnancy topics, pediatric neurologists can ask RAYE how much and what information they would feel comfortable sharing with parents/caregivers, who can then be included in the discussion as well.

Contraception

RAYE who are not trying to conceive may benefit from contraceptive counseling. Unplanned pregnancy is common, including among RAYE [1, 49, 55]. RAYE desire contraceptive information from pediatric neurologists [7, 8, 56]. Contraceptive counseling by a neurologist may increase the likelihood that a person with epilepsy chooses a highly-effective method such the subdermal implant or IUD [57]. Pediatric neurologists should be familiar with different contraceptives, including their efficacy and potential for interactions with ASMs [58] (Figure 3).

Figure 3.

Birth control for people with epilepsy. Note, the caption is the text at top, “Birth control for people with epilepsy”

Drug interactions with ASMs that induce Cytochrome P450 enzyme 3A4 (CYP3A4) can reduce the efficacy of certain hormonal contraceptives including pills, transdermal patches, vaginal rings, subdermal implants, and medroxyprogesterone acetate injections, increasing the risk of unintended pregnancy [59–62]. Such drug-drug interactions can also decrease the efficacy of contraceptives for other indications such as menstrual regulation [63].

The degree to which an ASM increases the risk of contraceptive failure is influenced by the baseline efficacy of the contraceptive and the magnitude of enzyme induction by the ASM. For example, the implant has the highest baseline efficacy among contraceptives (with 0.1%–0.3% of users becoming pregnant within the first year of use) [64]. In a study of HIV-positive females in Kenya, individuals using an implant and efavirenz (a moderate inducer of CYP3A4) experienced a failure rate of 3.3% per person-year – increased over baseline but lower than the 7% one-year failure rate experienced by typical users of contraceptive pills [64–66].

There are important interactions between lamotrigine and estrogen-containing contraception. Estrogen can reduce lamotrigine serum concentrations [67–70]. For patients on lamotrigine starting estrogen-containing contraception, we empirically increase the dose of lamotrigine by 25–50%, obtain a serum concentration to ensure lamotrigine remains in the therapeutic range, and advise use of continuous rather than cyclic methods (i.e. no placebo weeks or hormone-free weeks) to avoid labile lamotrigine serum concentrations.

There are potential bidirectional interactions between lamotrigine and progestins. Drospirenone and possibly levonorgestrel can reduce lamotrigine serum concentrations [71]. RAYE starting the drospirenone-only pill may require therapeutic drug monitoring and dose adjustment. There is mixed evidence on whether lamotrigine affects serum progestin concentrations. One study found that lamotrigine reduced serum levonorgestrel concentrations, though concentrations remained above the threshold for ovulation suppression [63]. Another study found that lamotrigine did not significantly reduce serum concentrations of drospirenone or levonorgestrel [71]. To our knowledge, there is no published evidence that lamotrigine reduces the efficacy of any contraceptive in a clinically relevant manner, though more research is needed.

Conversations about Contraception

RAYE report desiring confidential counseling about contraception from their pediatric neurologist, as well as family involvement in contraceptive discussions following confidential counseling [7, 56, 72]. Whether speaking to the RAYE alone or with others, normalizing discussions about contraception (i.e. stating that you bring up contraception with every RAYE) can build rapport. Particularly when speaking with parents, it can be helpful to mention that contraception can be started for many reasons other than pregnancy prevention, such as menstrual regulation or acne treatment. RAYE and caregivers are both particularly interested in drug-drug interactions between ASMs and contraception.

Pediatric neurologists should be prepared to conduct at least basic discussions of contraceptive options, though can defer detailed counseling and prescriptions to reproductive health providers (such as obstetrician-gynecologists including complex family planning specialists, or adolescent medicine specialists). Pediatric neurologists should respect patient autonomy in contraceptive counseling (i.e. not be coercive toward any method). We encourage shared decision-making approaches about initiation and selection of a contraceptive method, tailored to individual patient goals. RAYE are especially interested in learning about different types of contraceptive methods and potential side effects. Discussions about contraception for pregnancy prevention should also address the importance of condom/barrier use for prevention of sexually transmitted infections.

Heritability of Epilepsy

Pediatric neurologists should be prepared to counsel RAYE and families about heritability of epilepsy. Genetic testing has transformed understanding of the heritability of epilepsy. With numerous monogenic epilepsies now identified, there is compelling evidence supporting both the diagnostic yield and clinical utility of genetic testing [73, 74]. Currently, the National Society for Genetic Counselors strongly recommends genetic testing for all individuals with unexplained epilepsy, without limitation of age and that genetic testing be selected, ordered, and interpreted by a qualified healthcare provider with appropriate pre-test and post-test counseling [75]. Yield of genetic testing may be higher in patients with epilepsy-onset before 36 months of life, epilepsy with intellectual/neurodevelopmental disability, developmental and epileptic encephalopathies, malformations of cortical development, or family history in multiple generations [74–78]. Testing should be strongly considered in these patients.

Risk of epilepsy in children

At the population level, children of people with epilepsy have a higher risk of epilepsy (3–6%) than the general population (1–2%) [79]. There is some evidence of increased risk of heritability in children of female parents with epilepsy compared with male parents with epilepsy [80]. The greatest increase in risk has been observed in idiopathic generalized epilepsies (Standardized Incidence Ratio (SIR) 6.0), suggesting a correlation between incidence rate of epilepsy in children with a parent’s epilepsy type. A substantially elevated risk (SIR 4.3) was found for epilepsy associated with intellectual or motor disabilities presumed present from birth. Counseling should be tailored to RAYE based on epilepsy etiology, prior genetic testing results, family history, age of onset, and epilepsy syndrome/type [79].

Conversations About Heritability

Many RAYE are curious about their risk of having a child who has epilepsy. Counseling should be individually tailored with consideration of the risk factors discussed above. Where appropriate, statistics can be helpful. Particularly in the absence of strong individual risk factors, pediatric neurologists can inform RAYE that, while the risk of epilepsy in children of people with epilepsy is increased compared to the general population, the absolute risk remains low. As above, pediatric neurologists can offer genetic counseling and testing to RAYE when desired and available. Pediatric neurologists can also reassure RAYE and caregivers that, even if they were to have a child with epilepsy, support and medical care would be available.

Menstrual and Hormonal Disorders

Menstrual disorders, such as irregular, painful, or excessive bleeding, may be common among RAYE and can impact quality of life [81–83]. Factors that may increase the likelihood of developing a menstrual disorder include early-onset of epilepsy and experience of at least one seizure per 12-month period [80]. Valproic acid increases the risk for Polycystic Ovarian Syndrome (PCOS) and related symptoms including hyperandrogenism and anovulatory cycles [84]. Other ASMs may potentially increase this risk, though further research is needed. At least annually, pediatric neurologists should ask RAYE about menses, screen for symptoms of PCOS, and refer when appropriate to an obstetrician-gynecologist or adolescent medicine specialist. Screening for symptoms of PCOS and hyperandrogenism may be particularly important for RAYE who may be considering planning pregnancy in the near future. Table 2 outlines appropriate menstrual/hormonal history questions.

Table 2.

Suggested Questions about Menstrual and Hormonal Disorders

Screening for Menstrual Disorders	Example Questions
Onset of menstruation	“Have you started having periods?” If so: “At what age?”
Menstrual regularity	“Do your periods occur at regular monthly intervals?” In a child with menarche within the past two years, it can be helpful to normalize irregular period frequency [84].
Menstrual symptoms	“Are your periods very heavy (for example you’re needing to change your tampon or pad every 2 hours or less, passing big clots, or having periods longer than a week)?” “Are your periods very painful (for example preventing you from participating in typical activities, like school, sports, etc.)?” There is clinical concern for heavy menstrual bleeding if bleeding occurs for more than 7 days at a time, if the patient passes clots larger than 1 cm, if tampons/pads need to be changed every 2 hours or less, or if the patient reports problems with their quality of life or daily activities due to their symptoms [85].
PCOS/Hirsutism	“Do you have excessive hair growth (including areas like face, chest, abdomen) or severe acne?”

Catamenial Epilepsy

Catamenial Epilepsy (CE) is the exacerbation of seizures relative to the menstrual cycle [87–89]. CE can occur with focal or generalized epilepsy. CE is attributable to neuroactive properties of steroid hormones and the cyclic variation in their serum levels [87–89]. Traditionally, estrogen has been thought to exert primarily proconvulsant effects with progesterone exerting primarily anticonvulsant effects, resulting in potentially predictable patterns of seizure risk throughout the menstrual cycle [87–90]. However, more recent research suggests that relationships between sex hormones and seizure risk may be more complex than previously known [91–93].

While there is no guideline from any professional organization that officially defines catamenial epilepsy, scientific literature defines catamenial epilepsy as at least a twofold increase in seizures during a specific period in the menstrual cycle (with tracking over a minimum of three cycles) [89]. Pediatric neurologists should consider a diagnosis of catamenial epilepsy in women who have cyclical increases in seizures or unexplained drug-resistant epilepsy [94].

There are three CE patterns: perimenstrual (C1), preovulatory (C2), and luteal (C3). The C1 perimenstrual pattern occurs around the onset of menses, thought to be driven by progesterone withdrawal. The C2 preovulatory pattern occurs concurrently with the rapid rise in estrogen that precedes ovulation. C3 patterns may occur in women who experience anovulatory cycles with low progesterone concentrations in the luteal phase [87–89]. Despite catamenial epilepsy being common, the effects of hormonal changes during pregnancy in females with catamenial epilepsy are not well understood [95, 96].

There are no clear guidelines or FDA-approved agents for treatment of CE [97, 98]. Experts have proposed non-hormonal and hormonal therapies. Non-hormonal options may include ASMs; cyclical clobazam and cyclical or continuous acetazolamide have been described in small studies [99, 100]. Hormonal options may include medroxyprogesterone acetate or contraceptive pills with the goal of suppressing the hypothalamic-pituitary-ovarian axis to prevent hormonal cycling [97, 98, 101, 102, 103]. Additional therapies include ganaxolone, natural progesterone, clomiphene, gonadotrophin-releasing hormone analogs, and norethindrone acetate [97, 98]. A partnership between the pediatric neurologist and reproductive health provider is often useful in creating an individualized treatment plan given complex interplay between endogenous sex hormones, hormonal pharmacotherapy, and ASMs.

Conversations about CE

Pediatric neurologists should consider advising RAYE and caregivers to document seizures and menses, for instance using a diary, calendar, or mobile health application. CE is notoriously difficult to diagnose by patient report without tracking data [96].

Taking a Sexual History

Developing the skill to take a confidential, developmentally appropriate, and affirming sexual history from RAYE is important for pediatric neurologists. Pediatric neurologists should encourage confidential time during visits with RAYE at least annually. Confidential discussions can include a sexual history. Sexual histories should not be taken with caregivers/family present.

Confidentiality helps create a safe environment for RAYE to feel comfortable discussing sensitive information, such as sexual behavior, mental health, and substance use [104–107]. Clinicians are encouraged to normalize sensitive discussions [108]. The CDC and National Coalition for Sexual Health developed a structured approach for taking a sexual history using the “6 P’s” framework (Partners, Practices, Protection, Past history, Pregnancy intentions, and Pleasure) [109], to ensure a comprehensive sexual history.

Sexual history-taking should be tailored to the chronological and developmental age of the patient, since many people with epilepsy have intellectual disability (ID) [110]. Because degrees of intellectual disability are highly variable, some individuals with mild ID might be able to be interviewed independently and others might not. The approach will need to be individualized for each patient and family. Patients who are capable of speaking and articulating concrete ideas, in general, should be interviewed alone. Most people with mild-to-moderate ID are sexually active at some point in their lifetime [111–113] yet many receive limited sexual education [113, 114]. Therefore, patients with ID who are capable of being interviewed independently should also be asked similar questions about relationships and sexual activity, though clinicians may need to communicate in more concrete language or provide additional explanations for questions than with some patients of typical intellectual development. In addition, sexual abuse is alarmingly prevalent in this population, experienced by up to one-third of adults [115]. Universal education on abuse risk for patients and families is an essential component of counseling this patient population.

Periodic discussions about gender identity can help gender-diverse youth feel comfortable, particularly as gender-diverse youth are at elevated risk for psychiatric illness and suicidal behavior [116–120]. Inclusive histories that incorporate gender identity and assessment for suicide risk are important. Tables 3 and 4 outline principles and components of confidential sexual and psychosocial histories.

Table 3.

Suggested principles for a confidential sexual and psychosocial history

Principles for taking SRH	Examples/Notes
Confidential	Patients who are capable of communicating independently should be interviewed separately from their guardians
Use transition statements	“I am now going to ask you questions about...”
Normalize discussions	“I ask all my patients questions about....”, Use nonjudgmental language avoiding assumptions or stigma
Framing	The provider can begin with strengths-based questions and future goals, which can help build rapport and trust, prior to taking a sexual history or other sensitive history.

Table 4.

Suggested Components of a Confidential Psychosocial and Sexual History

Suggested minimum set of questions for neurotypical RAYE	Example phrasing
Get to know the patient Start with a strengths or hobby-based question Ask about future goals, including potential parenthood. Understanding the individual’s goals can help frame conversations about their sexual and contraceptive practices.	“What is something you’re really good at?” or “What is something you do for fun?” “When you picture your future, what is important to you?” “When thinking about your future, do you picture yourself becoming a parent?”
Gender/Identity Ask about gender identity and pronouns	“I identify as [a woman] and my pronouns are [she/her]. How about you– what is your gender and what pronouns do you prefer?”
Sexual Activity Screen and Contraception Ask about sexual preferences Ask about sexual activity Ask about current or desired contraceptive practices	“Which genders are you attracted to?” “Have you ever had sex before?” “Have you ever been sexually active in the past?” “What method do you use (or would you like to use) for contraception (birth control)?” Provide counseling on effective pregnancy prevention as well as condoms
Pregnancy Plans Ask about reproductive goals	“Do you see yourself becoming pregnant in the next 1–2 years?”
Sexual Trauma Screen Screen for relationship safety and sexual abuse history	“Do you feel safe in your relationships?” “Have you ever been hurt in a sexual way or forced to have sex when you didn’t want to?”

Limitations

Our framework on counseling reproductive-age youth with epilepsy may be more readily applied in higher-income countries with greater resources. However, implementation may vary significantly depending on ASM availability, healthcare systems, and specific underserved populations. In lower- and middle-income countries with limited resources—such as reduced access to contraceptives or reliance on older-generation ASMs—application may be more challenging. Nonetheless, this framework could still serve as a benchmark for improvement.

An additional limitation is that most of the literature reviewed in this article is not specific youth, pertaining either exclusively to adults or including adults in addition to youth. However, we anticipate that it is biologically plausible that findings present in adults may also be pertinent to younger reproductive-age people, such as teratogenicity risk of different ASMs or relevant cytochrome P450-based drug interactions between ASMs and methods of contraception.

Conclusion

Sexual and reproductive health (SRH) counseling is critical for comprehensive care of RAYE. Yet many pediatric neurologists face challenges in addressing SRH due to limited knowledge, discomfort with sensitive discussions, and time constraints [5–7]. This review introduces a framework for incorporating SRH discussions into outpatient care for RAYE. The framework outlines key content areas including ASM teratogenicity, folic acid supplementation, pregnancy, contraception, menstrual/hormonal disorders, catamenial epilepsy, and sexual/psychosocial histories. The framework emphasizes essential communication strategies: initiating confidential conversations with RAYE, involving caregivers as appropriate; using an affirming, supportive, and non-judgmental tone; and balancing universally relevant information with individualized counseling. Table 5 summarizes key content points for these discussions. Table 6 summarizes recommended communication techniques. Widespread adoption of this framework can facilitate routine, efficient SRH discussions, enhancing care quality for RAYE.

Table 5.

Key Content Areas for Sexual and Reproductive Health Counseling of RAYE

Content Area	Key Points
Antiseizure Medication Teratogenicity	1. Most children of individuals with epilepsy are healthy, without major congenital malformations (MCMs) and with typical neurocognitive outcomes 2. RAYE should be counseled regarding possible risks of their specific antiseizure medications, including risk of MCMs and adverse neurocognitive outcomes.  2a. ASM polytherapy may increase risk for MCMs and adverse neurodevelopmental outcomes more than monotherapy  2b. Levetiracetam, lamotrigine, and oxcarbazepine monotherapy exposure in utero has not been shown to substantially increase risk for MCMs. There is no association of levetiracetam or lamotrigine with intellectual disability or autism. There is little data about neurocognitive outcomes with oxcarbazepine, but limited findings are favorable.  2c. Topiramate exposure in utero is associated with moderately increased risk for MCMs, specifically risk for cleft palate. It is also associated with small gestational age status. There is conflicting data on its association with intellectual disability and autism.  2d. Carbamazepine exposure in utero is associated with moderately increased risk for MCMs. No definitive correlation with intellectual disability or autism has been shown.  2e. Phenytoin and phenobarbital exposure in utero are associated with moderately increased risk for MCMs. Among all ASMs, phenobarbital is associated with the highest known risk of cardiac malformations. No definitive correlation with intellectual disability or autism has been shown for phenytoin. There is limited data for neurocognitive outcomes with phenobarbital exposure in utero.  2e. Valproic acid exposure in utero is associated with the highest known risk for MCMs among ASMs, with particularly increased risk of neural tube defects, urogenital malformations, and renal malformations. It is also associated with adverse neurocognitive outcomes including decreased IQ (intellectual disability) and increased risk for autism.
Folic Acid Supplementation	We recommend folic acid supplementation of 0.4 milligrams – 1 milligram daily for all reproductive age youth with epilepsy (RAYE) starting at menarche (or, for patients with precocious puberty and early menarche, generally no later than 12 years old).
Pregnancy Planning and Fertility	1. RAYE should be counseled that planning pregnancy is important for optimizing health for mother and fetus, most pregnancies are healthy, and there is most likely not reduced fertility compared to the general population. 2. RAYE should be counseled that prior to conception anti-seizure medication choices should be optimized to minimize teratogenicity when possible.  2a. Serum concentrations of anti-seizure medications should be checked prior to pregnancy. Consider annual ASM serum concentrations for RAYE.  2b. When feasible, RAYE who are pregnant or are planning to become pregnant should be referred to a neurologist/epileptologist with experience in managing pregnancy for consultation given more complex and intensive management.
Contraception	1. Pediatric neurologists should counsel RAYE about relevant drug interactions between contraceptive options and antiseizure medications.  1a. Antiseizure medications without known clinically significant drug interactions with contraception include gabapentin, pregabalin, lacosamide, levetiracetam, valproate, zonisamide, clonazepam, ethosuximide, stiripentol, vigabatrin, and tiagabine.  1b. Antiseizure medications that can potentially reduce the efficacy of susceptible hormonal contraceptive methods include carbamazepine, cenobamate, clobazam, felbamate, oxcarbazepine, eslicarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, and topiramate.  1c. Estrogen-containing contraception can decrease serum concentrations of lamotrigine. For patients adding estrogen-containing contraception to lamotrigine, consider empirically increasing the dose of lamotrigine, obtaining a serum level to ensure it remains therapeutic, and to advise use of continuous rather than cyclic methods of contraception. Many progestin-only methods of contraception do not alter lamotrigine concentrations, but consider evaluating lamotrigine levels if drospirenone is used.  1d. Effective methods of contraception without known drug interactions with any antiseizure medications include the hormonal and copper intrauterine devices, tubal ligation, and vasectomy. 2. Pediatric neurologists should be able to provide referrals to reproductive health providers (i.e. obstetrician-gynecologists, complex family planning specialists, and/or adolescent medicine specialists) who can perform in-depth contraceptive counseling and prescribe contraception to RAYE if desired. 3. Pediatric neurologists should be prepared to discuss contraceptive options with RAYE, including highly-effective methods such as long-acting reversible contraception.
Heritability of Epilepsy	1. If history or exam factors are present that increase suspicion for a monogenic etiology, genetic counseling and testing should be strongly recommended 2. All RAYE should be counseled by their healthcare provider regarding risk of epilepsy in offspring. Though most children of people with people will not have epilepsy, there is a slightly increased risk of epilepsy amongst children of people with epilepsy (3–6% vs 1–2%).
Menstrual and Hormonal Disorders	1. Pediatric neurologists should screen all RAYE at least once yearly for menstrual disorders and symptoms of PCOS following menarche or no later than at age 12 years. 2. Pediatric neurologists should counsel RAYE taking valproic acid on risk of PCOS. 3. If a menstrual disorder is identified, the patient should be referred to a menstrual disorders specialist such as a gynecologist, adolescent medicine specialist, or primary care provider with expertise in menstrual disorders.
Catamenial Epilepsy	1. Changes in sex hormones (progesterone and estrogen) during the menstrual cycle can make it more or less likely that a person has a seizure. When these fluctuations cause seizure exacerbation, it is called catamenial epilepsy (CE). CE requires a greater than two times increase in seizures during one of three periods of the menstrual cycle. 2. There are three patterns of CE: Perimenstrual (Days −3 to 3) (C1), Periovulatory (Day 10 to −13) (C2), Inadequate luteal phase (Days 10 to 3) (C3). 3. Menstrual history and calendars with seizure frequencies can help to identify patients with unexplained breakthrough seizures due to catamenial patterns, potentially leading to drug resistant epilepsy. RAYE with concern for catamenial epilepsy should be counseled to track their seizures and menstrual cycles on a calendar. Without direct tracking, there may be over or under reporting of catamenial patterns. 4. Treatment of catamenial epilepsy is at the discretion of the treating provider as there is no FDA approved treatment for catamenial epilepsy due to limited available research. An individualized treatment plan is needed due to complex metabolic interactions between endogenous sex hormones, hormonal pharmacotherapy, and ASMs. Hormonal and nonhormonal options may provide some seizure reduction.
Taking a Sexual History	1. RAYE have disease-specific needs for sexual and reproductive health care counseling and want counseling from their pediatric neurologist. Reproductive health discussions with adolescent patients with epilepsy should be explicitly confidential, developmentally appropriate, nonjudgmental, and affirming. 2. Pediatric neurologists should be aware of increased risk for suicide and self harm for PWECP who have gender diverse identities. Therefore, a complete confidential history with PWECP should include gender identity. 3. Pediatric neurologists should take sexual histories from patients with intellectual disabilities (ID) and provide appropriate counseling, since most people with ID will have sex and romantic relationships during their lifetime with limited sex education.  3a. Counseling with people with ID should be tailored to their developmental age with consideration of their chronological age.  3b. Since up to 1 in 3 of people with ID will experience sexual abuse, most commonly from relatives or peers, pediatric neurologists should provide universal education to patients about safety and have appropriate referral/safety procedures in place.

Table 6.

Suggested Communication Techniques for Discussing Sexual and Reproductive Health with RAYE

Content Area	Key Communication Techniques
Antiseizure Medication Teratogenicity	-Honest and direct discussions of risk -Tailor risk discussions to the individual patient and their ASM regimen -Provide reassurance where appropriate -Illustrative statistics can be helpful -Examples of specific malformations can be helpful where appropriate -Avoid jargon such as “congenital malformation” or “teratogenic” -Clearly indicate that patients can become pregnant and deliver, but that children may be affected by congenital malformations or adverse neurocognitive outcomes -Consider using shared decision-making approaches in medication selection -Counsel about potential fetal risk when starting or changing ASMs
Folic Acid Supplementation	-Explain that folic acid is a vitamin that the human body cannot produce -Explain that folic acid supplements have minimal common side effects at low doses, such as a risk of minor GI upset -Explain why you are recommending folic acid supplements -Share all health benefits of folic acid to the patient (including but not limited to perinatal benefits). Perinatal benefits include reduced risks to children of major congenital malformations particularly neural tube defects (in the general population) and adverse neurocognitive outcomes such as intellectual disability or autism (in the epilepsy population). Benefits to the patient (rather than child) include prevention of anemia, cardiovascular disease, and skin disease. -Explain that folic acid supplements can be taken once daily -Provide recommendations for how to integrate folic acid supplements into a daily routine alongside takin ASMs such as through use of a pill organizer and/or phone alarms -Emphasize patient autonomy in choosing to take folic acid supplements -Consider prescribing folic acid supplements, especially when covered by insurance, rather than solely recommending over-the-counter pickup
Pregnancy Planning and Fertility	-Ask about reproductive goals as part of a confidential history -Advise RAYE that people with epilepsy can become pregnant -Where appropriate, advise RAYE that people with epilepsy can have healthy pregnancies and healthy children, particularly with consistent prenatal and neurologic care -Advise planning future pregnancies if possible
Contraception	-Initiate contraceptive counseling confidentially -Normalize conversations about contraception (i.e. “This is something that I discuss with all of my patients”) -Discuss different contraceptive options, including but not limited to long-acting reversible contraception -Discuss relevant interactions between ASMs and contraceptives -Consider briefly introducing relevant side effects of different contraceptive methods -Respect patient autonomy. Do not pressure the patient to initiate contraception or choose any particular method. -If the patient is comfortable with this idea, consider sharing anticipatory general information about contraception and epilepsy with the parent/caregiver -When speaking with caregivers, consider including that contraception can be initiated for many reasons other than pregnancy prevention, such as treatment of menstrual symptoms, acne, or headaches -Be prepared to offer referrals to providers (such as gynecologists, complex family planning specialists, or adolescent medicine specialists) who can prescribe contraception
Heritability of Epilepsy	-Provide individually tailored counseling to RAYE about their risk of having a child with epilepsy, considering their epilepsy etiology, type, and syndrome -Consider sharing statistics about the risk of epilepsy in the general population compared to the risk of children of parents with epilepsy -Offer genetic counseling and testing to patients and families when desired
Menstrual and Hormonal Disorders	-Screen at least annually for symptoms of menstrual and hormonal disorders (see Table 1 for suggested questions) -Refer patients with symptoms or concerns to a clinician with appropriate expertise (i.e. gynecologist, adolescent medicine specialist, or expert primary care provider).
Catamenial Epilepsy	-Consider catamenial epilepsy in RAYE reporting concerns for cyclical seizures or with otherwise unexplained drug-resistant epilepsy -Recommend use of tracking (i.e. calendars, diaries, or mobile health applications) menses and seizures for identification of catamenial epilepsy
Taking a sexual history	-Sexual history questions should only be asked confidentially -See Table 3 for suggested questions

Highlights:

• Guidance for child neurologists on counseling about epilepsy and reproductive health.

• Provides key content statements and communication best practices.

• Developed by the Epilepsy in the Child-Bearing Ages through Menopause Consortium.