Pregnancy and fetal outcomes following maternal exposure to glatiramer acetate in all three trimesters of pregnancy.

BACKGROUND AND PURPOSE: Data on disease-modifying therapy (DMT) exposure throughout pregnancy in patients with multiple sclerosis are scarce. In this analysis, we assessed pregnancy and fetal outcomes following maternal glatiramer acetate (GA) exposure in all three trimesters among cases reported between 1997 and 2020. METHODS: Pregnancy reports of maternal in utero exposure to 20 and 40 mg/mL GA in all three trimesters from 1997 to 2020 were eligible. Both prospective pregnancy data, reported prior to knowledge of pregnancy outcome, and retrospective data were included. The primary endpoint was major congenital malformations (MCMs) based on the European Surveillance of Congenital Anomalies and Twins (EUROCAT) classification. Additional endpoints included fetal death, preterm birth, and low birth weight. The MCM rate was compared to the EUROCAT background rate. RESULTS: A total of 618 GA-exposed pregnancies in all three trimesters resulted in 634 fetuses, including 14 twin pregnancies. One fetal death was reported. All 414 fetuses with data reported prior to knowledge of pregnancy outcome (prospective data) were live births and no fetal death was reported. Preterm birth was reported in 23/213 (10.8%) pregnancies with known gestational age. Low birth weight was reported in 13/203 (6.4%) infants with known birth weight. The prevalence of MCM in prospective live births ranged from 2.2% to 2.4%, which was similar to background rates (2.1%-3.0%). The frequency of these pregnancy and infant outcomes was comparable across GA doses. CONCLUSIONS: In utero exposure to 20 and 40 mg/mL GA in three trimesters of pregnancy does not appear to be related to adverse pregnancy or infant outcomes.

Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes.

OBJECTIVES: Leflunomide is known to be embryotoxic and teratogenic in rodents. However, there is less evidence in humans. We quantified the risk of major congenital malformation (MCM), prematurity, low birth weight (LBW) and spontaneous abortion associated with leflunomide exposure during pregnancy in humans. METHODS: From a cohort of 289 688 pregnancies in Montreal, Quebec, Canada, from 1998 to 2015, first-trimester leflunomide exposure and other antirheumatic drug exposures were studied for their association with MCM and spontaneous abortions. Also second or third-trimester leflunomide exposures were examined for associations with prematurity and LBW. Logistic regression model-based generalised estimating equations were used. RESULTS: 51 pregnancies were exposed to leflunomide during the first trimester, and 21 during the second/third trimesters. Adjusting for potential confounders, use of leflunomide during the first trimester of pregnancy was not associated with the risk of MCM (adjusted OR (aOR) 0.97, 95% CI 0.81 to 1.16; 5 exposed cases). No association was found between second/third-trimester exposure to leflunomide and the risk of prematurity (aOR 4.03, 95% CI 0.91 to 17.85; 7 exposed cases) nor LBW (aOR 1.06, 95%CI 0.90 to 1.25; 8 exposed cases). Pregnancy exposure to leflunomide was also not associated with the risk of spontaneous abortion (aOR 1.09, 95% CI 0.90 to 1.32; 11 exposed cases). CONCLUSIONS: Maternal exposure to leflunomide during pregnancy was not associated with statistically significant increased risk of MCMs, prematurity, LBW or spontaneous abortions. However, given that relatively few women were exposed to leflunomide during pregnancy in this cohort, caution remains warranted.

[Potential teratogenicity of modafinil - Conflicting evidence, need for research]. / Tératogénicité potentielle du modafinil ­ des données contradictoires, un besoin de recherche.

Central disorders of hypersomnolence include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia and hypersomnia associated with medical or mental disorders. Treatment is both non-pharmacological and pharmacological, including wake enhancing drugs and stimulants. One of the first-line treatment (modafinil, MODIODAL®) was the subject of a health authority alert in 2019 concerning a risk of major congenital malformations when taken during organogenesis. Since this date, three epidemiological studies have presented contradictory results. Given their methodological weaknesses, it is not possible at this stage to confirm or deny such a risk for the embryo and its nature if there is one. In clinical practice, because of these uncertainties, it is preferable if possible to suspend the treatment of a pregnant woman during the first 10 weeks from last menstrual period (organogenesis). There is an unmet clinical need for research to clarify the potential teratogenic impact of modafinil.

Major congenital malformations in offspring of women with chronic diseases-impact of the disease or the treatment?

In a narrative review, we summarized previous findings on the risk of major congenital malformations in offspring of women with chronic hypertension, hypothyroidism, or depression compared with the background population, and evaluated whether exposure to medical treatment in the first trimester affected this risk. In a literature search in the PubMed database, cohort studies were included if they were published from 2010 to 2022 and contained data on major congenital malformations from ≥500 offspring of women with chronic hypertension, hypothyroidism, or depression during the first trimester of pregnancy, and data on both untreated and treated women. Data were compared with the background population of women without these diseases. In total, 7 cohort studies were identified. In comparison with the background population, 2 studies including 54,996 offspring of women with chronic hypertension showed an adjusted odds ratio of 1.20 to 1.30 for major congenital malformations in the offspring, regardless of antihypertensive treatment. One study including 16,364 offspring of women with hypothyroidism showed an adjusted odds ratio of 1.14 (1.06-1.22) for major congenital malformations in the offspring, regardless of thyroid substitution. Four studies including 48,913 offspring of women with depression showed adjusted odds ratios of 1.07 to 1.27 (0.91-1.78) for major congenital malformations in the offspring of untreated women. Three of these 4 studies showed similar prevalence of malformations in women treated for depression. The findings of this narrative review suggest that chronic hypertension and hypothyroidism, rather than exposure to their medical treatments in the first trimester, were associated with increased risk of major congenital malformations, whereas depression was generally not associated with major congenital malformations.

Treatment and care of women with epilepsy before, during, and after pregnancy: a practical guide.

Women with epilepsy (WWE) wishing for a child represent a highly relevant subgroup of epilepsy patients. The treating epileptologist needs to delineate the epilepsy syndrome and choose the appropriate anti-seizure medication (ASM) considering the main goal of seizure freedom, teratogenic risks, changes in drug metabolism during pregnancy and postpartum, demanding for up-titration during and down-titration after pregnancy. Folic acid or vitamin K supplements and breastfeeding are also discussed in this review. Lamotrigine and levetiracetam have the lowest teratogenic potential. Data on teratogenic risks are also favorable for oxcarbazepine, whereas topiramate tends to have an unfavorable profile. Valproate needs special emphasis. It is most effective in generalized seizures but should be avoided whenever possible due to its teratogenic effects and the negative impact on neuropsychological development of in utero-exposed children. Valproate still has its justification in patients not achieving seizure freedom with other ASMs or if a woman decides to or cannot become pregnant for any reason. When valproate is the most appropriate treatment option, the patient and caregiver must be fully informed of the risks associated with its use during pregnancies. Folate supplementation is recommended to reduce the risk of major congenital malformations. However, there is insufficient information to address the optimal dose and it is unclear whether higher doses offer greater protection. There is currently no general recommendation for a peripartum vitamin K prophylaxis. During pregnancy most ASMs (e.g. lamotrigine, oxcarbazepine, and levetiracetam) need to be increased to compensate for the decline in serum levels; exceptions are valproate and carbamazepine. Postpartum, baseline levels are reached relatively fast, and down-titration is performed empirically. Many ASMs in monotherapy are (moderately) safe for breastfeeding and women should be encouraged to do so. This review provides a practically oriented overview of the complex management of WWE before, during, and after pregnancy.

Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register.

BACKGROUND: Animal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. OBJECTIVE: To calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. METHODS AND MATERIALS: Data were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. RESULTS: From December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5-32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0-15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). CONCLUSION: These data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.

Malformation risk of new anti-epileptic drugs in women with epilepsy; observational data from the Kerala registry of epilepsy and pregnancy (KREP).

OBJECTIVES: We aim to report the major congenital malformation (MCM) rates for new and old anti-epileptic drugs (AED) exposures during the first trimester of pregnancy in women with epilepsy (WWE). METHODS: We extracted relevant data on drug exposure and malformation rate from the records of a prospective observational registry (Kerala Registry of Epilepsy and Pregnancy) for all completed pregnancies between 1998 and 2019. A comprehensive and uniform criterion with detailed guideline was used for assessment of malformations. We employed generalised linear model to generate adjusted incidence rate ratios (aIRR) of MCM in AED exposed group as compared to AED unexposed group, after adjustment for age and educational status of mothers' and epilepsy classification. RESULTS: The unadjusted MCM rate was 6.2% for all the infants included in the study (148/2328); 4.7% for the unexposed group (16/340), and 6.6% for the exposed group (132/1988). The aIRR of MCM as compared to unexposed group was similar for all monotherapies; lamotrigine (0.50; 95% CI 0.07-3.68), levetiracetam (1.16; 0.43-3.11), oxcarbazepine (1.61; 0.62-4.21) valproate (1.71, 0.93-3.19), phenytoin (1.21, 0.51-2.90), carbamazepine (0.99, 0.54-1.82), and phenobarbitone (1.20, 0.52-2.74). However, the point estimates suggest least risk with lamotrigine and highest risk with valproate. Polytherapy with high-dose valproate carried significantly higher risk of MCM as compared to the unexposed group (aIRR=4.12; 2.18-7.79, p<0.001). The aIRR of GTCS during pregnancy was 1.63 (95% CI 1.12-2.37, p = 0.011) for monotherapy with new AEDs (lamotrigine, levetiracetam or oxcarbazepine) as compared to old AEDs (phenobarbitone, phenytoin, carbamazepine, or valproate). CONCLUSION: The MCM risk was significantly higher for polytherapy with high dose valproate. It did not differ substantially between different AED monotherapies although point estimate was lowest with lamotrigine. Pregnant women on new AEDs report higher likelihood of GTCS than women on old AEDs during pregnancy.

Epilepsy.

The management of epilepsy during pregnancy involves optimizing seizure control for the mother, while ensuring the best outcome for the developing fetus. Preconception counseling regarding contraception, folic acid, and antiseizure medications (ASMs) will maximize positive outcomes. Folic acid supplementation is recommended to decrease risk of neural tube defects, similar to the general population, and has been associated with improved cognitive outcomes and decreased risk of autistic traits in offspring. Efforts should be made to optimize the ASM regimen before pregnancy to the fewest number of ASMs, lowest effective doses, with avoidance of more teratogenic agents such as valproic acid. Valproic acid is associated with the highest increased risk of major congenital malformations, as well as reduced cognitive outcomes and neurodevelopmental disorders. Decreasing or changing ASMs during pregnancy should be done with caution, as convulsive seizures have been associated with adverse fetal outcomes including cognitive impairment. Physiologic changes during pregnancy affect ASM levels and in turn, risk for seizures, necessitating frequent monitoring of ASM serum concentrations. Mothers should also be counseled postpartum about how the benefits of breastfeeding outweigh the transmission of medication into breast milk. Communication between providers (obstetrics and neurology) and pregnant women with epilepsy is essential.

Shifting Valproic Acid to Levetiracetam in Women of Childbearing Age With Epilepsy: A Retrospective Investigation and Review of the Literature.

Objective: Valproic acid is the most high-risk teratogenic antiepileptic drug, and it may lead to fetal major congenital malformations. However, it is still used in women of childbearing age with epilepsy. The aim of this study was to report our experience of discontinuing or lowering valproic acid by adding levetiracetam, a low-risk teratogenic antiepileptic drug. Methods: We reviewed the medical records of childbearing age female patients with epilepsy who were treated with valproic acid initially and then switched to levetiracetam. The clinical profiles were recorded. The primary outcome was successful switching, which was defined as a decrease in the daily valproic acid dosage, after levetiracetam had been added. Results: Twenty-four female patients were enrolled (median age 22 years). The successful switching rate was 83.3% (20/24), and 55% (11/20) discontinued valproic acid after levetiracetam had been added. There were no significant differences between the successful and unsuccessful groups in etiology, electroencephalogram, and magnetic resonance imaging findings. Pharmacoresistant to levetiracetam was much higher in the unsuccessful group (45 vs. 100%). The median switching duration was 19.5 months in the successful group. There were improvements in metrorrhagia and alopecia in all of the patients in the successful group after valproic acid had been tapered. Conclusions: Our experience supports switching valproic acid to levetiracetam in childbearing age women with epilepsy as an effective strategy to lower the teratogenic rate and adverse effects. A long switching period was noted in this study. We suggest starting early in childbearing age women with epilepsy.

Therapeutic strategies for treating epilepsy during pregnancy.

INTRODUCTION: Counseling for women with epilepsy of childbearing potential surrounding pregnancy issues is of the utmost importance and should be done when antiepileptic medications are prescribed and reviewed regularly at clinic visits. Physicians must be familiar with risks associated with antiepileptic medication, and endeavor to minimize risks to a fetus while selecting best medications for epilepsy type. AREAS COVERED: The authors discuss the role of folic acid, updated evidence relating to the occurrence of major congenital malformations and neurocognitive risks associated with antiepileptic medication. They also examine the rationale for monitoring drug levels, optimum delivery strategies, and evidence for the safety of breastfeeding while taking antiepileptic medication. EXPERT OPINION: Valproate carries the highest known teratogenic risk in pregnancy and should only be prescribed to women of child-bearing potential in a specialist setting. There is a need for the ongoing register collection of risks associated with newer AEDs which lack substantial (major) data. Choosing these newer medications can create a dilemma for physicians, particularly when seizures are not well controlled or where treatment options are limited. The authors advocate a multidisciplinary team approach to managing women with epilepsy so that pregnancies in such women can be well managed in an optimum and individualized fashion.

Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome?

OBJECTIVE: The management of Women With Epilepsy (WWE) in pregnancy is a challenge that demands balancing the risks of Major Congenital Malformation (MCM) on one hand with adequate seizure control on the other. While most studies have analysed the risks of Anti-Epileptic Drugs (AED) exposure in the first trimester, AED changes during the second and third trimester and their effects on fetal outcome has not been studied adequately. MATERIALS AND METHODS: Data of WWE who were prospectively followed up and completed pregnancy with live birth under the Kerala registry of epilepsy and pregnancy (KREP) between 1998 and 2014 were analysed. The AED addition, dose escalation, unchanged continuation, dose reduction or stoppage during the second or third trimester in comparison to the first trimester was tabulated for each drug. The outcome measures evaluated were malformation status and Developmental Quotient (DQ) at one year as extracted from the clinical records of the registry. RESULTS: The first trimester AED exposure was nil for 231, monotherapy for 925 and polytherapy for 391 WWE. WWE on monotherapy in first trimester were more likely to remain on the same number of AEDs in second or third trimester than those who were on polytherapy (OR 3.1, 95% CI 2.2 - 4.46). AED naïve women had a higher likelihood (OR 16.7; 95% CI 10.9-25.8) of being started on AED than women on monotherapy being switched to polytherapy. At least one AED was reduced or stopped during second or third trimester more often in women on polytherapy (15.1%) than in women on monotherapy (3.7%) (OR 4.7; 95% CI 2.9-7.2). Malformation rates for the infants of women whose AED dosage was increased or added were not significantly different from those of others. There was no statistically significant change in DQ with increase in dose or addition of drugs in the second or third trimester. CONCLUSION: AEDs were reduced in a significant proportion of patients on polytherapy while more than a third of women who were not on AEDs in the first trimester were subsequently started on AEDs. Increase in dose or addition of AEDs after the first trimester is unlikely to influence malformation outcome but the potential adverse effect on the DQ needs to be explored on a larger set of data.

Fetal safety of levetiracetam use during pregnancy.

The aim of this study is to evaluate the effect of levetiracetam treatment during pregnancy on fetus.. The pregnant women with epilepsy (PWWE) who were exposed to levetiracetam treatment during pregnancy in the form of monotherapy or polytherapy were retrospectively evaluated. They were compared with the PWWE who did not use the antiepileptic drug (AED) during pregnancy. A total of 102 pregnancies were examined. While 35 patients never used AED during pregnancy, 30 patients received only levetiracetam therapy, and 37 patients received levetiracetam with at least one combined AED. While no major congenital malformation (MCM) was determined in the group of patients who never used AED and who received levetiracetam monotherapy, 2 MCMs were determined in the group receiving multiple AED therapy with levetiracetam. This study showed that the use of levetiracetam as monotherapy during pregnancy was at the same risk level as the group who never used AED and that the risk increased when it was used as a part of polytherapy. In conclusion, these findings support the current understanding that LEV may be a feasible option for PWWE.

Impact of planning of pregnancy in women with epilepsy on seizure control during pregnancy and on maternal and neonatal outcomes.

PURPOSE: To investigate whether planning of pregnancy in women with epilepsy affects seizure control during pregnancy and to compare the maternal and neonatal outcomes in planned and unplanned pregnancies. METHODS: This was a retrospective cohort study of 153 pregnant women with epilepsy who were treated at the University of Tsukuba Hospital and Hokkaido University Hospital between 2003 and 2011. Twenty-one pregnancies were excluded due to insufficient data. Data of patients followed by neurologists during their planned pregnancies (planned-pregnancy group, n=51) were compared to those of patients referred to neurologists after conception for managing epilepsy during pregnancy (unplanned-pregnancy group, n=81). The treatment profile for epilepsy, seizure control, and maternal and neonatal outcomes in both groups were compared using Chi-square test or Fisher's exact test and Mann-Whitney U test. RESULTS: Compared to the unplanned-pregnancy group, the planned-pregnancy group showed a significantly greater proportion of patients receiving monotherapy with antiepileptic drugs (80% vs. 61%: planned vs. unplanned, P=0.049) and those not requiring valproic acid (77% vs. 56%, P=0.031). Furthermore, the frequency of epileptic seizures (16% vs. 35%, P=0.018) and changes in antiepileptic drugs (24% vs. 41%, P=0.042) were significantly lower in the planned-pregnancy group than in the unplanned-pregnancy group. No significant intergroup differences were noted in the obstetric complications and neonatal outcomes, including congenital malformations. CONCLUSION: For women with epilepsy, planning of pregnancy is associated with good seizure control during pregnancy and less fetal exposure to antiepileptic drugs.