Epilepsy during pregnancy: focus on management strategies

Figures & data

Table 1 AED pregnancy category and risk

Drug name	Previous FDA pregnancy categorya	Documented pregnancy outcomes
AZA^Citation42^–^Citation46,b	C	One case of congenital glaucoma, microphthalmia, and patent ductus arteriosus One case of sacrococcygeal teratoma One case of metabolic complications postpartum (metabolic acidosis, hyperbilirubinemia, hypocalcemia, and hypomagnesemia) Animal studies: ureter and kidney abnormalities in mice; vertebral malformations occurred more frequently when dose was higher in rabbits
BRV^Citation47	C	There are limited amount of data in pregnant women Animal studies did not detect any teratogenic potential
CBZ^Citation48^–^Citation53	D	EURAP Registry: 2% rate of MCM with <400 mg/d: neural tube defects, spina bifida, hypospadias, craniofacial defects, cardiovascular malformations No strong evidence of increase in MCM compared to general population Developmental delays
CLB	C	Withdrawal symptoms Animal studies: neurobehavioral and immunological function defects, decreased fetal body weights, and increased incidences of visceral and skeletal malformations
CZP^Citation54	D (US)	Withdrawal symptoms
	C (AUS)	Animal studies: cleft palates
Diazepam^Citation55^–^Citation61	D	Congenital malformations and developmental abnormalities One case of OEIS complex Low birth weight Withdrawal symptoms (three cases)
Divalproex sodium (VPA)	X	See valproic acid
ESL^Citation62	C	Animal studies: teratogenicity, developmental delays, skeletal abnormalities, and fetal growth retardation
ESM^Citation63^–^Citation68	Not formally assigned (pregnancy risk factor C)	Cases of hemorrhage in the neonate, patent ductus arteriosus, cleft lip/palate, hydrocephalus Significant increase in MCM risk when coadministered with phenobarbital
EZG (Retigabine)	C	Animal studies: pre- and postnatal mortality, growth deficit, developmental toxicity
FBM^Citation69^–^Citation71	C	Animal studies: higher death rate and decreased body weight
GBP^Citation72^–^Citation75	C	One MCM out of 59 exposures (1.7%) in Danish cohort Animal studies: delayed ossification, impaired synaptogenesis
LAC^Citation76	C	Animal studies: pre- and postnatal mortality, growth deficit
LTG^Citation56,Citation73,Citation77^–^Citation80	C (immediate release)	No strong evidence of facial cleft compared to general population
	D (XR)	EURAP study: lowest MCM rate (1.7%) among AED with exposure <300 mg/day The malformation rate was 5.2% in the Australian Registry The MCM rate was 3.7% in Denmark cohort
LVT^Citation23,Citation73,Citation80^–^Citation83	C	Only two MCM (0.7%, inguinal hernia and reflux requiring surgery) out of 304 first trimester exposures in UK; 2.4% MCM in US; 0 MCM out of 22 exposures in Australia; 0 MCM out of 58 exposures in Danish cohort Animal studies: structural and developmental toxicity
Lorazepam^Citation84,Citation85	D (US)	Withdrawal symptoms
	C (AUS)	Cases of anal atresia
Methsuximide^Citation86	Not formally assigned (pregnancy risk factor C)	Insufficient evidence regarding birth defect risk
OXC^Citation73,Citation87^–^Citation89	C (US)	2.8% MCM were seen in Danish cohort
	D (AUS)	Animal studies: developmental toxicity, malformations, embryo fetal death, decreased fetal body weight
PER^Citation90	C	Animal studies: visceral abnormalities, embryo lethality, reduced fetal body weight, and embryo-fetal developmental toxicity
PB^Citation91^–^Citation93	D	Teratogenicity (first trimester): heart defects and facial clefts Withdrawal symptoms (third trimester)
Phenytoin/Fosphenytoin^Citation91^–^Citation101 (PHT)	D	Fetal hydantoin syndrome, cases of orofacial clefts, cardiac defects, microcephaly, developmental delay, malignancies (neuroblastoma)
PGB^Citation102,Citation103	C	One case of malformation (out of 30) in one study Animal studies: structural and developmental abnormalities
PRM^Citation104,Citation105	Not assigned	Cases of neonatal hemorrhage Animal studies: dose-related cleft palate
RUF^Citation106	C	Animal studies: decreased fetal weights and increased incidences of fetal skeletal abnormalities, observed in cases of maternal toxicity
TGB^Citation107	C	Animal studies: high doses teratogenic effect
TPM^Citation23,Citation73,Citation80,Citation108^–^Citation110	D	Cleft lip or palate (1.4% in US, 2.2% in UK, both ~ten-fold the general population), hypospadias Small for gestational age (lower birth weight and shorter length): seems 1.8- to 3.3-fold more likely to happen than with lamotrigine One malformation out of 31 exposures (3.2%) was seen in the Australian Registry 4.6% MCM were seen in Danish cohort
VPA^Citation23,Citation26,Citation53,Citation57,Citation80,Citation111^–^Citation131	X	Strong evidence of human teratogenicity: neural tube defects, higher rate of spina bifida (1%–2%) than other AEDs, craniofacial defects (cleft palate), malformations of the limbs, cardiovascular malformations (atrial septal defects), hypospadias MCM reported 6%–9% (fourfold compared to any monotherapy) Increased risk of MCM both when used in monotherapy and polytherapy Dose-related risk of MCM (6% under 700 mg/day, 10% between 700 and 1,500 mg/day, >20% above 1,500 mg/day) Developmental delay: lower IQ scores (verbal more than nonverbal) compared to no AED or monotherapy, increased risk of ADHD at age 6 years Withdrawal syndrome if taken during the third trimester Cases of hypoglycemia and hypothyroidism
VGB^Citation132,Citation133	C	Cases of congenital malformations (eg, cardiac, genital, and renal defects) Two cases of visual field loss in children (6- and 7-year-old) exposed in utero
ZNS^Citation109,Citation134,Citation135	C	Small for gestational age (lower birth weight and shorter length): seems 0.9 to 2.8-fold more likely to happen than with lamotrigine One case of anencephaly and one case of atrial septal defect

Notes:

a FDA pregnancy category definitions: A – Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). B – Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. C – Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. D – There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. X – Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

b Used in epilepsy; however, not an AED.

Abbreviations: AED, antiepileptic drug; ADHD, attention-deficit hyperactivity disorder; AZA, acetazolamide; BRV, brivaracetam; CBZ, carbamazepine; CLB, clobazam; CZP, clonazepam; ESL, eslicarbazepine acetate; ESM, ethosuximide; EZG, ezogabine; FDA, Food and Drug Administration; FBM, felbamate; GBP, gabapentin; LAC, lacosamide; LTG, lamotrigine; LVT, levetiracetam; MCM, major congenital malformations; OEIS, omphalocele-exstrophy-imperforate-anus-spina bifida; OXC, oxcarbazepine; PER, perampanel; PB, phenobarbital; PGB, pregabalin; PRM, primidone; RUF, rufinamide; TGB, tiagabine; TPM, topiramate; VPA, valproic acid; VGB, vigabatrin; ZNS, zonisamide.

Table 2 Recommendations for epilepsy and pregnancy

Topic	AAN/AES^Citation1	UK NICE guidelines^Citation136	ETDP – EFA^Citation137
Year of publication	2009	2012 (update 2016)	2007
Counseling on seizure-induced harm during pregnancy	Tonic–clonic seizures: Not mentioned	Tonic–clonicseizures: Relatively higher risk of harm to fetus	Tonic–clonic seizures: Can particularly increase the risk of brain or other injuries, congenital malformations, and developmental delay (verbal IQ affected by seizure frequency) in the fetus
	Status epilepticus: Possible in 0%–1.8% of WWE	Status epilepticus: Can possibly occur	Status epilepticus: Poses risks of maternal and fetal survival, excellent seizure control is therefore needed, particularly for complex partial and tonic–clonic seizures
	SUDEP: Not mentioned	SUDEP: Possible	SUDEP: Not mentioned
Counseling on seizure frequency during pregnancy	Increase in seizure frequency: Might occur in 14%–32% of WWE	Increase in seizure frequency: Not likely to occur	Increase in seizure frequency: Occur in one-fourth to one-third of WWE
	Seizure freedom at least 9 months prior to pregnancy: Probably associated with a high likelihood (84%–92%) of remaining seizure-free during pregnancy	Seizure freedom at least 9 months prior to pregnancy: Not mentioned	Seizure freedom at least 9 months prior to pregnancy: Not mentioned
	Frequency of tonic–clonic seizures: May affect the risk of harm to the fetus	Frequency of tonic–clonic seizures: Not mentioned	Frequency of tonic–clonic seizures: Not mentioned
Counseling on risks for pregnant WWE	There is probably no more than a 1.5-fold increased risk of premature contraction, labor, or delivery, but there is possibly more than a twofold increase in such risk in WWE who smoke Probably increased risk of SGA and possibly at increased risk of 1-minute Apgar scores of <7 Probably no increased risk of late pregnancy-related bleeding complications, insufficient evidence for hemorrhagic complications in the newborn	More likely to have complications during pregnancy and labor	In some studies, WWE have an increased risk of vaginal bleeding, hypertension, preeclampsia, antepartum hemorrhage, and cesarean delivery Higher-than-expected rates of preterm delivery, failure to progress, and cesarean section are still evident in WWE 95% of WWE have a safe normal delivery without a seizure; generalized epilepsy women are more likely than those with partial epilepsy to have a seizure at this time WWE are more likely to have labor induced, abruptio placentae, cesarean sections, and maternal death around delivery (tenfold for the latter but risk still low 8/10,000)
Prenatal screening	Not mentioned	Pregnant women and girls who are taking AEDs should be offered a high-resolution ultrasound scan at 18–20 weeks of gestation by an appropriately trained ultrasonographer, but earlier scanning may allow MCM to be detected sooner	Ultrasound at 11–13 weeks is recommended to rule out neural tube defects (along with serum alpha-fetoprotein at 16 weeks) and other MCM Ultrasound at 18–22 weeks to determine cardiac development, head and spine anatomy, and cleft lip or cleft palate
Dose of AED	Dose of VPA and LTG should be limited since it is correlated to MCM	Lowest effective dose for each AED	Seizure control with the minimum effective AED dose is the goal, minimizing fetal exposure to AED
Polytherapy	Should be avoided: During the first trimester to prevent MCM Throughout pregnancy to prevent cognitive impairment, especially when VPA is included	Should be avoided	Monotherapy is preferable whenever possible, while still maintaining good seizure control VPA is most likely to induce malformations when used as polytherapy
Monitoring of AED serum levels	Should be considered routinely for LTG (seizure frequency is probably increased when 65% of target level is reached), CBZ, and PHT may be considered routinely for OXC and LVT Not enough evidence for other AED	Recommended if seizures increase or are likely to increase Recommended if dose needs to be adjusted Not recommended otherwise in routine Lamotrigine and phenytoin are at risk of low serum levels	Careful monitoring of AED levels is needed throughout pregnancy AED levels should be monitored closely in the weeks following delivery since they may increase gradually LVT, OXC, and LTG showed elevated levels with days of delivery
Folic acid administration	Time frame: Prior to conception and during pregnancy may be considered to prevent MCM	Time frame: Before any possibility of pregnancy	Time frame: Before conception and throughout pregnancy
	Dose: At least 0.4 mg/day	Dose: 5 mg/day	Dose: 0.4 mg/day for nonpregnant women, 0.6 mg/day for pregnant women and those contemplating pregnancy, and 0.5 mg/day for lactating women. Many epileptologists recommend higher doses (0.8–4 mg/day) for women with epilepsy. However, for women with a family history of a neural tube defect, 4 mg/day is the recommended dosage
Vitamin K administration	To pregnant WWE: Insufficient evidence to support supplementation	To pregnant WWE: Not mentioned	To pregnant WWE: Oral dose of 10–20 mg/day suggested during the last month of pregnancy, especially if taking enzyme-inducing AED
	Neonates: Not mentioned	Neonates: All children born to mothers taking enzyme-inducing AEDs should be given 1 mg parenterally at delivery	Neonates: 1 mg IM or IV at birth besides monitoring for bleeding
Specific use of VPA	Risk summary and recommendations: Avoidance during the first trimester should be considered to decrease the risk of MCM (neural tube defects, facial clefts, and hypospadias) VPA is very likely to induce more MCM than CBZ, and possibly PHT and LTG, so VPA should be avoided VPA is probably associated with poor cognitive outcomes, probably more than CBZ and possibly more than PHT, so VPA should be avoided	Risk summary and recommendations: Should not be used unless other therapies are ineffective or not tolerated; patient should be counseled on the risk of malformations and developmental impairments	Risk summary and recommendations: VPA has been shown to carry a high risk of spina bifida aperta, cardiovascular complications, urogenital malformations, and skeletal defects VPA has been shown to decrease verbal IQ (22% of children had mental retardation versus 7% in unexposed)
	Dose-dependent risk: Not mentioned	Dose-dependent risk: Greater risk with doses >800 mg/day	Dose-dependent risk: VPA is most likely to induce malformations when used above doses of 1,000 mg/day; decrease in verbal IQ is dose-dependent
	Polytherapy: Higher evidence of such risk if VPA is taken as part of polytherapy AED	Polytherapy: Greater risk	Polytherapy: Not mentioned
Specific use of other AED	Older AED: CBZ, PHT, PB: avoidance may be considered to reduce the risk of cleft palate (PHT and CBZ), cardiac malformations (PB), and poor cognitive outcomes (PHT and PB)	Older AED: Not mentioned	Older AED: Barbiturates have been found to be associated with MCM PHT has been associated with facial clefts, congenital heart, and urogenital defects CBZ has been associated with neural tube defects, heart defects, hypospadias, hip dislocations, and inguinal hernia
	Newer AED: Not enough data to assess teratogenicity and make recommendations		Newer AED: Lamotrigine has the most data available at this time, with possibly no substantially increased risk of MCM Preliminary studies have found a good pregnancy safety profile with levetiracetam, but more data are needed

Abbreviations: AED, antiepileptic drug; AAN, American Academy of Neurology; AES, American Epilepsy Society; CBZ, carbamazepine; ETPD – EFA, Epilepsy Therapy Development Project – Epilepsy Foundation of America; IM, intramuscular; LTG, lamotrigine; LVT, levetiracetam; MCM, major congenital malformations; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; SUDEP, sudden unexpected death in epilepsy; VPA, valproic acid; WWE, women with epilepsy.

Table 3 Websites for various pregnancy registries

Name of pregnancy registry	Website
The North American AED Pregnancy Registry	www.aedpregnancyregistry.org/
Australian Pregnancy Register for Women on Antiepileptic Medication	www.epilepsy.org.au/research/australian-pregnancy-register
UK Epilepsy and Pregnancy Register	www.epilepsyandpregnancy.co.uk
The International Registry of AED and Pregnancy (EURAP)	www.eurapinternational.org

Abbreviation: AED, antiepileptic drug.

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