Risks associated with epilepsy during pregnancy and the postpartum period

INTRODUCTION — While most pregnancies in women with epilepsy are uncomplicated, the risk for some perinatal complications may be increased compared with the general population. Offspring are at increased risk for major congenital malformations and adverse neurodevelopmental outcomes. However, many potential risks can be mitigated with informed antiseizure medication (ASM) choice and management, and, for many women with epilepsy, risks are not much greater than in the general population.

This topic will discuss the risks associated with epilepsy and pregnancy. The management of pregnancy in women with epilepsy is discussed separately. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period".)

MORBIDITY AND MORTALITY

Obstetric complications — Studies of pregnancy complications in women with epilepsy have shown mixed results, with a tendency towards a small but increased risk of obstetric complications in this population [1-13]. A meta-analysis found that compared with pregnant women without epilepsy, pregnant women with epilepsy had an increased risk of cesarean delivery, induced labor, preterm birth, gestational diabetes, pre-eclampsia, intrauterine growth restriction, placental abruption, and stillbirth [12]. These complications were increased in pregnant women with epilepsy regardless of whether they were taking antiseizure medications (ASMs); the magnitude of the effect for these complications ranged from 1.11 to 1.89 in pooled odds ratios [12].

Maternal mortality — A few studies have found that mortality rates during pregnancy are increased for pregnant women with epilepsy compared with the general population of pregnant women [3,12,14,15]. Since maternal mortality is a rare event, this translates to a low absolute increase in risk of less than 0.1 percent. In a meta-analysis based upon four available observational studies, the incidence of maternal death in pregnant women with epilepsy was 0.077 percent, which was higher than the incidence in unaffected pregnant women (0.0085 percent). The unadjusted pooled odds ratio (OR) for maternal mortality was 5, with very wide confidence intervals, but the risk difference between groups was not measurable (unadjusted OR 5.00, 95% CI 1.38-18.04; risk difference [RD] 0.00, 95% CI 0 to 0 percent) [12]. One of the four studies contributed 88 percent of the patients and thus was primarily responsible for this finding; patients in this study were identified based on hospital diagnosis codes, which precluded confirmation of the epilepsy diagnosis or etiology [3]. These studies did not have a comparison group of nonpregnant patients with epilepsy. Thus, it is not clear if the possible increased risk is specifically related to pregnancy.

There are several possible explanations for increased maternal mortality among pregnant women with epilepsy in these reports, including an increase in medical comorbidities, an increase in life-threatening complications of pregnancy, and an increase in seizure-related complications, including sudden unexpected death in epilepsy (SUDEP). In one study of epilepsy-related deaths in a United Kingdom population-based registry, 11 out of 14 deaths (79 percent) were attributed to SUDEP; approximately one-third occurred during the postpartum period [15]. Two-thirds of the deaths were in patients treated with lamotrigine (a possible risk factor for SUDEP in females). However, since lamotrigine is the most frequently prescribed medication in this population, it is not clear if this was merely a reflection of prescribing practices. It is also possibly related to the substantial lowering of lamotrigine concentrations that occur during pregnancy if doses are not adjusted. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period".)

SUDEP is discussed in more detail separately. (See "Sudden unexpected death in epilepsy".)

Fetal death or stillbirth — There may be an increase in the risk of fetal death or stillbirth among offspring of individuals with epilepsy. Both a 2023 systematic review and meta-analysis [12] and a large population-based retrospective cohort study of delivery in United States hospitals between 2007 and 2011 [3] found a small increased risk of miscarriage or stillbirth. In the meta-analysis, stillbirth was more frequent among pregnant women with epilepsy compared with pregnant women without epilepsy (0.86 versus 0.60 percent, unadjusted OR 1.37, 95% CI 1.29-1.47, RD 0.0 percent, 95% CI 0 to 0 percent) [12]. Similarly, In the United States study, the risk of stillbirth was higher for pregnant women with epilepsy compared with women without epilepsy (0.8 versus 0.6 percent, adjusted OR 1.27, 95% CI 1.17-1.38), but the absolute increase in risk was only 0.2 percent [3].

Reports of miscarriage rates have varied by study and are subject to ascertainment bias. However, in a prospective observational study at four United States academic medical centers, miscarriage rates in the women with epilepsy were the same as in control women who were recruited prior to pregnancy [16].

The mechanism of an increased risk of fetal death among pregnant women with epilepsy is also not well understood. In a large European registry, only 1 of 165 reported miscarriages or stillbirths was associated with seizures or status epilepticus (SE); two-thirds of these pregnancies were seizure free [17]. Whether ASM exposure contributes to risk of spontaneous miscarriage is uncertain, but in aggregate the contribution appears to be minimal [1]. In a large population-based observational study that included nearly one million pregnancies, use of ASMs during pregnancy conferred a slightly higher risk of spontaneous abortion compared with not using ASMs (adjusted risk ratio [aRR] 1.13, 95% CI 1.04-1.24); however, when limited to women with an epilepsy diagnosis, the use of ASMs was not associated with increased risk (aRR 0.98, 95% CI 0.87-1.09) [18].

Preterm birth — ASM exposure is associated with an increased risk of preterm birth [12,19]. Interestingly, the effect was also present among females prescribed ASMs for a psychiatric indication, suggesting that the effect may be medication associated [19]. These results are similar to those of an earlier national registry of 679,762 Danish singleton births, of which 2982 were exposed to ASMs [20]. In this cohort, however, the risk of prematurity was limited to those without a history of epilepsy. In the 2023 meta-analysis, preterm birth was increased in pregnant women with epilepsy compared with pregnant women without epilepsy (10.5 versus 7.2 percent, OR 1.41, 95% CI 1.32-1.51; RD 2 percent, 95% CI 1 to 3 percent) [12].

Cesarean delivery — Most experts agree that epilepsy alone is not an indication for cesarean delivery [13]. However, pregnant women with epilepsy may be more likely to be delivered by cesarean. In the 2023 meta-analysis, cesarean delivery was more common among pregnant women with epilepsy compared with pregnant individuals without epilepsy (36.9 versus 31.6 percent, pooled OR 1.54, 95% CI 1.43-1.65; RD 8 percent, 95% CI 6 to 9 percent) [12].

Mode of delivery may depend on provider preference, however. In the prospective Maternal Outcome of Antiepileptic Drugs (MONEAD) study, pregnant subjects with epilepsy were not more likely than control pregnant subjects to be delivered by cesarean [21]. The likelihood of cesarean delivery without a trial of labor was the same in pregnant women with epilepsy and controls if they delivered at a tertiary care center. However, outside of the recruitment centers, women with epilepsy were more than twice as likely as pregnant controls to have a cesarean section without a trial of labor.

Other outcomes — Epilepsy is also associated with a small but significant increase in risk for several other perinatal outcomes. In a 2023 systematic review and meta-analysis of 76 studies, risk was moderately higher among women with epilepsy compared with women without epilepsy, for the following outcomes [12]:

●Pre-eclampsia – 6.8 versus 5.2 percent (OR 1.36, 95% CI 1.05-1.77; RD 1 percent, 95% CI 0 to 3 percent)

●Antepartum hemorrhage – 2.2 versus 1.6 percent (OR 1.38, 95% CI 1.32-1.45; RD 0 percent, 95% CI 0 to 1 percent)

●Small for gestational age (SGA) – 7.7 versus 4.6 percent (OR 1.38, 95% CI 1.22-1.55; RD 2 percent, 95% CI 1 to 3 percent)

Effect of seizures on the fetus — In addition to concerns about fetal exposure to ASMs, there are risks to the fetus from maternal seizures. In particular, generalized tonic-clonic seizures can lead to hypoxia and lactic acidosis, which may harm the fetus via placental transfer [13]. Although probably less harmful, other types of seizures may increase the risk of fetal growth restriction, fetal injury, and premature delivery. However, few studies have evaluated the direct effects of maternal seizures on the fetus.

Fetal hypoxia may occur because of maternal hypoxia or decreased placental blood flow, but no information is available on the number or length of seizures that may jeopardize the fetus. One report of fetal heart rate monitoring during a maternal generalized tonic-clonic seizure lasting 2.5 minutes revealed significant fetal heart rate deceleration lasting up to 30 minutes after the seizure [22]. While nonconvulsive seizures are believed to be less dangerous [13], another case report documented significant fetal bradycardia during a one-minute, focal impaired awareness seizure (also called complex partial seizure) [23].

Other risks of maternal seizures include injury to the fetus, placental abruption, or fetal loss due to maternal trauma sustained during a seizure.

In a population-based data set in Taiwan, compared with women with epilepsy who did not suffer seizures during pregnancy, epileptic seizures during pregnancy were marginally associated with SGA infants (adjusted OR 1.34, 95% CI 1.01-1.84) but not with preterm birth (OR 1.12, 95% CI 0.73-1.71) [24]. Of note, seizures during pregnancy in this study were defined as presenting to a hospital or emergency department with seizures, which may have selected for more severe seizure types. A study of 249 children in the United Kingdom found that the number of generalized tonic-clonic convulsive seizures during pregnancy was a negative predictor of verbal intelligence quotient (IQ) in the children; in particular, the occurrence of five or more convulsive seizures during pregnancy was associated with developmental delay [25].

In a large European registry of 1956 pregnancies in 1882 women with epilepsy, SE occurred in 1.8 percent, one-third of which were convulsive type [17]. Only one case of SE was associated with stillbirth; the remaining cases were not clearly associated with fetal or maternal complications.

EFFECT OF PREGNANCY ON SEIZURES

Seizure control — The effect of pregnancy and antiseizure medications (ASMs) management on seizure control is reviewed in the following sections.

●Evidence of seizure worsening during pregnancy – Although there is variability in the published literature, most earlier studies reported that 20 to 50 percent of women have worsening of seizures during pregnancy compared with their baseline [7,26-31]. The 2006 International Registry of Antiepileptic Drugs and Pregnancy (EURAP) also reported on seizure control in pregnancy, but the comparator was the first trimester rather than the nonpregnant baseline [17]. Among 1956 pregnancies in 1882 women with epilepsy, seizure frequency and ASM treatment remained unchanged in 62 to 64 percent; 59 percent were seizure free during pregnancy; only 17 percent reported increased seizure frequency. Status epilepticus (SE) occurred in approximately 2 percent, one-third of which were convulsive type. A 2019 systematic review of the literature from the International League Against Epilepsy (ILAE) Task Force on Women and Pregnancy concluded that approximately two-thirds of women with epilepsy maintain baseline seizure control during pregnancy [13]. However, none of these studies compared seizure frequency among pregnant women with the gold standard of seizure frequency among nonpregnant women with epilepsy followed over the same length of time and in the same manner; therefore, the evidence was insufficient to determine the change in seizure frequency for pregnant women with epilepsy [7]. A 2020 report from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study Group did this and found that pregnancy did not alter seizure frequency in a prospective more recent cohort [32]. The apparent increase in seizures seen in past studies may have been due, at least in part, to lack of awareness of increased ASM metabolism during pregnancy when those studies were conducted. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Antiseizure medication monitoring and dose adjustment'.)

●Prevention of seizure worsening during pregnancy – In the context of meticulous ASM management with therapeutic drug monitoring during pregnancy, seizure frequency does not seem to increase during pregnancy. Supporting evidence is provided by a 2020 prospective observational study from the MONEAD Study Group, which compared the proportion of women with increased seizure frequency during pregnancy with a matched, nonpregnant control group followed for the same length of time and with the same protocol [32]. The main analysis included 299 pregnant women and 93 controls who had a history of seizures that impaired awareness. Seizure frequency was higher during pregnancy than in an individual woman's nongravid baseline in 23 percent of pregnant women compared with 25 percent of controls during the corresponding time epochs (OR 0.93, 95% CI 0.54-1.60). In other words, the risk of seizure increase over two similar time periods was the same in both pregnant and nonpregnant women with epilepsy. However, the two groups differed in medication management. The ASM dose was changed at least once in 74 percent of the pregnant women compared with only 31 percent of the controls (OR 6.36, 95% CI 3.82-10.59). Moreover, doses of individual ASMs were increased during pregnancy in alignment with reported alterations in the clearance of that ASM during pregnancy, and doses were decreased again after delivery. These findings will help clinicians to counsel women with epilepsy on expectations for seizure control during pregnancy. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Counseling'.)

●Seizures during the peripartum period – Seizures may be more likely to occur during the peripartum period. A study of women enrolled in the Kerala Registry of Epilepsy and Pregnancy in India found that seizure relapse was the highest during the three peripartum days (one day prior to one day after the day of delivery) [31]. EURAP reported that seizures occurred during delivery in 3.5 percent of the enrolled women, and one woman had convulsive SE [17]. In most cases, however, labor and delivery were not associated with increased complications.

Predictors of seizure worsening — The main risk factor for seizures during pregnancy is baseline seizure frequency before pregnancy; women who are seizure free in the nine months prior to pregnancy are less likely to have seizure worsening [13,17,31,32]. Other reported predictors are focal epilepsy syndromes [13,17,31], ASM type, polytherapy, patient adherence, and the use of therapeutic drug monitoring [7,26-31,33,34].

Some women who experience increased seizure frequency are sleep deprived or nonadherent with their medications because of concerns about the effects of the medication on the developing fetus [13,35,36]. Altered ASM pharmacokinetics also contribute to increased seizure frequency during pregnancy. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Antiseizure medication monitoring and dose adjustment'.)

DEPRESSION AND ANXIETY — Individuals with epilepsy have an increased prevalence of comorbid depression and anxiety symptoms compared with individuals without epilepsy, and this appears to be true during pregnancy and the postpartum period as well.

Detection of depression and anxiety during pregnancy and the postpartum period is important because both pharmacologic and nonpharmacologic treatments are available, and untreated illness may have consequences for both mother and child. Several studies have suggested that females with epilepsy may be undertreated for depression compared with females without epilepsy [37,38], emphasizing the importance of screening and appropriate treatment. (See "Comorbidities and complications of epilepsy in adults", section on 'Depression and anxiety' and "Unipolar major depression during pregnancy: Epidemiology, clinical features, assessment, and diagnosis", section on 'Potential adverse outcomes' and "Mild to moderate episodes of antenatal unipolar major depression: Choosing treatment" and "Severe antenatal unipolar major depression: Choosing treatment".)

In a population-based study that included 706 pregnancies in women with epilepsy and over 100,000 pregnancies in controls without epilepsy, peripartum depression affected 27 percent of those with epilepsy compared with 23 percent of those with other chronic diseases and 19 percent of the entire nonepilepsy population [37]. These rates were similar to those reported in a subsequent prospective single-center study [39]. Rates of anxiety were similarly elevated in women with epilepsy compared with all others (22 versus 15 percent) [37]. In the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, 7.3 percent of the pregnant participants with epilepsy met criteria for major depression during pregnancy or the postpartum period, as defined by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV (SCID) [40]. Statistically, this did not differ from the incidence of major depression in control participants without epilepsy or nonpregnant controls with epilepsy. However, depressive symptoms, as measured by the Beck Depression Inventory II (BDI), were elevated in postpartum mothers with epilepsy when compared with control mothers. Anxiety symptoms, as measured by the Beck Anxiety Inventory (BAI), were elevated in individuals with epilepsy both during pregnancy and in the postpartum state when compared with pregnant controls. Additionally, compared with nonpregnant participants with epilepsy, pregnant participants had higher levels of depression during pregnancy and both depression and anxiety in the postpartum state. The authors draw attention to the importance of monitoring pregnant participants with epilepsy for anxiety and depressive symptoms. Anxiety was associated with suicidal ideation [40], and maternal anxiety has been linked to poorer neurodevelopmental outcomes [41].

These studies suggest that risk factors for depression or anxiety among women with epilepsy include ongoing seizures, history of physical and/or sexual abuse, adverse socioeconomic factors, multiparity, previous loss of a child, antiseizure medication (ASM) use (in particular polytherapy), unplanned pregnancy, and prepregnancy depression or anxiety [37,39,40].

EFFECTS OF ASMs ON THE FETUS AND CHILD — The risks of major congenital malformations (MCMs) are the best-studied effects of in utero antiseizure medication (ASM) exposure. Congenital malformations are defects of organs or body parts, most often occurring due to a defect in embryonic development; malformations are considered major (ie, MCMs) when they have medical, surgical, and/or social implications. (See "Congenital anomalies: Epidemiology, types, and patterns", section on 'Malformations'.)

For some ASMs, the risks of MCMs are very well characterized thanks to several prospective and population-based registries, though data are lacking for many other ASMs. The risk of being born small for gestational age (SGA) is another fetal outcome that has meaningful data related to specific ASM exposure. Finally, some cohort studies have shed light on the effects of certain ASMs on child neurodevelopment. The ASM-specific risks will be summarized here.

Risks associated with ASM use during pregnancy can be minimized by preconception planning and careful management during pregnancy. Choosing ASM(s) with lower risks for the fetus and child and ensuring the lowest therapeutic dose is used during pregnancy can reduce potential risks. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period".)

Major congenital malformations and their risk factors — When all ASMs are considered, the reported risk of MCMs with fetal exposure is 4 to 6 percent, compared with a population estimate of 2 to 3 percent [26,42-46]. The increased risk seems to be primarily due to the risk of ASM exposure rather than to an exposure to parental epilepsy. This conclusion is based on the fact that ASM-related teratogenesis varies by drug and that mothers with epilepsy not taking ASMs during pregnancy do not have an increased risk of MCMs in their children compared with the general population [44]. The effect of maternal epilepsy alone is difficult to study, however, as it can be argued that mothers with epilepsy not taking ASMs during pregnancy may have a milder condition. Paternal epilepsy does not seem to increase the risk of fetal malformations [47].

Data on major fetal malformations come from several international prospective and population-based registries that have been collecting data on ASM-exposed pregnancies for three decades (figure 1). These studies have differing methodologies, which accounts for some variability in findings. For the most part, however, they have yielded complementary results. Several of the registries do not have a control group of mothers without epilepsy. Thus, direct statistical comparison to the general population risk is not always possible. However, these registries do make it possible to compare MCM risk between different ASMs.

It is our practice to present absolute malformation risk where possible, as this is most meaningful to patients. As a reference, it is helpful to note that rates of malformations in the general population typically range from 2 to 3 percent.

●Types of malformations – The most common major malformations associated with ASMs are neural tube, congenital heart, and urinary tract defects, as well as skeletal abnormalities and oral clefts [42,48,49].

●Different ASMs have different risks – Different ASMs carry substantially different levels of risk for major malformations. The risk associated with some ASMs is very close to that in the general population, while other ASMs (eg, valproate, phenobarbital, and topiramate) have a several-fold increased risk for major malformations [50].

Across all pregnancy registries, valproate monotherapy is associated with the highest rates of major malformations compared with other ASMs [45,46,50]. A 2019 report from the International League Against Epilepsy (ILAE) concluded that valproate is associated with the highest risk of MCMs, while phenobarbital and topiramate are associated with an intermediate risk and lamotrigine and levetiracetam are associated with the lowest risk [13]. The consistency of findings across different pregnancy studies and in varied regions of the world strengthen the conclusion that some ASMs are associated with a higher risk for major malformations than others (figure 1). (See 'Risks with specific ASMs' below and "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Changing antiseizure medications during pregnancy'.)

●Timing and dose of ASM – In addition to the specific ASM exposure, the gestational timing of the exposure and the dose of the ASM used are also likely to be important. These have been best associated with valproate [45,49,51-53]. The International Registry of Antiepileptic Drugs and Pregnancy (EURAP) investigators analyzed the dose at the time of conception and reported a dose-dependent increase in the major malformation rates for monotherapy with valproate, phenobarbital, carbamazepine, and lamotrigine (figure 2) [49,50]. The ILAE working group concluded that the risk is dose dependent for valproate and is probably dose dependent for other ASMs including carbamazepine, phenobarbital and lamotrigine [13].

●Polytherapy – In general, ASM polytherapy is a risk factor for fetal major malformations, as identified in a number of prospective registry studies, with the rates of major malformations increasing to 6 to 8.6 percent [44,46]. However, the risk is probably more dependent upon the specific ASMs used as polytherapy, as well as the dose of those ASMs, rather than just the number of ASMs used [13]. Polytherapy with a regimen that includes valproate or topiramate is associated with a particularly high risk for MCMs [54-56]. By contrast, some polytherapy combinations, particularly lamotrigine and levetiracetam, are not associated with a substantially elevated risk for major malformations and are being used more commonly to avoid valproate use during pregnancy [57].

●History of malformation – There are likely yet undefined genetic risk factors that predispose to ASM-associated teratogenesis. A family history of congenital malformations, including from the paternal side, and a low maternal level of education have been identified as additional risk factors for fetal major malformations, at least in some studies [44,45,49,51,58-61]. A previous ASM-exposed pregnancy resulting in MCMs is associated with an increased risk in subsequent pregnancies [62,63]. The risk appears to be particularly high for valproate and topiramate but may also be increased for other ASMs and in pregnancies exposed to polytherapy. In two different registry studies, women taking valproate who had a previous child with a major malformation had a recurrence risk of approximately 50 percent if they continued valproate during the subsequent pregnancy [62,63].

●Mechanism – The mechanism for ASM-induced teratogenicity has not been determined. One possibility is that some fetuses have low or deficient epoxide hydrolase activity that results in increased levels of teratogenic oxidative metabolites when they are exposed to ASMs [54,64]. Another mechanism involves oxidative damage to deoxyribonucleic acid (DNA) from free radical intermediates produced by prostaglandin H synthase bioactivation of ASMs [65]. Deficiency of folic acid has also been suggested to play a role in teratogenicity associated with ASMs, some of which are folic acid antagonists. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Folic acid supplementation'.)

Fetal growth restriction — There is an increased risk of fetal growth restriction and delivery of an SGA infant with prenatal exposure to ASMs [13,19,20]. ASMs associated with increased risk in various studies include topiramate, zonisamide, carbamazepine, valproate, and phenobarbital [13,20,66]. The risk appears to be most pronounced with topiramate (see 'Topiramate' below). ASM polytherapy is also associated with an increased risk of fetal growth restriction [13,67]. One population-based study from Taiwan also found an increased risk of SGA infants in mothers with seizures during pregnancy (see 'Effect of seizures on the fetus' above) [24]. In this study, seizures were defined as those requiring emergency department or hospital treatment for seizures during pregnancy. However, the study could not control for specific ASM exposure, so the possibility that ASM effects contributed to SGA risk cannot be excluded.

Neurodevelopmental risks — Accumulating evidence from observational studies suggests that ASM treatment during pregnancy can be associated with cognitive and behavioral effects that manifest later in the life of the offspring. Neurodevelopmental outcomes are well characterized for a few ASMs. Some but not all prospective studies have included children born to mothers without epilepsy, and some have accounted for parental intelligence quotient (IQ), which is an important determinant of child neurodevelopment. The degree of neurodevelopmental risk varies with the type of ASM and possibly the level of in utero exposure [42,68-75]. Where possible, ASM-specific information on exposure and neurodevelopment is included below for individual ASMs (see 'Risks with specific ASMs' below). Across all studies, valproate has consistently stood out as the ASM most clearly associated with poorer neurodevelopmental outcomes [13].

●Polytherapy – ASM polytherapy may present a higher risk of cognitive impairment than monotherapy [8,72,76], and verbal abilities may be particularly affected [77,78].

●Risk with malformations – Some studies find that the risk of cognitive impairments with ASM exposure is highest in children who also have one or more of the major malformations described above [79-81]. However, ASM-related neurocognitive effects can be seen in the absence of malformations.

Risks with specific ASMs — The spectrum of fetal malformations and neurodevelopmental risks for different ASM monotherapies is depicted in the figure (figure 3). A summary of available data on the risks of exposure to specific ASMs is reviewed in the sections that follow.

Decisions about selecting or changing ASMs with pregnancy are discussed in detail separately. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period".)

Valproate — Valproate (VPA) should be avoided in females of childbearing age if possible.

●Malformations – First-trimester maternal exposure to VPA increases the risk of major malformations, independent of any contribution of the epilepsy syndrome itself [5,8,82]. VPA exposure in utero is associated with the development of neural tube-like defects (eg, spina bifida, open lumbosacral myelocele) in 1 to 2 percent of fetuses, which represents a 10- to 20-fold increase over the general population [50,83-85]. Additional patterns of major malformations associated with first-trimester VPA exposure include oral clefts, cardiovascular and urogenital malformations, and multiple malformations [49,50,79,86].

The North American Antiepileptic Drug Pregnancy Registry (NAAPR) followed 323 VPA-exposed pregnancies to completion [87,88]. The prevalence of MCMs in offspring of women who received VPA monotherapy was 9 percent, as compared with 3 percent in offspring of women receiving other ASMs and 1 percent in an unexposed control group. Thus, the relative risk of major malformations in VPA-exposed women was 9.0 (95% CI 3.4-23.3) [88]. Increased dose of VPA was also associated with increased risk (OR 3.7 for VPA ≤1500 mg/day versus OR 10.9 for VPA >1500 mg/day) [45], a finding also seen in other studies [49-51].

A case-control study using the European Surveillance of Congenital Anomalies database (registering a combined total of 98,075 MCMs) found that VPA was associated with an increased risk for several congenital malformations [89]. Compared with no ASMs, adjusted ORs for specific malformations were as follows: spina bifida (12.7), atrial septal defect (2.5), cleft palate (5.2), hypospadias (4.8), polydactyly (2.2), and craniosynostosis (6.8). ORs were similarly elevated for the comparison of VPA use with other ASM use.

The effect of VPA on malformation risk is dose dependent, but a lowest safe dose has not been established [52,53,90,91].

●Neurodevelopment – Of all ASMs, VPA is the most strongly associated with adverse neurodevelopmental outcomes [8,13,77,92-103]. It has been specifically associated with a risk of lower IQ in exposed children [77,95,96,98,100] as well as an increased risk of autism spectrum disorder.

•IQ and language – The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective study of 309 children who had been exposed to ASMs in utero, found that at age three years, children exposed to VPA had IQ scores that were on average six to nine points lower than those exposed to lamotrigine, phenytoin, or carbamazepine [95]. These findings persisted at six years [100]. In addition, the relationship between IQ score and VPA exposure was dose related, and children's IQ scores were related to maternal IQ scores in all exposure groups except for VPA [77].

A prospective blinded study of 182 children of mothers with epilepsy and 141 controls found significantly lower verbal IQ scores associated with exposure to VPA and ASM polytherapy but not to carbamazepine monotherapy [96]. In another registry-based study, 102 school-aged children exposed to VPA in utero had lower than mean average language test scores on blinded assessments [97]. Similarly, in a prospective study of 172 infants (mean age of 15 months), in utero exposure to VPA monotherapy was associated with lower mental and motor developmental quotients compared with carbamazepine monotherapy [98].

VPA-associated language deficits persist to school age. An Indian study of 55 eleven-year-old children exposed to VPA in monotherapy or polytherapy in utero found that they had poorer standardized language scores than unexposed peers [104].

•Autism spectrum disorders – In utero exposure to VPA also appears to increase the risk of autism spectrum disorders [13,99,105-108]. In a population-based study of more than 650,000 children born in Denmark from 1996 through 2006 that included 6584 women with epilepsy, 2655 ASM-exposed pregnancies, and 508 VPA-exposed pregnancies, the risk of autism spectrum disorder was increased in children exposed to VPA in the overall study population (hazard ratio [HR] 2.9, 95% CI 1.7-4.9; absolute risk 4.4 percent), and there was a trend towards increased risk in VPA-exposed children born to mothers with epilepsy (HR 1.7, 95% CI 0.9-3.2; absolute risk 4.2 percent) [108]. For the more narrowly defined diagnostic code of childhood autism, the relative risk was increased fivefold (absolute risk 2.5 percent). Analyses were adjusted for parental age at conception, parental psychiatric history, gestational age, birth weight, sex of the child, congenital malformations, and parity. An increased risk of autism spectrum disorders was also seen in children exposed to VPA whose mothers had diagnoses other than epilepsy, but not in children of women who were previous users of VPA but stopped at least 30 days before conception; both factors increase confidence in the association. An increased risk was not seen in association with other ASMs, including carbamazepine, oxcarbazepine, lamotrigine, and clonazepam, although the number of events in these subgroups was low.

●Neonatal coagulopathy – Rare cases of neonatal coagulopathy due to VPA-induced hypofibrinogenemia have been reported [109,110].

Carbamazepine

●Malformations – The rates of major malformations associated with carbamazepine monotherapy range from 2.6 to 5.9 percent in the prospective observational epilepsy and pregnancy registries [46,50,66,88,111-114]. Carbamazepine does have a specific association with neural tube defects [8,48,85,115-117]. In the European Registration of Congenital Anomalies and Twins (EUROCAT) database, exposure to carbamazepine monotherapy was associated with an increased risk of neural tube defects compared with controls on no ASM (OR 2.6; 95% CI 1.2-5.3) [115]. However, the EUROCAT study also showed that the risk of neural tube defects with carbamazepine exposure was lower than the risk with valproate exposure (OR 0.2; 95% CI 0.1-0.6). Based on aggregate data from several ASM pregnancy registries, the rate of specific malformations with carbamazepine monotherapy was 0.3 percent for neural tube defects, 0.8 percent for cardiac malformations, 0.4 percent for hypospadias, and 0.36 percent for oral clefts, respectively [86].

●Neurodevelopment – Studies on the neurodevelopmental effects of carbamazepine exposure have presented mixed results. However, much of this variability is felt to be due to differences in methodology [101,118]. The majority of studies, including well-designed prospective studies, support normal cognitive performance in children exposed to carbamazepine in utero [8,73,76,77,100-102,119-121]. In the NEAD study, the IQ of six-year-old children exposed to carbamazepine monotherapy in utero did not differ from that of children exposed to phenytoin or lamotrigine [100]. However, compared with valproate-exposed children, carbamazepine-exposed children had a higher mean full-scale IQ score. In an overlapping prospective study from the United Kingdom, the adjusted mean IQ of children exposed to carbamazepine monotherapy did not differ from that of unexposed control children [102]. However, there was an increased risk of having an IQ <85 in the carbamazepine group.

There are limited data on the risk of behavioral abnormalities in children exposed to carbamazepine. In a population-based study from Denmark, there was no increased risk of formally diagnosed autism spectrum disorder in school-aged and teenaged children exposed to carbamazepine in utero [108]. Similarly, a prospective study from the United Kingdom did not identify any increased risk of a formally diagnosed neurodevelopmental disorder [107].

Gabapentin

●Malformations – Several small case-control studies as well as larger registry-based studies that include a limited number of gabapentin-exposed pregnancies have found no association between gabapentin and MCMs [88,122-124]. A prospective cohort study reported on 223 gabapentin-exposed pregnancies compared with 223 unexposed [123]. Rates of major malformations were similar. However, the gabapentin-exposed group had higher rates of preterm births and low birth weight <2500 grams. The admission rate to either the neonatal intensive care unit or special care nursery for observation with continued gabapentin use was 38 percent, versus 3 percent in the comparison group. Only one-third of women were prescribed gabapentin for epilepsy, and most pregnancies involved other neuropsychiatric medications.

●Neurodevelopment – Data on neurodevelopmental outcomes with in utero gabapentin exposure are too limited to draw firm conclusions [119].

Lamotrigine

●Congenital malformations – Prospective pregnancy registries have reported a 2 to 4.9 percent incidence of major malformations after first-trimester exposure to lamotrigine monotherapy [88,125,126]. However, the data regarding dose-related risk of lamotrigine have been conflicting. While the International Lamotrigine Pregnancy Registry found no effect of lamotrigine dose, up to 400 mg/day, on the incidence of major malformations [126,127], the United Kingdom Epilepsy and Pregnancy Registry did observe a dose relationship [46]. In the EURAP registry, the incidence of fetal malformations with lamotrigine at any dose was 3 percent, but it was significantly higher for patients taking >325 mg per day at conception than for patients taking lower doses (4.3 versus 2.5 percent) [50]. They did not have data on doses during the remainder of the first trimester or lamotrigine blood concentrations.

A report from the NAAPR noted a higher-than-expected prevalence of cleft palate and/or cleft lip in infants exposed to lamotrigine in the first trimester (8.9 per 1000 compared with the expected 0.7 to 2.5 per 1000) [128]. However, population-based case-control studies derived from a European congenital anomaly register found that lamotrigine monotherapy did not specifically increase the risk of isolated orofacial clefts relative to other malformations [129,130]. These studies were not designed to study whether lamotrigine was associated with an overall risk of malformations and therefore could not determine an association.

Data released from the manufacturer's pregnancy registry in January 2008 reported that the risk of major malformations after exposure to lamotrigine used in polytherapy with other ASMs, not including valproate, was similar to that of lamotrigine monotherapy but was increased in those exposed to lamotrigine and valproate (16 of 143 pregnancies, 11 percent) [125]. These findings were similar in the final report of the International Lamotrigine Pregnancy Registry [126].

●Neurodevelopment – In multiple independent studies, developmental and cognitive abilities of lamotrigine-exposed children have been consistently measured as not different from unexposed control groups and improved compared with valproate-exposed children [13,119,131,132]. While some studies have suggested an increase in parent-reported "autistic traits" in lamotrigine-exposed children, this was not associated with increases in neurodevelopmental referrals [119]. Furthermore, studies examining the rates of formally diagnosed attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder have not found an increased risk in lamotrigine-exposed children compared with controls [119].

Levetiracetam

●Malformations – Across prospective pregnancy registries, rates of major malformations with levetiracetam monotherapy exposure have ranged from 0.7 to 4.7 percent [114]. A Cochrane review reported an aggregate malformation rate of 1.77 percent for levetiracetam in 817 published pregnancies [133].

●Neurodevelopment – Data are limited and inconsistent regarding intrauterine exposure to levetiracetam monotherapy and early developmental outcomes. Most studies found no harmful effects [92,119,132,134,135], and some suggested that levetiracetam monotherapy exposure in utero was not associated with later cognitive deficits up to age nine years [92,135]. However, in a population-based cohort study of over 38,000 children of mothers with epilepsy from Scandinavian countries (SCAN-AED), prenatal exposure to levetiracetam was associated with increased rates of anxiety (adjusted hazard ratio [aHR] 2.17; 95% CI 1.26-3.72) and attention deficit hyperactivity disorder (aHR 1.78; 95% CI 1.03-3.07) [136].

The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study did show that higher third-trimester blood levels of levetiracetam were associated with poorer developmental scores in the language domain at ages two years and three years [41,131]. The significance of this finding will need to be clarified as this cohort of children grows older.

Oxcarbazepine

●Malformations – Oxcarbazepine cohorts in the prospective pregnancy registries have been small, and the incidence of major malformation rates ranges from 2.2 to 7 percent [114]. In a registry-based study in Denmark, MCMs were detected in 11 of 393 infants (2.8 percent) exposed to oxcarbazepine, a rate that was not significantly higher than in nonexposed infants [122].

●Neurodevelopment – Data on neurocognitive outcomes related to oxcarbazepine exposure are too limited to draw meaningful conclusions [119]. In the SCAN-AED cohort, which included 1460 oxcarbazepine-exposed children, prenatal oxcarbazepine exposure was not associated with any clinically diagnosed psychiatric disorders, including intellectual disability and autism spectrum disorders [136].

Phenobarbital

●Malformations – Cardiac, orofacial, and urogenital malformations occur with increased frequency with in utero phenobarbital exposure [8,48,86,137-140]. A study from the NAAPR reported a 5.5 percent incidence of major malformations among 199 pregnancies associated with phenobarbital use, a rate that was somewhat higher than for unexposed pregnancies and for those exposed to lamotrigine [88]. Similar rates have been seen in the Kerala (5.8 percent) and EURAP (6.5 percent) registries [50,113].

●Neurodevelopment – Data on neurocognitive outcomes of children exposed to maternal epilepsy and phenobarbital are limited [118,141]. One study of 61 school children (average age 11 years) in India demonstrated that children exposed to phenobarbital monotherapy or polytherapy in utero had poorer standardized language scores compared with their unexposed peers [104]. Another study from the United States of 34 children (average age nine years) who were exposed to phenobarbital in utero found that they had lower full-scale IQ (adjusted difference 8.51; 95% CI 1.88-15.13) and verbal IQ (adjusted difference 9.2; 95% CI 2.76-15.65) scores compared with control children [141].

Phenytoin

●Malformations – The overall rates of MCMs among pregnancies exposed to phenytoin monotherapy in the EURAP and NAAPR registries were 2.9 and 6.4 percent, respectively (figure 1) [50,88]. Orofacial clefts, cardiac malformations, and genitourinary defects are the major malformations described with phenytoin [8,48,52,86,137,138,142].

●Neurodevelopment – Historical studies on the impact of phenytoin exposure on neurocognitive development have been small, with methodologic limitations [101,118]. In the NEAD study, six-year-old children exposed to phenytoin monotherapy in utero had a mean IQ that was superior to the IQ of children exposed to valproate and similar to the mean IQ of children exposed to carbamazepine or lamotrigine [100].

Pregabalin

●Malformations – In a multicenter observational study, first-trimester exposure to pregabalin (mostly for indications other than seizure disorder) was associated with an increased rate of MCMs compared with no exposure (6 versus 2 percent) [143]. The small number of exposed pregnancies (n = 164), high rates of polytherapy and tobacco use among women taking pregabalin, and differences in medical comorbidities between exposed and unexposed women limit confidence in these findings, and more studies are needed [144]. A subsequent population-based study nested in the United States Medicaid Analytic eXtract did not find a difference in malformation rates in pregabalin exposed pregnancies compared with the general population (aRR 1.03, 95% CI 0.56-1.90) [145].

●Neurodevelopment – There are no meaningful data on neurocognitive outcomes in infants and children exposed to pregabalin in utero.

Topiramate

●Malformations – The overall risk of malformations with topiramate monotherapy exposure ranges from 3.9 to 4.2 percent in larger cohorts (figure 1) [114]. The risk of fetal malformations is increased further in association with polytherapy regimens that include topiramate. In an Australian registry cohort study, for example, the fetal malformation rate was more than two times higher in polytherapy pregnancies that included topiramate compared with those that did not (14.9 versus 6.6 percent) [54]. Additionally, a significant and reproducible risk of oral clefts with topiramate exposure has raised concerns that it is a significant teratogen.

•Oral clefts – Across multiple studies, the estimated absolute risk of oral clefts in a topiramate-exposed pregnancy has ranged from approximately 4 to 29 per 1000 births, compared with an expected unexposed risk in the background population of 1 to 2 per 1000 births [88,122,146-149]. At the lower end of this range, a population-based study nested in the United States Medicaid Analytic eXtract found that the risk of oral clefts at birth was 4.1 per 1000 in the infants born to women exposed to topiramate compared with 1.1 per 1000 in the unexposed group (RR 2.90, 95% CI 1.56-5.40) [146]. The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses, and is likely another example of a dose-dependent risk for a major malformation.

•Growth – Topiramate use in pregnancy is associated with an increased risk for fetal growth restriction and low birth weight [13]. In studies from the NAAPR, the prevalence of SGA was 18 percent in topiramate-exposed neonates compared with 7 and 5 percent in lamotrigine-exposed neonates and unexposed controls, respectively [19,66]. The risk of SGA was significantly elevated for topiramate (RR 3.5, 95% CI 2.1-5.7) compared with controls after adjusting for multiple factors, including maternal age, parity, smoking status, education, and periconceptional folic acid intake.

●Neurodevelopment – Limited data suggest that in utero topiramate exposure is associated with an increased risk of neurodevelopmental problems, leading the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency to recommend avoidance of topiramate exposure in pregnancy unless there is no other suitable treatment available [150].

In a population-based study from the SCAN-AED cohort of over 38,000 children of mothers with epilepsy, prenatal exposure to topiramate (n = 290) was associated with an increased risk of attention deficit hyperactivity disorder (aHR 2.38; 95% CI 1.40-4.06) and trends toward increased risk of autism spectrum disorder (aHR 1.93; 95% CI 0.95-3.94) and intellectual disability (aHR 2.23; 95% CI 0.90-5.50) [136].

Zonisamide

●Malformations – Zonisamide monotherapy cohorts have been small, with malformation rates ranging from 0 to 13 percent [11,50,66,151]. When pooled, out of the 138 prospective pregnancies published, a major malformation was present in 2.9 percent.

Zonisamide has also been associated with fetal growth restriction. In reports from the NAAPR, the prevalence of SGA was 12 percent in zonisamide-exposed neonates compared with 7 and 5 percent in lamotrigine-exposed neonates and unexposed controls, respectively (RR 2.2, 95% CI 1.1-4.4) [19,66].

●Neurodevelopment – There is no meaningful evidence on neurocognitive outcomes in infants and children exposed to zonisamide in utero.

Other ASMs — There is limited human information on the fetal risks of other ASMs (eg, cenobamate, clobazam, eslicarbazepine, felbamate, lacosamide, perampanel, tiagabine). Patients should be counseled that the risks of in utero exposure to these medications are largely unknown.

INHERITANCE OF EPILEPSY

●Risk – The prevalence of epilepsy is approximately 0.5 to 1 percent of the general population. The likelihood of developing epilepsy is modestly higher in children of a parent with epilepsy, and the degree of risk varies with the type of epilepsy syndrome [152-156].

The best estimates of familial risk come from a population-based study that included 660 individuals with epilepsy and nearly 2500 first-degree relatives living in a single county in the northern United States [156]. The cumulative incidence of any form of epilepsy by age 40 years was 4.5 percent among individuals with a first-degree relative with epilepsy, which was threefold higher than the incidence in the general population. The risk was highest for relatives of individuals with generalized epilepsy (standardized incidence ratio [SIR] 8.3) and lowest for relatives of those with focal epilepsy (SIR 2.6). If a parent had epilepsy, the risk to offspring was 3.9 percent. The risk to a child was greater if the mother had epilepsy; children born to a mother with generalized epilepsy had the highest risk of developing epilepsy (8.3 percent). These epidemiologic data are useful for most prospective parents with epilepsy, as the risk of epilepsy in their children is often much lower than they assume. However, it is best applied to patients without a known genetic syndrome.

The ability to stratify risk based on specific genetic findings is clinically available for some patients with epilepsy, and the use of genetic testing in adults with epilepsy is growing.

●Genetic counseling – Genetic counseling and testing for epilepsy are not typically included in standard preconception genetic testing and carrier screening. During preconception counseling for any prospective parent with epilepsy, regardless of sex, it is important to consider the etiology of their epilepsy and whether they could have an epilepsy syndrome with implications for a child.

A referral for genetic counseling should be considered for patients with first-degree relatives with epilepsy. However, many patients with heritable genetic syndromes may not have affected relatives. Thus, it is also important to recognize the clinical hallmarks of specific epilepsy syndromes that should prompt genetic counseling even in the absence of family history (table 1). Some examples of specific syndromes include:

•Autosomal dominant lateral temporal epilepsy (ADLTE) (see "Focal epilepsy: Causes and clinical features", section on 'Genetic focal epilepsy syndromes')

•Familial focal epilepsy with variable foci (FFEVF) (see "Focal epilepsy: Causes and clinical features", section on 'Genetic focal epilepsy syndromes')

•FLNA-associated periventricular nodular heterotopia [157]

•Genetic epilepsy with febrile seizures plus (GEFS+)/SCN1A spectrum disorder (see "Clinical features and evaluation of febrile seizures", section on 'Genetic epilepsies with febrile seizures' and "Dravet syndrome: Genetics, clinical features, and diagnosis")

•Mitochondrial disorders (see "Mitochondrial myopathies: Clinical features and diagnosis")

•Tuberous sclerosis complex (see "Tuberous sclerosis complex: Clinical features")

Finally, patients with epilepsy in the setting of intellectual disability or autism spectrum disorder should also be offered genetic counseling, even in the absence of family history.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Epilepsy and pregnancy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Morbidity and mortality – While most pregnancies will be uncomplicated, there can be a higher risk of certain complications. Morbidity and mortality are increased during pregnancy among women with epilepsy compared with the general population across a range of maternal and neonatal outcomes, including pre-eclampsia, preterm labor, bleeding, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The magnitude of the increase in risk appears to be relatively small for most complications (ie, between 1 and 1.5 times expected rates), with the exception of maternal mortality, which may be as much as five-fold higher among women with epilepsy during the delivery hospitalization. Despite the large increase in relative risk of maternal death, the increase in absolute risk is less than 0.1 percent. (See 'Morbidity and mortality' above.)

●Seizures and fetal harm – Seizures, particularly convulsive seizures, are believed to be harmful to the fetus. Fetal bradycardia has been documented during nonconvulsive maternal seizures with impaired awareness (focal impaired awareness seizures, previously known as complex partial seizures). (See 'Effect of seizures on the fetus' above.)

●Pregnancy and its effect on epilepsy – Most pregnant patients with epilepsy will have no alteration of their seizure pattern during pregnancy, especially if nonadherence and sleep deprivation are minimized and the individual antiseizure medication (ASM) target concentrations are maintained with therapeutic drug monitoring. The main risk factors for increased seizures during pregnancy include baseline seizure frequency before pregnancy and focal epilepsy syndromes. Others include ASM type, polytherapy, and medication adherence. Altered pharmacokinetics of ASMs during pregnancy can contribute to increased seizure frequency if therapeutic drug monitoring is not used to maintain the target blood concentration. (See 'Effect of pregnancy on seizures' above.)

●Risk of malformations – Major congenital malformations are more common in fetuses exposed to ASMs in utero compared with offspring of untreated women with epilepsy and women without epilepsy. The overall risk varies substantially by the ASM prescribed (figure 3). Across all pregnancy registries, valproate monotherapy is associated with the highest rates of major malformations. The dose of the ASM at the time of conception has also been associated with malformation risk for several ASMs. Some ASM polytherapy regimens, particularly those that include valproate or topiramate, also increase the risk. (See 'Major congenital malformations and their risk factors' above and 'Risks with specific ASMs' above.)

●Neurodevelopmental risks – In utero exposure to some ASMs is associated with impaired cognitive and behavioral development (figure 3). The evidence for this association is strongest with valproate, which has been associated with impaired cognitive development as well as an increased risk of autism spectrum disorders. There is increasing concern about the impact of topiramate exposure on neurodevelopmental risk, though additional research is needed. (See 'Neurodevelopmental risks' above and 'Risks with specific ASMs' above.)

●Ideally, avoid valproate – Valproate should be avoided in women of childbearing age if possible. If valproate is essential for seizure control, lowering the dose of valproate should be tried, ideally well in advance of pregnancy. (See 'Valproate' above.)

●Risk of inheriting epilepsy – For most prospective parents with epilepsy, the risk of passing epilepsy on to their child is 3.9 percent based on epidemiologic data. However, it is important to consider the etiology of epilepsy in preconception genetic counseling and to refer appropriate or interested patients for epilepsy-specific genetic counseling. (See 'Inheritance of epilepsy' above.)

●Mitigating risks – Risks associated with pregnancy and epilepsy can be minimized by preconception planning and careful management during pregnancy, as reviewed separately. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Page B Pennell, MD, who contributed to earlier versions of this topic review.