Fetal anticonvulsant syndrome (FACS) is a constellation of diverse congenital malformations that can affect some fetuses if they are exposed to certain antiepileptic drugs (AEDs) while in utero.
Most women with epilepsy will have a healthy child. Women with epilepsy who are pregnant and worried about their medication should be advised not to stop taking them without consulting their doctor. Stopping the medication makes them more likely to have seizures which in itself can be a risk to the fetus.
In women with epilepsy not exposed to AEDs, the incidence of major congenital malformations is similar to the background risk for the general population. A prospective Finnish population-based study reported a 2.8% rate of congenital malformations in the fetus of women who were not taking AEDs in the first trimester.
In those who are taking AEDs, the risk of major congenital malformation to the fetus depends on the type, number and dose of the AED.
The risk for any one drug is about 6-7% (ie 2-3 times the background level of risk). The risk increases with the number of drugs, so for those taking two or more AEDs, the risk is 10-15%. For those taking the combination of valproate, carbamazepine and phenytoin, the risk is as high as 50%.
A systematic review and meta-analysis of 59 studies provided estimates of incidence of congenital malformation in fetuses born to women taking various AEDs. The risk was highest for women taking sodium valproate (10.7 per 100, 95% CI 8.16-13.29) or AED polytherapy (16.8 per 100, 95% CI 0.51-33.05) compared with the 2.3 per 100 (95% CI 1.46-3.1) observed in mothers without epilepsy.
There is evidence of a dose-dependent teratogenic effect for many AEDs. Fetuses of mothers using >1 g/day valproate are at a greater than two-fold increased risk of congenital malformations, compared with those exposed to 600 mg or less.
Data from the European Registry of Antiepileptic Drugs and Pregnancy (EURAP) study group suggest that the lowest rates of malformation were observed in women exposed to less than 300 mg per day of lamotrigine (2 per 100, 95% CI 1.19-3.24) and to less than 400 mg per day of carbamazepine (3.4 per 100, 95% CI 1.11-7.71).
The rates of major congenital malformation in the UK and Ireland registers were also lower in the levetiracetam monotherapy group (0.7 per 100; 95% CI 0.19-2.51) than the polytherapy group (5.6 per 100, 95% CI 3.54-8.56).
The risk of recurrence for major congenital malformation was increased (16.8 per 100) in women with epilepsy with a previous child with major congenital malformation. There was no significant association between epilepsy type and tonic-clonic seizures in the first trimester and major congenital malformations.
The sole risk factor for FACS is medicinal use of certain AEDs during pregnancy. There is no association between different types of epilepsy and the risk of major congenital malformations. It is thought that the AEDs most associated with FACS are the older drugs but some newer drugs may also cause problems. There are fewer reports investigating the impact of newer AEDs; however, research into this has started.
In those who are taking AEDs, the risk of major congenital malformation to the fetus is dependent on the type, number and dose of the AED.
The commonly known AEDs which are associated with FACS are:
- Sodium valproate
There is little difference in the level of risk between individual drugs except for sodium valproate. Data are accumulating from prospective registers for a particularly high risk associated with sodium valproate.
Lamotrigine and levetiracetam are reported to be associated with FACS but data are limited.
Amongst the AEDs listed above, lower-dose monotherapy with lamotrigine or with carbamazepine has the least risk of major congenital malformation in the fetus.
There is insufficient evidence to provide robust estimates of risk of major congenital malformation for other AEDs in monotherapy such as:
The benzodiazepines (eg, clobazam and clonazepam) normally used as adjunctive therapies are not teratogenic in monotherapy.
FACS includes structural abnormalities as well as developmental, behavioural and learning difficulties. Children with FACS can have a mixture of mild to more serious symptoms.
This can happen during the first trimester in the organ development phase because some AEDs can cross the placenta.
There can also be developmental delay as well as speech and language problems, autistic spectrum disorders and poor motor control.
The most common major congenital malformations associated with AEDs are:
- Neural tube defects including spina bifida: particularly with sodium valproate (1-3.8%) and carbamazepine (0.5-1%).
- Congenital heart disorders: particularly with phenytoin, phenobarbital and sodium valproate.
- Orofacial clefts: particularly phenytoin, carbamazepine and phenobarbital.
- Urogenital defects, hypospadias.
- Skeletal abnormalities.
Minor malformations associated with AEDs include:
- Dysmorphic features (v-shaped eyebrows, low-set ears, broad nasal bridge, irregular teeth).
- Hypoplastic nails and digits.
- Hypoplasia of the midface (could be a marker for cognitive function).
AEDs, especially sodium valproate, can have a possible adverse impact on the long-term neurodevelopment of the newborn following in-utero exposure.
A 2014 Cochrane review showed that there were no significant differences in the developmental quotient of children exposed to carbamazepine, lamotrigine and phenytoin when compared with infants of mothers without epilepsy or with children of mothers with epilepsy not taking AEDs. However, children exposed to sodium valproate in utero had a significantly lower developmental quotient including intelligence quotient (IQ), verbal IQ and performance IQ when compared with those born to women with epilepsy but who were not taking AEDs, and to those born to women without epilepsy.
According to one study, children exposed to sodium valproate had lower IQ at 6 years of age compared with those exposed to carbamazepine (P = 0.0015), lamotrigine (P = 0.0003) or phenytoin (P = 0.0006). They also performed poorly on measures of verbal and memory abilities compared with children exposed to other AEDs and had lower non-verbal and executive functions compared with children exposed to lamotrigine (but not carbamazepine or phenytoin). High doses of sodium valproate were negatively associated with verbal ability, IQ, non-verbal ability, memory and executive function, and this was not observed with other AEDs. In-utero exposure to sodium valproate is associated with increased rates of childhood autism (adjusted hazard ratio 2.9, 95% CI 1.4-6.0).
There is very little evidence for levetiracetam but initial outcomes based on limited numbers have been reassuring.
Little is known about other new AEDs or combination therapies and the absence of data should not be taken as an indication of fetal safety.
It is advisable to inform the parents of the above but that the evidence on long-term outcomes is based on small numbers of children.
Various theories exist to explain the mechanism for teratogenesis of AEDs, including:
- A genetic deficiency of the detoxifying enzyme epoxide hydrolase, leading to accumulation of toxic metabolites.
- Cytotoxic free radicals.
- Folic acid deficiency. Phenytoin and phenobarbital are particularly known to affect folate metabolism. However, carbamazepine and sodium valproate also interfere with folate metabolism. Lamotrigine carries a theoretical risk because it is a weak inhibitor of dihydrofolate reductase and may interfere with folate metabolism.
The diagnosis of FACS may be suspected by ultrasound imaging in pregnancy in the presence of suggestive history. A number of structural malformations are detectable by ultrasound in pregnancy - eg, spina bifida, cardiac defects or facial defects. These can be dealt with as per the woman's choice and preference, after in-depth counselling. However, the facial dysmorphism is often subtle and likely to be noticed only after birth. As with any other infant with facial dysmorphism, the differential diagnosis includes genetic or chromosomal causes which may prompt karyotyping and microarray analysis.
This will depend on the type of birth defect. Each birth defect is managed individually and usually will require a multidisciplinary approach with involvement of specialists. The children born with developmental delay require supportive treatment under the guidance of a developmental paediatrician. This might include a physiotherapist and a speech and language therapist. Children with special educational needs benefit from additional educational support.
Minimising the occurrence of FACS
Pregnant women with epilepsy should have access to regular, planned antenatal care with a designated epilepsy care team. Women with epilepsy taking AEDs who become unexpectedly pregnant, should be able to discuss therapy with an epilepsy specialist on an urgent basis. It is never recommended to stop or change AEDs abruptly without an informed discussion.
All pregnant women with epilepsy should be provided with information about the UK Epilepsy and Pregnancy Register and invited to register.
All women with epilepsy should be offered a detailed ultrasound in line with the NHS Fetal Anomaly Screening Programme standards. Early pregnancy can be an opportunity to screen for structural abnormalities. The fetal anomaly scan at 18-20 weeks of gestation can identify major cardiac defects in addition to neural tube defects.
In order to reduce the incidence of major congenital malformation in women with epilepsy, all women with epilepsy should be advised to take 5 mg/day of folic acid prior to conception and to continue the intake until at least the end of the first trimester. Studies evaluating the effects of folic acid supplementation in pregnancy on major congenital malformation have shown varied results. Two studies have shown an association between low folate levels or no supplementation and major congenital malformation. A further two studies have failed to show a benefit with folic acid in reducing major congenital malformation. The latter can be due to different mechanisms involved in causation of FACS. However, the recommendation to take folic acid supplementation is still appropriate.
Moreover, pre-pregnancy folic acid 5 mg/day may be helpful in reducing the risk of AED-related cognitive deficits. The long-term follow-up of children born to women with epilepsy taking lamotrigine, carbamazepine, phenytoin or sodium valproate monotherapy in pregnancy showed that compared with unexposed children (95% CI 98-104), the mean IQs were higher in children exposed to peri-conceptional folate (95% CI 106-111) (P = 0.0009).
Given the potential benefit of folate on long-term cognitive outcomes, the known safety of the supplement and the absence of evidence of its ineffectiveness in preventing major congenital malformation, it is advised that women with epilepsy be prescribed high-dose folic acid 5 mg daily from at least three months prior to conception to the end of the first trimester.
Furthermore, the lowest effective dose of the most appropriate AED should be used. Similarly, avoid any AED closely associated with FACS and adhere to monotherapy over polytherapy. Exposure to sodium valproate and other AED polytherapy should be avoided where possible or minimised by changing the medication prior to conception, as recommended by an epilepsy specialist after a careful evaluation of the potential risks and benefits. However, if the risk of maternal seizure deterioration from changing the AED is deemed to be high, women will need to be advised to continue the sodium valproate or AED polytherapy. The dosage can be changed to three or four times the daily regime, or to a modified-release preparation to lower peak concentrations.
Communicating risks to women with epilepsy
Women with epilepsy have concerns regarding the effect of epilepsy and its treatment on motherhood. This includes fear of harming the baby or not being able to fulfil the role of being a mother to their expectations. Women with epilepsy also feel that there is a lack of understanding among healthcare professionals about epilepsy and the specific issues related to pregnancy. A survey of women with epilepsy showed that 87% of women would like to be counselled about the risk of epilepsy and AEDs to their unborn child and that about one-half of them would like a more proactive role in the discussions about treatment decisions.
Women with epilepsy should be provided with verbal and written information on prenatal screening and its implications, the risks of self-discontinuation of AEDs and the effects of seizures and AEDs on the fetus and on the pregnancy, breast-feeding and contraception.
Women with epilepsy should be informed that the introduction of a few safety precautions may significantly reduce the risk of accidents and minimise anxiety. Healthcare professionals should acknowledge the concerns of women and be aware of the effect of such concerns on their adherence to AEDs. Women with epilepsy should be fully aware of the implications of future pregnancy on their epilepsy and the health of their children in the short and long term.
Any information on prenatal screening for major congenital malformation should highlight the detection rates, limitations of the test performance and the implications, such as termination of pregnancy. Pregnant women with epilepsy tend to overestimate the risks of teratogenicity associated with intake of AEDs in pregnancy. Risk perception is likely to have an effect on adherence to AEDs in pregnancy. An observational study on pregnant women with epilepsy taking levetiracetam or carbamazepine showed that 15% of mothers self-discontinued their AED in pregnancy. This rate may be higher for women with epilepsy taking sodium valproate, due to its high teratogenic potential. The risk:benefit ratio for both mother and baby from seizures and exposure to AEDs should be communicated by providing relevant estimates.
Further reading and references
Epilepsy in Pregnancy - Green-top Guideline No.68; Royal College of Obstetricians and Gynaecologists (2016)
Nelson-Piercy C; Neurological problems. Chapter 9. Handbook of Obstetric Medicine. Third edition Informa Healthcare, 2006.
Hill DS, Wlodarczyk BJ, Palacios AM, et al; Teratogenic effects of antiepileptic drugs. Expert Rev Neurother. 2010 Jun10(6):943-59. doi: 10.1586/ern.10.57.
Tomson T, Battino D, Bonizzoni E, et al; Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011 Jul10(7):609-17. doi: 10.1016/S1474-4422(11)70107-7. Epub 2011 Jun 5.
Meador K, Reynolds MW, Crean S, et al; Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008 Sep81(1):1-13. doi: 10.1016/j.eplepsyres.2008.04.022. Epub 2008 Jun 18.
Bromley R, Weston J, Adab N, et al; Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev. 2014 Oct 3010:CD010236. doi: 10.1002/14651858.CD010236.pub2.
Meador KJ, Baker GA, Browning N, et al; Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013 Mar12(3):244-52. doi: 10.1016/S1474-4422(12)70323-X. Epub 2013 Jan 23.
Kaaja E, Kaaja R, Hiilesmaa V; Major malformations in offspring of women with epilepsy. Neurology. 2003 Feb 2560(4):575-9.
Williams J, Myson V, Steward S, et al; Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis. Epilepsia. 2002 Aug43(8):824-31.
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