Fetal anticonvulsant syndrome

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.

In utero exposure to antiepileptic drugs (AEDs) can result in several different teratogenic effects including major malformations, dysmorphic facial features, and learning and behavioural problems. It is estimated that there is a 2–3‐fold increase in the risk of malformations compared with the general population. The risk of cognitive impairment and behavioural problems is less clear.¹

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 receiving specialist advice. Stopping the medication makes them more likely to have seizures which in itself can be a risk to the fetus.²

See also the article on Epilepsy and Pregnancy.

Fetal anticonvulsant syndrome epidemiology³

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 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.⁴

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).⁵

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.⁶

Risk factors²

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.

Valproate

Valproate (Epilim) is highly teratogenic and evidence supports a rate of congenital malformations of 10% in infants whose mothers took valproate during pregnancy, and neurodevelopmental disorders in approximately 30% to 40% of children. Therefore, valproate should not be used in girls and women of childbearing potential unless other treatments are ineffective or not tolerated, as judged by an experienced specialist.

Valproate is contraindicated in women of childbearing potential unless a pregnancy prevention programme is in place. All healthcare professionals must continue to identify and review all female patients on valproate, including when it is used outside the licensed indications, and provide them with the patient information materials every time they attend their appointments or receive their medicines (including the patient information leaflet at dispensing).

Other AEDs

In those who are taking other AEDs, the risk of major congenital malformation to the fetus is dependent on the type, number and dose of the AED.

• Lamotrigine: studies involving more than 12,000 pregnancies exposed to lamotrigine monotherapy consistently show that lamotrigine at maintenance doses is not associated with an increased risk of major congenital malformations.

• Levetiracetam: studies involving more than 1,800 pregnancies exposed to levetiracetam do not suggest an increased risk of major congenital malformations

• For both lamotrigine and levetiracetam, the data on neurodevelopmental outcomes are more limited than those for congenital malformations. The available studies do not suggest an increased risk of neurodevelopmental disorders or delay associated with in-utero exposure to either lamotrigine or levetiracetam; however, the data is inadequate to rule out definitively the possibility of an increased risk.

• There is an increased risk of major congenital malformations associated with carbamazepine, phenobarbital, phenytoin, and topiramate use during pregnancy

• There is a possibility of adverse effects on neurodevelopment of children exposed in utero to phenobarbital and phenytoin.

• There is an increased risk of fetal growth restriction associated with phenobarbital, topiramate, and zonisamide use during pregnancy.

• A study has suggested pregabalin may slightly increase the risk of major congenital malformations if used in pregnancy. Patients should continue to use effective contraception during treatment and avoid use in pregnancy unless clearly necessary.⁹

• A study has reported an increased risk of neurodevelopmental disabilities in children with prenatal exposure to topiramate (Topamax).¹⁰

Fetal anticonvulsant syndrome symptoms (presentation)

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.¹¹

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).

• Hypertelorism.

• Hypoplastic nails and digits.

• Hypoplasia of the midface.

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:¹²

• 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:¹³

• 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).¹³

• 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.

Diagnosis

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.

Fetal anticonvulsant syndrome treatment and management

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.

Prevention

Minimising the occurrence of FACS²

At initiation and as part of the recommended annual review for patients with epilepsy, specialists should discuss with women the risks associated with antiepileptic drugs and with untreated epilepsy during pregnancy and review their treatment according to their clinical condition and circumstances.

Urgently refer women who are planning to become pregnant for specialist advice on their antiepileptic treatment.

All women using antiepileptic drugs who are planning to become pregnant should be offered 5mg per day of folic acid before any possibility of pregnancy.

For lamotrigine, levetiracetam or any antiepileptic drugs that can be used during pregnancy, it is recommended to:

• Use monotherapy whenever possible.

• Use the lowest effective dose.

• Report any suspected adverse effects experienced by the mother or baby to the Yellow Card scheme.

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.¹⁴

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.

Communicating risks to women with epilepsy³

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. 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.¹⁵