Increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death have occurred with valproate administration to pregnant animals at clinically relevant doses. In human pregnancy, data have shown exposure in utero can have adverse effects on mental and physical development. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established. Polytherapy with antiepileptic drugs (AEDs) has been associated with an increased frequency of congenital malformations compared with AED monotherapy. The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur throughout pregnancy. Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children exposed to valproate monotherapy during pregnancy suffer from congenital malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems. Epidemiologic studies in children exposed in utero show that up to 40% experience delays in early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems. Intelligence quotient (IQ) measured in children at 6 years was on average 7 to 10 points lower in children exposed to this drug in utero than those children exposed to other AEDs. The role of confounding factors cannot be excluded, but there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ. There is increasing evidence supporting a causal relationship between valproate exposure during pregnancy and increased risk of autism spectrum disorders and attention deficit/hyperactivity disorder (ADHD).

Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate, including death. Women may develop hepatic failure; fatal cases of hepatic failure have been reported in infants exposed to valproate in utero. Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy.

For women who are planning a pregnancy:
--A specialist experienced in the management of epilepsy, should reassess valproate therapy and consider alternative treatment options.
--Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued.
--If switching is not possible, the woman should receive further counseling regarding the risks of valproate for the unborn child.
--Pregnant women with epilepsy should not discontinue valproate abruptly.

For women taking valproate during pregnancy:
--If it is determined that this drug must be given during pregnancy, use the lowest effective dose in divided doses throughout the day; the use of a prolonged release formulation may be preferable to other treatment formulations to avoid high peak plasma concentrations.
--Folate supplementation should be provided.
--Available prenatal diagnostic testing to detect neural tube and other defects should be offered.
--Clotting parameters should be monitored in the mother; if abnormal, these parameters should also be monitored in the neonate.

There have been reports of male infertility coincident with valproate therapy; in animal studies, oral administration of valproate at clinically relevant doses has resulted in adverse reproductive effects in male rats and dogs.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Contraindicated in women of child-bearing potential unless they are using effective contraception

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned

Risk Summary: This drug is associated with a significant risk of birth defects and developmental disorders in children exposed during pregnancy; up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects. Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another AED in utero or to no AEDs in utero.

Medicines and Healthcare products Regulatory Agency (MHRA): Valproate must not be used in females of childbearing potential unless there is a pregnancy prevention programme (PPP) in place. The MHRA bans the use of valproate for migraine or bipolar disorder during pregnancy and its use as treatment for epilepsy is contraindicated unless there is no suitable alternative. The Commission on Human Medicines has performed a comprehensive safety review of the risks of major congenital malformations and adverse neurodevelopmental outcomes for other key antiepileptic drugs (AEDs) during pregnancy and found that lamotrigine and levetiracetam are the safer of the medicines reviewed. These public assessment reports of the safety of AED during pregnancy are available on the MHRA website.

Comments:
-Pregnancy should be ruled out before staring treatment; women of childbearing potential should be counseled regularly regarding risks of using this drug during pregnancy and the use of effective contraception.
-If pregnancy is detected, women should be referred to a specialist experienced in prenatal medicine for evaluation and counseling; specialized prenatal monitoring should be offered to detect the possible occurrence of neural tube defects or other malformations. This drug should not be discontinued abruptly as this can precipitate status epilepticus with resulting maternal and fetal hypoxia.
-Folate supplementation before and during pregnancy may decrease the risk of neural tube defects (which may occur in all pregnancies); available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
-US: The North American Antiepileptic Drug (NAAED) Pregnancy Registry monitors pregnancy outcomes in women exposed to antiepileptic drugs including this drug; women should be encouraged to enroll by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/
-UK and EU countries: A requirement for use of this drug in women of childbearing potential is enrollment in a Pregnancy Prevention Program (PPP). As part of the PPP, the prescriber must ensure: the patient understands the risks to the unborn child and provides a patient guide; the patient understands the need to comply with contraception throughout treatment and undergoes pregnancy testing as needed; referrals for contraception services are provided, as needed; and the physician and patient must complete and sign an acknowledgement of risk form annually.

See references

No definitive adverse reactions have been reported in breastfed infants. Drug concentrations in milk have been reported to be 1% to 10% of maternal serum levels with infant serum levels ranging from undetectable to low. Monotherapy does not appear to adversely affect infant growth or development and in 1 study, breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years old. Thrombocytopenia was reported in a 2.5-month old breastfed infant, but causality was not established, and other experts believe this was more likely caused by idiopathic thrombocytopenic purpura following a viral infection. Theoretically, breastfed infants are at risk for valproate-induced hepatotoxicity. There have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy. Use of this drug in combination therapy with sedating anticonvulsants or psychotropics, will require consideration of the sedating or other reactions from these agents. There are no data on the effects of this drug on milk production or excretion.

Benefit should outweigh risk

Excreted into human milk: Yes

Comments:
-Monitor breastfed infants for hepatotoxicity (e.g., jaundice, unusual bruising, or bleeding).
-Some experts recommend monitoring infant serum levels, platelets, and liver enzymes during therapy.

See references