Harmful effects of maternal use of antileptic drugs on the fetus/newborn and its long term effect

Epilepsy in a pregnant women:

Of all pregnant women, 0.3%-0.8% are affected with epilepsy which makes it the most common neurological disorder that needs a medical treatment during pregnancy. [1] Most women with epilepsy will need antiepileptic drugs (AEDs) throughout their pregnancy to control their seizures. [2] Therefore, use of AEDs raises concern related to the harmful effects on fetus while in her womb (teratogenicity) and afterwards (during its subsequent extra-uterine existence as a neonate and infant). 

Harmful effects on fetus and neonates: [3]

There is an increased risk in offspring of women with epilepsy exposed to the antiepileptic drugs, of structural and neurodevelopmental effects including, intrauterine growth retardation, cognitive dysfunction, microcephaly, both major and minor malformations (4-6%) and even infant mortality. [4] Infants exposed to antiseizure drugs in utero who are born with congenital malformations are termed to have fetal anticonvulsant syndrome. 

Major congenital malformations:

1.       Neural tube (spina bifida aperta, open lumbosacral myelocele)

2.   Congenital heart (ASD, VSD, PDA, PS, TOF) and urinary tract defects (glandular hypospadias) [3, 4]

3.       Skeletal abnormalities and cleft palate

Minor congenital malformations: 

1.       hypoplasia of the nails and distal phalanges

2.       hypertelorism

3.       the "anticonvulsant face" including

-          broad or depressed nasal bridge

-          short nose with anteverted nostrils

-          long upper lip

Individual antiepileptic drugs contributing in the congenital malformations:

·   Valproate: Neural-tube like defects (spina bifida aperta, open lumbosacral myelocele), meningomyelocele, cardiovascular, and urogenital malformations and craniofacial, skeletal, and genital anomalies. First trimester maternal exposure to valproic acid (VPA) increases the risk of major malformations, independent of any contribution of the epilepsy syndrome itself.

·         Phenytoin:  Orofacial clefts, cardiac malformations, and genitourinary defects

·         Phenobarbital: Malformations of the heart, orofacial, and urogenital structures

·         Carbamazepine: Associated with major malformations such as spina bifida.

·         Topiramate: oral clefts in infants

Long terms effects of antiepileptic drugs:

AEDs may have deleterious effects on the cognitive and neurologic function of the offspring that may manifest later in life. Valproate is the most strongly associated with adverse cognitive and developmental outcomes and it also increases the risk of autism spectrum disorders in children.

Mechanism for antiseizure drug-induced teratogenicity:

1.       Low or deficient epoxide hydrolase activity that results in increased levels of teratogenic oxidative metabolites.

2.       Oxidative damage to DNA from free radical intermediates produced by prostaglandin H synthase bioactivation of antiseizure drugs

3.       Deficiency of folic acid associated with antiseizure drugs (which are folic acid antagonists)

     Note: Mechanism for antiseizure drug-induced teratogenicity has not been determined and these are possible mechnisms underlies the teratogenicity.

 References:

1.       http://www.bmj.com/content/349/bmj.g5159

2.       https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970517/

3.       https://www.uptodate.com/contents/risks-associated-with-epilepsy-and-pregnancy?source=see_link&sectionName=EFFECT%20OF%20ANTISEIZURE%20DRUGS%20ON%20THE%20FETUS&anchor=H4#H4 : 2017
4.    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882069/