This document summarizes information from the Iraqi Pharmacovigilance Center on the risks of valproate use in female patients and pregnant women. It discusses new restrictions and a pregnancy prevention program for valproate, including a risk acknowledgement form for women of childbearing age. The document reviews several studies finding valproate is associated with 1-2% risk of neural tube defects and increased risks of other birth defects. It also analyzes risk data for various anti-epileptic drugs, finding valproate and several others are statistically significantly associated with major congenital malformations and other adverse pregnancy outcomes, while drugs like lamotrigine, levetiracetam, and oxcarbazepine generally lack

1. INFORMATION ON THE
RISKS OF VALPROATE
(DEPAKINE AND DEPAKINE
CHRONO) USE IN FEMALE
PATIENTS AND PREGNANT
WOMEN
By: Alaa Fadhel Hassan
Drug Information Center
Al-Mahmoudiya G. Hospital

2. Why this subject?
 To be aware of the program published by the
Iraqi pharmacovigilance center about using
Valproate in female pt.
 To check about different antiepileptic's safety
during pregnancy.

3. The program of the
risks of valproate
use in female patients and
pregnant women
generalized by IRAQI
Pharmacovigilance Center
Valproate: New restriction on use, pregnancy
program to be put in place
Guide for health care professionals:
Information on the risks of valproate use
in female patients and pregnant women
Annual risk acknowledgement form
for girls and women of childbearing
age treated with valproate
Guide for patient
& Patient card
1
2
3
4

4. Valproate: New restriction on use, pregnancy
program to be put in place & Guide for health
care professionals

5. Annual risk acknowledgement form for girls
and women of childbearing age treated with
valproate

6. Guide for patient & Patient card

7. What does the references say, about valproate
safety (1)?
 Associated with 1-2% of neural tube defects if taken
during 1st trimester of pregnancy
 Increase incidence of cardiovascular abnormalities
 Increase incidence of orofacial abnormalities
 Digital abnormality is been noted
 Also causes cognitive impairment in offspring

8. What does the study say, about valproate
safety?- An example

9. Over all major congenital malformation
Antiepileptics Vs control, depending on OR value (2)
Statistically sig. Marginally not
statistically sig.
Non statistically sig.
Ethosuximide * Clonazepam Gabapentin
Valproate * Lamotrigine
Topiramate * Levetiracetam
Phenobarbital * Clonazepam + valproate +
Carbamazepine
Phenytoin * Phenytoin + Primidone
Carbamazepine * Phenytoin + Valproate +
Topirmate
Valproate + Carbamazepine +
phenytoin *
Valproate + Carbamazepine +
Lamotrigine *
Lamotrigine + Valproate

10. Combined fetal losses
Antiepileptics Vs control, depending on OR value (2)
Statistically sig. Marginally statistically sig.
Topiramate * Phenobarbital + Phenytoin
Primidone *
Valproate *
Carbamazepine + Valproate *
Phenytoin + Valproate *
Carbamazepine + Phenobarbital *

11. Prenatal growth retardation
Antiepileptics Vs control, depending on OR value (2)
Statistically sig. Marginally statistically sig. Non statistically sig.
Clobazam * Phenobarbital + Phenytoin Lamotrigine
Topiramate *
Phenobarbital *
Carbamazepine *
Antiepileptics Vs Lamotrigine (2)
Carbamazepine * Phenytoin
Valproate *

12. Preterm Birth & Hypospadias
Antiepileptics Vs control,
depending on OR value (2)
Statistically sig.
Clobazam *
Primidone *
Vigabatrin
Oxcarbazepine
Antiepileptics Vs control, depending on OR
value (2)
Statistically sig.
Gabapentin *
Clonazepam *
Primidone *
Valproate *

13. Cardiac malformations
Antiepileptics Vs control, depending on OR value (2)
Statistically sig. Statistically sig.
Gabapentin * Levetiracetam *
Carbamazepine + Phenytoin * Lamotrigine *
Phenobarbital + Valproate *
Phenytoin + Valproate *
Carbamazepine + Clonazepam *

14. Cleft lip/palate
Antiepileptics Vs control, depending on OR value (2)
Statistically sig.
Ethosuximide *
Primidone *
Topiramate *
Phenobarbital *
Phenytoin *
Valproate *
Phenobarbital + Phenytoin + Primidone *
Phenytoin + Primidone *
Carbamazepine + Phenobarbital *
Carbamazepine + Valproate *

15. Club foot & Inguinal hernia
Antiepileptics Vs control, depending on OR
value (2)
Statistically sig.
Phenytoin *
Valproate *
Primidone *
Ethosuximide *
Carbamazepine + Phenobarbital *
Phenobarbital + Phenytoin + Primidone *
Antiepileptics Vs control,
depending on OR value
(2)
Statistically sig.
Phenobarbital + Phenytoin *
Phenobarbital + Primidone *

16. Minor congenital malformations
Antiepileptics Vs control, depending on OR value (2)
Statistically sig.
Carbamazeoine *
Carbazapeine + Phenytoin *
Valproate *
Phenobarbital + Phenytoin *
Carbamazepine + phenobarbital + Valproate *

17. Over all risks, summary
Drug Associated Risks (2)
Carbamazepine major & minor congenital malformations
Clobazam prenatal growth retardation & preterm birth
Ethosuximide major congenital malformations, cleft lip & club foot
Gabapentin cardiac malformations & hypospadias
Phenobarbital major congenital malformation, prenatal growth retardation & cleft
lip
Phenytoin major congenital malformation, cleft lip & club foot
Topiramate major congenital malformation, combined fetal loss, prenatal
growth retardation & cleft lip
Valproate major & minor congenital malformations, combined fetal losses,
hypospadias, cleft lip & club foot

18. Any safer drug?, What do you think
 Gabapentin- lack the statistical significance (2)
 Lamotrigine- not associated with statistical significance (2)
 Levetiracetam- not associated with statistical significance
(2)
 Oxcarbazepine- not associated with statistical significance
(2)
 Vigabatrin- not associated with statistical significance (2)

19. References
1. Katzung B.G. Basic & Clinical Pharmacology : Antiseizure
drugs. 14th Ed. McGraw-Hill Education (2018)
2. Veroniki A.A., Cogo E., Rios P. Et al. Comparative safety of
anti-epileptic drugs during pregnancy: a systematic review
and network meta-analysis of congenital malformations
and prenatal outcomes. BMC Medicine (2017) 15:95 DOI
10.1186/s12916-017-0845-1

20. Thank You