Dear Dr.,

Thank you for your information request on a young woman planning to become pregnant and inquiring if it is safe to continue taking her daily vitamin and 50 mg of topiramate twice daily to prevent her migraines during and after her pregnancy. Also, you requested to find clinical studies that assess the safety of topiramate during pregnancy. Topiramate (Topamax(R)) has been researched over the years and is mainly indicated for epilepsy as an anticonvulsant and for prophylaxis of migraines. The specific mechanisms by which topiramate applies its effects are unknown; however, studies have discovered four properties that cause the antiepileptic and anti-migraine effects. According to Micromedex, these include a blockage of voltage-gated sodium channels, augmentation of GABA-A receptors, antagonism of the AMPA/kainate subtype of the glutamate receptor, and inhibition of the carbonic anhydrase enzyme (particularly isozymes II and IV). Data shows that topiramate works to prevent seizures, by blocking the neurons’ electronic signals.1 According to the Topamax manufacturer website, migraines are thought to be caused by over-excitation of nerve cells in the brain. Topiramate helps suppress the signals of the neurons through the previously suggested pathways.2 Pain from migraines have been reported to improve or stay the same throughout pregnancy. Migraines might worsen after giving birth, however there was no time frame pertaining to when that effect might take place. 2 The tertiary resources we explored were the Micromedex, Facts and Comparisons, and Lexicomp compendia, Drugs in Pregnancy and Lactation, as well as, the Topamax manufacturer website and Food and Drug Administration guidelines. The secondary resources we searched were PubMed and Scopus to find our primary literature about clinical trials dealing with safety of topiramate during pregnancy.

The tertiary resources we searched do not recommend taking topiramate while pregnant.  Dozens of case studies and meta-analyses have shown an increase in cleft lip and/or cleft palate in newborns when the mother took topiramate during the first trimester of pregnancy. Due to these studies, the sources say that topiramate should be avoided during the first trimester of pregnancy due to risks of oral clefts or hypospadias (opening of the urethra). 1,4,5,6 Lexicomp reported findings from the NAAED Pregnancy registry stating that 1.2% showed signs of oral clefts during the first trimester of their pregnancy.  5 However, some evidence suggests that if it is necessary to continue topiramate therapy, then it should happen at the lowest effective dose with no additional therapy. 4 Another effect may be metabolic acidosis, which might cause decreased fetal growth and oxygenation and possibly fetal death. If topiramate is used during pregnancy, monitoring for metabolic acidosis is recommended, especially due to its effect on the ability of the fetus to tolerate labor.   The drug is a category D, which means there is fetal risk during pregnancy, but the potential benefits may outweigh the potential risks. The compendia also state it is not advised to take topiramate while breastfeeding because infant risk cannot be ruled out. Through limited data of nursing infants, the plasma levels of topiramate in infants were 10-20% of their mothers’ topiramate plasma levels. However, the effects of topiramate at these concentrations in nursing infants are unknown If taken while lactating, infants should be monitored for signs of bone marrow suppression, headache, nausea, vomiting, diarrhea/constipation, abdominal pain, alopecia, and hepatic toxicity, or changes in alertness, behavior, and feeding habits due to this medication being excreted into the breast milk. (1,4,5,6)    

The FDA website provided information regarding the effects taking topiramate while pregnant. Topiramate can slow the growth rate of children and can the fetus if pregnant.

It is important that a woman who is pregnant and taking topiramate talk to her healthcare provider about whether or not she may have metabolic acidosis. Metabolic acidosis is one of the side effects derived from taking topiramate. As far as effects on the fetus, the FDA source stated that if one takes topiramate during their pregnancy, their baby has a higher risk of inheriting cleft lip and cleft palates. These effects can begin to take place before one knows they are pregnant. This source also stated that a patient should register with the North American Antiepileptic Drug Pregnancy Registry (NAADPR) if she is pregnant while taking this medication. The program’s main priority is to collect and report data regarding the safety of antiepileptic drugs for pregnant women.7

    According to the information provided by Topamax.com, topiramate could be very toxic to the fetus and can cause cleft lips and palates. Topiramate can cause metabolic acidosis in the woman and can also cause metabolic acidosis in the fetus. When topiramate was tested in pregnant animals, the results included structural malformations (craniofacial effects) and decrease in weight at birth. If taking this medication while pregnant, the potential benefit should outweigh the risk in regards to protecting the fetus occur in the first trimester of pregnancy. This guideline described side effects which included a decrease in fetal growth, a decrease in fetal oxygenation, and fetal death.3

Two secondary sources, Scopus and PubMed were also searched in regard to topiramate use for prophylaxis of migraines.  An article by Cosentino et. al. from PubMed included the most relevant information regarding topiramate in migraine prophylaxis. The article included a study done in which two different formulations of topiramate (Sincronil and Topamax) were tested for factors such as effectiveness and tolerability. This study analyzed sixty patients with ages ranging from 18-65. The patients were taking 25mg twice a day for three months and then evaluated. Results concluded that both formulations were equally effective and well tolerated in regard to migraine prophylaxis.8  In addition to this, Castilla-Puentes et. al. proposes the effects of topiramate in pregnancy may differ according to the indication.  A total of 1163 cases of women who used topiramate monotherapy during pregnancy (for any indication) were retrieved from the Global Medical Safety database. From their research, individuals taking topiramate for epilepsy had a greater fetal risk than those taking it for migraines or other indications. Even though incidence rates cannot be calculated based on spontaneous adverse event reporting, this suggests that the risk for major fetal or neonatal abnormalities may differ based on the indication for topiramate.9 Also information from Öhman et. al. shows that plasma levels of topiramate in infants increase, if their mothers are taking it during pregnancy and lactation. Five women taking topiramate during pregnancy and lactation were tested. Blood samples were taken from the women before and for three days after delivery, as well as from the infants during breast-feeding. Samples of breast milk were also taken. They found that the plasma levels in infants were higher after delivery, indicating that most of the drug is transferred from the placenta. Topiramate levels were high in the breast milk, however infants had low levels of topiramate during breast feeding and no adverse effects were observed. 10 Nevertheless, this study was done on a small number of people and may not be representative of a larger population.

    Based off our findings, we do not recommend taking topiramate while pregnant.  There have been multiple research studies which have shown topiramate increases the risk of teratogenicity, the most common case being formation of cleft palates. The drug is also excreted in the breast milk and has the possibility of transferring to the infant. Therefore, we also would not advise the patient taking this while lactating. Considering evidence provided by UpToDate, we recommend for a patient, if pregnant or planning to become pregnant, to take acetaminophen 1000 mg daily.2 Oral acetaminophen falls under category B according to the United States Food and Drug Administration which means that is has failed to show risk in the fetus. 1

Thank you for your time and consideration.  If you have any questions about this subject or anything else in the future, please do not hesitate to contact us. We are always here and more than happy to help.

Bibliography

  1. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: 10/6/2014).
  2. Lee MJ, Guinn D, Hickenbottom S, Lockwood CJ, Swanson JW. Headaches in pregnant and postpartum women. In: UpToDate, Barss VA (Ed), UpToDate, Waltham, MA. (Accessed on October 8, 2014.
  3. Topamax.com [Internet]. Janssen Pharmaceutical, Inc., [updated 2012 Sep 13; cited 2014 Oct 6]. Available from: http://www.topamax.com/
  4. Briggs GG, Freedman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. p. 1459-1463.
  5. Lexi-Comp OnlineTM, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; October 6, 2014
  6. Topiramate. Minoxidil oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; October 6, 2014
  7. Fda.gov [Internet]. New Jersey:  Janssen Pharmaceuticals, Inc., [updated 2014 March; cited 2014 October 6]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM152837.pdf
  8. Cosentino G, Paladino P, Maccora S, Indovino S, Fierro B, Brighina F. Efficacy

            and safety of topiramate in migraine prophylaxis: an open controlled randomized

            study comparing Sincronil and Topamax formulations. Panminerva Med. 2013

            Sep;55(3):303-7.

  • Castilla-Puentes R, Ford L, Manera L, Kwarta RF, Ascher S, Li Q. Topiramate monotherapy use in women with and without epilepsy: Pregnancy and neonatal outcomes.Epilepsy Research. 2014. 108(4):717-724.
  • Öhman I, Vitols S, Luef G, Söderfeldt B, Tomson T. Topiramate kinetics during delivery, lactation, and in the neonate: Preliminary observations.Epilepsia. 2002.43(10)):157-1160.