A new study confirms that the risk for oral clefts is increased among children born to women taking higher doses of topiramate, which are typically used to treat epilepsy, in early pregnancy.
The analysis showed a much weaker association between oral clefts and the lower doses of topiramate used to treat nonepilepsy indications, such as migraine and bipolar disorder.
Dr Sonia Hernandez-Diaz
“My recommendation for clinicians and women of childbearing age, or who are planning pregnancies, would be to try to avoid high doses of topiramate unless the benefits outweigh the potential risks,” lead author, Sonia Hernandez-Diaz, MD, professor, epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, told Medscape Medical News
The study was published online December 27, 2017, in Neurology.
Unplanned Pregnancies
Previous studies suggest that for women with epilepsy taking topiramate at daily doses of around 200 mg, there is about a fivefold increased risk for oral clefts in their babies, but it has been unclear whether lower doses carry the same increased risk.
To assess this requires “huge sample sizes” because relatively few women use the drug at lower doses, said Dr Hernandez-Diaz.
It’s important to know the risk for lower doses, especially because an extended-release capsule that combines low-dose topiramate with phentermine (Qsymia, Vivus Inc) is approved in the United States for obesity, said Dr Hernandez-Diaz. She added that this drug is not indicated in pregnancy but that many pregnancies are unplanned.
The new population-based cohort study investigated data on pregnant women within the nationwide Medicaid Analytic eXtract (MAX) from 2000 to 2010. MAX captures demographic and Medicaid enrollment information, healthcare use, all diagnoses and procedures, and all prescriptions filled outside the hospital.
The study included 2425 women who were exposed to topiramate, defined as filling at least one prescription for the drug during the first trimester of pregnancy.
The primary reference group included 1,322,955 pregnant women who did not fill a prescription for topiramate or other anticonvulsant during the first trimester.
Potential confounders included maternal age, race, topiramate indication (epilepsy, migraine, bipolar disorder, pain condition), obesity, smoking, comorbidities, concomitant medications, and overall health status.
A diagnosis of oral cleft included cleft lip or cleft palate.
The study showed the risk for oral clefts was 4.1 per 1000 live births in the topiramate group and 1.1 per 1000 in the unexposed group. The adjusted risk ratio (RR) for oral clefts was 2.90 (95% confidence interval [CI], 1.56 – 5.40) for the topiramate-exposed group compared with the unexposed group.
A second reference group included 2796 pregnant women exposed to lamotrigine who filled at least one prescription for this anticonvulsant medication in the first trimester. The risk for oral clefts in this group was 1.5 per 1000 live births. The adjusted RR for oral clefts with topiramate use was 2.38 (95% CI, 0.71 – 7.96) compared with the lamotrigine group.
An analysis of only women with epilepsy found an adjusted RR for those exposed to topiramate of 8.30 (95% CI, 2.65 – 26.07). For women without epilepsy, the adjusted RR was 1.45 (95% CI, 0.54 – 3.86).
The adjusted RR for oral clefts in those taking daily topiramate doses of 100 mg or less was 1.64 (95% CI, 0.53 – 5.07), and the adjusted RR for those taking higher doses was 5.16 (95% CI, 1.94 – 13.73).
“Our best estimate is that women with epilepsy using 200 mg or more of topiramate have around an 8-fold increased risk, and those using lower doses had a twofold or lower risk,” said Dr Hernandez-Diaz. “The results suggest that the risk with lower doses, if it is there, is much less than for higher doses.”
However, the authors stressed that the finding of less risk for oral clefts at lower doses should be interpreted with caution because the sample size was relatively small. As well, those receiving the lower dose may have different adherence levels, and there may be interactions between the underlying indication and the drug, they note.
Additional Prescriptions
The researchers carried out several sensitivity analyses. In one, they looked at women who filled a minimum of two topiramate prescriptions in the first trimester, the assumption being that these women are more likely to have adhered to at least the first one. Here, the RR was 3.50 (95% CI, 1.46 – 8.41).
Another analysis restricted topiramate exposure to the window in pregnancy during which an oral cleft develops. The association between topiramate exposure and increased oral cleft risk remained in this and other sensitivity analyses.
“The literature suggests that oral clefts are not typically a reason for women to terminate a pregnancy,” Dr Hernandez-Diaz noted, possibly because the malformation is identified relatively late in the pregnancy and it’s correctable with surgery, she said.
The current findings echo those of previous studies. “It’s always good to have replication,” said Dr Hernandez-Diaz.
The researchers pooled the current results with six other studies reporting a risk for oral clefts among prenatally exposed live births and found the pooled RR was 5.27 (95% CI, 2.88 – 9.65).
It’s important to keep the risks in perspective, said Dr Hernandez-Diaz. Oral clefts occur in about 1 in 1000 births. “With an increased risk of say fivefold, that would mean that out of 1000 women exposed to topiramate, we would see five more cases of oral cleft.”
In some instances, the benefits — for example, improved seizure control — may outweigh these risks, she said.
The numbers were too small to explore cleft lip and cleft palate separately. Topiramate does not appear to increase the risk for fetal malformations other than oral clefts, said Dr Hernandez-Diaz.
Dose Matters
Reached for comment, Laura A. Kalayjian, MD, assistant professor of clinical neurology, University of Southern California (USC), and co-director of the USC Epilepsy Center, Los Angeles, praised the study.
“It definitely confirms what was previously reported,” she said, adding that “the new information is that the dose does matter in regards to the risk of oral cleft lip and cleft palette.”
In addition to possibly raising the oral cleft risk, higher doses of topiramate can also interfere with hormonal contraception, said Dr Kalayjian.
“If women are taking 200 mg of topiramate and are taking birth control pills, they may think they’re not going to get pregnant, but there’s a risk that they will.” The unplanned pregnancy rate may be higher in women with epilepsy than in the general population, “probably because of this contraception failure.”
Such women should switch to nonhormonal types of contraception, she said. “One of the most important messages is that they need to be on a barrier method of birth control, such as condoms or an IUD [intrauterine device].”
Because the study included only a Medicaid sample, it’s not clear how generalizable the results are, said Dr Kalayjian. “We know that these women are in lower socioeconomic status and that, in and of itself, increases the risk of oral cleft lip and cleft palette.”
As well, the researchers could not control for folic acid use, said Dr Kalayjian. Women wishing to become pregnant who take antiseizure medications should also take folic acid, which can prevent neural tube defects and possibly also lower the risk for oral clefts.
However, Dr Kalayjian noted that most women don’t realize they’re pregnant until after a cleft lip or palette develops. This occurs very early in the pregnancy, 14 to 60 days after conception, she said.
While oral clefts are correctible, they are “very disturbing” to moms because their baby is unable to latch on, “so feeding is a big issue.”
The study was supported by a grant from the National Institute of Mental Health. Dr Hernandez-Diaz received salary support from the North American AED Pregnancy Registry; has received research funding from GSK, Lilly, and Pfizer; and consulted for UCB, Teva, and Boehringer-Ingelheim. Her institution received training grants from Pfizer, Takeda, Bayer, and Asisa. Dr Kalayjian’s spouse owns stock in Johnson & Johnson, a subsidiary of which markets topiramate
Neurology. Published online December 27, 2017. Abstract.
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