Pregnancy Outcome Following Prenatal Exposure to Triptan Medications: A Meta-analysis

Alexander Marchenko, MD; Fatma Etwel, MSc; Olukayode Olutunfese, MD; Cheri Nickel, BSW; Gideon Koren, MD; Irena Nulman, MD

Disclosures

Headache. 2015;55(4):490-501. 

In This Article

Discussion

For obvious reasons, randomized control trials have not been conducted to assess the teratogenicity of triptan medications; therefore, a meta-analysis of the existing evidence-based research may provide stronger evidence of the reproductive safety of triptans.

While prior reviews[14,24] reassured clinicians that triptans may be safely used during the first trimester, recommendations regarding use of triptan medications during pregnancy have remained cautious.[18] The present analysis supports evidence[25] regarding a lack of association between prenatal triptan exposure and MCMs. However, it strengthens the association reported by Bérard and Kori[26] of triptans with increased rates of spontaneous abortions, signaling a need for further confirmation.

Fox and Chambers attempted to analyze all available research prior to 2001 regarding sumatriptan tolerability and pregnancy outcomes, including MCMs. Following the discussion of the limits of their report, the study (published in Headache, 2002) conclusion was reassuring for use in early pregnancy.[24] However, it is important to note that among the studies they analyzed, the largest study did not control for either the disease or treatment effects.

Our meta-analysis, based on the analysis of 6 studies that surpassed our quality threshold, has demonstrated results that may help to clarify previously published data about the safety of antimigraine agents from the triptan group. One of the included studies had data overlapping with a previous publication by the same authors. Thus, after analysis and contacting the authors, we included the more recent study in our meta-analysis.[27] The previously published study, using the data from Norwegian Mother and Child Cohort and national registry of the large population (with 1387 offspring of women who used triptans during the first trimester of their pregnancy out of 68,021 of pregnant women), found that MCMs occurred in 3.1% of the offspring of mothers using triptans vs the 2.9% they expected in a similar population (OR = 1.0; 95% CI [0.7–1.4]).[25] This study also did not disclose any other adverse pregnancy outcomes. Bérard and Kori performed a case–control analysis, including 139 women who filled prescriptions during the month prior to conceiving and repeated during the first month of gestation, which showed OR = 1.49 (95% CI 0.89–2.52) for MCMs, OR = 0.76 (95% CI 0.34–1.66) for prematurity, and OR = 2.65 (95% CI 1.57–4.48) for spontaneous abortion.[26] One of the limitations of Bérard and Kori's study is that within the Quebec Pregnancy Registry, information on potential confounding variables, such as smoking, maternal obesity, and folic acid use, was not extensively available.

The potential limitations of population-based, large-scale studies are that the investigators use prescribing or dispensing as a proxy for drug consumption and that the records may fail to recognize associated comorbidities. Furthermore, many of the included studies provided incomplete information regarding the dose, duration, and timing of fetal exposure to concomitant medications, all of which is essential information in determining teratogenicity. There might also be a difference related to the dose of triptan medication, rate of administration, and duration of treatment. Another potential confounder is concomitant medication use, particularly in the migraine no-triptans group. Some of these medications are known to be associated with preterm birth,[28] and depression in particular is often present in patients suffering from migraines.[29]

Although the results of the present meta-analysis are largely impacted by the outcomes of the 2 large studies included,[27,30] they revealed that the use of triptan medications during pregnancy does not increase the rates of premature deliveries or rates of MCMs in the triptan-exposed children when compared with healthy controls. These results are in agreement with numerous previous studies and are also supported by a 2014 report from international registries including 680 pregnancies exposed to triptans, despite the registries' potential methodological limitations and lack of comparison groups.[31]

The comparisons of the pregnancy outcomes of women with migraine no-triptans and healthy controls revealed a statistically significant increase in the rate of MCMs (OR = 1.41 [1.11–1.80]).

This conclusion was also arrived at in a publication by Bánhidy et al in 2006. These authors found that migraines experienced by mothers during the first trimester of pregnancy were associated with an increased rate of congenital limb defects; no such association was found in relation to other types of maternal headaches during pregnancy.[32]

Migraines may also be associated with other comorbidities such as depression, anxiety, bipolar disorder, and epilepsy, which may require polytherapy. Control of psychiatric disorders in 70–80% of patients requires polytherapy, which has been found to be associated with increased rates for MCMs.[33]

Moreover, women who suffer from migraine and are untreated could have less awareness toward their disease and also toward pregnancy follow-up. In our analysis, however, it is shown that there is no increase in rate of MCMs among women taking triptan medications compared to healthy controls, indicating beneficial effect of treatment. While there were no specific patterns of malformations found in any of the included studies, the results of this meta-analysis suggest that untreated migraine may confer a teratogenic risk that will need to be explored in future studies.

The meta-analysis of 2 included studies revealed a significantly increased rate of spontaneous abortions (OR = 3.54 [2.24–5.59] in the triptan-exposed group. Although this result is biologically plausible with the seratonergic effects of triptans,[34,35] more research is needed to support this outcome.

Potential strengths of these studies include that selection and recall biases are minimized because drug exposure and outcomes are recorded prospectively, and controls are selected randomly from the source populations.

In conclusion, synthesized data from included studies do not suggest that the use of triptan medications during pregnancy increases the rates of MCMs or prematurity. This conclusion is more accurate toward the sumatriptan than other triptan medications due to the availability of research data. Increased rates of spontaneous abortions require further research to support this result. While sumatriptan is the most studied medication from the triptan group in regard to reproductive safety, none of the evaluated triptan medications can unequivocally be classified as nonteratogenic on the basis of available research. The absence of evidence of MCMs across several large recent studies and our meta-analysis is reassuring and suggests an acceptable risk of using these medications during pregnancy.

Although more research studies of high methodological quality are needed, the potential reproductive risks of untreated migraines on both mother and the newborn should be taken into consideration when making therapeutic decisions.

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