Risk Factor: CM
Class: Central nervous system drugs/ Antimigraine agents
Fetal Risk Summary
Sumatriptan (GR 43175) is a selective serotonin (5-hydroxytryptamine1; 5-HT) receptor subtype agonist used for the acute treatment of migraine headaches. It has also been used for the treatment of cluster headaches. The compound is available in oral tablets and as a subcutaneous (SC) injection.
Sumatriptan was embryolethal in rabbits when given in daily IV doses approximately equivalent to the maximum recommended single human SC dose of 6 mg on a body surface area basis (MRHD) (1). The doses were at or close to those producing maternal toxicity. Fetuses of rabbits administered oral sumatriptan (at doses greater than 50 times the MRHD) during organogenesis had an increased incidence of cervicothoracic vascular and skeletal anomalies (1). In contrast, embryo or fetal lethality was not observed in pregnant rats treated throughout organogenesis with IV doses approximately 20 times the MRHD. Moreover, no rat embryo/fetal lethality or teratogenicity was observed with daily SC doses before and throughout gestation (1). Shepard described a study in which no fetal adverse effects were observed in rats given up to 1000 mg/kg orally during organogenesis (2).
No studies examining the placental transfer of sumatriptan in animals or humans have been located. The molecular weight of the drug (about 414) is low enough, however, to allow passage to the fetus.
Individual reports and data from Medicaid studies totaled 14 spontaneous abortions with the use of sumatriptan during early pregnancy (F. Rosa, personal communication, FDA, 1996). Seven birth defect case reports received by the FDA included two chromosomal anomalies (both of which could have been exposed before conception), one infant with an ear tag, one case of a phocomelia, a reduction defect of the lower limbs (tibial aplasia), a case of developmental retardation, and one unspecified defect (some of these defects appear to be also included in data from the Pregnancy Registry cited below).
In an interim report of the Sumatriptan Pregnancy Registry, covering the period of January 1, 1996, through October 31, 2000, the outcomes of 361 prospectively enrolled pregnancies exposed to sumatriptan were described (3). Some of the data were also reported in a 1997 abstract (4). The outcomes of 29 pregnancies were still pending and 45 were lost to follow-up. Of the remaining 289 outcomes (287 pregnancies, 2 sets of twins), 264 had earliest exposure in the 1st trimester, 18 in the 2nd trimester, 3 in the 3rd trimester, and 4 were exposed at an unspecified time. In the 1st-trimester group, there were 15 spontaneous abortions (
Although retrospective reports (reported after the pregnancy outcome was known) are often biased (only adverse outcomes are reported), there were 15 cases of birth defects reported to the Registry, all involving 1st-trimester exposure to sumatriptan (3). The details of the defects are shown below. (See required statement below.) Prospective Reports Earliest exposure 1st trimester: Hypertrophic pyloric stenosis Stillbirth at 23 weeks, left hand anomaly (one digit missing and concretion and shortening of two others) Odd cry, low ears, abnormal head circumference, single palmar crease, and soft systolic murmur Cerebral abnormality with developmental delay Diaphragmatic hernia at 18 months of age Ventricular septal defect Anterior displacement of the anus Polydactyly Down’s syndrome (induced abortion) Partial small cleft lip Earliest exposure 2nd trimester: Congenital hypothyroidism Earliest exposure unknown: Down’s syndrome (induced abortion) Retrospective Reports Earliest exposure 1st trimester: Triploid fetus (karyotype 69,XXY) with single umbilical artery, splenomegaly, small adrenal glands, hypoplastic lungs (induced abortion) Head circumference above 97th percentile, sagittal synostosis Central cleft palate, fused flexion deformity of left thumb, single palmar crease on left hand, absent left kidney, and tight anus with fibrous ring; chromosomal analysis normal Shortened legs and decreased chest circumference, karyotyping normal Bilateral club feet, deformed ulna, absence of both hands, right wrist, and one toe on left foot, extra toe on right foot, retrognathia, bilateral talipes, bilateral acheiria Delayed myelination on magnetic resonance imaging, delayed development, slow movement and motor development, delayed speech, muscle flaccidity), unable to walk or talk at 17 months of age Glycogenosis Frontal nasal encephalocele, agenesis absent corpus callosum Holoprosencephaly Tracheoesophageal fistula and esophageal atresia (esophagus connected to lungs by trachea not to stomach) Severe malformations of the heart and connection of the heart with the lungs, no spleen Pulmonary stenosis Cardiac axis-lungs, diaphragm, stomach, bowel, right kidney, right hand and foot, clubbing of right leg, left and right arms Spina bifida, hydrocephalus, absence of bladder, absence of rectal function, paresis in legs Hypoplastic left ventricle A 1998 report (first published in 1997 as an abstract ) described the prospectively determined pregnancy outcomes of 96 women exposed to sumatriptan (95 exposed during 1st trimester) (6). No difference in the rate of major birth defects was found between the study patients and non-teratogen-exposed controls or disease-matched controls. One major birth defect was reported in a sumatriptan-exposed infant: vesicoureteral reflux requiring bilateral reimplant (6).
A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (7). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Sumatriptan was taken during the 1st trimester in 35 pregnancies. The outcomes of these pregnancies included 4 spontaneous abortions, 3 elective abortions, 5 pregnancies lost to follow-up, and 23 normal infants (2 premature) (7).
In summary, although sumatriptan caused toxicity and malformations in one animal species, the drug does not appear to present a major teratogenic risk in humans. Moreover, there was no consistent pattern among the reported birth defects to suggest a common cause. The above studies, however, lack the sensitivity to identify minor anomalies because of the absence of standardized examinations. In one study, late appearing major defects may also have been missed due to the timing of the questionnaires. Thus, although the data are generally reassuring, the number and follow-up of exposed pregnancies are still too limited to assess, with confidence, the safety of the agent or its teratogenic potential.
Required statement: The number of exposed pregnancy outcomes accumulated to date represents a sample of insufficient size for reaching definitive conclusions regarding the possible teratogenic risk of sumatriptan. Specifically, the sample size to date remains too small for formal comparisons of the frequency of specific birth defects. If the baseline frequency of total birth defects is 3 in 100 live births, a sample size of 236 for first trimester exposure has an 80 percent chance (80% power) of correctly detecting at least a 2.1-fold increase from baseline in the frequency of birth defects. If the baseline frequency of specific birth defects is 1 in 1,000 live births, a sample size of 236 for first trimester exposure has an 80 percent (80% power) of correctly detecting at least a 9.9-fold increase from baseline in the frequency of a specific birth defect. It is expected that a teratogenic exposure in the first trimester would result in an increased frequency of one or a combination of individual defects or types of defects, but not in all defects. As reporting of pregnancies is voluntary, it is possible that even in prospectively reported pregnancies there could be bias in type of pregnancies reported. For example, differential reporting of low-risk or high-risk pregnancies may be a potential limitation to this type of registry. In addition, reporting of defects from maternal health care providers may limit detection of detects not immediately apparent at birth. Despite this, the Registry is intended both to supplement animal toxicology studies and other structured epidemiologic studies and clinical trial data, and to assist clinicians in weighing the risks and benefits of treatment for individual patients and circumstances. Moreover, accrual of additional patient experience over time will provide more definitive information regarding risks, if any, of exposure to sumatriptan during pregnancy.
Breast Feeding Summary
Sumatriptan is excreted in the milk of experimental animals (1) and humans (8). Five women with a mean duration of lactation of 22.2 weeks (range 10.828.4 weeks) were administered a 6-mg SC dose of sumatriptan (8). Milk samples were obtained hourly for 8 hours by emptying both breasts of each subject with a breast pump. Frequent blood samples were also obtained from the women. The mean milk:plasma ratio was 4.9. The mean cumulative excretion of drug in milk during the 8-hour sampling period was 12.6 g and, by extrapolation, a total recovery of only 14.4 g after a 6-mg dose. Using this latter value, the authors estimated that the mean weight-adjusted dose (i.e., g sumatriptan/kg of infant body weight as a percentage of the mother’s dose in g/kg) for the infants would have been 3.5% (8). The investigators considered the risk to a nursing infant from this exposure to be not significant.
In adults, the mean oral bioavailability of sumatriptan is 14%15% (range 10%26%) (1,9), indicating that absorption from the gastrointestinal tract is inhibited. Thus, although the oral absorption in infants may be markedly different from adults, the amount of sumatriptan reaching the systemic circulation of a breast-feeding infant is probably negligible. Discarding the milk for 8 hours after a dose, an interval during which about 88% of the amount excreted into milk can be recovered, would reduce even more the small amounts present in milk.
- Product information. Imitrex. Glaxo Wellcome, 1998.
- Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:397.
- Sumatriptan Pregnancy Registry. Interim Report. 1 January 1996 through 31 October 2000. Glaxo Wellcome, January 2001.
- Eldridge RE, Ephross SA. Monitoring birth outcomes in the sumatriptan pregnancy registry (abstract). Teratology 1997;55:48.
- Shuhaiber S, Pastuszak A, Schick B, Koren G. Pregnancy outcome following gestational exposure to sumatriptan (Imitrex) (abstract). Teratology 1997;55:103.
- Shuhaiber S, Pastuszak A, Schick B, Matsui D, Spivey G, Brochu J, Koren G. Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 1998;51:5813.
- Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:8829.
- Wojnar-Horton RE, Hackett LP, Yapp P, Dusci LJ, Paech M, Ilett KF. Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol 1996;41:21721.
- Fullerton T, Gengo FM. Sumatriptan: a selective 5-hydroxytryptamine receptor agonist for the acute treatment of migraine. Ann Pharmacother 1992;26:8008.