Prophylactic Mefloquine Use in Pregnancy
ABSTRACT & COMMENTARY
Synopsis: Post-marketing surveillance suggests that mefloquine can be safely used as malaria prophylaxis in early pregnancy.
Source: Vanhauwere B, et al. Post-marketing surveillance of prophylactic mefloquine (Lariam) use in pregnancy. Am J Trop Med Hyg 1998;58(1):17-21.
Since the introduction of mefloquine in 1985, data regarding its safety during pregnancy have been collected through the Roche International Spontaneous Reporting System. Most of the reports were collected prospectively (the outcome of the pregnancy was unknown at the time of reporting and was ascertained through prospective monitoring), and data obtained up to September 1996 were reviewed.
A total of 1627 reports of exposure to mefloquine were received; 1526 (94%) were reported during pregnancy and followed up to the end of pregnancy. Most of the cases originated from France, Germany, the United Kingdom, and the United States. The rest came from Switzerland, Canada, and Italy. The majority (97.7%) of exposures occurred within two months before and/or during the first trimester of pregnancy. More specifically, 391 cases involved exposure within two months before conception, 501 cases involved exposure both before conception and during the first trimester, and 608 cases involved exposure during the first trimester. Most (95.3%) of the women used the medication for malaria prophylaxis.
Of the 1526 pregnancies that were followed, 42% resulted in delivery, 21% resulted in abortions, and the rest were lost to follow-up or were ongoing pregnancies. The prevalence of spontaneous abortions in this study was 8.1%. Twenty-six (4%) of the delivered infants had congenital malformations. There were 33 other pregnancy-related and perinatal problems. One spontaneously aborted fetus had a chromosomal disorder, and five abortions were performed after ultrasound diagnosis of congenital malformation. Other adverse events reported included four spontaneously aborted fetuses with placental disorders and blighted ovum and four abortions that were induced for other perinatal problems.
In addition to these 32 prospectively followed cases of malformations, 24 malformations were reported retrospectively (outcomes of the pregnancies were known at the time of reporting). The malformations were varied and did not represent a specific pattern. Some additional disorders were noted in 41 prospective and 10 retrospective reports. These included intrauterine growth retardation, premature or low birth weight babies, placental disorders, hydramnios, neonatal jaundice, and neonatal death. However, there were no significant differences in fetal outcome corresponding to the time of exposure to mefloquine.
The weaknesses in the study, as Vanhauwere and colleagues point out, are the result of spontaneous reporting systems. These include reporting bias, lack of a suitable comparative group, and poor data on other possible teratogenic risk factors. For example, no information was available for the aborted fetuses in 236 of 246 induced abortions. Similarly, information was available on only six fetuses of 79 spontaneous abortions.
COMMENT BY LIN H. CHEN, MD
Malaria during pregnancy frequently leads to severe disease, attributed to depressed cell-mediated immunity. Pregnant women have a higher incidence of severe anemia and parasitemia, leading to increased maternal mortality.1 Fetal loss from abortion, stillbirth, and prematurity is high. In addition, the infant may have lower birth weight and congenital malaria infection. Both maternal and fetal outcomes are poor; thus, malaria should be prevented during pregnancy.
Mefloquine has been shown to be an effective prophylaxis against malaria, and it appears to be one of the few antimalarials that is safe during pregnancy.2 The CDC's Travel Information recommends that ". . . pregnant women who are traveling to a malaria risk area should consult a physician and take prescription drugs to prevent malaria. In areas with chloroquine-resistant P. falciparum, mefloquine may be used during pregnancy. "Neither mefloquine nor chloroquine has been demonstrated to have a harmful effect on the fetus when it is used to prevent malaria." Nonetheless, some concern remains because of teratogenicity reported in animals given high doses of mefloquine. The FDA currently classifies mefloquine as a Pregnancy Category C drug for this very reason.
A recent study showed low placental transfer of mefloquine,3 and two clinical studies have shown no increase in malformations associated with the use of mefloquine prophylaxis during pregnancy. One randomized trial of prophylaxis with mefloquine in the second half of pregnancy demonstrated no significant adverse outcomes, and follow-up of those infants up to 2 years of age showed no abnormalities.4 Another study on the inadvertent use of mefloquine during early pregnancy showed no association with subsequent congenital malformations; however, a worrisome rate (33%) of spontaneous abortions was noted.5
The current study is the largest series of women exposed to mefloquine during early pregnancy, and it shows some reassuring results. First of all, there was no significant increase in the prevalence of spontaneous abortions compared to the general population.6 Second, there appears to be no significant increase in the risk of congenital malformations. In addition, the observed malformations did not show a propensity toward any particular organ system that would indicate a clear pattern of drug influence.
This report lends evidence to the safety of mefloquine during pregnancy. The data should help to alleviate the concern about the pregnant woman who needs mefloquine for malaria prophylaxis. It should also make appropriate recommendation for malaria chemoprophylaxis easier for the travel medicine clinician. Nevertheless, it remains prudent practice to advise pregnant women against unnecessary travel to malarious areas and to emphasize personal protective measures. (Dr. Chen is Clinical Instructor, Harvard Medical School and Travel/Tropical Medicine Clinic, Lahey Hitchcock Medical Center.)
References
1. Silver HM. Malarial infection during pregnancy. Infect Dis Clin North Am 1997;11(1):99-107.
2. Phillips-Howard PA, Wood D. The safety of antimalarial drugs in pregnancy. Drug Safety 1996;14(3): 131-145.
3. Barzago MM, et al. Mefloquine transfer during in vitro human placenta perfusion. J Pharmacol Exp Ther 1994;269:28-31.
4. Nosten F, et al. Mefloquine prophylaxis prevents malaria during pregnancy: A double-blind, placebo-controlled study. J Infect Dis 1994;169:595-603.
5. Smoak BL, et al. The effects of inadvertent exposure of mefloquine chemoprophylaxis on pregnancy outcomes and infants of US Army servicewomen. J Infect Dis 1997;176:831-833.
6. Mackay HT, Evans AT. Gynecology and obstetrics. In: Tierney LM, et al (eds). Current Medical Diagnosis and Treatment. London: Prentice-Hall International, Inc.; 1995:652.
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