By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: In a retrospective study of American military women involving 50 treated with atovaquone-proguanil and 156 exposed to mefloquine, no increase in risk of fetal loss or adverse infant outcomes was identified. Atovaquone-proguanil seems safe for use in pregnancy, but data are limited.

SOURCE: Gutman JR, Hall C, Khodr ZG, et al. Atovaquone-proguanil exposure in pregnancy and risk for adverse fetal and infant outcomes: A retrospective analysis. Travel Med Infect Dis 2019;32:101519.

Gestational malaria is associated with significant risks to both the mother and the baby. Travel by pregnant women to malaria-endemic areas is not always avoidable. Chloroquine has been used widely in pregnancy without evidence of adverse effects, but it is ineffective against the malaria found in many parts of the world. Mefloquine is thought to be safe in pregnancy, but resistance is increasing. The typical expert advice is to avoid atovaquone-proguanil during pregnancy because of an uncertain safety profile, but the actual risks are unknown.

Gutman and colleagues reviewed data from 198,164 pregnancies of U.S. military women from 2003 to 2014. During that time, 50 women received atovaquone-proguanil during pregnancy, 156 received mefloquine, and 131 received chloroquine. Those who received atovaquone-proguanil were older and more likely to be in the first trimester of pregnancy (since the treatment policy was not to use atovaquone-proguanil when the woman was known to be pregnant).

Women receiving atovaquone-proguanil or mefloquine demonstrated no increased risk of either pregnancy loss (spontaneous abortion, stillbirth) or adverse infant outcome (preterm birth, small for gestational age, large for gestational age, or birth defects). Although the differences were not statistically significant, miscarriage and stillbirth were seen in 28% of women treated with atovaquone-proguanil and 16% of those treated with mefloquine. Pregnancy loss was seen in 6.1% of women treated with chloroquine. Statistically, the use of chloroquine was protective against pregnancy loss.

The authors summarized their findings by saying that a true assessment of the safety of atovaquone-proguanil was not possible with the small number of women included in the study. They suggested that further observational studies be done but, because of concerns for risk, they do not advocate for a randomized prospective study.

COMMENTARY

Pregnant women are at particular risk of contracting malaria. With pregnancy, women produce more exhaled carbon dioxide and release different concentrations of transcutaneous substances, making them more attractive to mosquito chemoreceptors.1 In addition, related to pregnancy-induced changes in immunity and specific parasite-placenta interactions, pregnant women are at risk of severe malaria and serious consequences of malarial infection.2

Malaria is dangerous for pregnant women and their babies. Mothers risk pregnancy loss, severe illness, anemia, premature labor, and death.1 Babies born to women with gestational malaria are at increased risk of congenital malaria, low birthweight, neonatal fever, neonatal death, infantile anemia, infantile malaria, and death during the first year of life.3

Thus, it is wise to try to prevent malaria during pregnancy.4 For women who must be in areas where malaria is endemic, mosquito bites should be avoided by wisely using insecticide-impregnated clothing to cover skin, insect repellents such as diethyl-meta-toluamide (DEET) or picaridin, and insecticide-impregnated bed nets. Behaviorally, pregnant women also can try to stay away from areas where Anopheles mosquitoes are active, especially during evening and night hours. In addition, because of the risk of malaria and its severe consequences, they should take chemoprophylaxis.

There are several sorts of malarial prevention medications.4,5 Chloroquine remains effective in parts of Central America but not in most other malarial areas of the world. Mefloquine is effective in most malarial areas, but it does cause bothersome side effects (nausea, unpleasant dreams) in nearly one-fifth of those who take it. It should not be used in those with active seizure disorders, cardiac rhythm disturbances, and psychiatric conditions. Atovaquone-proguanil is expensive but usually is well-tolerated and was the focus of Gutman’s study. Doxycycline usually is avoided during pregnancy because of concerns about altered bone and tooth development in the growing fetus, but experts in some countries accept its use, when truly necessary, during pregnancy.5 Finally, primaquine (like the new similar medication tafenoquine, see the February 2020 issue of Infectious Disease Alert) can be used to prevent malaria, but it carries a risk of triggering hemolysis in those with glucose-6-phosphate dehydrogenase deficiency (such as untested but affected fetuses). This summary of malaria preventive treatments serves as a reminder that atovaquone-proguanil, although incompletely tested, is the only agent without significant, proven risk (even though it is expensive). Thus, it was very helpful for Gutman and colleagues to try to determine through a retrospective observational study if atovaquone-proguanil actually is safe in pregnancy.

Previously, a study of 149 Danish women inadvertently exposed to atovaquone-proguanil during early pregnancy showed no unusual risk of birth defects.6 A retrospective review and a systematic review provided some (incompletely conclusive) optimism for the safety of atovaquone-proguanil.7,8

How should we interpret and apply the findings of the new study by Gutman and colleagues? Certainly, we can agree with the authors that the number of subjects was small and that a significant risk still could exist below the level of statistical significance of this study. Further studies are warranted.

At the same time, there are reasons to believe that the increased incidence of fetal loss with atovaquone-proguanil (28%) vs. mefloquine (16%) was not only statistically insignificant but, even if it is significant in larger studies, it likely is related to separate factors. First, the women in Gutman’s study who received atovaquone-proguanil were older overall than the women who received mefloquine, and twice as many were older than 35 years of age. Older age during pregnancy can be associated with increased risks.

Second, more of the atovaquone-proguanil exposed women were in their first trimester of pregnancy, and essentially all were unaware of their pregnancy at the time of treatment. Miscarriage is most common during the first trimester, and it could be that the timing of treatment (earlier, first trimester), rather than the treatment itself, could prompt the women in the atovaquone-proguanil group to have more miscarriages than those in the mefloquine group. Finally, it is not clear whether the women receiving atovaquone-proguanil might have been visiting geographical areas or participating in activities (such as brief, dangerous missions) during deployment that might have increased the risk of fetal loss separate from the medication use.

Thus, the new study from Gutman provides reassurance that even more data demonstrate no significant risk of poor outcomes related to the use of atovaquone-proguanil during pregnancy. However, that reassurance is incomplete since some risk still could exist for an individual traveler. We must mitigate risk wisely by using non-pharmacologic protection against mosquito bites and by carefully considering the risks and benefits as we make specific chemoprophylaxis recommendations for women who are pregnant or might become pregnant during travel to malarial areas.

Statistically, the finding that chloroquine protected against pregnancy loss is fascinating. The authors attributed this protection to the known anti-inflammatory properties of chloroquine. Although no one should suggest using chloroquine to prevent miscarriage, pregnant travelers to areas of the Caribbean and Central America where malaria is sensitive to chloroquine certainly can use chloroquine with confidence.

REFERENCES

  1. Lindsay S, Ansell J, Selman C, et al. Effect of pregnancy on exposure to malaria mosquitoes. Lancet 2000;355:1972.
  2. Cutts JC, Agius PA, Zaw L, et al. Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: A systematic review. BMC Med 2020;18:14.
  3. Hartman TK, Rogerson SJ, Fischer PR. The impact of maternal malaria on newborns. Ann Trop Paediatr 2010;30:271-282.
  4. Roggelin L, Cramer JP. Malaria prevention in the pregnant traveller: A review. Travel Med Infect Dis 2014;12:229-236.
  5. Schlagenhauf P, Grobusch MP, Leder K, et al. Complex choices: Which malaria chemoprophylaxis can be recommended for the pregnant traveller? Travel Med Infect Dis 2019:101525. doi: 10.1016/j.tmaid.2019.101525
  6. Pasternak B, Hviid A. Atovaquone-proguanil use in early pregnancy and the risk of birth defects. Arch Intern Med 2011;171:259-260
  7. Mayer RC, Tan KR, Gutman JR. Safety of atovaquone-proguanil during pregnancy. J Travel Med 2019;26. doi: 10.1093/jtm/tay138.
  8. Andrejko KL, Mayer RC, Kovacs S, et al. The safety of atovaquone-proguanil for the prevention and treatment of malaria in pregnancy: A systematic review. Travel Med Infect Dis 2019;27:20-26.