Obstetrics and Gynecology

Malaria in pregnancy

Malaria in Pregnancy

1. What every clinician should know

Key clinical features and incidence

Malaria is caused by a parasite that is transmitted by the bite of an infected Anopheles mosquito. Five species of malarial parasites infect humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi). P. vivax is the most common worldwide; P. falciparum is responsible for the most severe disease.

Like all parasites, malaria undergoes a complicated life cycle. In brief, after injection into the bloodstream, initial maturation of the parasites occurs in the liver. After a period of time, depending on the specific Plasmodium species, many fold more parasites are released into the bloodstream where they infect red blood cells. Further maturation and division occurs; ultimately, the erythrocyte membrane is lysed, thereby rereleasing more parasites into the bloodstream which infect other red blood cells.

Symptoms of malaria include fever, myalgias, chills, headaches and malaise. Anemia is prominent. Infected red blood cells can adhere to the microvasculature in the lungs and brain and cause endothelial damage leading to the severe manifestations of the disease. This includes seizures, mental confusion, coma, kidney failure, respiratory distress and even death. Deterioration in condition is unpredictable and can occur rapidly.

Presentation during pregnancy depends on the stability of transmission in the area the pregnant woman resides. In areas of unstable or episodic transmission, where women have developed little immunity, women can become quite sick if infected during pregnancy. Compared with nonpregnant women, those who are pregnant are more likely to have severe anemia and severe maternal symptoms such as cerebral malaria, respiratory distress and death. Their pregnancies are at risk of miscarriage, preterm birth, stillbirth as well as low birth weight and infant mortality. In areas where transmission is stable and occurs throughout the year, women have developed partial immunity and are often asymptomatic when infected, yet they remain at risk for severe anemia. Additionally, infected red blood cells can adhere to placental miscrovasculature, impairing fetal growth and increasing the risk for stillbirth.

Risk factors

Malaria transmission occurs in many parts of the world, including large areas of sub-Saharan Africa, Central and South America, parts of the Carribbean, India, South Asia, Southeast Asia and the Middle East. An estimated 200 to 300 million infections occur annually, resulting in more than half a million deaths.

In endemic areas, pregnant women, infants and children are the populations most vulnerable to the disease. Fifty million pregnancies occur in malaria endemic areas annually, resulting in an estimated 10,000 maternal deaths, 200,000 cases of severe maternal anemia and 200,000 low birth weight infants. In these areas, primigravid women are at the greatest risk for infection when compared with women of greater parity. In addition, women co-infected with HIV suffer increased morbidity and mortality from malaria during pregnancy.

Travelers to malarious areas with no prior immunity to malaria are at risk of malaria, as are immigrants who return to these endemic areas after having lost the partial immunity that develops through repeated exposure to malarial parasites. The risk for acquisition depends on the intensity of transmission in the region visited and the season, with increased transmission occurring during the rainy season.

2. Diagnosis and differential diagnosis

A. How do I know my pregnant patient has malaria?

Malaria should be urgently considered in the differential of a pregnant woman with a fever who has traveled to or emigrated from an endemic area, as virtually all non-immune individuals will experience fever. Suspected malaria is a medical emergency given the potential severe consequences of the disease as well as the unpredictability and potential rapidity of progression. Malaria should also be considered in pregnant travelers presenting with seizures, mental confusion or respiratory distress.

Early consultation with an infectious disease specialist knowledgeable about malaria is recommended even prior to diagnostic confirmation of the disease to help guide treatment options. A high index of suspicion is required for recent immigrants from malarious areas who may still have partial immunity. They may be asymptomatic or have only vague nonspecific complaints. Blood smears should be sent from these women if there is unexplained anemia or fetal growth restriction.

Diagnostic criteria and methods used to confirm the diagnosis of malaria

Detection of malarial parasites from a blood smear is the gold standard for malaria diagnosis. Smear microscopy is also used to quantify the degree of parasitemia and identify the species of Plasmodium circulating in the blood stream, both of which are useful for guiding treatment. An alternative to microscopy is a rapid diagnostic test (RDT) which detects various malaria specific antigens. Both positive and negative results require microscopic confirmation.

While RDTs are increasingly used worldwide given their rapidity and ease of diagnosis, only one RDT is FDA approved in the U.S. RDTs may be useful in hospitals lacking expertise in conventional smear microscopy. PCR detection of malarial parasites is both more sensitive and specific than conventional microscopy but currently available only in reference labs, limiting utility in the acute setting.

One challenging diagnostic situation during pregnancy arises in women living in, or recently emigrated from, areas of stable malaria transmission. These women may have placental parasitemia in the absence of peripheral parasitemia. Peripheral blood smears may therefore be negative although their placentas may still be harboring infected erythrocytes. Unfortunately, there is no peripheral biomarker as of yet that identifies placental infection. This requires histologic examination of the placenta after delivery.

What diagnostic tests should be done?

If malaria is suspected, Giemsa-stained thick and thin blood smears should be ordered. It is useful to call the microscopy laboratory to alert them to your concern for malaria and ensure that the smear is read in a timely fashion. If positive, the lab should report the density of parasitemia and the species identified (e.g. P. falciparum vs P. vivax). If the blood smear is negative, smears should be repeated every 12-24 hours for a total of three sets, as non-immune individuals may be symptomatic at very low parasite densities that may be missed on initial microscopy.

B. Differential diagnosis for malaria in pregnancy

Malaria often tops the differential of a fever in a traveler; however, there are a number of other tropical diseases that need consideration in addition to the myriad causes of fever during pregnancy that can occur even in the absence of travel. Dengue, typhoid fever, schistosomiasis, tick-borne rickettsial diseases, filariasis, histoplasmosis, and leptospirosis are among the infections in the differential depending upon the geographic region visited. An infectious disease consultant will be quite useful in guiding the additional workup required should malaria be excluded.

3. Management

Prevention

The best management strategy is prevention. Women should be encouraged to avoid malarious areas during their pregnancy. Pregnancy increases the chance of being bitten by a mosquito, becoming parasitemic if bitten, and suffering more severe malaria if infected. This risk appears to persist and may even be heightened in the postpartum period (40-60 days after delivery). Pregnancy complications such as miscarriage, preterm labor, fetal growth restriction, preeclampsia and stillbirth may ensue, particularly among those without preexisting immunity.

If travel cannot be avoided, preventive measures should be undertaken. Travelers should be prescribed chemoprophylaxis - chloroquine if traveling to areas without resistance and mefloquine to other endemic areas. Safety data regarding atovaguone/chlorguanide during pregnancy is more limited.

Vector control is equally important. The Anopheles mosquito that transmits malaria typically feeds at dusk and through the night. Therefore, pregnant women should be encouraged to stay indoors at these times and sleep under insecticide-treated bed nets. Clothes that minimize skin exposure (long sleeves, pants) should be worn when outside at dusk/night. Insect repellants should be applied. Available data on the use of N.N-Diethylmetatolumide (DEET) in human and animal pregnancies appears reassuring. Maternal toxic effects are not apparent until orders of magnitude greater than the typical human exposure. Emphasis should be placed on the real risks of malaria during pregnancy, underscoring the need to prevent acquisition of the parasites in the first place.

Treatment

A woman with malaria should be treated promptly with effective antimalarial medications. The World Health Organization publishes and updates guidelines, available online, for the treatment of uncomplicated and severe malaria with specific recommendations for pregnant women. Oral quinine and clindamycin are administered for uncomplicated malaria during the first trimester.

At the time of this writing, artemisinin combination therapies (ACTs) are increasingly considered first-line for uncomplicated malaria in the second and third trimester, given their effectiveness. However, ACTs should be avoided in the first trimester if alternative regimens exist, as they have been associated with an increased risk of embryonic loss in animals. Intravenous antimalarials should be administered in the setting of severe malaria (IV artesunate in the second or third trimesters and IV quinine or IV artesunate in the first trimester).

Consultation with an infectious disease specialist knowledgeable in the treatment of malaria is recommended to help guide treatment choice and duration. Should such a physician not be available in your practice setting, parasitologists at the Centers for Disease Control can be incredibly useful resources. Primaquine, which is used to clear the liver stage parasites in P. vivax nfections, should be deferred until postpartum, as it has the potential to cause hemolytic anemia in individuals with G6PD and the fetal G6PD status is unknown.

Antimalarial treatment is focused upon clearing the parasites from the maternal bloodstream. Repeated blood smears are useful in documenting improvement in parasite density and eventual clearance of the parasitemia. Symptoms such as fever and myalgias can be treated with acetaminophen. Antipyretics should be used with caution if typhoid fever remains in the differential of the fever as they may cause precipitous drops in temperature and shock.

Intermittent preventive therapy of pregnancy (IPTp): For women with underlying partial immunity, there may be undetectable placental infection in the absence of peripheral parasitemia. A policy of intermittent preventive therapy in pregnancy (IPTp) is endorsed for pregnant women living in areas of stable malaria transmission, typically with sulfadoxine-pyrimethamine. A curative dose of an antimalarial is given at monthly intervals at least twice after the first trimester under the assumption that parasites may not be detected in the peripheral bloodstream. IPTp should be considered for recent immigrants from areas of intense malaria transmission if they resided in such an area at any time point during the pregnancy.

Pregnancy management: Induced preterm delivery is not indicated, as adequate antimalarial treatment should clear parasites harbored by the placenta. The patient should be monitored for signs of miscarriage or preterm labor. If viable, fetal assessment is recommended, as nonreassuring fetal heart rate tracings may occur and amniotic fluid may decrease. For those women who remain pregnant after an episode of malaria, it is reasonable to obtain fetal growth ultrasounds. The placenta should be examined after delivery for evidence of residual parasites and an infant blood smear sent to rule out congenital malaria infection, which is fortunately rare.

4. Complications

A. What complications could arise as a consequence of malaria in pregnancy?

Potential maternal complications of malaria during pregnancy include:

  • Severe anemia

  • Seizures

  • Coma

  • Respiratory distress syndrome

  • Death

Potential obstetricand neonatal complications of malaria during pregnancy include:

  • Miscarriage

  • Preterm delivery

  • Fetal growth restriction

  • Perinatal death (stillbirth/neonatal death)

  • Congenital malaria infection

  • Increased susceptibility to malaria during infancy

  • Impaired response to pediatric vaccine

Prompt recognition and treatment is urged to avoid serious complications of the disease, but it is important to recognize that clinical deterioration can be rapid and unpredictable.

B. What complications could arise as a consequence of the management of malaria in pregnancy

The safety of most antimalarials during pregnancy has not been well established. Chloroquine has been used extensively, is well-tolerated and does not appear to cause harm in pregnancy. Unfortunately, there are very few malarious regions where parasites remain chloroquine-sensitive, although this may be changing with less overall use of chloroquine.

Quinine has also been used extensively in both oral and intravenous forms and does not appear to result in adverse pregnancy outcomes. Notably, quinine can cause maternal and consequently fetal hypoglycemia; therefore, serum glucose should be monitored carefully. Artemisinin drugs, which are very effective in treating malaria, are increasingly used in the second and third trimester. First trimester exposure in animals has been shown to be embryotoxic in early pregnancy leading to an increased risk of miscarriage.

It should be emphasized that the lack of extensive safety information on most antimalarials in pregnancy should not result in withholding of medication in women diagnosed with malaria, as nontreatment can be potentially fatal to the mother if no other alternative exists.

5. Prognosis and outcome

A. What would you tell the patient about the prognosis for pregnancy outcome?

A favorable prognosis of malaria in pregnancy for both mother and fetus depends upon early recognition and prompt treatment. Outcome is additionally dependent on many other factors, such as parasite species (P. falciparum most virulent), antimalarial resistance of the circulating parasite strains, parasite density, host factors (e.g. maternal age, blood type, presence of hemoglobinopathies).

After recovery, women should be monitored closely for recrudescence of parasitemia if not all parasites were cleared from the circulation during the original treatment course. P. vivax can remain dormant in the liver for extended periods of time (years) leading to much later relapses. Primaquine is required to clear these liver stage parasites, but this treatment is reserved for the postpartum period given its potential toxicity to fetuses with G6PD.

If a woman recovers from malaria without any obstetric complications such as preterm delivery, the growth of the fetus should be monitored during the remainder of the pregnancy. Oligohydramnios often resolves after the acute convalescence.

B. What would tell the patient about the impact on her long term health?

A long term impact on maternal health is unlikely if adequately treated and no serious complications arise.

6. What is the evidence for specific management and treatment recommendations

www.cdc.gov/malaria.

(Provides general information on malaria, epidemiology, geographic regions where malaria is present.)

wwwnc.cdc.gov/travel/content/yellowbook/home-2010.aspx.

(Outlines detailed information for travelers, including a full chapter on travel during pregnancy.)

Desai, M, ter Kuile, FO, Nosten, F. "Epidemiology and burden of malaria in pregnancy". Lancet Infect Dis. vol. 7. 2007. pp. 93.

(Provides an excellent overview of malaria during pregnancy and its potential complications.)

Duffy, PE, Fried, M. "Plasmodium falciparum adhesion in the placenta". Curr Opin Microbiol. vol. 6. 2003. pp. 371.

(Describes the pathophysiology underlying placental malarial infection during pregnancy with implications for pregnancy-specific vaccine development.)

Gamble, C, Ekwaru, JP, ter Kuile, FO. "Insecticide-treated nets for preventing malaria in pregnancy". Cochrane Database Syst Rev. vol. 2. 2006. pp. CD003755.

(Provides the evidence base underlying the recommendation for use of insecticide-treated bed nets during pregnancy.)

Garner, P, Gulmezoglu, AM. "Drugs for preventing malaria in pregnancy". Cochrane Database Syst Rev. vol. 4. 2008. pp. CD000169.

(Summarized evidence behind recommendations to use IPTp or chemoprophylaxis to reduce parasitemia and improve birth outcomes.)

Orton, LC, Omari, AA. "Drugs for treating uncomplicated malaria in pregnant women". Cochrane Database Syst Rev.. vol. 4. 2008. pp. CD004912.

(Reviews available evidence for treatment decisions for malaria in pregnant women, underscoring limitations in safety data.)

Steketee, RW, Nahlen, BL, Parise, ME, Menendez, C. "The burden of malaria in pregnancy in malaria-endemic areas". Am J Trop Med Hyg. vol. 64. 2001. pp. 28.

(Estimates the population-attributable risks of anemia, preterm birth, impaired fetal growth and infant mortality associated with malaria during pregnancy.)

"World Health Organization. Guidelines for the treatment of malaria, second edition". www.who.int/malaria/publications/atoz/9789241547925/index.html.

(As title suggests, this document details current treatment guidelines for malaria including pregnancy appropriate choices and is updated online.)

"The Malaria in Pregnancy Library". www.update-software.com/publications/malaria.

(The Malaria in Pregnancy Library is a regularly updated, comprehensive bibliographic database of published and unpublished literature relating to malaria in pregnancy, including a trial registry of planned and ongoing trials.)
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