Malaria in Pregnancy: What the Obstetric Provider in Non-endemic Areas Needs to Know

Abstract

Importance

Globally, over 125 million women each year are at risk of malaria during pregnancy. Endemic regions carry the greatest burden; however, with globalization, providers in non-endemic regions are encountering increasing numbers of women with exposed to or infected with malaria.

Objectives

The aim of this paper is to provide obstetric providers in non-endemic areas with updated information on malaria infection in pregnancy focusing on pregnancy management, and malaria prevention and treatment.

Evidence Acquisition

This paper is based on review of the most recent peer-reviewed articles and guidelines from the Centers for Disease Control and the World Health Organization.

Findings

Malaria infection in pregnancy causes maternal anemia, low-birthweight, preterm birth, stillbirth and miscarriages through placental malaria and severe infections. Pregnant women traveling to malaria-endemic areas should be advised against travel. If travel must occur, they should be provided with region-specific chemoprophylaxis and given methods for preventing infection. In the event that a pregnant patient has an acute malarial infection, prompt evaluation is needed to determine whether there are severe features. Medications for uncomplicated or severe malaria infection should be started as soon as the diagnosis is made.

Conclusions and Relevance

Malaria in pregnancy causes significant perinatal complications. Obstetric providers should be aware of the impact and how to prevent and treat malaria infection during pregnancy. Malaria infection should be suspected in women with concerning symptoms and recent travel to endemic areas. Providers should know the management of uncomplicated and severe malarial infection in pregnancy.

BACKGROUND

Malaria in pregnancy is an important public health issue that affects more than 25 million pregnant women who give birth in malaria-endemic areas each year.(1) Malaria is caused by the protozoan parasite Plasmodium. Human malaria is caused by five different species of Plasmodium: P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. Of these, P. falciparum and P. vivax are the most prevalent, and P. falciparum is the most dangerous, with the highest rates of complications and mortality.(2,3) While P. vivax causes a less fatal infection, infections with this species require treatment for the hypnozoite forms that remain dormant in the liver and can cause a relapsing infection.( 4)

Global Trends

The World Health Organization (WHO) reports that 90% of all malaria cases occurred in Africa in 2016, followed by Southeast Asia (7%) and Eastern Mediterranean Region (2%).(5) The great majority of malaria infections in Africa are due to P. falciparum.(2,6) Vivax malaria is much less common in this region because the human population is largely Duffy antigen receptor negative, a red-blood cell surface protein that P. vivax uses to invade the reticulocytes.(6) In Asia and Oceania, malaria case numbers are generally lower and proportions caused by P. vivax and P. falciparum are similar, whereas in the Americas, P. vivax cases exceed P. falciparum by more than two-fold.(6) Figure 1 demonstrates the global transmission risk of P. falciparum.

Figure 1: Plasmodium falciparum Transmission Risk.

The map reviews the spatial limits of P. falciparum transmission in 2015.

Areas in red are regions with stable, or endemic, transmission. Areas in pink are regions with unstable, or epidemic, transmission. Areas in grey have no transmission of P. falciparum.

Malaria Atlas Project: WHO Collaborating Centre. Explorer Map - Plasmodium falciparum Spatial Limits of Transmission. Legend added; no other changes made. Image located at: map.ox.ac.uk/explorer/#/. Available through open access via the Creative Commons Attribution 3.0 Unported License accessible through: creativecommons.org/licenses/by/3.0/

Disclaimer: Authors of this paper were not involved in the making of this map. This image was made through the Malaria Atlas Project. See open access attribution information above for details on accessing the map.

As efforts to eradicate malaria have ramped up in these endemic areas, the incidence of infections has decreased. The WHO reports that malarial infections decreased 18% globally from 2010 to 2016.(5) However, studies are finding that less parasite exposure, in endemic areas, are associated with decreased immunity. One study done in Mozambique compared the prevalence of malaria infection during pregnancy between 2003 and 2012.(7) They found that as malaria prevalence declined in this time interval, antimalarial immunity also decreased. This was accompanied by an increase in the severity of adverse pregnancy outcomes in women who acquired infection.(7) These results suggest that as global efforts to reduce malaria transmission increase, malaria in pregnancy may become a less prevalent but more serious disease.

Additionally, there is mounting evidence that traditional regimens for preventing malaria have growing resistance in regions most impacted by the parasite. A cross-sectional study of 915 pregnant women in Uganda found that using sulfadoxine–pyrimethamine, the recommended regimen for preventive treatment during pregnancy, was not effective due to growing P. falciparum resistance.(8)

Trends in the United States

Malaria rates in the United States have generally been increasing since the mid-1970s with 1,517 cases reported in 2015 (most recent Center for Disease Control (CDC) data).(3) Of these cases, 32 were pregnant patients none of whom had adhered to chemoprophylaxis.(3) While the WHO notes that the risk of malaria is most present in endemic areas, pregnant women are considered a high-risk group due to the adverse obstetrical complications including the risk of vertical transmission of malaria to the fetus.(2,9) Thus, pregnant women traveling to endemic areas are a high-risk group and those traveling to rural areas in these regions during peak malaria season are at the greatest risk.

Risk to Travelers

Globalization has led to the resurgence of travel-related malaria impacting women in regions of the world where malaria had been eliminated. While global efforts focused on endemic areas have decreased the overall yearly amount of malarial infection (237 million cases in 2010 v. 216 million cases in 2016), the WHO reports that incidence rates are increasing in previously low-transmission regions: Americas and Western Pacific.(5) These findings align with CDC reports that malarial infections in US travelers decreased from sub-Saharan Africa in 2015 but increased for travelers from South and Central America and the Caribbean (54 of the 1485 total imported cases (3.4%) in 2014 to 92/1485 (6.4%) in 2015).(3)

The WHO warns that international travelers to countries and territories with ongoing local malaria transmission arriving from countries with no transmission are at high risk of malaria infection and its consequences because they lack immunity.(2) A European study surveying infectious disease physicians found that 85% of pregnant women who imported malaria did not use chemoprophylaxis.(10) With the increase in travel to malaria endemic areas and the risk of malarial infection, the CDC advocates that prevention strategies and health communication messages for protecting travelers from infectious diseases are becoming even more important.(3)

Studies of travelers’ behavior have shown that adherence to chemoprophylaxis can be improved if travelers are informed of the risk of infection and believe in the benefit of prevention strategies.(2) It has been found that pre-travel consultation significantly lowers the proportionate morbidity ratios for malaria; demonstrating the importance and effectiveness of pre-travel prevention strategies.(10) When it comes to malaria in pregnancy, healthcare providers caring for women should be aware of pregnancy outcomes and preventive options in endemic areas.

Thus, despite decreasing world-wide incidence of malaria, it remains an important global health issue for pregnant women. Here, we summarize the adverse consequences of malaria in pregnancy, and focus on recommendations for pregnancy management, infection prevention, and treatment options with the goal to prepare obstetric providers in the United States (and other non-endemic areas) to care for women affected by malaria.

CLINICAL PRESENTATION AND OUTCOMES

Malaria Clinical Presentation

Uncomplicated Malaria

Symptoms of uncomplicated malaria are generally non-specific and often can be asymptomatic. The most frequent symptoms at presentation include: fever, chills, malaise, headache, myalgia, muscle weakness, vomiting, cough, diarrhea and abdominal pain.(2,4)

The initial presentation of a P. vivax malaria is similar to that detailed above. However, P. vivax differs from P. falciparum in that it tends to initially cause milder disease.(6) Additionally, because P.vivax can survive in a dormant form in the liver and cause relapsing disease greater than 45 days from exposure.(3) These relapsing infections may become more severe despite effective prophylaxis.(6,11,12)

Severe Malaria

Pregnant women have a reduced immune response to malaria and can have the parasite sequester in the placenta, making them less likely to clear a malaria infection; thus, increasing their risk of developing severe malaria.(4,13) Severe malaria is characterized by one or more of the following clinical criteria: impaired consciousness, coma, severe normocytic anemia (hemoglobin <7), renal failure, acute respiratory distress syndrome, hypotension, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of > 5%. (2–4) The morbidity of severe malaria increases the risk of miscarriage and stillbirth.(14) Severe malaria can also lead to maternal death. Because symptoms can begin as non-specific clinical features, suspicion must be high, especially in pregnant travelers to malaria-endemic regions with symptoms.

Malaria in Pregnancy

Impact of Gravidity and Localization of Infection

In endemic areas, malaria in pregnancy is more common in younger women, and in first and second pregnancies, compared with subsequent pregnancies.(15–17) Additionally, malaria prevalence is highest in the first and second trimesters of pregnancy, and the risk may not immediately return to pre-pregnancy levels after delivery.(18) The reduced risk in later pregnancies is mediated primarily by the development of antibodies against Plasmodium falciparum VAR2CSA, a parasite variant surface antigen that leads to pregnancy-specific pathology. (19,20)

Malaria’s negative impact on pregnancy can occur even when women are asymptomatic with negative peripheral blood smear results. Studies have demonstrated that a feature of malaria infection is the sequestration of parasite in the placenta with low to undetectable peripheral results. (21) Thus, understanding placental malaria has become the focus of research attempting to find the linkage between malaria infection and pregnancy outcomes.

Pregnancy Outcomes

Placental malaria occurs in a 13–63% of pregnant women with malaria and is thought to incur the greatest risk to the pregnancy.(22) Placental malaria is defined by histological, molecular, or microscopic evidence of parasite infection of the placenta. Placental malaria is categorized into three phases: active-acute when parasites are present in the placenta with absent or minimal pigment deposition within fibrin, active-chronic when parasites are present with substantial amounts of pigment in fibrin or in cells, and past when there is presence of pigments without parasites.(13,23) Placental malaria is thought to occur through Plasmodium avoidance of spleen clearance through expression of the VAR2CSA protein that binds to the chondroitin sulphate A (CSA) in the placental intervillous space.(13,24) Infected red cells sequester in the placenta disrupting nutritional exchange between mother and fetus through decreased placental blood flow and the induction of local inflammatory responses.(13,24) This pathophysiology aligns with many studies that have found that increasing malaria burden (amount of parasite in the blood) is associated with higher risks of placental malaria and that obstetrical outcomes, such as low-birth weight, were primarily noted in groups of women where parasites were detected in the placenta.(18,25,26)

Malaria is the leading global cause of low birth weight, from either preterm birth and/or fetal growth restriction. Additionally, malaria is a leading cause of maternal anemia, a significant cause of maternal mortality in low-resource settings. Although detailed studies of obstetric outcomes are difficult in malaria-endemic regions, recent studies of pregnant women with and without placental malaria demonstrated that placental malaria had a significant association with low-birth weight (RR 3.45, 95% CI 1.44–8.23, p = 0.005), preterm birth (RR 7.52, 95% CI 1.72–32.8, p = 0.007), small for gestational age (RR 2.30, 95% CI 1.10–4.80, p = 0.03), and higher rates maternal anemia (aOR 2.22, 95% CI 1.02–4.84; p= 0.045).(25,27) (Table 1 summaries these findings).

Table 1:

Placental Malaria and Obstetrical Outcomes

Obstetrical Outcomes	RR or aOR (95% CI)	P value
Low-birth Weight [25]	RR 3.45 (1.44–8.23)	p = 0.005
Preterm Birth [25]	RR 7.52 (1.72–32.8)	p = 0.007
Small for Gestational Age [25]	RR 2.30 (1.10–4.80)	p = 0.03
Maternal Anemia [27]	aOR 2.22 (1.02–4.84)	p= 0.045

Abbreviations: RR, relative risk; aOR, adjusted odds ratio; CI, confidence interval

[] used to assign results to the reference.

Compiled from Kapasi et al²⁵ and Lufele et al²⁷.

It is important to note that malaria infection during pregnancy commonly leads to severe maternal anemia (hemoglobin < 7).(17) Pregnant women with severe anemia are at significant risk for morbidity and mortality including low-birth weight infants and death from postpartum hemorrhage.(16,17) Studies have found that acute and chronic placental malaria are associated with maternal anemia whereas peripheral parasitemia was not a significant association. (16,27) These findings further emphasize the complex impact of placental malaria on adverse pregnancy outcomes.

Placental malaria, acute or chronic infection, has been associated with a 2-fold increase in stillbirth risk.(22) This risk is thought to occur through decreased blood flow through the placenta that restricts the transport of oxygen and nutrients to the fetus. Studies done throughout Sub-Saharan Africa have found this association; given the large number of women living in this region, research has noted that malaria may be the most important preventable infectious cause of stillbirth globally.(22,28)

Other pregnancy outcomes such as congenital malaria and preeclampsia have been studied with unclear associations. Congenital malaria is thought to occur when the parasite crosses the placenta, leading to maternal-child transmission, with the presence of malaria parasites in the peripheral blood of the neonate within 1 week of life.(16,29) However, the incidence of congenital malaria is rare and strong evidence of true vertical transmission is lacking.(17,29) Similarly, preeclampsia as a result of placental malaria has limited evidence. Some studies demonstrate a significant association between placental malaria and preeclampsia while others demonstrate no association.(21,30) When an association was found, it was explained through malaria’s negative impact on placenta development and subsequent vascular dysfunction. This vascular dysfunction causes placental insufficiency leading to preeclampsia. However, these studies often had cofounders such a patients with a family history of hypertension and primigravida.(21,30) Thus the true association between preeclampsia and malaria remains unclear.

Although the complete pathophysiology of malarial infection in pregnancy and its impact on the placenta are not fully known; the above discussion demonstrates that placental malaria infection is the likely link between malaria and adverse obstetrical outcomes such as, maternal anemia, low-birth weight, preterm birth, small for gestational age, and stillbirth.(1,2,18,25,31) While these associations are clear, others such as congenital malaria and preeclampsia require more evidence to discern the pathophysiology and significance.

MALARIA PREVENTION

This section reviews strategies for malaria prevention in pregnant women. The first section addresses care for pregnant women who live in non-endemic areas and are traveling to endemic regions, usually for a short period of time. The second section addresses the pregnant woman that has traveled from an endemic region to a non-endemic region; we summarize the standard preventative management recommended in endemic areas and address how to continue their pregnancy care.

Temporary Travel to Malaria-endemic Regions

If a pregnant woman desires to travel to a malaria endemic area, the WHO recommends that healthcare providers advocate for the avoidance of these regions or delaying the visit, especially during the first trimester.(2) However, if travel must occur during pregnancy, the patient should be aware of high-risk areas and methods of decreasing the risk of infection, including: 1) discussing that infection in endemic regions are highest at the end of, or soon after the rainy season, 2) explaining that most cases occur in rural areas and at altitudes below 1500m, and 3) reviewing anti-mosquito methods and chemoprophylaxis because pregnant women are particularly susceptible to mosquito bites and should therefore be vigilant in using protective measures.(2,4)

Anti-Mosquito Methods

Insect-repellents

The CDC and WHO recommend a repellent containing DEET (N,N-diethyl-3-methylbenzamide), IR3535 (3-[N-acetyl-N-butyl]- aminopropionic acid ethyl ester) or icaridin (1-piperidinecarboxylic acid, 2-(2-hydroxyethyl)-1- methylpropylester).(2,32) Side effects of include hypotension, seizures or comas if accidentally ingested orally.(32) Currently, there is no data on the safety of DEET in women during the first trimester. However, when used at concentrations at or beneath 50%, there has not been evidence to suggest adverse effects.(2,32) There are few data on icaridin available from clinical trials. Nevertheless, a good tolerability has been described and systemic uptake of icaridin after topic application seems to be less compared to DEET.(32,33) When using insect repellents, care must be taken to avoid contact with mucous membranes. Additionally, it is recommended to not spray the face, eyelids or lips and to avoid application to sensitive, sunburned or damaged skin or deep skin folds. It is recommended to always wash the hands after applying the repellent. Repeated applications may be required every 3–4 h with the caveat that applying repellent to clothes last longer than directly applying to the skin.

Insecticide-treated Nets

Insecticide-treated nets (ITN) have been shown to increase mean birth weight and to reduce miscarriage/stillbirth as well as placental parasitemia in Africa.(34,35) Pyrethroids, the insecticide used in most ITNs, are about 2250 times more toxic to insects than mammals and mammals are protected by poor dermal absorption as well as more rapid metabolism to non-toxic metabolites.(32)

Other Methods

Air conditioning and minimizing exposed skin is also recommended.(2,32) For a complete list of anti-mosquito methods to recommend, see Table 2.

Table 2:

Anti-Mosquito Methods

• Appropriate use of insecticide-treated bed-nets (pyrethroids like permethrin)

• Intact window-screens

• Air-conditioning and ceiling-fans

• Minimizing skin exposure by wearing long-sleeved shirts and long pants

• Avoiding outdoor stays during peak activity periods of mosquito bites (dusk to dawn)

• Application of repellents (containing DEET 20–50% or Icaridin 20%) every 3–4hrs with use on clothing for more effect.

• Impregnation of clothes (pyrethroids like permethrin)

Compiled from Roggelin et. al³² and WHO².

Chemoprophylaxis

Pharmacologic prophylaxis to prevent malaria is recommended by the CDC for all travelers to endemic regions, including in pregnancy. Chemoprophylaxis is typically initiated prior to travel, and depending on the drug used, may be continued after return from endemic areas. For the most up-to-date recommendations on chemoprophylaxis based on the region of travel, we recommend visiting the CDC website (see Table 3 for website link).

Table 3:

Resources for Providers

Malaria Hotline

• 770-488-7788 (or toll free 855-856-4713) Monday – Friday, 9:00 am to 5:00 pm.

• Off-hours, weekends and federal holidays, call 770-488-7100 and ask to have the malaria clinician on-call to be paged.

• Provides 24 hours on-call CDC clinician to provide advice on the diagnosis and treatment of malaria.

CDC Website for Country-Specific Information

• www.cdc.gov/malaria/travelers/country_table/a.html

Compiled from CDC Guidelines ^4,11.

The CDC and WHO recommend mefloquine as the first choice for chemoprophylaxis in pregnant women in areas of P. falciparum transmission.(2,11) For those traveling to regions with exclusive P. vivax transmission, chloroquine or hydroxychloroquine prophylaxis may be used. However, if the primary malaria species is unknown, mefloquine is recommended as it will prevent malaria in regions where there is chloroquine-resistance.(10,32)

Of these medications, chloroquine is the most studied in pregnancy. It crosses the placenta and can be measured in cord blood; however, no negative effect of chloroquine during pregnancy has been shown.(11,36) Hydroxychloroquine, the alternative to chloroquine, is also not associated with adverse obstetrical outcomes, congenital defects, or developmental delay in the first-year of life after delivery.(37,38) While these two medications are generally considered safe for the developing fetus, due to high chloroquine resistance in most malaria-endemic areas, their efficacy is limited.(2,3,32)

Mefloquine carries the FDA warning related to neurologic and psychiatric side effects. In July 2013, the FDA strengthened these warnings to emphasize that some of the neurologic symptoms like dizziness and loss of balance could become permanent while psychiatric effects like depression could persist for months or even years.(39) Additionally, animal studies have shown a teratogenic effect of mefloquine if the dose several-fold exceeded the dose recommended for treatment in humans; the CDC (along with the other international health organizations in the U.K and Switzerland) recommends use for chemoprophylaxis in all trimesters of pregnancy.(3,10,32) Table 4 lists the chemoprophylaxis options along with their contraindications.

Table 4:

Malaria Chemoprophylaxis in Pregnancy

Generic Name	Dose Regimen	Duration of Prophylaxis	Contraindications
Chloroquine Hydroxychloroquine	• 300 mg base (500mg salt) orally, once/week  • 310mg base (400mg salt) orally, once/week	• Begin 1–2 weeks before travel to malarious areas.  • Take weekly on the same day of the week while in the malarious area  • Continue for 4 weeks after leaving such areas.	• Avoid use in chloroquine-resistant regions  • Hypersensitivity to chloroquine and 4-aminoquinoline compounds  • The presence of retinal or visual field changes of any etiology.a
Mefloquine	• 228 mg base (250 mg salt) orally, once/week	• Begin ≥2 weeks before travel to malarious areas.  • Take weekly on the same day of the week while in the malarious area  • Continue for 4 weeks after leaving such areas.	• Hypersensitivity to mefloquine, related compounds  • Patients with a history of seizures or psychiatric disorder.b

^a.Specifically when used for indications other than acute malaria

^b.Including active or recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders

Compiled from CDC Guidelines¹¹ and Cash-Goldwasser et. al⁴⁰.

However, care must be taken to focus on the pregnancy-safe drugs listed above. Three common regimens listed on the site, atovaquone/proquanil, doxycycline, and primaquine are not recommended in pregnancy. Due to insufficient data on the use of atovaquone/proquanil (a combination regimen consisting of a mitochondrial electron transport chain inhibitor (atovaquone) and a dihydrofolatereductase inhibitor (proquanil)) in pregnancy, the CDC recommends this drug not be used routinely in pregnancy.(40) However, if the pregnancy-safe medications for chemoprophylaxis cannot be given, the benefit of use may outweigh the risk of malarial infection. Doxycycline, a tetracycline antibiotic, crosses the placenta and is not recommended in pregnancy given the association between tetracyclines and the suppression of bone growth and staining of developing teeth.(41) Primaquine, used for chemoprophylaxis in P.vivax endemic regions, causes a fatal hemolysis in patients with G6PD deficiency.(4,37,40) For this reason, its use is considered unsafe in pregnancy because the G6PD status of the fetus is usually unknown.

Travelers from Endemic Regions Receiving Care in Non-endemic Areas

The current strategy of malaria prevention in malaria endemic regions relies on intermittent preventive treatment in pregnancy. This is distinct from malaria chemoprophylaxis, in that treatment doses are administered at regular intervals in pregnancy in order to treat subclinical infections. There is no need for screening or testing of asymptomatic women. The WHO currently recommends sulfadoxine-pyrimethamine every four weeks during antenatal visits starting in the second-trimester.(26,42,43) However, there are recent studies presenting evidence that the effectiveness of this drug combination as intermittent preventive treatment during pregnancy may be compromised due to growing resistance in Sub-Saharan Africa.(31,44–46)

In areas where sulfadoxine-pyrimethamine -resistance is growing, dihydroartemisinin–piperaquine is emerging in studies as a viable choice for intermittent preventive treatment in pregnancy. A randomized-control trial in Uganda compared sulfadoxine-pyrimethamine to dihydroartemisinin–piperaquine given for three-doses or every four weeks. They found that the prevalence of moderate-to-high-grade pigment deposition was significantly higher in the SP group that the monthly dihydroartemisinin–piperaquine group (55.6% vs. 20.6%, P = 0.003); and that the risk of any adverse birth outcome (low-birth weight, preterm delivery, stillbirth, and spontaneous abortions) was significantly lower in the monthly dihydroartemisinin–piperaquine (9.2%) than in the three-dose dihydroartemisinin–piperaquine group (21.3%, P = 0.02).(44) The PREGACT Trial had similar findings. They compared four artemisinin-based treatments, artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, and dihydroartemisinin–piperaquine, in pregnant African women in Burkina Faso, Ghana, Malawi, and Zambia. This trial found that dihydroartemisinin–piperaquine had the best efficacy, an acceptable safety profile, and the additional benefit of a longer post-treatment prophylactic effect, supporting its suitability as a chemoprophylaxis or chemoprevention agent.(45) Table 5 reviews the dosing for SP and dihydroartemisinin–piperaquine for women in endemic areas along with side effect profiles.

Table 5:

Intermittent Preventive Treatment in Pregnancy

Generic Name	Dose Regimen	Duration of Prophylaxis	Side Effects
Sulfadoxine-pyrimethamine	• 500 mg sulfadoxine/25 mg pyrimethamine  • Take 3 tablets as one dose (1,500mg/75mg)	• Take 3 doses qlmonth starting early 2nd trimester	• Nausea  • Abdominal Pain  • Diarrhea  • Headache  • Liver toxicity (rare)a  • Hematologic toxicity (rare)b  • Hypersensitivity to sulfadoxine component (rare)
Dihydroartemisinin-piperaquine	• 40mg dihydroartemisinin/320mg piperaquine  • Take 3 tablets, as one dose, daily for three consecutive days	• Take daily x3 consecutive days every 4 weeks starting at 16–20 weeks	• Post-treatment headache  • Weakness  • Dizziness  • Nausea  • Vomiting  • Insomnia  • Palpitations  • Dyspnea  • Nightmares  • Pruritus

^a.Hepatitis, acute hepatic necrosis

^b.Thrombocytopenia, leucopenia, megaloblastic anemia

Compiled from Deloron et.al⁴⁶, WHO Guidelines⁴², Chattopadhyay et. al³⁷, and Kakuru et. al⁴⁴.

To care for women who travel from endemic areas, healthcare providers should be aware of the WHO recommendations discussed above as well as the rising resistance to this regimen in Sub-Saharan Africa. For women that recently arrived from endemic areas, we recommend an additional treatment one week after arrival to clear any subclinical infections.

MALARIA DIAGNOSIS AND TREATMENT

Infection with P. falciparum can be fatal if treatment is delayed beyond 24 hours of clinical onset, because of this, the WHO and the CDC advocate that P. falciparum malaria be considered in all cases of unexplained fever starting at any time between 7 days after the first possible exposure to malaria and 3 months (or, rarely, later) after the last possible exposure.(2,3) In pregnancy, this consideration is even more critical because pregnant woman with malaria infections are three times more likely to develop severe disease than their non-pregnant counterparts.(4)

Diagnosis

Healthcare providers should promptly get a travel history and order peripheral blood smear (gold standard test), malaria rapid diagnostic test, or parasite nucleic acid PCR for patients who are symptomatic from endemic regions and for patients with fever of unknown origin if the suspicion is high.(3,4) However, the diagnosis of malaria can be challenging, even when using a peripheral blood smear, as non-immune individuals may be symptomatic at very low parasite densities.(4) If clinical suspicion remains high and the initial blood smear is negative, the CDC recommends repeating a blood smear every 12–24 hours for a total of 3 sets, if all 3 sets are negative, malaria can be excluded.(4). Given the challenge of diagnosing malaria in non-endemic regions, we recommend consulting with infectious disease physicians if they are available.

Availability of Diagnostic Testing

While peripheral blood smear is the gold standard, it requires that thick and thin blood films must be prepared correctly because diagnostic accuracy depends on both blood film quality and examination by experienced laboratory personnel.(4,6) Parasite nucleic acid detection with PCR has high sensitivities and specificities and is a great option if peripheral blood smears are not available.(4) However, PCR can only be performed in reference laboratories and results are often not quickly available.(4) Thus, having the availability of rapid diagnostic tests, such as BinaxNOW, is important. The WHO recommends rapid diagnostic tests as part of their universal access to malaria diagnostic testing manual.(12) If the rapid diagnostic test is done due to not having available personnel to conduct blood smears or PCRs, the CDC recommends that confirmatory testing be done.(3,4) See Table 3 for CDC resources to help in diagnosing malaria.

Treatment

Once the diagnosis is made, the treatment in pregnancy depends on the severity of the malarial infection (assessment is detailed above under clinical features). Clinicians should also assess the region of travel to provide information on the type of parasite and the resistance pattern of the region. This will guide the drug regimen used for treatment. Additionally, it is important to be aware of whether chemoprophylaxis was used; because if infection occurs despite medication use, that medication should not be used as part of the treatment regimen.(4)

Uncomplicated Malaria

For uncomplicated P.vivax or chloroquine-sensitive P. falciparum infection, prompt treatment with chloroquine or hydroxychloroquine is recommended.(4) In patients with confirmed P.vivax infection, chloroquine should be continued for the duration of the pregnancy to prevent relapsing disease during pregnancy.(4)

For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection or with an unknown species, treatment varies based on the trimester of pregnancy. During the first trimester, treatment with either mefloquine or quinine sulfate and clindamycin is recommended.(2,4) In the second and third trimesters, WHO and UK guidelines recommends a artemisinin-based combination therapy, artemether-lumefantrine as the first-line treatment of choice and in the first trimester if other options are not available.(12,47)

In 2018, the CDC approved artemether-lumefantrine as an alternative regimen for uncomplicated malarial infections in the second and third trimester of pregnancy, giving U.S. patient’s more options for treatment.(48) This decision was made based on 16 studies with >1000 women that evaluated the use of Artemether-lumefantrine in the second and third trimester without significant increases in adverse pregnancy outcomes and with great effectiveness, ≥94.9% cure rates, in treating malaria infection.(12,48) Additionally, there is growing evidence to suggest that artemether-lumefantrine is also safe in the first-trimester. A metanalysis of 717 women from 6 observational studies found that women on artemisinin-based combination therapies during the first trimester did not have more miscarriages or stillbirth than women on quinine-based regimens.(49) However, because these studies are not randomized-control trials, the CDC advices that artemether-lumefantrine should only be considered as an option in the first trimester if first-line options are unable to be tolerated.

Based on this evidence, we recommend artemether-lumefantrine as a first-line treatment option in the second and third trimesters of pregnancy given its effectiveness and safety profile. Table 6 reviews the treatment options and dosing for uncomplicated malaria infection.

Table 6:

Uncomplicated Malaria Treatment

Generic Name	Dose Regimen
Chloroquine Hydroxychloroquine	• 600mg base (1000mg salt) PO as initial dose  • 300mg base (500mg salt) PO at 6,24, and 48 hours after initial dose  • Total dose: 1500mg base (2000mg salt)  • ________________________________________________________  • 620mg base (800mg salt) PO as initial dose  • 310mg base (400mg salt) PO at 6,24, and 48 hours after initial dose  • Total dose: 1550mg base (2000mg salt)
Mefloquine	• 684 mg base (750 mg salt) PO as initial dose  • 456 mg base (500 mg salt) PO given 6–12 hours after initial dose  •Total dose= 1,250 mg salt
Quinine Sulfate and Clindamycin	Quinine Sulfate  • 542mg base (650mg salt) PO TID for 3 or 7 days  • For infections acquired in Southeast Asia take quinine for 7 days. All other take for, 3 days. Clindamycin  • 20mg base/kg/day PO divided into TID dosing for 7 days
Artemether-lumefantrine	• 1 tablet = 20mg artemether and 120 mg lumefantrine  • 4 tablets = 1 dose  • 3-day treatment schedule with a total of 6 oral doses  • The patient should receive the initial dose, followed by the second dose 8 hours later, then 1 dose PO BID for the following 2 days.

Adapted from CDC Guidelines¹¹.

Severe Malaria

If severe malaria occurs in pregnancy, the WHO and CDC recommend immediate treatment as maternal mortality occurs in up to 50% of cases.(2) Treatment is with a minimum of 24-hours of parenteral antimalarial treatment quinidine gluconate, which is currently available for this use in the U.S, followed by oral medications for a total of 7 days.(2,4,50) Parenteral quinidine is cardiotoxic and may cause ventricular arrhythmia, hypotension, and prolongation of the QTc interval, as such, a baseline EKG should be obtained before initiating therapy.(2,4,12) Because of this side effect profile, the CDC recommends that the medication be started in the intensive care setting with continuous cardiac and frequent blood pressure monitoring.(4) Other side effects of quinidine to monitor during treatment are: hypoglycemia, acidosis and hepatotoxicity.(4,6,37)

Of note, artesunate and locally effective artemisinin-based combinations, are considered as the first line treatment of severe malaria by the WHO and are safe in pregnancy. (12,50) These regimens have the benefit of being able to be given intramuscularly, rectally, and orally when the patient is able to tolerate this route of administration.(12,50) While this regimen is not listed as a recommended choice by the CDC, artesunate is now being investigated in the United States and providers can contact the CDC for information on this medication.(11) Table 7 reviews the treatment options and dosing for severe malaria.

Table 7:

Severe Malaria Treatment

Generic Name	Dose Regimen
Quinidine Gluconate	• 6.25 mg base/kg (10 mg salt/kg) loading dose IV over 1–2 hours, then 0.0125 mg base/kg/min (0.02 mg salt/kg/min) continuous infusion for at least 24 hours.  • An alternative regimen is 15 mg base/kg (24 mg salt/kg) loading dose IV infused over 4 hours, followed by 7.5 mg base/kg (12 mg salt/kg) infused over 4 hours every 8 hours, starting 8 hours after the loading dose (see package insert).  • Once parasite density <1% and patient can take oral medication, complete treatment with oral quinine, dose as above in Table 5.  • Course of Quinidine/Quinine: 7 days for Southeast Asia and 3 days everywhere else.
Clindamycin	• 20mg base/kg/day PO divided into TID dosing for 7 days  • If patient not able to take oral medication, give 10mg base/kg loading dose IV followed by 5mg base/kg IV every 8 hours.  • Switch to oral clindamycin as soon as patient can take oral medication. For IV use, avoid rapid administration.  • Treatment course is 7 days.

Adapted from CDC Guidelines¹¹.

Delivery Planning in Severe Malaria

Severe malaria may precipitate preterm labor and having obstetricians and pediatricians available to care for preterm neonates is important in the management of these women.(50) Given the morbidity and mortality associated with severe malaria, maternal and fetal status must be evaluated often as decline in either status may be an indication for delivery.

MANAGEMENT OF THE PREGNANCY AFTER MALARIA

Special considerations should be given to the subsequent pregnancy care and management in women after malaria infection in pregnancy. We believe that women with high risk of having had subclinical infection during pregnancy should be managed similarly. This includes women who spent a considerable amount of time in malaria-endemic regions, even if they were compliant with intermittent preventative therapy, due to the high rates of drug resistance and high rate of placental malaria in this population.

Antenatal Management

Women should be screened for anemia and treated appropriately with oral or IV iron. We recommend an ultrasound for fetal growth surveillance at least once in the third trimester to monitor for fetal growth restriction. Women with malaria in pregnancy are at higher risk of preterm birth and should be counseled appropriately.

Given that malaria is a disease of resource-poor countries, there is no information on the benefit of antenatal testing or optimal timing of delivery after treated malaria infection. However, due to the increased risk of stillbirth with malaria in pregnancy, it is reasonable to offer antenatal testing at term (37 weeks gestation), and earlier if other indicators of severe disease are present, such as severe maternal anemia or fetal growth concerns. There is no data to guide optimal timing of delivery, which should be based on routine obstetric indications.

Labor, Delivery and Postpartum

There is no clear data on peripartum transmission of malaria to the neonate. If maternal anemia is severe at the time of labor, appropriate precautions for postpartum hemorrhage should be taken. After delivery, we recommend pathology evaluation of the placenta to pathology to evaluate for placental malaria. We also recommend communication with the pediatrics team if the placental pathology results show evidence of placental infection.

LEARNING OBJECTIVES.

After completing this activity, the learner will be better able to:

1. Assess the adverse pregnancy outcomes associated with malarial infection;

2. Evaluate and manage patients traveling to endemic areas during pregnancy; and

3. Formulate a treatment plan for acute malaria infection.

CME QUESTIONS AND ANSWERS.

1. Placental malaria has been shown in studies to be associated which of the following obstetrical outcomes?

   1. Low birth weight
   2. Preterm birth
   3. Small for gestational age
   4. All of the above
2. What is the gold standard test for diagnosing malaria?

   1. Parasite nucleic acid PCR
   2. Peripheral blood smear
   3. Malaria serum antibodies
   4. Rapid Malaria Diagnostic Test
3. You are seeing a 28yo G2P1 at 21w0d who is planning to go visit Liberia, West Africa for a wedding and vacation. She will be there for 3 weeks. She has no significant medical history and has had no complications this pregnancy. It will be her first time outside of the United States. She asks you want medications she should take to decrease her risk of getting malaria while in Liberia. You recommend which of the following medications for chemoprophylaxis?

   1. Doxycycline
   2. Primaquine
   3. Mefloquine
   4. Quinine
4. The patient from question 3 returns from Liberia and admits to not taking chemoprophylaxis. She is febrile and has malaise and myalgias. She otherwise has normal vital signs, denies obstetrical complaints or other symptoms. You are clinically concerned for malaria and send off testing, which comes back positive for malaria. You diagnose her with uncomplicated malaria. What is the best treatment choice?

   1. Primaquine
   2. Artemether-lumefantrine
   3. Sulfadoxine-pyrimethamine
   4. Clindamycin