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Malaria in pregnancy: Prevention and treatment

Malaria in pregnancy: Prevention and treatment
Authors:
Blair J Wylie, MD, MPH
Stephen J Rogerson, PhD
Section Editors:
Johanna Daily, MD, MSc
Vincenzo Berghella, MD
Deputy Editors:
Elinor L Baron, MD, DTMH
Vanessa A Barss, MD, FACOG
Literature review current through: Dec 2022. | This topic last updated: Dec 23, 2022.

INTRODUCTION — Malaria during pregnancy is a major cause of maternal morbidity worldwide and leads to poor birth outcomes. Pregnant women are more prone to complications of malaria infection than nongravid women. Prevention involves chemoprophylaxis and mosquito avoidance. Treatment involves antimalarial drugs and supportive measures [1].

Issues related to prevention and treatment of malaria in pregnant women will be reviewed here. Issues related to the prevalence, epidemiology, pathogenesis, clinical manifestations, diagnosis, and outcome of malaria in pregnancy are discussed separately, as are general details on treatment of uncomplicated and severe malaria.

(See "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome".)

(See "Treatment of severe malaria".)

(See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)

(See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

(See "Antimalarial drugs: An overview".)

PREVENTION — The major tools for preventing malaria in pregnant women are mosquito avoidance and preventive drug therapy. However, several interacting barriers impede access, delivery, and use of these tools in resource-limited areas. As a result, only about one-third of pregnant women in sub-Saharan African countries receive a full course of preventive therapy, and only about 60 percent use insecticide-treated mosquito nets, according to the 2021 World Health Organization (WHO) World Malaria Report [2].

Mosquito avoidance — Avoiding mosquitoes is a key intervention for reducing malaria acquisition. Mosquitoes capable of transmitting malaria infection (Anopheles species) usually feed at night; thus, women are advised to diminish exposure to these insects between dusk and dawn by remaining in screened areas whenever possible, using mosquito netting (ideally treated with permethrin), covering exposed skin with clothing, and applying insect repellent. The recommendations for N,N-diethyl-metatoluamide (DEET) use in pregnant and lactating women do not differ from those for nonpregnant adults. (See "Prevention of arthropod and insect bites: Repellents and other measures", section on 'DEET' and "Prevention of arthropod and insect bites: Repellents and other measures", section on 'Permethrin-treated clothing'.)

Use of insecticide-treated bed nets (ITNs) is an important tool for reducing the likelihood of malaria acquisition and associated adverse pregnancy outcomes among pregnant women in endemic areas [3,4]. A 2006 Cochrane review of the impact of ITNs during pregnancy included four randomized trials from sub-Saharan Africa that compared use of ITNs with no nets and one trial from Thailand that compared use of ITNs with use of untreated nets [4]. In the African trials, use of ITNs significantly reduced the risk of placental malaria in all pregnancies (risk ratio [RR] 0.79, 95% CI 0.63-0.98); in first through fourth pregnancies, ITNs reduced the risk of low birth weight (RR 0.77, 95% CI 0.61-0.98) and stillbirth/abortion (RR 0.67, 95% CI 0.47-0.97). The trial from Thailand demonstrated significant reductions in anemia and stillbirth in all pregnancies but no significant change in rates of low birth weight or clinical malaria.

Additional issues related to ITNs are discussed in detail separately. (See "Malaria: Epidemiology, prevention, and control", section on 'Long-lasting insecticide-treated nets (LLINs)'.)

Drug-based approaches

Travelers to endemic areas — Pregnant travelers should be advised to defer travel to areas where risk of acquiring malaria is high until after delivery, if feasible.

Nonimmune pregnant women (ie, those not living in an endemic area) who cannot defer travel to an endemic area should take chemoprophylaxis. The agents of choice are chloroquine (for travel to areas with chloroquine-sensitive malaria, but mefloquine is also acceptable) and mefloquine (for travel to areas with chloroquine-resistant malaria) [5]. Dosing is the same as in nonpregnant women and is described separately. (See "Prevention of malaria infection in travelers", section on 'Pregnant patients' and "Prevention of malaria infection in travelers", section on 'Chloroquine'.)

Residents of endemic areas

Intermittent preventive treatment in pregnancy (IPTp) — IPTp refers to the strategy of administering antimalarial medication at intervals during pregnancy regardless of clinical symptomatology. Human immunodeficiency virus (HIV)-negative pregnant women living in endemic areas of Africa who have developed natural immunity (due to prolonged exposure to malaria) still benefit from IPTp [6,7]. Benefits include fewer deliveries of low birth weight infants and less maternal anemia [8]. IPTp is the preferred approach in Africa because it is effective and more practical than continuous prophylaxis [9,10].

Sulfadoxine-pyrimethamine (SP) – For HIV-negative pregnant women who live in malaria-endemic areas in Africa, we agree with WHO recommendations for administration of intermittent doses of SP for IPTp, ideally at a minimum of three antenatal care visits starting early in the second trimester and spaced at least four weeks apart [1,11]. The dose of IPTp-SP is 1500 mg sulfadoxine/75 mg pyrimethamine; administration consists of three tablets (each containing 500 mg sulfadoxine/25 mg pyrimethamine); ideally IPTp should be administered as directly observed therapy.

The WHO recommendation was based on a 2013 systematic review and meta-analysis of IPTp trials comparing ≥3-dose SP regimens with a 2-dose SP regimen that found that the ≥3-dose SP regimens resulted in fewer low birth weight infants (RR 0.80, 95% CI 0.69-0.94), less moderate to severe maternal anemia (RR 0.60, 95% CI 0.36-0.99), and less placental malaria (RR 0.51, 95% CI 0.38-0.68) [12]. (See "Antimalarial drugs: An overview", section on 'Sulfadoxine-pyrimethamine'.)

Ideally, each SP dose suppresses or clears asymptomatic placental infection and provides up to six weeks of posttreatment prophylaxis. IPTp with SP appears to provide protection against adverse birth outcomes by mechanisms additional to its antimalarial effect, but the basis for these favorable effects is unclear [13].

Although SP remains an effective drug for IPTp, its benefit may be limited because IPTp-related improvements in maternal and neonatal outcomes diminish as local drug resistance increases. Pooled analyses suggest it remains effective in the presence of high, but not extreme, parasite resistance to SP [7]. However, individual studies have provided reasons for concern. High SP resistance among Plasmodium falciparum parasites (consisting of six resistance mutations in the genes encoding the targets of SP, dihydrofolate reductase [DHFR] and dihydropteroate synthase [DHPS], detected in a few discrete areas of eastern and southern Africa) appears to be eliminating previously observed pregnancy benefits. For example, in a study among 880 pregnant women in Muheza, Tanzania, where 68 percent of young children treated with SP failed treatment, SP-IPTp did not reduce the odds of placental malaria or raise the mean maternal hemoglobin level or neonatal birth weight [14]. Despite this, a subsequent study including 1222 pregnant women from six countries in eastern and southern Africa (with prevalence of the K540E DHPS resistance marker >90 percent, but few sextuple mutations) noted that the use of SP-IPTp remained associated with increases in birth weight and maternal hemoglobin [15].

Dihydroartemisinin-piperaquine (DP) – There is no consensus as to the level of resistance at which SP-IPTp should be discontinued and an alternative regimen substituted. DP is a promising alternative for pregnant women without HIV infection [16,17] and provided superior malaria protection to SP-IPTp in several studies [18-20]. DP requires daily dosing for three days (compared with a single dose for SP), limiting the ability for direct observation of therapy. Pharmacokinetic studies suggest that a daily dose of three tablets of 40 mg dihydroartemisinin and 320 mg piperaquine is suitable for most pregnant women [21].

In one randomized trial including more than 780 pregnant women from a high-malaria transmission region in Uganda who received IPTp with monthly DP or monthly SP starting early in the second trimester, the risk of a composite adverse birth outcome (low birth weight, preterm birth, or small for gestational age in live births) was comparable between the groups (16 versus 18 percent) [20]. However, mothers in the DP group had a ≥90 percent reduction in the rate of symptomatic malaria infection during antenatal follow up and at delivery compared with the SP group, and also reduced frequency of anemia. IPTp with DP was well tolerated but was associated with asymptomatic QTc prolongation in some recipients. In a 2020 study from Tanzania, IPTp with DP was associated with a decreased incidence of low birth weight compared with SP (4.6 versus 9.6 percent) [22].

Data suggest that while DP may have superior antimalarial effects over SP, SP conveys nonmalarial benefits (eg, improved birth weight) [13]. Larger trials will determine with greater precision whether DP results in improved maternal and fetal outcomes beyond its effect in reducing malaria infections. Benefits of IPTp with DP for maternal health, and potentially for malaria transmission, will be of particular interest.

Mefloquine – Mefloquine is effective for IPTp but is not generally used because of drug-related adverse events (eg, vomiting, fatigue, dizziness) and poor tolerability [23,24]. (See "Antimalarial drugs: An overview", section on 'Mefloquine'.)

Intermittent screening and treatment of malaria in pregnancy (ISTp) — Intermittent screening and treatment of malaria in pregnancy (ISTp) is an alternative strategy to IPTp for HIV-negative women. ISTp involves screening pregnant women for malaria with a rapid diagnostic test (RDT) at each antenatal visit, with antimalarial treatment reserved only for those with identified infection. We are in agreement with the WHO, which does not recommend ISTp alone as a replacement for IPTp [25]. ISTp may be useful in areas of lower transmission where the prevalence of malaria in pregnancy is low. ISTp may also be of benefit in areas of high SP resistance if an alternative to SP is administered.

In a randomized trial from Ghana comparing standard IPTp, SP-ISTp, and ISTp with artesunate-amodiaquine, no significant difference in maternal severe anemia or low birth weight was noted among the three groups [26]. A subsequent trial conducted in four West African nations randomly assigned primigravid and secundigravid women to SP-IPTp or ISTp with artemether-lumefantrine (AL) [27]. AL-ISTp was noninferior to SP-IPTp for prevention of placental malaria, low birth weight, and maternal anemia.

In a cluster-randomized trial among more than 4700 pregnant women in The Gambia, Benin, and Burkina Faso, addition of monthly screening and treatment with artemether-lumefantrine to standard IPTp was associated with no difference in placental malaria (adjusted odds ratio 1.06, 95% CI 0.78-1.44), peripheral parasitemia, maternal anemia, or low birth weight [28].

The poor sensitivity of available RDTs for low-density or placenta-only infections is a significant challenge. Further study in a diversity of endemic settings using more sensitive next-generation RDTs is warranted to establish the safety and efficacy of ISTp compared with IPTp.

HIV-infected women

For HIV-infected pregnant women in malaria endemic areas, we are in agreement with the WHO recommendation for cotrimoxazole prophylaxis, regardless of CD4 cell count and throughout all trimesters of pregnancy. Prophylaxis consists of a daily dose of sulfamethoxazole 800 mg and trimethoprim 160 mg [29]. This provides protection against malaria as well as HIV-related opportunistic infections [30-33].

The addition of SP-IPTp is unnecessary. Use of mefloquine IPTp in HIV-infected pregnant women on cotrimoxazole has been associated with fewer malaria infections but was poorly tolerated and associated with an unexplained increase in mother to child transmission of HIV [31]. Studies are exploring the possible benefit of DP-IPTp in HIV-infected pregnant women.

For HIV-infected women not taking cotrimoxazole prophylaxis, monthly SP-IPTp is recommended. (See 'Intermittent preventive treatment in pregnancy (IPTp)' above.)

Infants born in malaria-endemic areas with congenital HIV exposure warrant prophylaxis; this is discussed separately. (See "Malaria: Epidemiology, prevention, and control", section on 'Infants with congenital HIV exposure'.)

TREATMENT

Antimalarial therapy — Malaria in pregnancy can have severe consequences for both the mother and the fetus; therefore, pregnant women with malaria should be treated promptly with an effective antimalarial agent to rapidly clear parasites. Safety and efficacy data to guide treatment are limited [34]. In general, newer drugs are more likely to be effective than older drugs (in part because of insufficient time for emergence of resistance), but fewer data are available on fetal safety. Clinicians, therefore, have to make treatment decisions based on the clinical severity of infection, epidemiologic resistance patterns, and available data regarding safety of the drug or class of drug in pregnancy.

Uncomplicated P. falciparum malaria — Treatment regimens for pregnant women with uncomplicated P. falciparum malaria are summarized in the table (table 1).

Chloroquine-resistant P. falciparum malaria — Presence of chloroquine-resistant P. falciparum malaria should be assumed, unless infection is known to be acquired in the regions specified as chloroquine sensitive; these are summarized in the table (table 1).

First trimester – During the first trimester, we favor treatment of uncomplicated P. falciparum malaria with a three day course of artemether-lumefantrine (table 1), in agreement with 2022 World Health Organization (WHO) guidelines [1]. This recommendation is based on data from an updated meta-analysis commissioned by the WHO (see 'Drug safety' below) [35] and is a change from a prior WHO recommendation for treatment with quinine plus clindamycin. In situations where artemether-lumefantrine is not available, acceptable alternatives include artemisinin combination therapy (ACT) with artesunate-amodiaquine, artesunate-mefloquine, or dihydroartemisinin-piperaquine (DP). Quinine-based regimens may be used but are associated with poor adherence and less favorable outcomes [35].

Second and third trimesters – During the second and third trimesters, we favor treatment of uncomplicated P. falciparum malaria with an ACT (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, or DP) (table 1) [36-39]. Acceptable alternatives include oral artesunate plus clindamycin (seven days) or quinine plus clindamycin (seven days).

The efficacy of ACT for the treatment of pregnant women with uncomplicated P. falciparum malaria during the second and third trimesters is supported by a large trial including 3428 pregnant women in four African countries (Burkina Faso, Ghana, Malawi, and Zambia) randomly assigned to treatment with one of four ACT regimens (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, or DP) who had cure rates of 95 to 99 percent [37]. DP had the best efficacy and an acceptable safety profile, with the benefit of a longer posttreatment prophylactic effect. Artemether-lumefantrine was associated with the fewest adverse effects and acceptable cure rates but demonstrated the shortest posttreatment prophylactic effect; this may be particularly important in high-transmission settings where a prolonged posttreatment prophylactic effect can reduce morbidity by reducing the frequency of new infections. Data on ACT in pregnancy from other studies are also reassuring [40-42]. (See 'Drug safety' below.)

Chloroquine-sensitive P. falciparum malaria — For patients with chloroquine-sensitive P. falciparum infection, acceptable regimens in any trimester include chloroquine and hydroxychloroquine. Regions specified as chloroquine sensitive are summarized in the table (table 1).

Severe P. falciparum malaria — Issues related to treatment of severe malaria in pregnancy are discussed separately. (See "Treatment of severe malaria", section on 'Pregnancy'.)

Non-falciparum malaria — Non-falciparum malaria (eg, malaria infection due to P. vivax, P. ovale, P. malariae, and P. knowlesi) seldom results in death but can be a cause of significant morbidity in pregnancy. Non-falciparum malaria is discussed further separately. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae" and "Non-falciparum malaria: Plasmodium knowlesi".)

Management of non-falciparum malaria consists of antimalarial therapy followed by anti-relapse therapy, as discussed below.

Antimalarial therapy — Antimalarial dosing is summarized in the table (table 2).

Chloroquine-resistant infection

First trimester – During the first trimester, we favor treatment of uncomplicated chloroquine-resistant non-falciparum malaria with artemether-lumefantrine (table 2) [1]. We prefer artemether-lumefantrine over other ACTs because of more evidence of safety in pregnancy, but other ACTs are acceptable if artemether-lumefantrine is not available or is associated with treatment failure. Quinine is an alternative regimen. (See 'Drug safety' below.)

Second and third trimesters – During the second and third trimesters, we favor treatment of uncomplicated chloroquine-resistant non-falciparum malaria with any of the following ACT regimens: artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, or DP (table 2) [1]. Quinine is an alternative regimen.

Chloroquine-sensitive infection — We favor treatment of chloroquine-sensitive non-falciparum malaria with chloroquine or hydroxychloroquine. An ACT may be chosen as an alternative regimen (table 2); during the first trimester, we prefer artemether-lumefantrine over other ACTs because of more evidence of safety in pregnancy [1]. (See 'Drug safety' below.)

Antirelapse therapy — Following treatment of P. vivax or P. ovale infection, patients should receive treatment for prevention of relapse [6]. Nonpregnant and nonlactating patients are treated with primaquine or tafenoquine to eradicate hypnozoite forms that may remain dormant in the liver and cause relapse. However, primaquine and tafenoquine can cause hemolytic anemia in individuals with glucose-6-phosphate-dehydrogenase (G6PD) deficiency; thus, they are contraindicated in pregnancy since the fetal G6PD status is uncertain. Therefore, pregnant patients should be treated with chloroquine prophylaxis (300 mg base orally once weekly) for the duration of the pregnancy to prevent relapse [1]. In the setting of chloroquine prophylaxis failure (for example, due to chloroquine resistance), monthly prophylaxis with DP (table 1) may be a suitable alternative in the second and third trimesters [19].

Following delivery, postpartum patients should receive anti-relapse therapy after assessment of G6PD status; treatment of the infant is not warranted. Issues related to pretreatment G6PD testing are reviewed separately. (see "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'G6PD screening').

The management approach should be guided by G6PD status (for mother and infant) as well as lactation plans:

For patients who are not breastfeedingPrimaquine or tafenoquine should be administered after delivery, guided by G6PD status as summarized in the table (table 3).

For patients who are breastfeeding

Mother G6PD normal (>30 percent activity), infant G6PD normal (>30 percent activity)Primaquine should be administered after delivery. In such cases, primaquine dosing consists of 0.5 mg base/kg once daily for 14 days (total dose 7 mg/kg).

Mother G6PD deficient (<30 percent activity), infant G6PD normal (>30 percent activity)Primaquine should be administered after delivery, with close monitoring of maternal and infant hemoglobin. In such cases, primaquine dosing consists of 0.75 mg base/kg once weekly for 8 weeks (total dose 6 mg/kg).

Mother G6PD normal, infant G6PD deficientChloroquine should be administered weekly until cessation of breastfeeding. Thereafter, primaquine or tafenoquine should be administered as summarized in the table (table 3).

Mother and infant G6PD deficient or status unknownChloroquine should be administered weekly until cessation of breastfeeding. Thereafter, primaquine should be administered as summarized in the table (table 3). Tafenoquine should not be administered in the setting of unknown G6PD status [1].

Breast milk concentrations of primaquine appear to be very low and therefore unlikely to cause adverse effects in breastfeeding infants >28 days [43]; however, more data are needed. Primaquine remains contraindicated in pregnant females and in lactating females whose infant is G6PD deficient or G6PD status is unknown [1].

Role of tafenoquine – There is no information on the breast milk concentration of tafenoquine [44]. For females who are breastfeeding, the mother and infant should be tested for G6PD deficiency before the drug is given. If the mother is G6PD normal but the infant is G6PD deficient, the manufacturer recommends avoiding breastfeeding for three months after the maternal dose.

Patients with HIV infection — Pregnant women with malaria and HIV infection respond to standard treatment regimens, as described above. However, those on cotrimoxazole should avoid treatment with artesunate-sulfadoxine-pyrimethamine, and those on zidovudine should avoid treatment with artesunate-amodiaquine [39].

Drug safety — Pregnancy may alter the pharmacokinetics of many antimalarials [45].

Chloroquine – Chloroquine is well tolerated and without known harmful effects in pregnancy.

Quinine – Quinine is safe and effective and should be used when needed. Glucose levels should be monitored, as the drug can cause maternal and fetal hypoglycemia [46]. Quinine and quinidine at recommended therapeutic doses do not lead to an excess of adverse pregnancy outcomes above the baseline risk associated with malaria infection itself. At high drug levels, quinine is reported to have a weak abortifacient effect, but such levels are not achieved with recommended therapeutic doses.

Artemisinin derivatives A 2022 meta-analysis of pregnancy outcomes after first trimester use of artemisinin derivatives found no clear evidence of embryotoxicity or teratogenicity from artemisinin-based therapy (ABT, defined as any treatments with artemisinin compounds, including ACTs) [35]. The analysis of seven prospective studies included 12 cohorts with individual patient data from 737 pregnancies with confirmed first-trimester exposure to ABT, 1076 pregnancies with confirmed first-trimester exposure to non-ABTs, and over 32,000 pregnancies not exposed to an antimalarial in the first trimester. Overall adverse pregnancy outcomes were lower in the ABT group compared with the non-ABT group, although the difference was not significant (5.7 versus 8.9 percent; adjusted hazard ratio [aHR] 0.71, 95% CI 0.49–1.03). Results were consistent for the individual components of adverse pregnancy outcome: miscarriage (aHR 0.74, 95% CI 0.47–1.17), stillbirth (aHR 0.71, 95% CI 0.32–1.57), and major congenital anomalies (aHR 0.60, 95% CI 0.132.87). For artemether–lumefantrine, the risk of overall adverse pregnancy outcome was significantly lower compared with oral quinine (4.8 versus 9.2 percent; aHR 0.58, 95% CI 0.36–0.92) and more than 70 percent of the ABT exposures in the analysis were with this medication.

The number of ABT-exposed first trimester pregnancies remains relatively small and continued pharmacovigilance is indicated. Given the relative lack of safety data for ABTs other than artemether-lumefantrine, alternative ABTs should only be used when artemether-lumefantrine is not available or is not indicated. However, artesunate-sulfadoxine pyrimethamine and artesunate pyronaridine are contraindicated due to potential toxicity and lack of safety data, respectively [1,35].

More human data are available for second and third trimester exposure. In a systematic review and meta-analysis of artemisinin monotherapy or combination therapy in the second and third trimesters (11 cohort studies, 9 randomized trials, n = 3707 exposed pregnancies), artemisinin derivatives were not associated with increased risks for miscarriage, fetal anomalies, fetal loss, or stillbirth compared with quinine or no treatment [47].

Mefloquine – Mefloquine use during pregnancy has not been associated with increased risks of adverse pregnancy outcomes compared with other anti-malarials or to the general population [48].

Amodiaquine – Amodiaquine is used in Africa, where multidrug-resistant P. falciparum is common. In a small randomized trial of chloroquine, sulfadoxine-pyrimethamine, amodiaquine, or amodiaquine plus sulfadoxine-pyrimethamine, treatment with amodiaquine was not associated with an increased risk of preterm birth, stillbirth, or congenital anomalies, but there were too few exposures to conclude that its use was safe for the fetus [49]. Amodiaquine is generally not used by clinicians in the United States or United Kingdom due to risk of agranulocytosis.

Tetracycline and doxycycline – Tetracycline antibiotics may cause permanent tooth discoloration for children <8 years if used repeatedly. However, this is extremely rare with doxycycline, in part because it binds less readily to calcium than other tetracyclines. The body of evidence in both pregnancy and in children has supported the relative safety of doxycycline compared with older tetracyclines. However, data are low quality and insufficient to say that there is no risk. If there is a safer, effective drug that can be used as an alternative, it should be used. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

Tetracyclines should be avoided while breastfeeding [50].

Primaquine and tafenoquine – Pregnancy is a contraindication for primaquine and tafenoquine since it is not possible to assess G6PD status of a fetus in utero [51]. Tafenoquine should also be avoided while breastfeeding [50]. Issues related use of these agents for preventing relapse are discussed above. (See 'Non-falciparum malaria' above.)

Follow-up monitoring — Follow-up blood smears are appropriate to document declining parasite density [50,52,53]. In general, parasitemia typically clears within 48 to 72 hours with appropriate therapy [52,54,55].

We are in agreement with the United States Centers for Disease Control and Prevention (CDC) which advises repeat blood smears every 12 to 24 hours for patients with uncomplicated malaria (due to P. falciparum, P. knowlesi, or suspected chloroquine-resistant P. vivax) to monitor parasitologic response to treatment [53]. In resource-limited settings, many clinicians reserve follow-up smears for patients who do not improve clinically (with defervescence within 72 hours). Rapid diagnostic tests should not be used to be used to monitor parasite response to therapy; they can remain positive despite cure and do not provide quantitative information. (See "Laboratory tools for diagnosis of malaria", section on 'Quantification of parasitemia'.)

In individuals who do not clinically improve and have persistent parasitemia, considerations include inadequate drug dosing, poor absorption, inadequate adherence, and/or drug resistance. Issues related to dosing and adherence should be reviewed carefully. Consideration of treatment with an alternative regimen is warranted, particularly if drug resistance is a possibility. In the United States, CDC clinicians are available through the malaria hotline: 770-488-7788 or 855-856-4713; during off-hours, call 770-488-7100 and ask to have the malaria clinician on call paged.

Malaria can recrudesce; repeat evaluation for malaria should be pursued in the event of a subsequent febrile episode.

Pregnancy management — During an acute clinical malaria episode, an ultrasound examination should be performed to evaluate amniotic fluid volume, fetal size, and fetal well-being (eg, biophysical profile score), as gestational-age appropriate. For women who have recovered from an episode of clinical malaria during pregnancy, surveillance for fetal growth restriction should occur approximately every month after 28 weeks. Antenatal fetal testing, such as a biophysical profile, can be reserved for those with evidence of growth restriction or decreased fluid [56,57].

Iron deficiency appears to be protective against malaria; however, the benefits of routine iron supplementation in pregnant women outweigh possible risks [58,59]. In one randomized trial including 470 pregnant women in a malaria endemic area of rural Kenya (60 percent were iron deficient at baseline) treated with daily iron supplementation (60 mg of elemental iron) or placebo from the second trimester to one month postpartum, those who received iron supplementation had infants with higher birth weight; there was no difference in overall risk of maternal Plasmodium infection [58]. (See "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome", section on 'Clinical findings'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)

SUMMARY AND RECOMMENDATIONS

Malaria in pregnancy is a major cause of maternal morbidity and mortality worldwide and leads to poor birth outcomes. (See 'Introduction' above and "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome".)

Prevention of malaria involves chemoprophylaxis and mosquito avoidance. Pregnant travelers should defer travel to areas where there is a high risk of acquiring malaria, if feasible. For pregnant women who cannot defer travel or reside in malarious regions, we recommend chemoprophylaxis and mosquito avoidance (Grade 1A). (See "Prevention of malaria infection in travelers", section on 'Pregnant patients'.)

The optimal antimalarial agent, dose, and frequency for intermittent preventive treatment during pregnancy (IPTp) depend on regional transmission intensity, drug resistance patterns, and HIV prevalence.

For pregnant women without HIV infection residing in malarious areas during their first or second pregnancy, we recommend administration of IPT (Grade 1A). Sulfadoxine-pyrimethamine (at least three doses given at least four weeks apart, starting in second trimester of pregnancy) has been an effective drug for IPT, although its benefit may be limited in areas of high drug resistance; dihydroartemisinin-piperaquine (DP) is a promising alternative agent. (See 'Intermittent preventive treatment in pregnancy (IPTp)' above.)

For pregnant women with HIV infection, we are in agreement with the World Health Organization recommendation for cotrimoxazole prophylaxis for HIV-infected pregnant women in malaria endemic areas, regardless of CD4 cell count and throughout all trimesters of pregnancy. HIV-infected pregnant women taking cotrimoxazole for prophylaxis against opportunistic infections do not warrant an additional drug for IPTp since cotrimoxazole provides protection against malaria; studies are exploring the possible benefit of IPT with DP. HIV-infected women not taking cotrimoxazole prophylaxis should receive monthly IPT with sulfadoxine-pyrimethamine. (See 'HIV-infected women' above.)

Mosquito avoidance reduces the likelihood of malaria infection. Women should avoid mosquitoes between dusk and dawn (when mosquitoes are most active) by remaining in screened areas whenever possible, covering exposed skin with clothing, and applying insect repellent. Insecticide treated nets protect pregnant women and their unborn children from deleterious consequences of infection. (See 'Mosquito avoidance' above and "Prevention of arthropod and insect bites: Repellents and other measures" and "Malaria: Epidemiology, prevention, and control".)

Malaria treatment consists of antimalarial therapy and supportive care. Drug choice depends on the clinical severity of infection, local pattern of drug resistance, and available data about the safety of the drug in pregnancy. (See 'Antimalarial therapy' above.)

For pregnant women with uncomplicated Plasmodium falciparum malaria, our approach is as follows (see 'Uncomplicated P. falciparum malaria' above):

For treatment of uncomplicated chloroquine-sensitive P. falciparum malaria in any trimester, we suggest treatment with chloroquine (table 1) (Grade 2C). (See 'Chloroquine-sensitive P. falciparum malaria' above.)

For treatment of uncomplicated chloroquine-resistant P. falciparum malaria during the first trimester, we suggest treatment with artemether-lumefantrine, rather than a quinine-based regimen (table 1) (Grade 2B). We prefer artemether-lumefantrine over other ACTs because of more evidence of safety in pregnancy, but other ACTs are acceptable if artemether-lumefantrine is not available or is associated with treatment failure. A quinine-based regimen is a less preferred alternative because it is associated with poor adherence and less favorable outcomes. (See 'Chloroquine-resistant P. falciparum malaria' above.)

For treatment of uncomplicated chloroquine-resistant P. falciparum malaria during the second or third trimesters, we recommend treatment with an ACT regimen (table 1) (Grade 1B). Acceptable alternatives include oral artesunate plus clindamycin or quinine plus clindamycin. (See 'Chloroquine-resistant P. falciparum malaria' above.)

Issues related to treatment of severe malaria in pregnancy are discussed separately. (See "Treatment of severe malaria", section on 'Pregnancy'.)

For pregnant women with non-falciparum malaria, our approach is as follows (see 'Non-falciparum malaria' above):

For treatment of uncomplicated chloroquine-sensitive non-falciparum malaria in any trimester, we suggest treatment with chloroquine (table 2) (Grade 2C). An ACT may be used as an alternative regimen. (See 'Chloroquine-sensitive infection' above.)

For treatment of uncomplicated chloroquine-resistant non-falciparum malaria during the first trimester, we suggest treatment with artemether-lumefantrine (table 2) (Grade 2C). We prefer artemether-lumefantrine over other ACTs because of more evidence of safety in pregnancy, but other ACTs are acceptable if artemether-lumefantrine is not available or is associated with treatment failure. Quinine is an alternative regimen. (See 'Chloroquine-resistant infection' above.)

For treatment of uncomplicated chloroquine-resistant non-falciparum malaria during the second or third trimester, we suggest treatment with any of the following ACT regimens: artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, or DP (table 2) (Grade 2C). Quinine is an alternative regimen. (See 'Chloroquine-resistant infection' above.)

The approach to preventing relapse should be guided by maternal G6PD status and lactation plans, as discussed above.

During an acute clinical malaria episode, an ultrasound examination should be performed to evaluate amniotic fluid volume, fetal size, and fetal well-being (eg, biophysical profile score), as gestational-age appropriate. For women who have recovered from an episode of clinical malaria during pregnancy, surveillance for fetal growth restriction should occur approximately every month after 28 weeks. Antenatal fetal testing, such as a biophysical profile, can be reserved for those with evidence of growth restriction or decreased fluid. (See 'Pregnancy management' above.)

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Topic 4812 Version 64.0

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