Plasmodium species (Malaria) - Antiparasitic Therapy for Pregnant Women

Treatment of malaria in pregnancy (table 9)

            Pregnant women with symptomatic acute malaria are a high-risk group, and must receive effective antimalarials. There is insufficient information on the safety and efficacy of most antimalarials in pregnancy, particularly for exposure in the first trimester when organogenesis occurs and teratogenesis is of particular concern. The antimalarials considered safe in the first trimester of pregnancy include quinine, chloroquine, and proguanil. Sulfadoxine-pyrimethamine is considered to be safe during the 2^nd and 3^rd trimester. The artemisinins are considered safe in the 2^nd and 3^rd trimesters, but there are insufficient data to recommend these highly effective drugs in the 1^st trimester, and they are currently not recommended (unless there are no alternatives). Doxycycline, tetracycline, halofantrine (embryotoxic and cardiotoxic), primaquine (haemolysis of fetal RBC) and tafenoquine are contraindicated for use during pregnancy. Mefloquine has been associated with an increased risk of stillbirth but can be used if there is no available alternative.

Table 9. Treatment of Malaria in Pregnancy 

Falciparum Malaria in Pregnancy
Treatment group	Transmission region	Trimester	Current Treatment regimens
Uncomplicated malaria P. falciparum     Parasitemia <4% and no signs of severity	Chloroquine-sensitive		As this is only valid for a very limited number of regions in the world, we do not advise the use of this drug during pregnancy, unless reliable information on drug resistance is available.   Treat as for Chloroquine-resistant or unknown resistance (see below)
	Chloroquine-resistant or unknown resistance	1st	Supervised Oral Quinine plus Clindamycin Quinine sulfate: 10 mg salt/kg/dose 8 hourly for 7 days plus Clindamycin: 10 mg/kg 12-hourly for 7 days
		2nd & 3rd	1. Supervised Oral Artemisinin Combination Therapy1 ACT should be known to be effective in the region. For dosages see Tables 2, 3, 4 Since mefloquine has been associated with stillbirth, it should only be used if no safer alternative is available.   2. Supervised Oral Artesunate plus Clindamycin1 Artesunate 2 mg/kg once daily for 7 days plus Clindamycin 10 mg/kg 12-hourly p.os  full 7 days   3. Supervised Oral Quinine plus Clindamycin Quinine sulfate: 10 mg salt/kg/dose 8 hourly for 7 days plus Clindamycin: 10 mg/kg 12-hourly for 7 days   4. Supervised Artesunate-Atovaquone-Proguanil (AAP)1,2 can be used in case of recrudescence2 3 day oral regimen:  Artesunate 4 mg/kg/day, Atovaquone 20 mg/kg/day and Proguanil 8 mg/kg/day
Severe Malaria P. falciparum     One or more criteria for severity! (see Table 13)		All	1. Artesunate i.v. initial dose 2.4mg/kg, then 2.4mg/kg at 12h and 24h after admission, then once daily until patient can tolerate oral medication. Total course 7 days.   If artesunate is not available;                              2a. Artemether i.m. initial dose 3.2mg/kg i.m. anterior thigh day 1, then 1.6mg/kg i.m. once daily from day 2-7, or until patient can tolerate oral artesunate3   or   2b. Quinine i.v. loading dose 20mg/kg i.v. over 4h on admission, then 10mg/kg i.v. over 2 to 4h, 8-hourly for a total of 7 days, or until patient can tolerate oral medication.

¹ oral Artesunate 1 Tablet contains 50mg, a suspension is made by dissolving 1 tablet in 5ml of water, 1ml equals 10mg, using a syringe

² Malarone (AQ/PG) - one tablet contains 250 mg Atovaquone and 100 mg Proguanil. Give Atovaquone-Proguanil with food. If patient vomits within 30 minutes of taking a dose, then repeat the whole dose. If vomiting occurs after 30–60mins of taking a dose, repeat half the dosage.

³ to prevent recrudesence follow-on treatment should be given, when the patient is able to take oral medication. Follow-on treatment can be a full course of the ACT of choice in the region (see text).

 

Malaria in Pregnancy, other than Falciparum
Uncompl. malaria P. vivax	Chloroquine-sensitive (P. vivax and  P. ovale)	All	Oral Chloroquine; initial dose 10 mg base/kg then10 mg base/kg after 24 hours, followed by 5 mg base/kg after 48 hours (total dose 25 mg/kg). (for radical treatment see below)
	Chloroquine-resistant or unknown resistance	1st	No studies available but we would consider:   Quinine sulphate:  10 mg salt / kg every 8h for 7 days
		2nd and 3rd	Artesunate –amodiaquine or other ACT available in the region (see treatment of uncomplicated falciparum malaria during pregnancy)
Uncompl. malaria P. ovale	Chloroquine-sensitive		Chloroquine (dosage see above)
Uncompl. malaria P. malariae	All regions		Chloroquine (dosage see above)
Radical treatment of hypnozoites P. vivax & ovale	Primaquine is contraindicated during pregnancy. It is used for eradication of hypnozoites, dormant in the liver to prevent relapses, in P. vivax and P. ovale infections. During pregnancy radical treatment of hypnozoites is not possible. Pregnant patients with P. vivax and P. ovale infections should be maintained on chloroquine prophylaxis for the duration of their pregnancy.  The chemoprophylactic dose for chloroquine sulphate is 300 mg base (=500 mg salt) orally once per week.  Radical treatment with primaquine can then be startyed a few months after delivery. After delivery; because primaquine can cause hemolytic anemia in persons with G6PD deficiency, patients must be screened for G6PD deficiency prior to starting treatment with primaquine. For persons with borderline G6PD deficiency or as an alternate to the above regimen, primaquine may be given 45mg orally one time per week for 8 weeks; consultation with an expert in infectious disease and/or tropical medicine is advised if this alternative regimen is considered in G6PD-deficient persons.

 

First trimester: Quinine plus clindamycin to be given for 7 days remains the recommended treatment for falciparum malaria during the first trimester of pregnancy. If clindamycin is unavailable or unaffordable because of its high costs, then monotherapy with quinine should be given. Quinine has been associated with teratogenic effects and damage to fetal optic and auditory nerves, but only at very high (abortifacient) doses and is generally considered safe in pregnancy when taken at normal therapeutic doses. In a total of 376 Thai malaria cases, quinine for P. falciparum and chloroquine for P. vivax malaria in the first trimester of pregnancy, caused no increase of congenital abnormalities, stillbirths or low birthweight babies as compared to background levels. Clindamycin, a lincosamid antibiotic, has weak antimalarial properties and is only used in combination with other more potent drugs. It has been routinely used for bacterial infections in pregnant women without any evidence of adverse effects. The drug can cross the placenta and accumulate in fetal tissues perhaps to the point of therapeutic levels, but to date there is no evidence that this accumulation is harmful.

Second and third trimesters: Uncomplicated falciparum malaria in the second and third trimesters of pregnancy can be treated with an artemisinin-based combination therapy (ACT) known to be effective in the country/region. A seven-day course of artesunate plus clindamycin or quinine plus clindamycin is an alternative. Artesunate plus atovaquone/proguanil is also considered safe and effective, but is very costly. Systematic summaries of safety suggest that the artemisinin derivatives are safe in the second and third trimesters of pregnancy. The choice of the combination partner is more difficult. Mefloquine has been associated with an increased risk of stillbirth in large observational studies in Thailand, but not in Malawi. Amodiaquine, lumefantrine, and piperaquine have not been evaluated sufficiently to permit confident recommendations. Chlorproguanil-dapsone is a fixed combination, which, due to altered pharmacokinetics during pregnancy of the chlorproguanil, could have decreased efficacy during pregnancy (see below). Sulfadoxine-pyrimethamine (SP) is safe but may be ineffective in many areas because of increasing resistance. SP should also not be used for treatment where it has already been given for IPD. Clindamycin is also safe, but both medicines (clindamycin and the artemisinin partner) must be given for 7 days. Primaquine, halofantrine and tetracyclines should not be used in pregnancy.

            The artemisinins and partner drugs, as well as the use of atovaquone-proguanil in relation to pregnancy are further discussed below.

Artemisinin derivatives: Artesunate has proved to be more effective then quinine in preventing recrudescent disease in malaria in pregnancy. Treatment failure is an important problem in the treatment of malaria in pregnancy. A study on the Thai-Burmese border showed that treatment with artemisinin derivatives, (mainly artesunate), resulted in a cumulative failure rate of 7.8%, compared to 33% after a 7 day course of quinine. Treatment with artesunate of recrudescent infections showed a cumulative failure rate of 21% compared to 37% with quinine and 38% with mefloquine. Safety data for the artemisinins for use in the first trimester are still limited. A total of 287 pregnant women, of whom 80 were in the first trimester, in The Gambia were exposed to a single artesunate dose (4mg/kg) in combination with SP during a mass drug administration; no differences between exposed and non-exposed pregnancies were observed in the rates of abortions, stillbirths, or infant deaths. In a study of 28 Sudanese women, intramuscular artemether was used as salvage therapy (6 injections, total 480mg) after failure of chloroquine and quinine-based regimens. Parasitemia was successfully cleared after 3 days, no maternal side effects, abortions, stillbirths or congenital abnormalities occurred. A study in 83 women in Thailand treated with either artesunate or artemether, of whom 16 were accidentally exposed during the first trimester, found no increase in rates of spontaneous abortion or stillbirth. Follow-up of this cohort found no developmental delay in the exposed children.

            Another Thai study in 66 pregnant women treated with the combination of artesunate plus mefloquine or artesunate alone  showed no increase in adverse birth outcomes, and no developmental retardation compared to quinine treatment. The results of a study using artesunate (n=528) and artemether (n=11) to treat 539 episodes of acute falciparum malaria in a total of 461 pregnant women, including 44 first-trimester episodes, showed that the artemisinins were well tolerated, and there were no increased rates of abortion, stillbirth or congenital abnormalities. Mean gestation at delivery was unaltered. These data suggest the artemisinin derivatives are safe in the second and third trimesters.

            It has recently been shown, that the kinetics of antimalarials can be modified in pregnancy, as plasma levels of the active antimalarial metabolite Dihydro-artemisinin were found to be lower than reported previously in non-pregnant adults. Further dose-optimisation studies involving pharmacokinetics in pregnant women are needed and will directive for future regimens.

Mefloquine: Safety of mefloquine during pregnancy has been evaluated through post marketing surveillance, retrospective and prospective studies. An early dose-finding study in Thailand found no increase in adverse pregnancy outcomes among women (n=20) who took either 125 or 250 mg/week for prophylaxis during the third trimester. In a prospective study in pregnant women, mefloquine chemoprophylaxis was associated with an increase in stillbirths compared to sulfadoxin-pyrimethamin (9.1% vs. 2.6%), but this rate was not significantly different from the non-exposed population (7–10%). Among US soldiers in Somalia, 72 women used mefloquine as a chemoprophylaxis before learning of their pregnancies, resulting in an above average rate (16.7%) of spontaneous abortions. Data from a considerably larger retrospective study in Thailand (n=3,587) suggested a significantly increased risk of stillbirth among women exposed to treatment doses of mefloquine (n=208) during pregnancy compared to those exposed to quinine (n=656) [odds ratio (OR) 4.72], other treatments (n=909, OR 5.10) or pregnancies with no malaria episodes (n=2470, OR 3.50). No specific patterns of physical abnormalities or defects were found in the stillbirths associated with mefloquine use. Other studies confirm the absence of a teratogenic effect of mefloquine. Data from two studies in Thailand have shown no developmental changes in infants born to mothers exposed to mefloquine as chemoprophylaxis during pregnancy compared to those given placebo, or born to mothers treated for malaria infection with mefloquine plus artesunate compared to quinine. Post-marketing data collected by the manufacturer showed that among 1627 women exposed to the mefloquine drug during pregnancy (95% for chemoprophylaxis), there was no increase in congenital malformations over the expected background rate. Because of the association with stillbirth in the Thai studies, mefloquine cannot be recommended during the first trimester, but can be used in the second and third trimester if no safer alternative is available.

Lumefantrine: The safety profile of the artemether-lumefantrine combination has proven to be excellent in both children and adults (181), and the drug has a good safety profile from animal studies. The only evaluation so far for pregnant women is an ongoing pharmacokinetic study on the Thai-Burmese border. It is currently contraindicated in the first trimester of pregnancy.

Proguanil and chlorproguanil are used only in combinations in malaria treatment and are considered safe throughout all trimesters of pregnancy. In a cohort of pregnant travelers taking proguanil in combination with chloroquine, rates of spontaneous abortions or congenital anomalies were no higher than the expected background rate. A study in Nigeria found no increase in adverse outcomes among pregnant women receiving daily proguanil (100 mg) in addition to weekly chloroquine. Another study from Tanzania demonstrated no increase in adverse outcomes among women receiving proguanil alone or in combination with weekly chloroquine as compared to those receiving chloroquine alone.

Amodiaquine is generally used in combination with other drugs. Little information is available of its use during pregnancy.

Dapsone has been extensively used in pregnant women with leprosy, without reported adverse effects. In studies where Dapsone was given in combination with pyrimethamine (Maloprim) for malaria chemoprophylaxis during pregnancy no increase of adverse pregnancy outcomes were documented). Lapdap™ is a fixed combination of dapsone and chlorproguanil, of which the chlorproguanil component is likely to have decreased absorption during pregnancy. If the dose is increased, the risk of side effects related to dapsone will also be increased. It has been used thus far mainly in Africa. In a small study involving 158 pregnant women 62 were treated with Lapdap. No adverse effects were documented, but details on pregnancy outcome were not reported. If further safety data become available, it could be used in combination with an artemisinin derivative during pregnancy.

Sulphonamides and Pyrimethamine are generally considered safe in the second and third trimesters of pregnancy. Although sulpha drugs have been associated with kernicterus when given to premature neonates, this theoretical problem of risk of kernicterus when given in late pregnancy has not been noted in studies using sulphadoxine–pyrimethamine (SP) as intermittent prophylactic treatment (IPT) in pregnancy, where 2 to 3 doses are given, but not intentionally during late pregnancy when the risk of kernicterus is greatest. Studies on the safety of sulfadoxine-pyrimethamine in pregnancy have not reported increased risks in spontaneous abortions or congenital defects. Sulpha containing drugs are associated with rare but severe cutaneous reactions such as toxic epidermal necrolysis and Stevens–Johnson syndrome, but there is no evidence that this risk is any greater in pregnant women.

Atovaquone-proguanil: This fixed combination of two blood schizonticides either used alone or in combination with artesunate is a highly effective treatment even in areas of multidrug resistant malaria. In a study in a multidrug resistant area on the Thai-Burmese border, the combination of atovaquone/proguanil plus artesunate proved to be well tolerated, highly effective and practical for the treatment of uncomplicated malaria during the second and third trimester of pregnancy. A Thai study in 81 pregnant women comparing atovaquone/proguanil (3 days) to supervised quinine (7 days) showed that fever- and parasite clearance rates, and duration of anaemia were more favorable with atovaquone/proguanil and treatment failure rates were 7 times lower (5% vs. 37%). There were no significant differences in birth weight, duration of gestation, congenital abnormality rates in newborns or in growth and developmental parameters of the infants that were monitored for 1 year. So the combination of artesunate with atovaquone/proguanil is safe, efficacious, and practical (3-day course), and is a useful back-up treatment for areas with multidrug resistant malaria. However the high cost of this combination limits its global use. Pharmacokinetic studies on atovaquone and proguanil during pregnancy suggest that the recommended dose likely needs to be increased.

Treatment of vivax malaria during pregnancy

            Vivax malaria during pregnancy can be treated safely with the usual dose of chloroquine in areas where P. vivax is still sensitive to chloroquine. However, primaquine used for the treatment of liver hypnozoites, is contraindicated during pregnancy. To prevent relapse of the infection from liver hypnozoites, it can be recommended that pregnant patients with P. vivax and P. ovale infections should be maintained on chloroquine prophylaxis for the duration of their pregnancy, which completely prevents recurrence of P. vivax episodes. Chloroquine prophylaxis during pregnancy is well tolerated and safe. Since chloroquine crosses the placenta and concentrates in the retina, this study specifically examined the impact on neurological development or visual acuity in the infants at one year of age and showed that there were no adverse effects.

            The chemoprophylactic dose of chloroquine phosphate is 300 mg base (=500 mg salt) orally once per week. Curative treatment with primaquine can then be safely started a few months after delivery. Areas in New Guinea, Indonesia and South America have reported increasingly resistance of P. vivax resistance to chloroquine. Quinine, artesunate and amodiaquine are used under these circumstances, but no clinical studies on their efficacy and safety are available, yet.

Chloroquine: The safety profile of chloroquine for use in pregnancy is excellent and has been proved over the decades; children born to a cohort of 169 non-immune women who took chloroquine chemoprophylaxis throughout pregnancy had no more birth defects than 454 births to women who had not received chloroquine. Among >2500 women who received chloroquine (as IPT or weekly chemoprophylaxis), there was no reported increase in abortions, stillbirths, or congenital abnormalities, although there were frequent non-severe side effects such as itching, dizziness and gastrointestinal complaints. There are reports of increased spontaneous abortions, particularly in patients with systemic lupus erythematosus treated with high doses of chloroquine over prolonged periods, and in some settings, chloroquine has gained a reputation as an abortifacient when used in high doses, but its abortifacient effects are limited to these very high doses that are life-threatening to the mother.

Treatment of severe malaria in pregnancy

           Severe malaria is a medical emergency. Pregnant women are at increased risk of developing severe symptoms. Severe anaemia, hypoglycaemia and pulmonary edema are all more common manifestations of severe malaria during pregnancy. The primary objective of treatment is to save the life of the mother. Although not specifically shown for pregnant women, intravenous artesunate has proven to be the superior antimalarial compared to quinine in the treatment for severe malaria, and is safer - as hypoglycaemia is a severe and common adverse effect of quinine in this context. If parenteral artesunate is not available, parenteral artemether remains the best alternative. Treatment doses are the same as in non-pregnant individuals (Table 7). The related compound quinidine, is similar to quinine considered safe in pregnancy and there are no reports of congenital abnormalities associated with its use during pregnancy, although there have been reports of neonatal thrombocytopenia after maternal use. Quinidine is only used in the U.S.A., since quinine is not available there.

Table 7. Antimalarial Treatment of Severe Malaria

Artesunate1	2.4 mg/kg i.v. or i.m. on admission, at 12, 24 hours, then daily. Artesunic acid (60mg) is dissolved in 1ml of 5% sodium bicarbonate and further diluted into 5ml with 5% dextrose or normal saline for intravenous injection (given as a bolus over 2 min). 1 ampoule=60mg
Artemether	3.2 mg/kg i.m. on admission followed by 1.6 mg/kg daily. NOT for i.v. administration. 1 ampoule = 80mg. Injections to the anterior thigh.
Quinine	20mg /kg of dihydrochloride salt by intravenous infusion over 4 hrs followed by 10 mg/kg infused over 2 - 8 hrs every 8 hours. If intravenous route not possible then give by intramuscular injection to the anterior thigh. The first dose should be divided; 10mg salt/kg to each thigh. Quinine should be diluted, inject no more than 180mg/ml.
Quinidine	10 mg base/kg infused at constant rate over 1-2 hr followed by 0.02 mg/kg/min as constant infusion, with electrocardiographic monitoring.

 

¹ Parenteral artesunate is the drug of choice for the treatment of severe malaria in adults. For children in high transmission areas there is as yet insufficient evidence to recommend any of the above antimalarial medicines over another.

Breast Feeding

            Most antimalarial drugs are detectable in breast milk, but the doses received by the breast feeding infant would be very small. Only primaquine should not be used, and it would be probably be unwise to use sulfonamides if the newborn baby was markedly jaundiced.

Empiric Standby Treatment

            In situations where prophylaxis is not indicated, either because of resistance, potential toxicity, or because the risks of malaria are low or unpredictable, and diagnosis and treatment may be unavailable, then empiric "Standby treatment" is sometimes administered. Patients with fever and a negative blood smear do not usually have malaria, although there are exceptions. Occasionally in a non-immune individual, the fever precedes patent parasitemia. The smear should be repeated in 12-24 hours. Empiric antimalarial therapy administration is common in tropical countries, and the patient may even be unaware of the drugs administered. There are simple dipstick tests for antimalarial drug screening in blood and urine, but these are not generally available. If the patient is not severely ill, it is reasonable to withhold treatment and repeat the smears. On the other hand, if the patient cannot be followed reliably, or is seriously ill and no alternative diagnosis is likely, treatment should be continued. In these cases the HRP2 dipstick test is useful as HRP2 is cleared relatively slowly and the test is usually positive well after parasite clearance; it is particularly useful in assessing a severely ill patient who may have been treated. In addition intra-monocytic malaria pigment is often present in peripheral blood or intradermal blood smears.

Drug Deployment: In general chloroquine is still used widely despite resistance. In many endemic areas the adverse impact of chloroquine resistance is underestimated because the majority of treatment failures are in young children. In order children and adults, who have significant background immunity, partial or complete responses may be still seen despite high failure rates in younger children (or non-immune travelers). Where high-level resistance precludes its use, pyrimethamine-sulfadoxine has been the usual successor, although in some parts of Africa and Oceania amodiaquine has been used as an alternative. Where pyrimethamine-sulfonamide resistance occurred, the choice of antimalarials was limited. Amodiaquine may still be effective, and chlorproguanil-dapsone is more effective than the pyrimethamine-sulfonamide combinations. A triple combination of pyrimethamine-sulfonamide with amodiaquine was better than either alone. Now ACTs are recommended as first line treatment everywhere although in several areas amodiaquine-SP is a good alternative. Combinations with quinine are widely used, and in children over eight years of age, quinines combined usually with tetracycline. Combinations with clindamycin are equally effective and can be used at any age. Quinine is extremely bitter and reliably produces "cinchonism" and so compliance is very poor with the seven-day quinine treatment regimes required for optimum cure rates. In Thailand, mefloquine (15 mg base/kg) was deployed originally in combination with sulfadoxine and pyrimethamine but this triple combination failed to delay the development of resistance. From 1991 mefloquine in a higher dose (25 mg base/kg) has been deployed alone, and more recently has been used in combination with the artemisinin derivatives. This has improved cure rates and, where the combination has been deployed systematically, levels of mefloquine resistance have fallen by half and the incidence of falciparum malaria has also dropped. Interestingly Pfmdr amplification only confers a certain degree of resistance, at a considerable fitness cost, and so is outbred when the selective pressure is reduced. Early diagnosis and treatment with the artemisinin derivatives has also been associated with a marked reduction in the incidence of malaria in Northwest Thailand, Vietnam and in South Africa (in association with DDT spraying). There is now increasing acceptance that antimalarial drugs should be used only in combination to protect them from resistance, and that one of the combination partners should be an artemisinin derivative. The artemisinin derivatives are available in some tropical countries, but have not been registered in most northern countries. Pyronaridine, atovaquone-proguanil, artemether-lumefantrine, and dihydroartemisinin-piperaquine have yet to be deployed widely. Halofantrine is used in some countries although given its toxicity it should probably be withdrawn.