In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.
Classification of evidence levels (1++ to 4) and grades of recommendations (A-D) are defined at the end of the "Major Recommendations" field.
Diagnosis of Malaria in Pregnancy
How Should Malaria in Pregnancy Be Diagnosed?
A - Microscopic diagnosis allows species identification and estimation of parasitaemia, so that appropriate antimalarials can be prescribed.
C - Rapid detection tests may miss low parasitaemia, which is more likely in pregnant women, and rapid detections tests are relatively insensitive in Plasmodium vivax malaria.
C - In a febrile patient, three negative malaria smears 12–24 hours apart rules out the diagnosis of malaria.
Women who have taken prophylaxis may have their parasitaemia suppressed below the level of microscopic detection (total biomass 108 parasites) and details of prophylaxis (name, where it was bought – in case of fake drug – dosing and adherence) should be sought. Stop prophylaxis on admission to hospital. Pregnant women with a high background immune level may have negative peripheral blood thick films but parasites sequestered in the placenta (for example, a recently arrived woman from a high malaria-endemic country with an unexplained anaemia).
Other important prognostic factors that should be reported on a peripheral blood smear result are:
- The presence and count of mature trophozoites and schizonts of P. falciparum
- Finding malaria pigment in more than 5% of the polymorphonuclear leucocytes in the peripheral blood film.
How Is Malaria Infection Treated during Pregnancy?
B - Treat malaria in pregnancy as an emergency.
A - Admit pregnant women with uncomplicated malaria to hospital and pregnant women with severe and complicated malaria to an intensive care unit.
A - Intravenous artesunate is the treatment of choice for severe falciparum malaria. Use intravenous quinine if artesunate is not available.
B - Use quinine and clindamycin to treat uncomplicated P. falciparum (or mixed, such as P. falciparum and P. vivax).
A - Use chloroquine to treat P. vivax, P. ovale or P. malariae.
D - Primaquine should not be used in pregnancy.
B - Treat the fever with antipyretics.
A - Screen women with malaria for anaemia and treat appropriately.
B - Write a management plan for follow-up, to ensure detection of relapse.
Delay in diagnosis and treatment is associated with death from severe malaria. Use the treatment guidelines shown in the table below.
Table: U.K. Treatment Guidelines in Pregnancy
||Drug and Dosage
|Severe or complicated malariaa
||Any species (for specific cases after expert consultation; see Table 2 in the original guideline document)
||Artesunate IV 2.4 mg/kg at 0, 12, and 24 hours, then daily thereafter. When the patient is well enough to take oral medication she can be switched to oral artesunate 2 mg/kg (or IM artesunate 2.4 mg/kg) once daily, plus clindamycin. If oral artesunate is not available, use a 3-day course of Riamet® (GlaxoSmithKline [GSK]) or atovaquone-proguanil (Malarone®, Novartis) or a 7-day course of quinine and clindamycin at 450 mg 3 times a day 7 days.
||Quinine IV 20 mg/kg loading dose (no loading dose if patient already taking quinine or mefloquine) in 5% dextrose over 4 hours and then 10 mg/kg IV over 4 hours every 8 hours plus clindamycin IV 450 mg every 8 hours (maximum dose quinine 1.4 g). When the patient is well enough to take oral medication she can be switched to oral quinine 600 mg 3 times a day to complete 5–7 days and oral clindamycin 450 mg 3 times a day 7 days (an alternative rapid quinine-loading regimen is 7 mg/kg quinine dihydrochloride IV over 30 minutes using an infusion pump followed by 10 mg/kg over 4 hours).
Note: quinine dosing should be reduced to 12-hourly dosing if IV therapy extends more than 48 hours or if the patient has renal or hepatic dysfunction. Quinine is associated with severe and recurrent hypoglycaemia in late pregnancy.
||Oral quinine 600 mg 8 hourly and oral clindamycin 450 mg 8 hourly for 7 days (can be given together)
or Riamet® 4 tablets/dose for weight >35 kg, twice daily for 3 days (with fat)
or atovaquone-proguanil (Malarone®) 4 standard tablets daily for 3 days
|Vomiting but no signs of severe or complicated malaria
||Quinine 10 mg/kg dose IV in 5% dextrose over 4 hours every 8 hours plus IV clindamycin 450 mg every 8 hours. When the patient is well enough to take oral medication she can be switched to oral quinine 600 mg 3 times a day to complete 5–7 days and oral clindamycin can if needed be switched to 450 mg 3 times a day 7 days.
||P. vivax, P. ovale, P. malariae
||Oral chloroquine (base) 600 mg followed by 300 mg 68 hours later. Then 300 mg on day 2 and again on day 3.
|Resistant P. vivax
||As for uncomplicated malaria P. falciparum
|Preventing relapse DURING pregnancy
||Chloroquine oral 300 mg weekly until delivery
|Preventing relapse AFTER delivery
||Postpone until 3 months after delivery and G6PD testing
||Oral primaquine 15 mg single daily dose for 14 days
||Oral primaquine 30 mg single daily dose for 14 days
|G6PD (mild) for P. vivax or P. ovale
||Primaquine oral 45–60 mg once a week for 8 weeks
a Severe and complicated malaria published evidence, see Appendix 3.1 in the original guideline document
b Uncomplicated malaria published evidence, see Appendix 3.2 in the original guideline document
c Non-falciparum malaria published evidence, see Appendix 3.3 in the original guideline document
IM = intramuscular, IV = intravenous, G6PD = glucose-6-phosphate dehydrogenase
Who Should Prescribe Treatment for Malaria Infection in Pregnancy?
In the UK, treatment prescription is limited to physicians. Treatment in pregnancy, particularly of severe and recurrent malaria, is best given with expert advice (see Table 2 in the original guideline document).
Where Should Treatment of Uncomplicated Malaria Infection Take Place?
In the UK, it is advisable to hospitalise all pregnant women with P. falciparum, as the clinical condition can deteriorate rapidly. Blood films are usually monitored every 24 hours but clinical deterioration is an indication for a repeat blood film.
While non-falciparum malaria can be managed on an outpatient basis, admission ensures compliance and any risk of vomiting or rapid deterioration is minimised and allows time for planning post-treatment prophylaxis.
What Happens if the Patient Vomits?
If the patient vomits, use an antiemetic. There are no studies of their efficacy in malaria but metoclopramide is considered safe, even in the first trimester. After the antiemetic has had time to take effect, repeat the dose. Repeat vomiting after antiemetic is an indication for parenteral therapy.
What Other Medication Should Be Provided Alongside Treatment of Uncomplicated Malaria Infection?
The fever of malaria has been associated with premature labour and fetal distress. Prompt treatment with antipyretics (paracetamol at the standard dose) is fundamental to the treatment of fever from malaria in pregnancy. Evidence for the efficacy of paracetamol arises mostly from studies in children. [Evidence level 1]
Does Pregnancy Affect the Efficacy of Malaria Treatments?
Treatments in pregnancy may have lower efficacy than in non-pregnant patients but this apparent effect could result from lowered concentrations of antimalarials in pregnancy. Women should be advised of the risk of recurrence and a suitable follow-up plan devised; for example, if symptoms or fever return, a repeat blood film is necessary. Alternatively, weekly screening by blood film can provide early detection and treatment of malaria.
How Should Recurrence Be Treated?
Unfortunately, the options for treatment of recurrent infection in pregnancy in the UK are limited but, if quinine and clindamycin has failed as first-line treatment, an alternative should be considered. Atovaquone-proguanil-artesunate and dihydroartemisinin-piperaquine have been used in pregnant women with multiple recurrent infections with good effect. Atovaquone-proguanil (Malarone®, GlaxoSmithKline) is available in the UK and was highly effective against uncomplicated P. falciparum malaria even when it was not combined with artesunate. Note that oral artesunate can be obtained from IDIS Pharma (see Table 2 in the original guideline document). The World Health Organization recommended regimen of 7 days of artesunate (2 mg/kg/day or 100 mg daily for 7 days) and clindamycin (450 mg three times daily for 7 days) could be given.
How Are Pregnancy-Related Complications of Severe Malaria Managed?
B - Monitor for hypoglycaemia regularly, as it can be profound and persistent in malaria in pregnancy and can be exacerbated by quinine.
B - Prevent mortality from pulmonary oedema and acute respiratory distress syndrome by clinical assessment of jugular venous or central venous pressure, aimed at keeping right arterial pressure less than 10 cm H2O.
B - Women who are severely anaemic should be transfused slowly, preferably with packed cells and intravenous frusemide 20 mg. Alternatively, exchange transfusion may be considered in centres where this can be performed safely.
C - Secondary bacterial infection should be suspected if the patient becomes hypotensive.
Severe malaria in pregnancy is a medical emergency and women should be treated in a high-dependency or intensive care unit, according to their condition and without delay. The World Health Organization's 2006 malaria treatment guidelines detail the treatment of severe malaria and do not need to be repeated here. Common clinical manifestations and management of severe malaria have been summarised in Table 3 in the original guideline document. While hypoglycaemia, pulmonary oedema, severe anaemia, and secondary bacterial infection can occur in severe malaria in non-pregnant patients, they are more common and severe in pregnant women.
Obstetric Management Specific to Malaria Infection in Pregnancy
Common Obstetric Problems with Acute Symptomatic Malaria
D - Preterm labour, fetal growth restriction, and fetal heart rate abnormalities can occur in malaria in pregnancy.
C - In severe malaria complicated by fetal compromise, a multidisciplinary team approach (intensive care specialist, infectious disease specialist, obstetrician, neonatologist) is required to plan optimal management of mother and baby.
B - Stillbirth and premature delivery in malaria in pregnancy are best prevented with prompt and effective antimalarial treatment.
A - Uncomplicated malaria in pregnancy is not a reason for induction of labour.
C - Pharmacological thromboprophylaxis should be weighed up against the risk of haemorrhage and should be withheld if the platelet count is falling or less than 100, indicating thrombocytopaenia.
D - Peripartum malaria is an indication for placental histology and placenta, cord and baby blood films to detect congenital malaria at an early stage.
C - Inform women of the risk of vertical transmission and, in the presence of positive placental blood films, that fever in the infant could indicate malaria; a blood film from the baby is required for confirmation.
Commonsense obstetrics applies to the management of the adverse effects of malaria in pregnancy. Efficacious and prompt treatment of malaria in the woman reduces the systemic effects of parasitaemia and reduces the adverse effects on the fetus, such as fetal distress.
In severe malaria, cardiotocograph monitoring may reveal fetal tachycardia, bradycardia or late decelerations in relation to uterine contractions, indicating fetal distress, particularly in the presence of fever. Paracetamol 1 g every 4–6 hours (to a maximum of 4 g/day) is safe and effective and should be prescribed. Maternal hypoglycaemia should be excluded as the cause of fetal distress, particularly if treatment is with quinine. Tocolytic therapy and prophylactic steroid therapy at the usual obstetric doses should be considered if there are no contraindications. [Evidence level 4]
In women with severe malaria, obstetric advice should be sought at an early stage. The paediatrician should be alerted and the mother's blood glucose checked frequently, particularly when intravenous quinine is administered. Fetal distress is common and has been related to malaria fever. Standard obstetric principles apply: the life of the woman comes first. There are no formal studies but instrumental birth in the second stage of labour in the presence of maternal or fetal distress is indicated, if there are no contraindications. In severe malaria, the role of early caesarean section for the viable fetus is unproven. [Evidence level 3]
What Is the Risk of Vertical Transmission of Malaria Infection to the Baby?
B - Vertical transmission to the fetus can occur particularly when there is infection at the time of birth and the placenta and cord are blood film positive for malaria (see Appendix 2 in the original guideline document).
D - All neonates whose mothers developed malaria in pregnancy should be screened for malaria with standard microscopy of thick and thin blood films at birth and weekly blood films for 28 days.
Grades of Recommendations
A - At least one meta-analysis, systematic review or randomised controlled trial rated as 1++ and directly applicable to the target population; or
A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as 1+ directly applicable to the target population and demonstrating overall consistency of results
B - A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 1++ or 1+
C - A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 2++
D - Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
Good Practice Point - Recommended best practice based on the clinical experience of the guideline development group
Classification of Evidence Levels
1++ High-quality meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a low risk of bias
1– Meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias
2++ High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal
2+ Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal
2– Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal
3 Non-analytical studies; e.g., case reports, case series
4 Expert opinion