Management of malaria in pregnancy

Microscopy

Microscopy of stained blood smears remains widely used to monitor the prevalence of malaria. For point-of-care testing, rapid diagnostic tests (RDT) are very effective for the diagnosis of symptomatic malaria infection, which tends to be accompanied by high parasitaemia. These are less effective as screening tools, being unable to reliably detect low-density infections which are common11. New, high-sensitivity RDTs will soon be evaluated in pregnant women.

Polymerase chain reaction (PCR)

Polymerase chain reaction is highly sensitive, with quantitative PCR able to detect very low-density malaria infection12. However, a specialized laboratory with trained staff is required, and assays are relatively time-consuming. Loop-mediated isothermal amplification (LAMP) has similar sensitivity to PCR but is more rapid and robust, and potentially applicable at the point of care1314. Both are presently reserved for research settings.

We have a strong understanding of the relationship between infection detected by microscopy and adverse pregnancy outcomes2, but the significance of sub-patent infection detected by PCR but not by microscopy and/or RDT is not yet clear. The sub-patent infection has been found to be associated with lower mean haemoglobin, and with low birth weight in primigravidae and premature delivery in multigravidae15, but other studies have not found similar associations1617. A pooled analysis (currently in preparation) should more clearly determine whether these low-density infections affect pregnancy outcomes.

Placental histology

Histological examination of placental tissue at delivery is a sensitive tool for detection of active or past malaria infection. Past infection is detected as the malaria pigment, haemozoin, most commonly in fibrin deposits. Active infection can be accompanied by leucocytes infiltrates, principally monocytes, termed intervillositis, particularly in first-time mothers with little pregnancy-associated malaria immunity. In this group, it is strongly associated with low birth weight and maternal anaemia18.

Prevention

The World Health Organization (WHO) recommends19 a three-pronged strategy for control of malaria in pregnancy in Africa including case management (prompt treatment with highly effective drug), use of insecticide-treated nets (ITNs) and intermittent preventive treatment (IPTp), the administration of a full treatment course of an effective antimalarial at regular antenatal visits, usually a month apart.

Intermittent preventive treatment in pregnancy (IPTp)

Currently, IPTp is only recommended in Africa, using sulphadoxine-pyrimethamine (SP). A meta-analysis revealed that three doses of IPTp were superior to two20, and a multisite study showed that IPTp remains effective against low birth weight and anaemia, even when resistance to SP is high, which is common in Eastern and Southern Africa21. In the recent years, mefloquine and a combination of azithromycin and chloroquine have been evaluated for prevention of malaria in pregnancy. Mefloquine decreased parasite prevalence at delivery but was poorly tolerated22, and the trial of azithromycin and chloroquine was stopped due to futility (i.e. inability to show a clear benefit over the comparator, SP); it, too, was poorly tolerated23.

Recent studies2425 suggested that dihydroartemisinin-piperaquine (DHA-PQ) may be a suitable replacement for SP. It has also been studied in Indonesia as IPTp or intermittent screening and treatment (IST), and larger trials presently in progress should provide a definitive answer as to whether it is a suitable replacement for SP in Africa. We presently lack evidence regarding the benefit of IPTp in lower transmission countries (such as India). Challenges for SP IPTp include the lack of evidence regarding its effectiveness against P. vivax, and low levels of uptake26.

An alternative to IPTp is IST. Using this approach, at each antenatal visit, an RDT is performed, and women testing positive receive an effective antimalarial, most commonly an artemisinin combination treatment (ACT). In part due to the low sensitivity of current RDTs, IST was not more effective than IPTp in preventing malaria and its complications in several studies in Africa27, and it has not been endorsed by the Malaria Policy Advisory Committee (MPAC) to the WHO for wider use. A trial of IST has been recently concluded in India (personal communication) while high-sensitivity RDTs hold promise to overcome some of the weaknesses of the IST approach. A recent review summarized trials of IPTp and IST over the past five years28.

Insecticide-treated nets (ITNs) and indoor residual spraying

Evidence primarily from trials in Africa shows that ITNs can prevent malaria and decrease low birth weight and other adverse pregnancy outcomes. There are limited data from Asia29, where mosquito vectors and their biting behaviour are different30, and where P. vivax is prevalent. Nevertheless, ITNs are a relatively cheap and probably effective tool for malaria prevention in pregnancy in India. Indoor residual spraying is used in parts of Africa and Asia, but there is little pregnancy specific data on its impact.

Falciparum malaria in the first trimester

Currently, quinine and clindamycin is the recommended treatment for women in the first trimester of pregnancy31. In many places, clindamycin is unavailable, and quinine monotherapy is prescribed. Side effects of the seven-day quinine regime, such as tinnitus or fullness in the ears, result in poor compliance, and the risk of recrudescence.

ACTs are a logical alternative to quinine, but establishing their safety in the first trimester has been challenging, especially because in animal studies, the drugs show embryo toxicity33. Pharmacovigilance, the monitoring of drug safety, is particularly important in pregnancy where both mother and developing foetus are at risk. A recent meta-analysis investigated the safety of ACTs in early pregnancy. Compared to quinine treatment, ACTs were not associated with increased risk of miscarriage, stillbirth or embryotoxicity34. This analysis has informed the decision of the WHO's MPAC to endorse the use of ACTs in the first trimester35, although this is not yet recommended in the treatment guidelines31.

Second and third trimester

A recent large trial compared four different ACTs, namely artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin piperaquine (DHA-PQ), for treatment of uncomplicated malaria in the 2^nd and 3^rd trimesters of pregnancy, in 3428 pregnant women36. All drugs were highly effective (95% or more), with artemether-lumefantrine being associated with the fewest adverse events while DHA-PQ was associated with the greatest post-exposure prophylaxis. This evidence strongly supports the use of ACTs as first-line treatment for malaria in the second and third trimester31. In Papua, Indonesia both P. falciparum and P. vivax were resistant to previous first-line drugs, and the introduction of DHA-PQ was associated with substantial declines in maternal malaria and anaemia, congenital malaria and low birth weight37.

Vivax malaria

Chloroquine remains an effective treatment for vivax malaria in most of the world, although resistance that emerged in Papua New Guinea and Indonesia is spreading. ACTs (apart from artesunate-SP) are also highly effective for treatment of vivax malaria, and parenteral artesunate is highly effective in the severe vivax disease31. An increasing number of countries recommend ACTs for treatment of all forms of uncomplicated malaria38.

Primaquine is contraindicated in pregnancy due to the risk of severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Pregnant women may require suppressive treatment, usually with chloroquine, until delivery. Small amounts of primaquine enter breast milk, so G6PD testing of the infant is recommended in lactating women before they are prescribed primaquine31.

Special groups: HIV-infected women

HIV infection increases the risk of malaria in pregnancy39. HIV infected women who are prescribed co-trimoxazole to decrease opportunistic infections should not receive IPTp (where otherwise recommended) because of the increased risk of severe skin reactions such as Stevens-Johnson syndrome. Mefloquine decreased parasite prevalence in HIV-infected women but appeared to increase the risk of mother-to-child transmission of HIV40. DHA-PQ is currently being evaluated as an alternative for IPTp. An additional consideration is the risk of drug interactions between antimalarials and antiretrovirals41, which may require dose adjustment or even avoidance of certain drugs. To date, little is known about the impact of antiretroviral therapy or immune system reconstitution on the interactions between malaria and HIV.

Malaria elimination

Countries across the Asia-Pacific including India have committed to malaria elimination by 203042. There are implications for management of malaria in pregnant women, and for campaigns such as mass drug administration (MDA). Currently, DHA-PQ is the most widely used drug for MDA, but it does not yet have an established safety record in early pregnancy, and hence, women who are possibly in early stages of pregnancy should be excluded from such campaigns. Where pregnant women are excluded from MDA campaigns, a significant part of the remaining burden may be found in these women43.

Pregnant women may be a useful sentinel population to monitor malaria changes44. The majority of women attend antenatal care at least once, so they are readily accessed, and parasite prevalence can be easily monitored. The analysis suggests these measures correlate well with a more established measure, the parasite prevalence in children under 545.