British Medical Bulletin

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British Medical Bulletin 67:137-148 (2003)
© 2003 Oxford University Press

Malaria prevention strategies

Pregnancy-Associated Malaria (PAM)

M Cot and P Deloron

Institut de Recherche pour le Développement, UR 010, Paris, France

Correspondence to: Michel Cot, IRD UR 010, Faculté de pharmacie, Laboratoire de parasitologie, 4 Avenue de l’Observatoire, 75270, Paris Cedex 06, France. E-mail: Michel.Cot{at}ird.fr

	Abstract

Top Abstract Introduction Consequences of malaria during... Effect of malaria prevention... Conclusions and future research References

 
Acute and severe consequences of pregnancy-associated malaria (PAM), such as materno-fetal death or cerebral malaria, seem limited to unstable malaria areas. In areas of stable endemicity, the main consequences are maternal anaemia and low birth weight (LBW) babies, particularly in primigravidae. Placental malaria seems more frequent and its consequences more severe in HIV-infected women. Since 1964, several chemoprophylaxis controlled trials have been undertaken, mainly in Tropical Africa where malaria is stable. Most showed an increase in mean birth weight in the prophylaxis group, especially among primigravidae. Similar findings were made with anaemia. Prophylaxis seems less effective in the case of HIV–malaria co-infection, which may require an increase in the number of doses. At present, intermittent treatment with sulfadoxine–pyrimethamine given twice or thrice during pregnancy in antenatal clinics seems the best policy for preventing PAM. Such effective prophylaxis should be integrated with other antenatal clinic services. Recently identified molecular receptors involved in cytoadherence of parasitized erythrocytes to placenta could yield new therapeutic or vaccine approaches, specifically targeted to pregnant women.

	Introduction

Top Abstract Introduction Consequences of malaria during... Effect of malaria prevention... Conclusions and future research References

 
The burden of pregnancy-associated malaria in terms of perinatal death and morbidity is often mentioned but seldom incorporated into global initiatives that aim to improve the quality of health services for children and pregnant women, like Safe Motherhood (a partnership of national and international organizations, including UNICEF, WHO and the World Bank). The topic is generally studied by specialists of tropical disease rather than obstetricians or public health policy makers.

However, the impact of this disease during pregnancy was described nearly a century ago¹. These early observations were undertaken during epidemics in areas of low transmission. They showed the particularly dramatic impact of malaria on the health of pregnant women as well as on the outcome of pregnancy. These first studies highlighted the high frequency of maternal deaths and high rates of abortions and stillbirths. Several investigations were subsequently undertaken in hyperendemic areas, chiefly in the 1940s and the 1950s. These showed a lesser impact of malaria probably due to the acquisition of protective immunity by mothers living in these areas.

By the beginning of the 1980s, a general outline of the situation could be drawn², showing that the higher susceptibility of pregnant women to malaria and the association of low birth weight (LBW) and maternal anaemia to malarial infection of the placenta is a public health priority even in high transmission areas. At present, this problem is particularly important in sub-Saharan Africa, where it is estimated that, whereas 24 million women are exposed every year, fewer than 5% have access to effective interventions.

	Consequences of malaria during pregnancy

Top Abstract Introduction Consequences of malaria during... Effect of malaria prevention... Conclusions and future research References

 
Low endemicity areas

Ever since the first observations of epidemics, several epidemiological investigations have been carried out in different areas of low transmission^3–6. The impact of unstable malaria on pregnant women varies according to the intensity of transmission. This is also true for the level of immunity acquired by mothers. The more severe complications of Plasmodium falciparum infection, such as cerebral malaria or pulmonary oedema (which can lead to maternal deaths), affect women with the lowest levels of immunity. Clinical malaria attacks with high fever and maternal anaemia are also frequent in areas of lower endemicity and affect primigravidae and multigravidae indifferently. Abortion, stillbirth and LBW are frequent consequences for the fetus (see Table 1).

View this table: [in this window] [in a new window]   Table 1 Clinical effects of pregnancy-associated malaria

 

High endemicity areas

In settings with stable transmission of P. falciparum malaria, over a hundred studies were published on pregnancy-associated malaria from 1950 to 1990, most involving large samples of women. Comprehensive reviews of these studies have been undertaken^2,7–9. Their conclusions are generally in agreement, and very different from the observations made in areas of unstable malaria (see Table 1).

Maternal morbidity and mortality
Parasitaemia is more frequent and parasite density is higher during the first and, to a lesser extent, the second pregnancy, than in multigravidae or in non-pregnant women. Clinical signs of malaria are not frequent (e.g. fever).

Anaemia is more frequent in pregnant women, and more pronounced in primigravidae than in multigravidae^10–13. The aetiology of anaemia in pregnancy is multifactorial. Causes such as poor nutrition (which induces iron and folate deficiencies), haemoglobinopathies and infection with other parasites (mainly hookworm) add to this syndrome. Most studies show a strong association between malarial infection of the placenta or peripheral blood and haemoglobin levels, confirming that this is a major cause of anaemia, even when other factors are present^12,13.

The effect of maternal anaemia on the course and the outcome of pregnancy is difficult to establish. If WHO standards are considered (haemoglobin <11 g/dl), it appears that a very large proportion of pregnant women living in malaria-endemic areas should be considered anaemic [e.g. 72% in the Democratic Republic of Congo (former Zaire)¹¹ or 94% in Papua-New Guinea¹⁴]. Such mild anaemia does not seem to cause serious problems during pregnancy, as shown by recent studies conducted in developed countries¹⁵ as well as in malaria-endemic countries^5,14. In fact, only severe malaria (defined as haemoglobin <7 g/dl or haemoglobin <8 g/dl, depending on the authors^13,14,16) can be associated with adverse perinatal outcomes, such as maternal mortality (by increasing the severity of postpartum haemorrhage) or LBW of the baby. Prevalence of severe anaemia (<7 g/dl) in highly malaria-endemic zones varies greatly according to the study area (<3% in the Democratic Republic of Congo¹¹, 9–10% in Tanzania and coastal Kenya^12,13). There is a general lack of information on the outcomes for mothers and babies. However, in a comprehensive review of all studies published between 1985 and 2000, Steketee et al⁹ estimated that maternal anaemia contributed to 7–18% of LBW and to 25% of total infant mortality.

Maternal mortality is difficult to estimate in tropical countries where there is a paucity of reliable data. This is particularly true of deaths related to malaria, which have been found to be associated with an increase in pre-eclampsia or postpartum haemorrhage. In addition to the difficulty of assessing a causal relationship between the two factors, the main problem is that diagnosis of malaria is usually based on either clinical examination or verbal autopsy, thus lacking specificity. Parasitological proof is not available in most cases. Based on a review of 23 studies in Africa, Brabin and Verhoeff¹⁷ estimated that 0.5–23% of maternal deaths in hospital settings and 2.9–17.6% in community-based studies are due to malaria. It is interesting to note that one of the most reliable studies, set in Malawi in 1989, reported only 0.9% of deaths directly attributable to malaria. A year-long follow-up of 4053 pregnant women did not show an association between mortality and parasitaemia for mothers¹⁸.

Placental malaria infection
Parasitaemia of the maternal placental blood is more frequent than parasitaemia of the maternal peripheral blood. This affects 10–34% of all pregnant women, depending on the studies^2,7,8, and primigravidae are more heavily and more often infected (up to twice as much) than multigravidae.

Fetal and newborn morbidity
All studies show a constant association between placental infection and LBW, which has a strong impact on neonatal and infant morbidity, particularly for first births. The mean decrease in birth weight associated with placental infection ranges from 55 to 348 g (all parities), equivalent to roughly a two-fold increase in the proportion of LBW, which usually affects 10–15% of births in malaria-endemic areas^2,6,7. Although no complete understanding of the biological mechanism by which placental infection causes LBW has been reached, the combination of intrauterine growth retardation and prematurity is strongly suspected^7,14,19. The overall contribution of maternal malaria to LBW is estimated to be 8–14% of all deliveries in malaria-endemic areas⁹.

It is also difficult to assess the impact of maternal malaria infection on perinatal and infant mortality. Based on the few studies available, Steketee et al.⁹ estimated that pregnancy-associated malaria was responsible for 3–8% of infant deaths (approximately 75,000–200,000 infants every year).

Transplacental infection of the newborn was established as of the 1930s, and its frequency varies highly according to published studies²⁰ (0–29%). No clear explanation has been found to understand such divergence in highly endemic areas. It seems that congenital infection of the baby is well tolerated in such settings, as no adverse effect was reported. Rapid parasite clearance in newborns was observed in the absence of antimalarial treatment in two studies^20,21.

HIV–malaria interaction
Since the onset and the rapid spread of the AIDS epidemic in areas where malaria transmission occurs, questions have arisen concerning a possible interaction between both infections. As HIV infection occurs in 3–27% of pregnant women in areas where malaria is present⁹, this could represent a major public health problem. The first observations in Malawi, where nearly 3000 pregnant women were followed between 1987 and 1989, showed an increase in the parasite prevalence and density in HIV-positive compared with HIV-negative women²². These findings were recently confirmed by two studies in Malawi and Kenya^23,24. Moreover, several studies^22,24 have noted that the usual pattern of increased parasite prevalence and density in primigravidae is altered. HIV-positive primigravidae are at similar risk of malaria as HIV-positive multigravidae.

There are indications that malaria can increase viral loads and mother-to-child HIV transmission^9,25, but this is largely an unresolved question.

Dual infection also influences the outcome of pregnancy. It seems that primigravidae with both infections have a two-fold increase in the risk of delivering a LBW baby compared with women infected with HIV alone²⁶.

	Effect of malaria prevention strategies

Top Abstract Introduction Consequences of malaria during... Effect of malaria prevention... Conclusions and future research References

 
Chemoprophylaxis

The first published randomized trial of chemoprophylaxis by pyrimethamine was carried out in Kenya in 1964²⁷. It was followed by over 30 clinical trials comparing various drugs and regimens, more or less appropriate in terms of randomization and methodology. We refer here to systematic reviews that have been made of these studies^7,28,29.

Table 2 displays a list of the few drugs that are available for prophylaxis in pregnant women, along with their strengths and limitations. Table 3 is a selection of some of the main trials (prophylaxis versus placebo or no intervention) from 1964 to the present, showing a great variety of protocols, interventions, outcomes and results.

View this table: [in this window] [in a new window]   Table 2 Antimalarial drugs currently used for prophylaxis in pregnant women

 

View this table: [in this window] [in a new window]   Table 3 Effect of chemoprophylaxis on maternal and fetal outcomes

 

Regardless of their protocol, all published studies clearly show an important decrease in parasitaemia (of the placental or maternal peripheral blood) in the intervention group. According to the 14 trials included in the 2003 Cochrane database review²⁹, severe antenatal anaemia was less frequent in the group having received prophylaxis (RR = 0.62, 95% CI [0.50; 0.78]). In all studies but one³⁰ (Thailand: unstable malaria), there was an increase in birth weight and a reduction in LBW, particularly in first and second pregnancies (RR = 0.49, 95% CI [0.36; 0.65]), and perinatal mortality seemed to be reduced (see also Table 3).

One of the main problems that appeared during the chemoprophylaxis trials is the growing resistance of the parasites to antimalarial treatments. Very soon after the first trial in Nigeria²⁷, it became obvious that pyrimethamine alone could no longer be used for prophylaxis, as it had lost a great deal of its usefulness. This is why subsequent intervention studies in Africa used dapsone–pyrimethamine or sulfadoxine–pyrimethamine (SP) combinations^31,34. The same problem occurred (albeit to a lesser extent) with chloroquine. It is interesting to note that in our trial (1992) in Cameroon³³, although in vivo resistance attained 10% of the study population, there was still a substantial reduction in LBW in the treated group (Table 3). In areas of multiresistant malaria such as South East Asia, neither chloroquine nor SP combinations could be used, and mefloquine was administered to pregnant women initially³⁰.

Additionally, none of these drugs has been proven to be perfectly safe in pregnancy, except for chloroquine (Table 2). Questions remain about the teratogenic effects of folic acid antagonists (such as in the SP combinations), even if such risk appears to be significant only when treatment is given during the first trimester of pregnancy³⁵ (women usually do not start prophylaxis before the fourth or fifth month). There is also a possible association between the use of mefloquine and an increased risk of stillbirth³⁶. Other drugs, such as tetracycline or halofantrine, are strictly forbidden during pregnancy. Quinine or artemisinin compounds cannot be used as prophylaxis because of their short half-life.

Another concern is the poor compliance generally observed with weekly or bi-monthly chemoprophylaxis, and ineffective blood levels induced from missing out one or several doses of anti-malarial drugs. In contrast, attendance at antenatal clinics (ANC) is generally good, and an important change in prevention strategies has occurred with the introduction of intermittent treatment with SP combinations in Malawi³⁷. With this regimen, a single curative dose of three tablets is given two or three times (depending on the date of the first visit) at ANC visits (see Table 2). Though not evaluated as randomized trials (except one³⁴), this regimen appears to be better accepted by pregnant women as well as being effective on placental infection, severe maternal anaemia and on incidence of LBW^34,37–39. One of these studies³⁸ seems to indicate that placental malaria and LBW for HIV-positive women were improved through SP treatment at over two doses. If confirmed, this may have important consequences on prevention strategies, indicating that HIV-positive women should receive three SP doses at least.

Other protection measures

Vector control measures can act as a complement to prophylaxis to protect pregnant women against malaria. To our knowledge, only the effect of insecticide-treated bed nets (ITBNs) has been evaluated so far. The results are conflicting. Some studies (Thailand, The Gambia) indicate improvement in maternal anaemia, parasitaemia and LBW^40,41. Others (Kenya, Ghana) did not show any noticeable effect of ITBNs on either the mother or the fetus^42,43.

	Conclusions and future research

Top Abstract Introduction Consequences of malaria during... Effect of malaria prevention... Conclusions and future research References

 
The administration of chemoprophylaxis during pregnancy has been proven to prevent placental malaria, maternal anaemia and LBW thanks to the randomized trials carried out in the 1980s and 1990s in highly endemic areas. However, poor compliance with weekly or bi-monthly regimens has led to the promotion of alternative strategies: intermittent treatment with SP combination given at ANC visits. These seem to be effective and more acceptable to pregnant women. This is national policy in several African countries and should be extended to areas where intense transmission of chloroquine-resistant P. falciparum occurs.

Whether to target interventions at high risk groups, such as primigravidae, secundigravidae or HIV-infected women when cost/benefit considerations are taken into account is not an easy question to answer. HIV and malaria co-infection seems to alter the normal pattern of increased susceptibility in primigravidae compared with multigravidae. It may be difficult to differentiate these groups when providing the intervention, as well as to exclude some women from receiving benefit. Therefore, the administration of SP intermittent treatment to all women may be the best strategy, when local resources permit it.

Some problems remain to be resolved. The decreasing efficiency of SP in HIV-positive pregnant women should be confirmed. Alternative drugs to SP should be developed, in case drug resistance intensifies.

These measures should be implemented along with other interventions such as the use of ITBNs, the systematic treatment of all malaria infections (which includes the use of quinine, mefloquine, or artemisinin derivatives), and more generally with other prenatal care programmes, including prevention of maternal anaemia and reduction in mother-to-child HIV transmission.

For the future, recent work on the property of parasitized erythrocytes to adhere to chondroitin sulphate A (CSA) expressed by the syncytiotrophoblast and then to accumulate in the placenta gives some hope for preventative or therapeutic interventions. This phenomenon is mediated by parasite variant surface antigens (VSA) expressed on the surface of infected erythrocytes⁴⁴. Placental parasites bind to CSA, but not to the usual ligands of cytoadherence. The expression of a particular VSA by parasites binding to CSA in the placenta elicits variant-specific antibodies that are able to inhibit the cytoadherence of placental parasites to the human syncytiotrophoblast. The decreasing susceptibility to pregnancy-associated malaria with increasing parity is reflected in the acquisition of VSA_CSA-specific antibodies⁴⁵.

Recombinant CSA is efficient in inhibiting and reversing the placental cytoadherence of infected erythrocytes⁴⁶, and thus may constitute the basis of a causative therapy for placental malaria. VSA_CSA-specific antibodies react with placental parasites from all malaria endemic areas⁴⁷, and antibodies raised against the DBL3g domain of PfEMP-1 (the major antigen constituting VSA) also inhibit the binding of placental parasites to CSA⁴⁸. This represents a tremendous opportunity to develop a vaccine against pregnancy-associated malaria in the near future.

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Top Abstract Introduction Consequences of malaria during... Effect of malaria prevention... Conclusions and future research References

 

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