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Importance and prevention of malaria in pregnancy
TRANSACTIONSOF THE ROYALSOCIETYOF TROPICALMEDICINEAND HYGIENE (2003) 97, 30 35
Reducing childhood mortality in poor countries Importance and prevention of malaria in pregnancy C a r o l i n e E . S h u l m a n 1 a n d E d g a r K. D o r m a n 2
1London School of Hygiene and Tropical Medicine, London W C 1 E
7HT, UK; 2Homerton Hospital, London, UI( Abstract Malaria in pregnancy is one of the most important preventable causes of low birthweight deliveries worldwide. It is also a major cause of severe maternal anaemia contributing to maternal mortality. It is estimated that 40% of the world's pregnant women are exposed to malaria infection during pregnancy. Th e clinical features of Plasmodium falciparum malaria in pregnancy depend to a large extent on the immune status of the woman, which in turn is determined by her previous exposure to malaria. In pregnant women with little or no pre-existing immunity, such as women from non-endemic areas or travellers to malarious areas, infection is associated with high risks of severe disease with maternal and perinatal mortality. Women are at particular risk of cerebral malaria, hypoglycaemia, pulmonary oedema and severe haemolytic anaemia. Fetal and perinatal loss has been documented to be as high as 6 0 - 7 0 % in non-immune women with malaria. Adults who are long-term residents of areas of moderate or high malaria transmission, including large parts of sub-Saharan Africa, usually have a high level of immunity to malaria. Infection is frequently asymptomatic and severe disease is uncommon. During pregnancy this immunity to malaria is altered. Infection is still frequently asymptomatic, so may go unsuspected and undetected, but is associated with placental parasitization. Malaria in pregnancy is a common cause of severe maternal anaemia and low birthweight babies, these complications being more common in primigravidae than multigravidae. Preventative strategies include regular chemoprophylaxis, intermittent preventative treatment with antimalarials and insecticide-treated bednets. Keywords: malaria, Plasmodium falciparum, anaemia, prevention, chemotherapy, pregnancy, birthweight, antimalarials, insecticide-treated bednets Introduction This review concentrates mainly on the effects of Plasmodium falciparum in pregnancy. Virtually all of the work on malaria in pregnancy has been on P. falciparurn, as it is this species that is responsible for the main burden of malarial disease in pregnant women. Pregnant women have more complications of P. falciparum malaria infection than do non-pregnant women. However, the clinical features of malaria in pregnancy depend to a large extent on the immune status of the woman. In areas with low or unstable transmission of malaria, exposure is not constant enough to result in effective immunity in the population. People of all ages are at risk of severe disease if exposed to infection. In these settings, pregnant women of all parities appear to be at a two to three times greater risk of developing severe disease than non-pregnant women and at approximately three times greater risk of dying if they do develop severe disease (Looareesuwan et al., 1985; Luxemburger et al., 1997). Severe disease in pregnant women has been associated with 2 0 - 3 0 % maternal mortality and a very high risk of miscarriage, premature delivery or neonatal death, shown in some situations to be over 50% (Meek, 1988). It may be that much of the perinatal mortality is related to uncontrolled high maternal fever, causing subsequent uterine contractions. Particular dangers of malaria in pregnancy in these women with absent or low levels of immunity are hyperpyrexia, hypoglycaemia, severe haemolytic anaemia, cerebral malaria and pulmonary oedema. Women of all parities are affected. In most of sub-Saharan Africa and some parts of Asia, malaria transmission is moderate or high with malaria being present every year, commonly with seasonal peaks. Immunity to malarial disease takes a number of years to develop, so in these settings, children aged < 5 years are at particular risk of severe disease and
Address for correspondence: Dr Caroline E. Shulman, Senior Clinical Lecturer, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK; e-mail [email protected]
death. With continued exposure, older children and adults still get infected, may have a low-grade fever in association with infection, but rarely go on to develop severe disease. During pregnancy this immunity to malaria is altered. Pregnant women have higher rates of parasitaemia and higher density of parasitaemia than non-pregnant women. Primigravidae are affected most, with the risk of malaria decreasing with each successive pregnancy (McGregor et al., 1983). Severe disease is uncommon, though placental parasitization is frequent. The main clinical problems of malaria in pregnancy in these settings are the development of maternal anaemia, which is often severe, and low birthweight deliveries (Shulman et al., 2001). Infection is frequently asymptomatic. Consequently, malaria may go unsuspected and undetected. Though women from areas of moderate or high transmission often remain afebrile and asymptomatic despite high levels of parasitaemia (Steketee et al., 1996c), pregnant women suffer from more episodes of clinical malaria illness than non-pregnant women of the same age (Diagne et aI., 1997). Recent evidence also suggests that the risk of symptomatic episodes is increased into the post-partum period (Diagne et al., 2000). Diagnosis of malaria in pregnancy in semi-immune women Malaria infection is usually diagnosed by parasites being seen on a peripheral blood film. In pregnancy, however, a peripheral blood film may be negative despite placental parasitaemia. Parasitized maternal erythrocytes may sequester in the placenta in the intervillous space. If there is longer-standing infection, haemozoin (malaria pigment) is seen in perivillous fibrin deposits in the placenta. Thickening of the syncytiotrophoblast basement membrane and intervillous monocyte infiltration are common (Galbraith et al., 1980; Ismail et al., 2000). Figure 1 shows the prevalence of malaria measured by peripheral parasitaemia, placental smear and placental histology in women of different gravidities delivering
REDUCINGCHILDHOODMORTALITYIN POOR COUNTRIES
[ ] Peripheral film [ ] Placental smear Placental histology [ ] Past infection [ ] Active-chronic infection [ ] Active-acute infection
706050 4030 20-
~eA
10I
I
2
3, 4 Gravidity
31 existing immunity, it may be more insidious in onset and may therefore be overlooked until very severe. As peripheral parasitaemia may be absent despite placental parasitaemia, malaria may be overlooked as the cause of the anaemia. Figure 2 shows the prevalence of severe anaemia in women with and without placental infection in women delivering in Kilifi District Hospital, Kenya. It has been estimated that approximately 18% of severe anaemia is secondary to malaria in pregnancy (Brabin er al., 2000). An intervention trial in primigravidae demonstrated that by reducing malaria infection, severe anaemia prevalence in this high risk group could be reduced by 39% (Shulman et al., 1999). The maternal anaemia which develops in association with P. falciparum malaria infection is mediated through haemolysis of both infected and uninfected red cells. It is thought that the haemolysis of uninfected cells is immune complex mediated. Dyserythropoiesis may also contribute to the development of anaemia during and after malaria infection. In addition, folate deficiency may develop secondary to haemolysis and the already increased demands for folate in pregnancy (Fleming, 1989).
>~5
Fig. 1. Prevalence of malaria measured by peripheral film and placental smear, and active-acute, active-chronic and past placental histology in 910 study women delivering in Kilifi District Hospital, Kenya. (Taken from Shulman et al. (2001). Malaria in pregnancy: adverse effects on haemoglobin levels and birthweight in primigravidae and multigravidae. Tropical Medicine and International Health, 6, 770-778. Reproduced by permission of Blackwell Science.) in Kilifi District Hospital, Kenya between January 1996 and July 1997. Malaria transmission in IQlifi is perennial with two seasonal peaks and it has been estimated that people receive between 1 and 20 infected bites per year. It can be seen from Fig. 1 that the prevalence of infection is high in all women, but highest in primigravidae. It can also be seen that when just one peripheral film is read, it may often be negative despite placental infection. Therefore, in areas where women have a degree of pre-existing immunity to malaria, such as in this example from the Kenyan coast, it is important that there is a high index of suspicion of malaria infection in pregnancy, as women may be infected despite the absence of a fever and a positive peripheral film.
HIV and m a l a r i a in p r e g n a n c y A number of studies from Malawi and Kenya have shown that P. falciparum parasitaemia occurs more frequently in HIV-infected pregnant women (Steketee et al., 1996a; Parise etal., 1998; Verhoeff et al., 1999). This effect is apparent in primigravidae and multigravidae. HIV infection appears to impair malarial immunity from early in pregnancy, such that HIV-infected multigravidae may have higher malaria prevalence than non-HIV-infected primigravidae. Further studies are necessary to determine the consequences of higher parasite prevalence in HIV-infected women. The interaction may be synergistic in increasing the risk of maternal anaemia, and low birthweight and consequently reducing child survival. There is also concern that placental malaria infection may increase the risk of HIV transmission, but this is not yet clear. Maternal anaemia Severe maternal anaemia is an important contributor to maternal mortality. T h e W H O defines severe anaemia in pregnancy as haemoglobin (Hb) < 7 g / d L and very severe anaemia as Hb < 5g/dL. Haemolytic anaemia due to malaria may develop rapidly, in which case it is usually highly symptomatic. In women with pre-
Low b i r t h w e l g h t Malaria is an important cause of low birthweight (< 2500 g) in women from endemic areas. The increased low birthweight prevalence in primiparae is substantial, ranging from below 10% in low transmission areas to over 50% in moderate and high transmission areas. In Th e Gambia, using data on the relationship between birthweight and risk of death, reduction of low birthweight by chemoprophylaxis was estimated to reduce the neonatal death rate by 42% and infant mortality by 18% among children of primigravidae, and by 6% and 4% respectively among children of multigravidae (Greenwood et al., 1992). The low birthweight which commonly occurs in pregnancies affected by malaria results from a combination of intrauterine growth restriction (IUGR) and prematurity (Menendez et al., 2000). The mechanisms through which it occurs may include an effect of maternal anaemia; haemodynamic disturbance of uteroplacental circulation; placental damage leading to impaired nutrient supply (Dorman er al., 2002); and possibly an association with pre-eclampsia (PET) or a PET-like process (Sartelet et al., 1996). Recent data from Kilifi, Kenya suggest that in an area of high iron deficiency, the combination of severe maternal anaemia and placental infection has a very
30 25 20
8
15 10
I
Severe anaemia
[] No placental infection
Low birthweight
[] Placental infection I
Fig. 2. Association between placental malaria infection and severe anaemia and low birthweight in 910 women delivering in Kilifi District Hospital, Kenya.
32
REDUCINGCHILDHOODMORTALITYIN POOR COUNTRIES
Table. P r e v a l e n c e o f low b i r t h w e i g h t in babies b o r n to m o t h e r s d e l i v e r i n g in Kilifi D i s t r i c t Hospital, Kenya~ a c c o r d i n g to the p r e s e n c e or a b s e n c e o f past/chronic p l a c e n t a l m a l a r i a a n d severe anaemia
In areas of moderate or high transmission, urgent treatment of symptomatic disease is also vital. However, malaria in pregnancy is often asymptomatic. As peripheral films may be negative despite placental parasitization, malaria during pregnancy cannot always be diagnosed with certainty. The mainstay of management in areas of moderate or high transmission is prevention of infection and presumptive treatment, based on the knowledge that many pregnant women will be infected although asymptomatic. In addition, effective antimalarial treatment should be part of the management of all febrile or severely anaemic pregnant women.
Haemoglobin I> 7 g/dL
No malaria Past 4- active malaria
< 7 g/dL
Prevalence of low birthweight % (n) 11.9% (370) 23.1% (52) 19.8% (288) 63.4% (41)
detrimental effect on birthweight (Shulman et al., 2001). Over 63% of babies born to mothers with both severe anaemia and past/chronic placental infection were of low birthweight (Table). Congenital malaria Cord blood parasitaemia may be present where placental malaria has been active at the time of delivery. It is not clear how commonly parasites cross the placenta in the antenatal period or whether cord parasitaemia represents peripartum transfer of parasites. In babies of immune women the prevalence of cord parasitaemia shows very wide variation between different geographical sites (ranging between < 1% and 25%), with infection rates being higher in women who are HIV-infected (Steketee et al., 1996d). Clinically significant disease in the neonate is rare, although cord parasitaemia has been associated with pre-term delivery. Parasites are rapidly cleared in most cases, presumably as a result of passively acquired immunity, which continues to protect these infants for some months. Babies born to non-immune women with untreated or incompletely treated malaria may suffer overwhelming congenital infection (Wickramasuriya, 1937; Cove11, 1950). Hepatosplenomegaly is a common feature and the mortality is high. P a t h o p h y s i o l o g y of P l a s m o d i u m falciparum m a l a r i a in p r e g n a n c y A unique feature of P. falciparum is its ability to sequester in deep capillary beds during the asexual stages of parasite replication, thereby avoiding host immune surveillance and splenic clearance. Infected erythrocytes adhere to a variety of ligands on vascular endothelium (Roberts et al., 1992). It is this feature that is thought to result in P. falciparum being responsible for most of the severe disease and almost all of the mortality associated with malaria worldwide. Until recently, the mechanism through which placental parasite sequestration occurs has been unclear. Studies in Malawi and Kenya, however, have identified strains of parasite which are found with increased frequency in pregnant women and which may be selected by their ability to adhere to chondroitin sulphate A on the syncytiotrophoblast (Rogerson et al., 1995; Fried & Duffy, 1996; Maubert et al., 1999). Management of Plasmodiumfalciparum malaria in p r e g n a n c y Non-immune pregnant women with malaria infection are more ill, more anaemic, more hypoglycaemic and deteriorate faster than non-pregnant women. Thus they must be treated more aggressively and transfused earlier than non-pregnant women. Those with severe disease should be transferred to an intensive care facility if available (WHO, 2000a). In a non-malarious area, a travel history should be taken from all pregnant women with a fever.
A n t i m a l a r i a l s in p r e g n a n c y - - t r e a t m e n t o f Plasmodium falciparurn The most appropriate antimalarial therapy will depend on the local pattern of antimalarial drug resistance, the severity of the malaria and the degree of pre-existing immunity. The drugs used will often depend on what is locally available. Prompt treatment of symptomatic malaria with appropriate effective antimalarials is essential. Concerns about possible adverse drug effects will be outweighed by the danger of malaria to the mother and fetus. In the first trimester, quinine is usually the drug of choice. Chloroquine has been widely used in the past, but with widespread resistance this has been rendered useless in most parts of the world. There is less experience with most other antimalarials in the first trimester. Though there is a theoretical risk of teratogenicity with sulfadoxine-pyrimethamine (SP) when used early in the first trimester and of kernicterus (jaundice of the newborn) when used late in the third trimester, evidence suggests these risks are very low. It can therefore be used at any gestation for symptomatic disease, where the risks of the drug will be outweighed by benefits and where there is not likely to be drug-resistant strains. In the second or third trimesters, in addition to quinine and SP, artemesinin derivatives or amodiaquine can be used. Mefloquine should be used only if no other drug is available as it carries a higher risk of neuropsychiatric side effects and there is some evidence of increased risk of stillbirths in women who received this for treatment of malaria in South-East Asia (Nosten et al., 1999a). In many parts of South-East Asia, there is multidrug resistance. The following schedule is used in such an area on the Thai-Burmese border: uncomplicated malaria is treated with oral quinine sulphate for 7 d. A second infection is treated with either quinine for 7 d if first trimester or artesunate if second or third trimester. Third infections are treated with artesunate irrespective of trimester. Severe malaria is treated with either intramuscular artemether or intravenous quinine (F. N o s ten, personal communication). In areas of Africa where there is sensitivity to SP, it can be used for non-severe disease. Quinine should be used if there is SP resistance or severe malaria. P r e v e n t i o n of P l a s m o d i u m falciparum m a l a r i a Antenatal screening and case management In areas of low or unstable transmission, prompt treatment of women with symptomatic disease is usually the mainstay of management. At the Thai-Burmese border, in an area of low, seasonal transmission and a high proportion of non-immune pregnant women, weekly antenatal screening, with prompt treatment of women with parasitaemia has resulted in a huge reduction in maternal and perinatal morbidity and mortality (Nosten et aL, 1991). Weekly screening is however unlikely to be a feasible option in many other situations. However, in areas of moderate or high transmission, as already mentioned, examination for peripheral parasitaemia is not a sensitive way of screening for malaria infection. In some studies, as few as 50% of women
REDUCINGCHILDHOODMORTALITYIN POOR COUNTRIES with placental infection at delivery were found to have concurrent peripheral parasitaemia, on one peripheral film. Screening women and treating only those with a positive peripheral slide will therefore miss women with placental infection. As many women have asymptomatic infection, case management alone would also miss the majority of cases. Chemoprophylaxis or intermittent treatment Though most countries in malaria-endemic areas of sub-Saharan Africa have had policies for the prevention of malaria in pregnancy, they have often been poorly implemented. Historically, the mainstay of this prevention has been with weekly chloroquine prophylaxis, but with increasing levets of resistance and poor adherence, this is inadequate in the majority of countries. In parts of West Africa, weekly pyrimethamine prophylaxis has been used for many years. Though initially highly effective (Morley et al., 1964), high levels of parasite resistance have rendered this approach ineffective. Proguanil is safe in pregnancy but needs to be given daily, and must be preceded by effective parasite clearance (Mutabingwa et aL, 1993). In a trial in The Gambia, fortnightly pyrimethamine-dapsone (Maloprim, GlaxoSmithKline), was shown to be effective in increasing birthweight and reducing anaemia in primigravidae (Greenwood et al., 1989). Similarly, in SouthEast Asia and Malawi, weekly prophylaxis with mefloquine was effectively used (Nosten et al., 1994; Steketee et aL, 1996b). With a requirement for regular daily or weekly prophylaxis, there is often a problem of low effectiveness due to poor adherence and operational problems of regular drug supply. For these reasons, research has been carried out to investigate the effectiveness of intermittent preventative treatment, whereby full treatment doses of antimalarials are given to women (irrespective of peripheral parasite status) at specified intervals during the second and third trimesters of pregnancy. Intermittent treatment with SP can effectively reduce parasitaemia, improve birthweight (Parise et aL, 1998) and reduce severe anaemia in primigravid women (Shulman et al., 1999). Sulfadoxine-pyrimethamine can be given when women come to antenatal clinic, and does not rely on medication being taken regularly at home. I--IIV-positive women appear to respond less well to intermittent treatment than HIV-negative women, and may require more doses of treatment (Parise et al., 1998). The W H O recommends that intermittent treatment with an effective, preferably one-dose antimalarial drug should be provided as part of antenatal care and be made available in highly endemic areas to women in their first and second pregnancies. Such intermittent treatment should be started from the second trimester onwards and be given at intervals of not less than one month (WHO, 2000b). In most countries in subSaharan Africa, policy for the management of malaria in pregnancy has been the domain of malaria control programmes. However, for the strategy to be successful, the providers of reproductive health services need to drive implementation as part of an antenatal anaemia control strategy (Shulman, 1999). It is now policy in Malawi, Kenya, Tanzania and Uganda that pregnant women receive intermittent treatment with SP during the second and third trimesters of pregnancy. Parasite resistance to SP is increasing in many areas. While there is good evidence that immediate implementation of this policy should occur in areas with poor weekly compliance and chloroquine resistance, there is also an urgent need for alternative regimes to be identified and tested. Insecticide-treated bednets Work on the impact of insecticide-treated bednets
33 (ITBNs) in pregnant women has shown variable effects. In Kilifi, Kenya (Shulman et aL, 1998) and in Ghana (Browne et al., 1997), ITBNs had very little impact on maternal anaemia, malaria infection or birthweight. However, in Thailand (Dolan et al., 1993), ITBNs were associated with a halving of anaemia rates. In The Gambia (D'Alessandro et al., 1996), where transmission is limited to one short season a year, in the dry season women from villages with ITBNs had less severe anaemia than women from villages with untreated nets (odds ratio [OR] = 0.27, 95% confidence interval [95% CI] 0.07-0.93), though there was no difference in the rainy season. There was an improvement in birthweight in the rainy season of 135g (P = 0.04) but a reduction in birthweight in the dry season of the same amount (P = 0.05). More recently, in an area of intense transmission in Kenya, preliminary analysis of data have suggested that ITBNs are associated with a marked reduction in low birthweight (adjusted OR = 0.67, 95% CI 0.53-0.85) (F. O. ter Kuile, personal communication). Overall, the data suggest that in certain settings ITBNs offer women substantial protection from some of the adverse outcomes of malaria in pregnancy. However, this impact is not consistent. The difference seen may be due to differences in the usage of nets during pregnancy by different populations. In view of this, and in the light of the substantial benefit from intermittent treatment with SP in Kilifi District among the populations both with and without ITBNs (Shulman et al., 1999), some form of chemoprevention (either as chemoprophylaxis or intermittent treatment) should be offered in addition to bednets. N o n - i m m u n e travellers Non-immune pregnant travellers need to understand the risks of contracting malaria. If travel is unavoidable, they need to take effective chemoprophylaxis and use measures to avoid being bitten between dusk and dawn, such as ITBNs, repellents and long-sleeved clothing. In areas of chloroquine resistance and mefloquine sensitivity, mefioquine prophylaxis is currently recommended in the second and third trimesters. Non-Plasmodium falciparum malaria The other species of malaria parasites that infect humans are P. vivax, P. ovale and P. malariae. These are not associated with severe disease and usually present with fever. There is evidence that infection with P. vivax during pregnancy is associated with mild anaemia and low birthweight delivery (Nosten et al., 1999b; Singh et al., 1999). In P. vivax and P. ovale there is a stage of the parasite that can lie dormant in the liver (as hypnozoites) and can relapse many months or years later. Non-P. falciparum malaria can be treated with chloroquine sulphate with relapses of P. vivax and P. ovale prevented by chloroquine 600 mg base weekly for the remainder of the pregnancy and during breastfeeding. After cessation of breastfeeding, the liver stage parasites of these species may be cleared with primaquine 15 mg twice daily for 2 weeks, provided the patient is not glucose-6-phosphate dehydrogenase-deficient. Conclusions Plasmodium faldparum malaria in pregnancy is a potentially life-threatening condition demanding urgent treatment. The clinical features of P. falciparum malaria depend on the immune status of the woman, which is a consequence of her exposure to malaria over the last 5 - 1 0 years. Non-immune pregnant patients with malaria are more prone to acquiring and to dying from severe disease than non-pregnant women. Particular dangers are hyperpyrexia, hypoglycaemia, severe haemolytic anaemia, cerebral malaria and pulmonary oedema. The
34
REDUCING CHILDHOOD MORTALITY IN POOR COUNTRIES
fever puts w o m e n at h i g h risk of suffering f r o m a miscarriage or p r e m a t u r e delivery. W o m e n f r o m a m a l a r i a - e n d e m i c area m a y n o t p r e s e n t with a h i g h fever b u t are at h i g h risk of severe a n a e m i a a n d of delivering a low b i r t h w e i g h t baby. A n y severely a n a e m i c w o m a n f r o m a m a l a r i o u s area s h o u l d b e t r e a t e d for malaria irrespective of w h e t h e r or n o t she has a fever or positive b l o o d slide. T h e m a i n s t a y for p r e v e n t i n g the complications of malaria in p r e g n a n c y in areas of m o d erate or h i g h t r a n s m i s s i o n is antimalarial c h e m o p r o p h y laxis or i n t e r m i t t e n t preventative t r e a t m e n t . A regime t h a t has b e e n s h o w n to b e safe a n d effective in E a s t Africa is i n t e r m i t t e n t t r e a t m e n t with SP.
Luxemburger, C., Ricci, F., Nosten, F,, Raimond, D., Bathet, S. & White, N. J. (1997). The epidemiology of severe malaria in an area of low transmission in Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91, 256-262. Maubert, B., Fievet, N., Tami, G., Cot, M., Boudin, C. & Detoron, P. (1999). Development of antibodies against chondroitin sulfate A-adherent Plasmodium falciparum in pregnant women. Infection and Immunity, 67, 5367-5371. McGregor, I. A., Wilson, M. E. & Billewicz, W. Z. (1983). Malaria infection of the placenta in The Gambia, West Africa; its incidence and relationship to stillbirth, biithweight and placental weight, Transactions of the Royal Society of TropicalMedicine and Hygiene, 77, 232-244. Meek, S. R. (1988). Epidemiology of malaria in displaced K~hmers on the Thai-Kampuchean border. Southeast Asian Journal of TropicalMedicine and Public Health, 19, 243-252. Menendez, C., Ordi, J., Ismail, M. R., Ventura, P. J., Aponte, J. J., Kahigwa, E., Font, F. & Alonso, P. L. (2000). The impact of placental malaria on gestational age and birth weight. Journal of Infectious Diseases, 181, 1740-1745. Morley, D., Woodland, M. & Cuthbertson, W. F. J. (1964). Controlled trial of pyrimethamine in pregnant women in an African village. British Medieal Journal, 1, 667-668. Mutabingwa, T. K., Malle, L. N., de Geus, A. & Oosting, J. (1993). Malaria chemosuppression in pregnancy. II. Its effect on maternal haemoglobin levels, placental malaria and birth weight. Tropical and Geographical Medicine, 45, 49-55. Nosten, F., ter Kuile, F., Maelankirri, L., Decludt, B. & White, N. J. (1991). Malaria during pregnancy in an area of unstable endemicity. Transactions of the Royal Society of Tropical Medicine and Hygiene, 85, 424-429. Nosten, F., ter Kuile, F., Maelankiri, L., Chongsuphajaisiddhi, T., Nopdonrattakoon, L., Tangkitchot, S., Boudreau, E., Bunnag, D. & White, N. J. (1994). Mefloquine prophylaxis prevents malaria during pregnancy: a double-blind, placebocontrolled study. Journal oflnfectious Diseases, 169, 595-603. Nosten, F., Vincenti, M., Simpson, J., Yei, P., Thwai, K., de Vries, A., Chongsnphajaisiddhi, T. & White, N. (1999a). The effects of mefloquine treatment in pregnancy. Clinical Infections Diseases, 28, 808-815. Nosten, F., McGready, R., Simpson, J. A., Thwai, K. L., Balkan, S.~ Cho, T., Hkirijaroen, L., Looareesuwan, S. & White, N. J. (1999b). The effects of Plasmodium vivax in pregnancy. Lancet, 354, 546-549. Parise, M. E., Ayisi, J. G., Nahlen, B. L., Schultz, L. J., Roberts, J. M., Misore, A., Muga, R., Oloo, A. J. & Steketee, R. W. (1998). Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. American Journal of Tropical Medicine and Hygiene, 59, 813-822. Roberts, D. J., Craig, A. G., Berendt, A. R., Pinches, R., Nash, G., Marsh, K. & Newbold, C. I. (1992). Rapid switching to multiple antigenic and adhesive phenotypes in malaria. Nature, 357, 689-692. Rogerson, S. J., Chaiyaroj, S. C., Ng, K., Reeder, J. C. & Brown, G. V. (1995). Chondroitin sulphate A is a cell surface receptor for Plasmodium falciparum infected erythrocytes. Journal of Experimental Medicine, 182, 15-20. Sartelet, H., Rogier, C., Milko-Sartelet, I., Angel, G. & Michel, G. (1996). Malaria associated pre-eclampsia in Senegal [letter]. Lancet, 347, 1121. Shulman, C. E. (1999). Malaria in pregnancy: its relevance to safe-motherhood programmes. Annals of Tropical Medicine and Parasitology, 93, supplement 1, $59-$66. Shulman, C. E., Dorman, E. K., Talisuna, A. O., Lowe, B. S., Nevill, C., Snow, R. W., Jilo, H., Peshu, N., Bulmer, J. N., Graham, S. & Marsh, K. (1998). A community randomized controlled trial of insecticide-treated bednets for the prevention of malaria and anaemia among primigravid women on the Kenyan coast. TropicalMedicine and International Health, 3, 197-204. Shulman, C. E., Dorman, E. K., Cutts, F., Kawuondo, K., Bnlmer, J. N., Peshu, N. & Marsh, K. (1999). Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebocontrolled trial. Lancet, 353, 632-636. Shulman, C, E., Marshall, T. O., Dorman, E. K., Bulmer, J. N., Cutts, F., Peshu, N. & Marsh, K. (2001). Malaria in pregnancy: adverse effects on haemoglobin levels and birthweight in primigravidae and multigravidae. Tropical Medicine and International Health, 6, 770-778. Singh, N., Shukla, M. M. & Sharma, V. P. (1999). Epidemiol-
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Brabin, B. J., Hakimi, M. & Pelletier, D. (2000). An analysis of anaemia and pregnancy-related mortality. Journal of Nutrition, 131, supplement, 604S-615S. Browne, E. N. L., Maude, G. H. & Binka, F. N. (2001). The impact of insecticide-treated bednets on malaria and anaemia in pregnancy in Kassena-Nankana district, Ghana: a randomised controlled trial. Tropical Medicine and International Health, 6, 667-676. Covell, G. (1950). Congenital malaria. Tropical Diseases Bulletin, 47, 1147-1167. D'Alessandro, U., Langerock, P., Bennett, S., Francis, N., Chain, K. & Greenwood, B. M. (1996). The impact of a national impregnated bed net programme on the outcome of pregnancy in primigravidae in The Gambia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 90, 487-492. Diagne, N., Rogier, C., Cisse, B. & Trape, J. F. (1997). Incidence of clinical malaria in pregnant women exposed to intense perennial transmission. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91, 166-170. Diagne, N., Rogier, C., Sokhna, C., Tall, A., Fontenille, D., Roussilhon, C., Spiegel, A. & Trape, J. (2000). Increased susceptibility to malaria during the early postpartum period. New England ffournal of Medicine, 343, 598-603. Dolan, G., ter Kuile, F. O., Jacoutot, V., White, N. J., Luxemburger, C., Malankirii, L., Chongsuphajaisiddhi, T. & Nosten, F. (1993). Bed nets for the prevention of malaria and anaemia in pregnancy. Transactions of the Royal Society of TropicalMedicine and Hygiene, 87, 620- 626. Dorman, E. K., Shulman, C. E., Kingdom, J., Bulmer, J. N., Mwendwa, J., Peshu, N. & Marsh, K. (2002). Impaired utero-placental blood flow in pregnancies complicated by falciparum malaria. Ultrasound in Obstetrics and Gynecology, 19, 165-170. Fleming, A. F. (1989). Tropical obstetrics and gynaecology. 1. Anaemia in pregnancy in tropical Africa. Transacffons of the Royal Society of TropicalMedicine and Hygiene, 83, 441-448. Fried, M. & Duffy, P. E. (1996). Adherence of Plasmodium faleiparum to chondroitin sulfate A in the human placenta. Science, 272, 1502-1504. Galbraith, R. M., Fox, H., Hsi, B., Galbraith, G. M. P., Bray, R. S. & Faulk, W. P. (1980). The human matemo-foetal relationship in malaria. II. Histological, ultrastructural and immunopathological studies of the placenta. Transactions of the Royal Society of Tropical Medicine and Hygiene, 74, 61-72. Greenwood, B. M., Greenwood, A. M., Snow, R. W., Byass, P., Bennett, S. & Hatib-N'lie, A. B. (1989). The effects of malaria chemoprophylaxis given by traditional birth attendants on the course and outcome of pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 83, 589-594. Greenwood, A. M., Armstrong, J. R. M., Byass. P., Snow, R. W. & Greenwood, B. M. (1992). Malaria chemopropbylaxis, birth weight and child survival. Transactions of the Royal Society of TropicalMedicine and Hygiene, 86, 483-485. Ismail, M. R., Ordi, J., Menendez, C., Ventura, P. J., Aponte, J. J., Kahigwa, E., Hirt, R., Cardesa, A. & Alonso, P. L. (2000). Placental pathology in malaria: a histological, immunohistochemical and quantitative study. Human Pathology, 31, 85-93. Looareesuwan, S., Phillips, R. E., White, N. J., Kietinun, S., Karbwang, J., Rackow, C., Turner, R. C. & Warre11, D. A. (1985). Quinine and severe falciparum malaria in late pregnancy. Lancet, 2, 4-8.
REDUCING CHILDHOOD MORTALITY IN POOR COUNTRIES
35
ogy of malaria in pregnancy in central India. Bulletin of the World Health Organization, 77, 567-572. Steketee, R. W., Wirima, J. J., Bloland, P. B., Chilima, B., Hermin, J. H., Chitsulo, L. & Breman, J. G. (1996a). Impairment of a pregnant woman's acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type- 1. American Journal of Tropical Medicine and Hygiene, 55, supplement 1, 42-49. Steketee, R. W., Wirima, J. J., Hightower, A. W., Slutsker, L., Heymann, D. L. & Breman, J. G. (1996b). The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi. American Journal of Tropical Medicine and Hygiene, 55, supplement 1, 33-41. Steketee, R. W., Wirima, J. J., Slutsker, L., Breman, J. G. & Heymann, D. L. (1996c). Comparability of treatment groups and risk factors for parasitemia at the first antenatal clinic visit in a study of malaria treatment and prevention in pregnancy in rural Malawi. American Journal of Tropical Medicine and Hygiene, 55, supplement 1, 17-23. Steketee, R. W., Wirima, J. J., Slutsker, L., Roberts, J. M., Fdaoromana, C. O., Heymann, D. L. & Breman, J. G. (1996d). Malaria parasite infection during pregnancy and at
delivery in mother, placenta, and newborn: efficacy of chloroquine and mefloquine in rural Malawi. American 3ournal of Tropical Medicine and Hygiene, 55, supplement 1, 24-32. Verhoeff, F. H., Brabin, B. J., Hart, C. A., Chimsuku, L., Kazembe, P. & Broadhead, R. L. (1999). Increased prevalence of malaria in HIV-infected pregnant women and its implications for malaria control. Tropical Medicine and International Health, 4, 5-12. WHO (2000a). Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 94, supplement 1. WHO (2000b). WHO Expert Committee on Malaria. Twentieth Report. Geneva: World Health Organization, Technical Report Series, No. 892. Wickramasuriya, G. A. W. (1937). Malaria and Ankylostomiasis in the Pregnant Woman. London: Oxford University Press.
Received 28 M a y 2002; accepted for publication 28 M a y 2002
Announcement R O Y A L S O C I E T Y OF T R O P I C A L M E D I C I N E A N D H Y G I E N E Prizes U n d e r g r a d u a t e Project P r i z e T h e Royal Society of Tropical M e d i c i n e and Hygiene offers an annual prize of £ 5 0 0 for an account of work carried out of relevance to a tropical or developing country by a non-medical student of any nationality. T h e work (which may be laboratory-based and not necessarily carried out in a tropical or developing country) will add to the knowledge of h u m a n or veterinary health or hygiene in the tropics. Particular attention will be directed towards originality and quality in the award of the prize. It is anticipated that the prize will act as a stimulus for the pursuit of excellence in research carried out by undergraduates. Medical Student Elective Prize T h e Royal Society of Tropical M e d i c i n e and Hygiene offers an annual prize of £ 5 0 0 for an account of work carried out by a medical student of any nationality during an elective period spent in a tropical or developing country. In awarding this prize emphasis will be laid on the originality of the work and on its contribution to knowledge or understanding of tropical diseases. Particular weight will be given to projects which have been developed and carried out by the students themselves. Rules 1. T w o prizes of £ 5 0 0 may be awarded annually in recognition of outstanding projects which increase knowledge of tropical medicine and hygiene in the broadest sense. Abstracts of the winning reports will be published in the Transactions. 2. Candidates shall be n o m i n a t e d by their head of department, supervisor or Dean, with a supporting statement of up to 500 words. 3. T h e closing date for receipt of project reports is 31 December. T h e project should have been done or completed in the previous twelve months. 4. A committee of three shall choose the prize winners. 5. T h e a n n o u n c e m e n t of the prize winners will be m a d e at the M a r c h meeting of the Society. 6. T h e prizes will be presented by the President of the Society at the Annual General Meeting in June or July. Please note that the Society cannot provide funds to cover students' elective travel expenses. Application forms may be obtained from the Administrator, Royal Society of Tropical Medicine and Hygiene, M a n s o n House, 26 Portland Place, L o n d o n , W1B 1EY, U K ; fax + 4 4 (0)20 7436 1389, e-mail [email protected]
Reducing childhood mortality in poor countries Importance and prevention of malaria in pregnancy C a r o l i n e E . S h u l m a n 1 a n d E d g a r K. D o r m a n 2
1London School of Hygiene and Tropical Medicine, London W C 1 E
7HT, UK; 2Homerton Hospital, London, UI( Abstract Malaria in pregnancy is one of the most important preventable causes of low birthweight deliveries worldwide. It is also a major cause of severe maternal anaemia contributing to maternal mortality. It is estimated that 40% of the world's pregnant women are exposed to malaria infection during pregnancy. Th e clinical features of Plasmodium falciparum malaria in pregnancy depend to a large extent on the immune status of the woman, which in turn is determined by her previous exposure to malaria. In pregnant women with little or no pre-existing immunity, such as women from non-endemic areas or travellers to malarious areas, infection is associated with high risks of severe disease with maternal and perinatal mortality. Women are at particular risk of cerebral malaria, hypoglycaemia, pulmonary oedema and severe haemolytic anaemia. Fetal and perinatal loss has been documented to be as high as 6 0 - 7 0 % in non-immune women with malaria. Adults who are long-term residents of areas of moderate or high malaria transmission, including large parts of sub-Saharan Africa, usually have a high level of immunity to malaria. Infection is frequently asymptomatic and severe disease is uncommon. During pregnancy this immunity to malaria is altered. Infection is still frequently asymptomatic, so may go unsuspected and undetected, but is associated with placental parasitization. Malaria in pregnancy is a common cause of severe maternal anaemia and low birthweight babies, these complications being more common in primigravidae than multigravidae. Preventative strategies include regular chemoprophylaxis, intermittent preventative treatment with antimalarials and insecticide-treated bednets. Keywords: malaria, Plasmodium falciparum, anaemia, prevention, chemotherapy, pregnancy, birthweight, antimalarials, insecticide-treated bednets Introduction This review concentrates mainly on the effects of Plasmodium falciparum in pregnancy. Virtually all of the work on malaria in pregnancy has been on P. falciparurn, as it is this species that is responsible for the main burden of malarial disease in pregnant women. Pregnant women have more complications of P. falciparum malaria infection than do non-pregnant women. However, the clinical features of malaria in pregnancy depend to a large extent on the immune status of the woman. In areas with low or unstable transmission of malaria, exposure is not constant enough to result in effective immunity in the population. People of all ages are at risk of severe disease if exposed to infection. In these settings, pregnant women of all parities appear to be at a two to three times greater risk of developing severe disease than non-pregnant women and at approximately three times greater risk of dying if they do develop severe disease (Looareesuwan et al., 1985; Luxemburger et al., 1997). Severe disease in pregnant women has been associated with 2 0 - 3 0 % maternal mortality and a very high risk of miscarriage, premature delivery or neonatal death, shown in some situations to be over 50% (Meek, 1988). It may be that much of the perinatal mortality is related to uncontrolled high maternal fever, causing subsequent uterine contractions. Particular dangers of malaria in pregnancy in these women with absent or low levels of immunity are hyperpyrexia, hypoglycaemia, severe haemolytic anaemia, cerebral malaria and pulmonary oedema. Women of all parities are affected. In most of sub-Saharan Africa and some parts of Asia, malaria transmission is moderate or high with malaria being present every year, commonly with seasonal peaks. Immunity to malarial disease takes a number of years to develop, so in these settings, children aged < 5 years are at particular risk of severe disease and
Address for correspondence: Dr Caroline E. Shulman, Senior Clinical Lecturer, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK; e-mail [email protected]
death. With continued exposure, older children and adults still get infected, may have a low-grade fever in association with infection, but rarely go on to develop severe disease. During pregnancy this immunity to malaria is altered. Pregnant women have higher rates of parasitaemia and higher density of parasitaemia than non-pregnant women. Primigravidae are affected most, with the risk of malaria decreasing with each successive pregnancy (McGregor et al., 1983). Severe disease is uncommon, though placental parasitization is frequent. The main clinical problems of malaria in pregnancy in these settings are the development of maternal anaemia, which is often severe, and low birthweight deliveries (Shulman et al., 2001). Infection is frequently asymptomatic. Consequently, malaria may go unsuspected and undetected. Though women from areas of moderate or high transmission often remain afebrile and asymptomatic despite high levels of parasitaemia (Steketee et al., 1996c), pregnant women suffer from more episodes of clinical malaria illness than non-pregnant women of the same age (Diagne et aI., 1997). Recent evidence also suggests that the risk of symptomatic episodes is increased into the post-partum period (Diagne et al., 2000). Diagnosis of malaria in pregnancy in semi-immune women Malaria infection is usually diagnosed by parasites being seen on a peripheral blood film. In pregnancy, however, a peripheral blood film may be negative despite placental parasitaemia. Parasitized maternal erythrocytes may sequester in the placenta in the intervillous space. If there is longer-standing infection, haemozoin (malaria pigment) is seen in perivillous fibrin deposits in the placenta. Thickening of the syncytiotrophoblast basement membrane and intervillous monocyte infiltration are common (Galbraith et al., 1980; Ismail et al., 2000). Figure 1 shows the prevalence of malaria measured by peripheral parasitaemia, placental smear and placental histology in women of different gravidities delivering
REDUCINGCHILDHOODMORTALITYIN POOR COUNTRIES
[ ] Peripheral film [ ] Placental smear Placental histology [ ] Past infection [ ] Active-chronic infection [ ] Active-acute infection
706050 4030 20-
~eA
10I
I
2
3, 4 Gravidity
31 existing immunity, it may be more insidious in onset and may therefore be overlooked until very severe. As peripheral parasitaemia may be absent despite placental parasitaemia, malaria may be overlooked as the cause of the anaemia. Figure 2 shows the prevalence of severe anaemia in women with and without placental infection in women delivering in Kilifi District Hospital, Kenya. It has been estimated that approximately 18% of severe anaemia is secondary to malaria in pregnancy (Brabin er al., 2000). An intervention trial in primigravidae demonstrated that by reducing malaria infection, severe anaemia prevalence in this high risk group could be reduced by 39% (Shulman et al., 1999). The maternal anaemia which develops in association with P. falciparum malaria infection is mediated through haemolysis of both infected and uninfected red cells. It is thought that the haemolysis of uninfected cells is immune complex mediated. Dyserythropoiesis may also contribute to the development of anaemia during and after malaria infection. In addition, folate deficiency may develop secondary to haemolysis and the already increased demands for folate in pregnancy (Fleming, 1989).
>~5
Fig. 1. Prevalence of malaria measured by peripheral film and placental smear, and active-acute, active-chronic and past placental histology in 910 study women delivering in Kilifi District Hospital, Kenya. (Taken from Shulman et al. (2001). Malaria in pregnancy: adverse effects on haemoglobin levels and birthweight in primigravidae and multigravidae. Tropical Medicine and International Health, 6, 770-778. Reproduced by permission of Blackwell Science.) in Kilifi District Hospital, Kenya between January 1996 and July 1997. Malaria transmission in IQlifi is perennial with two seasonal peaks and it has been estimated that people receive between 1 and 20 infected bites per year. It can be seen from Fig. 1 that the prevalence of infection is high in all women, but highest in primigravidae. It can also be seen that when just one peripheral film is read, it may often be negative despite placental infection. Therefore, in areas where women have a degree of pre-existing immunity to malaria, such as in this example from the Kenyan coast, it is important that there is a high index of suspicion of malaria infection in pregnancy, as women may be infected despite the absence of a fever and a positive peripheral film.
HIV and m a l a r i a in p r e g n a n c y A number of studies from Malawi and Kenya have shown that P. falciparum parasitaemia occurs more frequently in HIV-infected pregnant women (Steketee et al., 1996a; Parise etal., 1998; Verhoeff et al., 1999). This effect is apparent in primigravidae and multigravidae. HIV infection appears to impair malarial immunity from early in pregnancy, such that HIV-infected multigravidae may have higher malaria prevalence than non-HIV-infected primigravidae. Further studies are necessary to determine the consequences of higher parasite prevalence in HIV-infected women. The interaction may be synergistic in increasing the risk of maternal anaemia, and low birthweight and consequently reducing child survival. There is also concern that placental malaria infection may increase the risk of HIV transmission, but this is not yet clear. Maternal anaemia Severe maternal anaemia is an important contributor to maternal mortality. T h e W H O defines severe anaemia in pregnancy as haemoglobin (Hb) < 7 g / d L and very severe anaemia as Hb < 5g/dL. Haemolytic anaemia due to malaria may develop rapidly, in which case it is usually highly symptomatic. In women with pre-
Low b i r t h w e l g h t Malaria is an important cause of low birthweight (< 2500 g) in women from endemic areas. The increased low birthweight prevalence in primiparae is substantial, ranging from below 10% in low transmission areas to over 50% in moderate and high transmission areas. In Th e Gambia, using data on the relationship between birthweight and risk of death, reduction of low birthweight by chemoprophylaxis was estimated to reduce the neonatal death rate by 42% and infant mortality by 18% among children of primigravidae, and by 6% and 4% respectively among children of multigravidae (Greenwood et al., 1992). The low birthweight which commonly occurs in pregnancies affected by malaria results from a combination of intrauterine growth restriction (IUGR) and prematurity (Menendez et al., 2000). The mechanisms through which it occurs may include an effect of maternal anaemia; haemodynamic disturbance of uteroplacental circulation; placental damage leading to impaired nutrient supply (Dorman er al., 2002); and possibly an association with pre-eclampsia (PET) or a PET-like process (Sartelet et al., 1996). Recent data from Kilifi, Kenya suggest that in an area of high iron deficiency, the combination of severe maternal anaemia and placental infection has a very
30 25 20
8
15 10
I
Severe anaemia
[] No placental infection
Low birthweight
[] Placental infection I
Fig. 2. Association between placental malaria infection and severe anaemia and low birthweight in 910 women delivering in Kilifi District Hospital, Kenya.
32
REDUCINGCHILDHOODMORTALITYIN POOR COUNTRIES
Table. P r e v a l e n c e o f low b i r t h w e i g h t in babies b o r n to m o t h e r s d e l i v e r i n g in Kilifi D i s t r i c t Hospital, Kenya~ a c c o r d i n g to the p r e s e n c e or a b s e n c e o f past/chronic p l a c e n t a l m a l a r i a a n d severe anaemia
In areas of moderate or high transmission, urgent treatment of symptomatic disease is also vital. However, malaria in pregnancy is often asymptomatic. As peripheral films may be negative despite placental parasitization, malaria during pregnancy cannot always be diagnosed with certainty. The mainstay of management in areas of moderate or high transmission is prevention of infection and presumptive treatment, based on the knowledge that many pregnant women will be infected although asymptomatic. In addition, effective antimalarial treatment should be part of the management of all febrile or severely anaemic pregnant women.
Haemoglobin I> 7 g/dL
No malaria Past 4- active malaria
< 7 g/dL
Prevalence of low birthweight % (n) 11.9% (370) 23.1% (52) 19.8% (288) 63.4% (41)
detrimental effect on birthweight (Shulman et al., 2001). Over 63% of babies born to mothers with both severe anaemia and past/chronic placental infection were of low birthweight (Table). Congenital malaria Cord blood parasitaemia may be present where placental malaria has been active at the time of delivery. It is not clear how commonly parasites cross the placenta in the antenatal period or whether cord parasitaemia represents peripartum transfer of parasites. In babies of immune women the prevalence of cord parasitaemia shows very wide variation between different geographical sites (ranging between < 1% and 25%), with infection rates being higher in women who are HIV-infected (Steketee et al., 1996d). Clinically significant disease in the neonate is rare, although cord parasitaemia has been associated with pre-term delivery. Parasites are rapidly cleared in most cases, presumably as a result of passively acquired immunity, which continues to protect these infants for some months. Babies born to non-immune women with untreated or incompletely treated malaria may suffer overwhelming congenital infection (Wickramasuriya, 1937; Cove11, 1950). Hepatosplenomegaly is a common feature and the mortality is high. P a t h o p h y s i o l o g y of P l a s m o d i u m falciparum m a l a r i a in p r e g n a n c y A unique feature of P. falciparum is its ability to sequester in deep capillary beds during the asexual stages of parasite replication, thereby avoiding host immune surveillance and splenic clearance. Infected erythrocytes adhere to a variety of ligands on vascular endothelium (Roberts et al., 1992). It is this feature that is thought to result in P. falciparum being responsible for most of the severe disease and almost all of the mortality associated with malaria worldwide. Until recently, the mechanism through which placental parasite sequestration occurs has been unclear. Studies in Malawi and Kenya, however, have identified strains of parasite which are found with increased frequency in pregnant women and which may be selected by their ability to adhere to chondroitin sulphate A on the syncytiotrophoblast (Rogerson et al., 1995; Fried & Duffy, 1996; Maubert et al., 1999). Management of Plasmodiumfalciparum malaria in p r e g n a n c y Non-immune pregnant women with malaria infection are more ill, more anaemic, more hypoglycaemic and deteriorate faster than non-pregnant women. Thus they must be treated more aggressively and transfused earlier than non-pregnant women. Those with severe disease should be transferred to an intensive care facility if available (WHO, 2000a). In a non-malarious area, a travel history should be taken from all pregnant women with a fever.
A n t i m a l a r i a l s in p r e g n a n c y - - t r e a t m e n t o f Plasmodium falciparurn The most appropriate antimalarial therapy will depend on the local pattern of antimalarial drug resistance, the severity of the malaria and the degree of pre-existing immunity. The drugs used will often depend on what is locally available. Prompt treatment of symptomatic malaria with appropriate effective antimalarials is essential. Concerns about possible adverse drug effects will be outweighed by the danger of malaria to the mother and fetus. In the first trimester, quinine is usually the drug of choice. Chloroquine has been widely used in the past, but with widespread resistance this has been rendered useless in most parts of the world. There is less experience with most other antimalarials in the first trimester. Though there is a theoretical risk of teratogenicity with sulfadoxine-pyrimethamine (SP) when used early in the first trimester and of kernicterus (jaundice of the newborn) when used late in the third trimester, evidence suggests these risks are very low. It can therefore be used at any gestation for symptomatic disease, where the risks of the drug will be outweighed by benefits and where there is not likely to be drug-resistant strains. In the second or third trimesters, in addition to quinine and SP, artemesinin derivatives or amodiaquine can be used. Mefloquine should be used only if no other drug is available as it carries a higher risk of neuropsychiatric side effects and there is some evidence of increased risk of stillbirths in women who received this for treatment of malaria in South-East Asia (Nosten et al., 1999a). In many parts of South-East Asia, there is multidrug resistance. The following schedule is used in such an area on the Thai-Burmese border: uncomplicated malaria is treated with oral quinine sulphate for 7 d. A second infection is treated with either quinine for 7 d if first trimester or artesunate if second or third trimester. Third infections are treated with artesunate irrespective of trimester. Severe malaria is treated with either intramuscular artemether or intravenous quinine (F. N o s ten, personal communication). In areas of Africa where there is sensitivity to SP, it can be used for non-severe disease. Quinine should be used if there is SP resistance or severe malaria. P r e v e n t i o n of P l a s m o d i u m falciparum m a l a r i a Antenatal screening and case management In areas of low or unstable transmission, prompt treatment of women with symptomatic disease is usually the mainstay of management. At the Thai-Burmese border, in an area of low, seasonal transmission and a high proportion of non-immune pregnant women, weekly antenatal screening, with prompt treatment of women with parasitaemia has resulted in a huge reduction in maternal and perinatal morbidity and mortality (Nosten et aL, 1991). Weekly screening is however unlikely to be a feasible option in many other situations. However, in areas of moderate or high transmission, as already mentioned, examination for peripheral parasitaemia is not a sensitive way of screening for malaria infection. In some studies, as few as 50% of women
REDUCINGCHILDHOODMORTALITYIN POOR COUNTRIES with placental infection at delivery were found to have concurrent peripheral parasitaemia, on one peripheral film. Screening women and treating only those with a positive peripheral slide will therefore miss women with placental infection. As many women have asymptomatic infection, case management alone would also miss the majority of cases. Chemoprophylaxis or intermittent treatment Though most countries in malaria-endemic areas of sub-Saharan Africa have had policies for the prevention of malaria in pregnancy, they have often been poorly implemented. Historically, the mainstay of this prevention has been with weekly chloroquine prophylaxis, but with increasing levets of resistance and poor adherence, this is inadequate in the majority of countries. In parts of West Africa, weekly pyrimethamine prophylaxis has been used for many years. Though initially highly effective (Morley et al., 1964), high levels of parasite resistance have rendered this approach ineffective. Proguanil is safe in pregnancy but needs to be given daily, and must be preceded by effective parasite clearance (Mutabingwa et aL, 1993). In a trial in The Gambia, fortnightly pyrimethamine-dapsone (Maloprim, GlaxoSmithKline), was shown to be effective in increasing birthweight and reducing anaemia in primigravidae (Greenwood et al., 1989). Similarly, in SouthEast Asia and Malawi, weekly prophylaxis with mefloquine was effectively used (Nosten et al., 1994; Steketee et aL, 1996b). With a requirement for regular daily or weekly prophylaxis, there is often a problem of low effectiveness due to poor adherence and operational problems of regular drug supply. For these reasons, research has been carried out to investigate the effectiveness of intermittent preventative treatment, whereby full treatment doses of antimalarials are given to women (irrespective of peripheral parasite status) at specified intervals during the second and third trimesters of pregnancy. Intermittent treatment with SP can effectively reduce parasitaemia, improve birthweight (Parise et aL, 1998) and reduce severe anaemia in primigravid women (Shulman et al., 1999). Sulfadoxine-pyrimethamine can be given when women come to antenatal clinic, and does not rely on medication being taken regularly at home. I--IIV-positive women appear to respond less well to intermittent treatment than HIV-negative women, and may require more doses of treatment (Parise et al., 1998). The W H O recommends that intermittent treatment with an effective, preferably one-dose antimalarial drug should be provided as part of antenatal care and be made available in highly endemic areas to women in their first and second pregnancies. Such intermittent treatment should be started from the second trimester onwards and be given at intervals of not less than one month (WHO, 2000b). In most countries in subSaharan Africa, policy for the management of malaria in pregnancy has been the domain of malaria control programmes. However, for the strategy to be successful, the providers of reproductive health services need to drive implementation as part of an antenatal anaemia control strategy (Shulman, 1999). It is now policy in Malawi, Kenya, Tanzania and Uganda that pregnant women receive intermittent treatment with SP during the second and third trimesters of pregnancy. Parasite resistance to SP is increasing in many areas. While there is good evidence that immediate implementation of this policy should occur in areas with poor weekly compliance and chloroquine resistance, there is also an urgent need for alternative regimes to be identified and tested. Insecticide-treated bednets Work on the impact of insecticide-treated bednets
33 (ITBNs) in pregnant women has shown variable effects. In Kilifi, Kenya (Shulman et aL, 1998) and in Ghana (Browne et al., 1997), ITBNs had very little impact on maternal anaemia, malaria infection or birthweight. However, in Thailand (Dolan et al., 1993), ITBNs were associated with a halving of anaemia rates. In The Gambia (D'Alessandro et al., 1996), where transmission is limited to one short season a year, in the dry season women from villages with ITBNs had less severe anaemia than women from villages with untreated nets (odds ratio [OR] = 0.27, 95% confidence interval [95% CI] 0.07-0.93), though there was no difference in the rainy season. There was an improvement in birthweight in the rainy season of 135g (P = 0.04) but a reduction in birthweight in the dry season of the same amount (P = 0.05). More recently, in an area of intense transmission in Kenya, preliminary analysis of data have suggested that ITBNs are associated with a marked reduction in low birthweight (adjusted OR = 0.67, 95% CI 0.53-0.85) (F. O. ter Kuile, personal communication). Overall, the data suggest that in certain settings ITBNs offer women substantial protection from some of the adverse outcomes of malaria in pregnancy. However, this impact is not consistent. The difference seen may be due to differences in the usage of nets during pregnancy by different populations. In view of this, and in the light of the substantial benefit from intermittent treatment with SP in Kilifi District among the populations both with and without ITBNs (Shulman et al., 1999), some form of chemoprevention (either as chemoprophylaxis or intermittent treatment) should be offered in addition to bednets. N o n - i m m u n e travellers Non-immune pregnant travellers need to understand the risks of contracting malaria. If travel is unavoidable, they need to take effective chemoprophylaxis and use measures to avoid being bitten between dusk and dawn, such as ITBNs, repellents and long-sleeved clothing. In areas of chloroquine resistance and mefloquine sensitivity, mefioquine prophylaxis is currently recommended in the second and third trimesters. Non-Plasmodium falciparum malaria The other species of malaria parasites that infect humans are P. vivax, P. ovale and P. malariae. These are not associated with severe disease and usually present with fever. There is evidence that infection with P. vivax during pregnancy is associated with mild anaemia and low birthweight delivery (Nosten et al., 1999b; Singh et al., 1999). In P. vivax and P. ovale there is a stage of the parasite that can lie dormant in the liver (as hypnozoites) and can relapse many months or years later. Non-P. falciparum malaria can be treated with chloroquine sulphate with relapses of P. vivax and P. ovale prevented by chloroquine 600 mg base weekly for the remainder of the pregnancy and during breastfeeding. After cessation of breastfeeding, the liver stage parasites of these species may be cleared with primaquine 15 mg twice daily for 2 weeks, provided the patient is not glucose-6-phosphate dehydrogenase-deficient. Conclusions Plasmodium faldparum malaria in pregnancy is a potentially life-threatening condition demanding urgent treatment. The clinical features of P. falciparum malaria depend on the immune status of the woman, which is a consequence of her exposure to malaria over the last 5 - 1 0 years. Non-immune pregnant patients with malaria are more prone to acquiring and to dying from severe disease than non-pregnant women. Particular dangers are hyperpyrexia, hypoglycaemia, severe haemolytic anaemia, cerebral malaria and pulmonary oedema. The
34
REDUCING CHILDHOOD MORTALITY IN POOR COUNTRIES
fever puts w o m e n at h i g h risk of suffering f r o m a miscarriage or p r e m a t u r e delivery. W o m e n f r o m a m a l a r i a - e n d e m i c area m a y n o t p r e s e n t with a h i g h fever b u t are at h i g h risk of severe a n a e m i a a n d of delivering a low b i r t h w e i g h t baby. A n y severely a n a e m i c w o m a n f r o m a m a l a r i o u s area s h o u l d b e t r e a t e d for malaria irrespective of w h e t h e r or n o t she has a fever or positive b l o o d slide. T h e m a i n s t a y for p r e v e n t i n g the complications of malaria in p r e g n a n c y in areas of m o d erate or h i g h t r a n s m i s s i o n is antimalarial c h e m o p r o p h y laxis or i n t e r m i t t e n t preventative t r e a t m e n t . A regime t h a t has b e e n s h o w n to b e safe a n d effective in E a s t Africa is i n t e r m i t t e n t t r e a t m e n t with SP.
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Received 28 M a y 2002; accepted for publication 28 M a y 2002
Announcement R O Y A L S O C I E T Y OF T R O P I C A L M E D I C I N E A N D H Y G I E N E Prizes U n d e r g r a d u a t e Project P r i z e T h e Royal Society of Tropical M e d i c i n e and Hygiene offers an annual prize of £ 5 0 0 for an account of work carried out of relevance to a tropical or developing country by a non-medical student of any nationality. T h e work (which may be laboratory-based and not necessarily carried out in a tropical or developing country) will add to the knowledge of h u m a n or veterinary health or hygiene in the tropics. Particular attention will be directed towards originality and quality in the award of the prize. It is anticipated that the prize will act as a stimulus for the pursuit of excellence in research carried out by undergraduates. Medical Student Elective Prize T h e Royal Society of Tropical M e d i c i n e and Hygiene offers an annual prize of £ 5 0 0 for an account of work carried out by a medical student of any nationality during an elective period spent in a tropical or developing country. In awarding this prize emphasis will be laid on the originality of the work and on its contribution to knowledge or understanding of tropical diseases. Particular weight will be given to projects which have been developed and carried out by the students themselves. Rules 1. T w o prizes of £ 5 0 0 may be awarded annually in recognition of outstanding projects which increase knowledge of tropical medicine and hygiene in the broadest sense. Abstracts of the winning reports will be published in the Transactions. 2. Candidates shall be n o m i n a t e d by their head of department, supervisor or Dean, with a supporting statement of up to 500 words. 3. T h e closing date for receipt of project reports is 31 December. T h e project should have been done or completed in the previous twelve months. 4. A committee of three shall choose the prize winners. 5. T h e a n n o u n c e m e n t of the prize winners will be m a d e at the M a r c h meeting of the Society. 6. T h e prizes will be presented by the President of the Society at the Annual General Meeting in June or July. Please note that the Society cannot provide funds to cover students' elective travel expenses. Application forms may be obtained from the Administrator, Royal Society of Tropical Medicine and Hygiene, M a n s o n House, 26 Portland Place, L o n d o n , W1B 1EY, U K ; fax + 4 4 (0)20 7436 1389, e-mail [email protected]