Bibliography

1. Malaria in pregnancy in sub-Saharan Africa: Relationships with mothers’ anemia and their infants’ birth weightMohamed Ag Ayoya, MD, PhD CandidateCornell University, Ithaca, NY 14850

2. IntroductionMalaria is the world’s most important parasitic infection, ranking among the major health and developmental challenges for the poor countries of the world (Sachs et al., 2002). More than a third of the world’s population (about 2 billion people) lives in malaria-endemic areas. In Africa alone there are an estimated 200-450 million cases each year (Philippe et al., 2002). In sub-Saharan Africa countries, where stable transmission is common, Plasmodium falciparum malaria is the most important parasitic disease (Marchant et al., 2002).

3. The main objective of this paper is to describe the relationships between malaria infection during pregnancy, and women’s anemia and their infants’ weight at birth in sub-Saharan Africa.The hypotheses to be tested are that: 1) pregnant women with malaria infection have a poorer iron status compared to those without malaria; 2) children born to women who have had malaria infection have a lower birth weight compared to those born to women who have not had malaria.

4. Background1. Definition of malariaMalaria is an infectious disease caused by protozoan organisms of the genus Plasmodium (falciparum, ovale, vivax, malariae). It is characterized by high fever and erythrocytic infection resulting in anemia. In pregnant women, it causes a placental infection that impacts the fetus development.

5. 2. Definition of anemiaAnemia is defined as hemoglobin (Hb) concentration below – 2 standard deviations of the age- and sex- specific reference. The most commonly used cut-off for anemia is Hb < 110 g/L for pregnant women (Yip, 2001). Unless stated otherwise, anemia in this paper will be referred to a Hb level less than 110 g/L and iron deficiency will be referred to a serum ferritin level < 12 μg/l.

6. 3. Definition of LBWThe World Health Organization (WHO) defines LBW as a birth weight < 2500g (WHO,1970). LBW infants include both those who are preterm (<37 weeks gestational age) and those who are small for their gestational age (< 10th percentile for gestational age) (Rasmussen, 2001). This paper will consider both definitions.

7. 4. Malaria, iron deficiency, anemia and LBWThe major consequences of malaria during pregnancy are maternal anemia and reduced birth weight of the newborn. It has been postulated that malaria might contribute to iron depletion through decreasing intake during malaria-induced anorexia, reducing absorption and causing iron loss through haemoglobinura, but these factors have never been quantified (Menendez et al., 2000). Iron deficiency and malaria both coincide in several anemic subjects, and anemia is also taught to be associated with LBW. It has been postulated that malaria might contribute to iron depletion (Menendez et al., 2000), and iron depletion contributes to anemia.

8. Conceptual framework to analyze the literature findingsThe conceptual framework (malaria - iron deficiency – anemia - LBW) used in this review is adapted from Rasmussen (Rasmussen, 2001) and Elder (Elder, 2000) and is presented in the annex (figure 1). It shows that malaria during pregnancy could lead to anemia either directly or via iron deficiency. Malaria could also lead to LBW through placental infection or through malaria-related anemia. In the discussion section, I will look at other possible determinants of iron deficiency, anemia and LBW in sub-Saharan Africa other than malaria, and assess if these have been taken into account in the design and analysis of the studies described.

9. Methodology used to collect informationTo identify articles for this paper, Index Medicus was searched electronically using Medline citations in English. Malaria, pregnancy and, sub-Saharan Africa were used as search terms along with the following outcomes of interest: iron deficiency, anemia and LBW.The articles obtained were grouped into four categories: those establishing an association between maternal malaria infection and iron deficiency, and/or anemia; those establishing an association between anemia and LBW; those establishing an association between malaria infection and LBW; and those establishing a causal association between any of these factors.

10. ResultsThere is a large literature that reviews the impact of malaria in pregnancy on maternal and birth outcomes (Brabin, 1983 and 1991; Steketee et al., 1996a). The parity pattern of malaria susceptibility in highly endemic areas (whereby primigravidae and, to a lesser extent, secundigravidae are more affected than other parities) has been well established (McGregor et al., 1983). The tendency of Plasmodium falciparum parasites to invade the placenta in semi-immune women has been described also (Bray et al., 1979). Regardless of the level of endemicity, the main effects of malaria during pregnancy are maternal anemia and reduced birth weight of the newborn (McGregor, 1987; Meuris et al., 1993).

11. 1. Malaria and iron deficiency or anemia during pregnancy:Iron deficiency affects mostly young children and pregnant women, the same populations who suffer the bulk of the morbidity due to malaria (Shankar, 2000). During acute malaria, iron is mobilized in haemazoin complexes and intestinal iron absorption is reduced (Brabin, 1992) resulting in iron deficiency and then in anemia.

12. In contrast with the studies above, Matteelli et al. (1994) in a cross-sectional study conducted in an urban area of Zanzibar, Tanzania found that the proportion of women with anemia was similar in those with (85%) and without (80%) malaria infection. But, when primigravidae were considered alone, malaria infection was significantly more frequent among anemic women (65.2%) than in those with normal Hb values (40%), and malaria was significantly associated with anemia in this group with an odds ratio of 3.2 (95% confidence interval:1.1-9.6; P<0.05). In the same country, but in a different municipality, anemia was found in 95% of pregnant women and was predominantly due to iron, folate and B12 deficiencies (Msolla et al., 1997).

13. In Ghana, Mockenhaupt et al. (2000) found out of 530 pregnant women that 54% were anemic (Hb < 110 g/L); and 63% harboured malaria parasites at predominantly low numbers. Ferritin levels were considerably influenced by malaria and inflammatory processes (CRP > 0.6 multigravidae/dL). The prevalence of iron deficiency, depending on the definition applied, ranged between 5% and 46%.

14. 2. Anemia and LBWTo identify risks associated with teenage pregnancy, 704 teenagers out of 4,649pregnant women were followed in an antenatal clinic of Ibadan, Nigeria (Onadeko et al., 1996). The investigators observed a significantly higher proportion of LBW infants and anemia (51% with Hb < 11g/L) in teenage mothers compared with those with normal levels (35.5% with Hb > 11 g/L).

15. 3. Placental malaria and LBW The studies, whose results are presented below, covered a range of malaria endemicities and both rural and urban areas. A study conducted in Malawi (Steketee et al., 1996b) found a difference in the incidence of LBW between women with and without placental malaria (diagnosed by placenta smear) of 7.6% in primigravidae, 10.1% in secundigravidae and 7.4% in women of gravidity 3 or more.A prospective study of primigravidae women attending an antenatal clinic in Malawi found that among 178 singleton deliveries, 35% of infants were preterm or had IUGR (Sullivan et al., 1999).

16. A study in Tanzania (Menendez et al., 2000) assessed the effects of placental malaria-related changes on birth weight and gestational age in 1,177 mothers and their newborns. The authors found that massive mononuclear intervillous inflammatory infiltration was associated with increased risk of LBW (OR = 4.0), whereas maternal parasitized red blood cells and perivillous fibrin deposition both were associated independently with increased risk of preterm delivery (OR = 3.2; OR = 2.1 respectively).

17. In Kenya, the effects of malaria on pregnancy outcomes were measured among 912 women who delivered in Kilifi district hospital (Shulman et al., 2001). The authors performed placental histology to assess the prevalence of active or past malaria and its association with anemia and LBW. They found a high prevalence of active or past malaria in all gravidities, ranging from 64% in primigravidae to 30% in gravidities 5 and above. In gravidities 1-4, active malaria infection was associated with severe maternal anemia, adjusted OR 2.21 (95% CI, 1.36-3.61).

18. The possible impact of placental malaria infection on infant mortality through reduced birthweight was modeled by analyzing several studies (Guyatt et al., 2001). The authors found that the proportion of LBW associated with infected and uninfected placentas for all-parities (primigravidae and multigravidae) was higher in those with infected placenta than in those without. The overall proportions with LBW were higher for primigravidae than all-parities, but a similar relative difference was observed in the median values between infected (0.320, 0.280-0.360) and uninfected (0.160, 0.065-0.235) placentas (P = 0.001).

19. 4. Impact of malaria prevention interventions on the adverse consequences of malaria in pregnancy (causal inferences)The main interventions aimed at the prevention of malaria and its consequences in pregnancy have been anti-malarial chemoprophylaxis taken during pregnancy and the use of insecticide-treated bednets (ITBN).

20. The studies that looked at the effect of placental malaria on LBW suffer more or less from the same weaknesses. In some of them, the investigators either did not control for any confounding factors (Menendez et al., 2000) or did for few of them such as seasons (Sullivan et al., 1999; Moormann et al., 1999); HIV (Stekettee et al., 1996a; Verhoeff et al., 2001; Shulman et al., 2001); hypertension, socio-economic status, education and maternal height and weight (Shulman et al., 2001); maternal weight and maternal syphilis infection (Stekettee et al., 1996a).

21. Evidence for the importance of malaria as a contributor to LBW, iron deficiency, and anemia comes from randomized controlled trials of interventions directed against malaria such as antimalarial drug chemoprophylaxis and ITBNs studies. While those conducted on chemoprophylaxis (Steketee et al., 1996a; Steketee et al., 1996a; Mutabingwa et al., 1993; Parise et al., 1998; Fleming et al., 1986, Shulman et al., 1999; Salihu et al., 2000) seem to agree on the impact on malaria infection, those on ITBNs’ findings (D’Alessandro et al., 1996; Browne, 1997; Shulman et al., 1998; Marchant et al., 2002) are contradictory.

22. Most of the data on malaria, LBW, iron deficiency and anemia presented in this paper are facility-based (clinics or hospitals), therefore it is unclear whether the probability of the infections’ outcomes at facilities would be higher than within communities. As those who attend these facilities might be more “privileged”, the prevalence of malaria and LBW may not be representative of the community as a whole.

23. VII. Conclusions Malaria during pregnancy is highly prevalent in sub-Saharan Africa. Its main cause is Plasmodium falciparum. Iron deficiency and anemia related to malaria are shown to be prevalent in several countries. Low birth weight, maternal iron deficiency and anemia during pregnancy are associated with malaria but these associations (though shown significant in several studies) should not be interpreted as always causal given the other factors that could impact these outcomes.

24. Malaria still remains an important public health problem in the region and negatively impacts children’s and pregnant women’s health. A multifaceted approach directed both towards prevention and treatment of malaria and other socio-economic and political factors (education, poverty, health infrastructures, political commitment and collaboration between scientists and policy-makers etc.) would be more efficient in the control of the disease and its adverse effects on maternal and child health. Therefore, there is a need to explore new other control strategies to prevent malaria in these high risk groups.

25. Bibliography