Bakken and Iversen Malar J (2021) 20:348 https://doi.org/10.1186/s12936-021-03883-z Journal

RESEARCH Open Access The impact of malaria during on low in East‑Africa: a topical review Line Bakken1 and Per Ole Iversen1,2*

Abstract Background: Globally, approximately 15% of all babies are born with low birth weight (< 2.5 kg) and 90% of them are born in low- and middle-income countries. Malaria infection in pregnancy remains a public health≥ concern as it can afect both the mother and the newborn. Notably, it increases the risk of newborns with low birth weight. The World Health Organization (WHO) recommends intermittent preventive treatment with 3 doses of sulfadoxine- pyrimethamine (SP) during pregnancy in areas with moderate to high malaria transmission≥ in Africa. The aim of this topical review is to give an overview of the impact of malaria infection during pregnancy on low birth weight, with focus on East Africa where malaria is endemic. Methods: Eleven studies were selected according to a predefned set of criteria. Results: Three studies showed a signifcant reduction in the prevalence of low birth weight with intermittent preven- tive treatment with SP, whereas four studies found no signifcant impact of such treatment on low birth weight. The number of SP doses and compliance to this treatment may in part explain these discrepancies. Pregnant women with frequent symptomatic malaria infection had signifcantly higher risk of placental malaria. Conclusion: The WHO recommendation of 3 doses of intermittent preventive treatment with SP during pregnancy seem efective in preventing low birth weight,≥ but treatment compliance is a challenge. Malaria prophylaxis is impor- tant during pregnancy, especially in endemic areas of malaria, such as East Africa. Keywords: East Africa, Low birth weight, Malaria, Pregnancy, Sulfadoxine-pyrimethamine

Background Tere are several adverse outcomes associated with Malaria in pregnancy afects more than 25 million preg- malaria, which afect both the mother and the newborn, nant women every year, both in high and low malaria- including stillbirth, , maternal and neo- endemic areas [1]. Pregnancy is a period of increased natal mortality, congenital malaria, maternal anaemia vulnerability, even for those living in malaria-endemic and low birth weight (LBW, i.e. birth weight < 2.5 kg) [2, areas, who develop immunity against malaria [2]. Tere- 5]. Importantly, LBW ranks among the most commonly fore, malaria infection (especially with Plasmodium falci- documented adverse birth outcomes. In 2019, there were parum) during pregnancy remains a major public health an estimated 33 million in 33 moderate-to- problem, especially in sub-Saharan Africa [3, 4]. high malaria transmission countries in the World Health Organization (WHO) African Region [1]. Tirty-fve per- cent of these pregnancies were exposed to malaria infec- *Correspondence: [email protected] tion, and it is estimated that malaria infection during the 1 Department of Nutrition, University of Oslo, Oslo, Norway pregnancy resulted in 822.000 with LBW. In line Full list of author information is available at the end of the article with this, Eisele et al. [6] estimated that 11% of neonatal

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deaths in sub-Saharan Africa are due to LBW associated literature-search, however we included such reports if with malaria infections during pregnancy. Te WHO relevant in our discussion. Te inclusion of studies were therefore recommends intermittent preventive treatment not restricted to any particular study design, hence e.g. during pregnancy (IPTp) with sulfadoxine-pyrimeth- randomized trials and observational studies were eligi- amine (SP) in all areas with high or moderate malaria ble for inclusion. Studies that did not examine associa- transmission in Africa, and all women should receive tions between infants with LBW and malaria infection least 3 doses of IPTp-SP during their pregnancy, each during pregnancy in East Africa, were excluded. Stud- dose being given at ≥ 1 month apart, starting as early as ies that did not have LBW as a primary outcome were possible in the second trimester [7]. also excluded. According to a systematic review from 2019, 20.5 mil- lion infants worldwide were born with LBW, which rep- Results resents 14.6% of all births. Of these LBW infants, about Te literature search initially retrieved 42 arti- 90% were born in low- and middle-income countries cles (Fig. 1). Taking into account the exclusion criteria (LMICs), and in sub-Saharan Africa the prevalence of listed above, we were left with 11 articles summarized LBW was 24% [1]. in Tables 1 and 2. In pregnancy, P. falciparum tends to sequester on the placenta and thus the density of blood parasites avail- Intermittent preventive treatment able is below the detection limit of microscopy and, with sulfadoxine‑pyrimethamine in pregnancy therefore, can only be detected by sensitive molecular on prevalence of low birth weight tools, thus being a submicroscopic parasitaemia [8, 9]. Table 1 summarizes the studies that examined the efect Placental malaria infection is characterized by seques- of intermittent preventive treatment during pregnancy tration of malaria-parasite-infected erythrocytes and with IPTp-SP on birth weight and LBW in particular. infltration of immune cells in, as well as thickening of Braun et al. [11] did a cross-sectional study among the placenta, which cause altered exchange of 915 delivering women in Western Uganda to examine and waste products between mother and her [10]. the association between IPTp-SP and malaria infection, Tere is a paucity in compiling data from studies of maternal anaemia, LBW and preterm delivery. At the malaria and LBW in East Africa, a part of sub-Saharan time this study was conducted, the Ugandan policy rec- Africa endemic for falciparum malaria. Such informa- ommendation was to have at least two doses of IPTp-SP tion might be important, not only for the pregnant during pregnancy. Malaria infection was signifcantly woman herself and the antenatal care staf, but also for associated with LBW. Moreover, more than 50% of the other stake-holders and policy-makers. To address this women had taken two doses, and about 80% had taken knowledge gap, provide a topical review is here pro- at least one dose of SP. Importantly, this treatment had vided of the relationship between malaria during preg- no signifcant impact on the presence of malaria infec- nancy and LBW with focus on East-Africa. tion compared with women who did not take SP. Tey Literature search‑strategy found a non-signifcant reduction in anaemia, LBW and preterm delivery, and thus concluded that IPTp-SP In this topical review a list of relevant MeSH words was did not provide an observable beneft. generated and used to search for relevant articles from In a non-randomized community trial in Uganda, the database PubMed. Te search was performed on 25 Mbonye et al. [12] investigated two doses of IPTp-SP January, 2021. Te search covered research conducted on malaria during pregnancy. Tis study assessed a new in East African countries, which according to PubMed delivery system and its efect on and consists of Burundi, Djibouti, Eritrea, Ethiopia, Kenya, pregnancy outcomes. Te intervention group received Rwanda, Somalia, South Sudan, Sudan, Tanzania and IPTp-SP through community resource people (the new Uganda. Te search covered peer-reviewed research delivery system), whereas the control group received published between January 2000 and January 2021, and IPTp-SP at health units. Te intervention group reg- the articles from PubMed were imported into an End- istered a signifcantly lower prevalence of LBW (6%) Note library. Search terms included “, Low Birth compared with the control group (8.3%). Weight”, “Malaria”, and “Africa, Eastern”. Studies were Mikomangwa et al. [13] did a facility-based observa- included in this review if they focused on (i) infants tional cross-sectional study in Dar-es- Salaam, Tanza- with LBW; (ii) malaria infection in pregnancy; (iii) were nia. Tey investigated adverse birth outcomes among conducted in East Africa, and (iv) included an abstract 631 pregnant women who received IPTp-SP in a low and the free full text in English was available. Reviews malaria transmission region. Women who used at least or meta-analysis were not included in the selected Bakken and Iversen Malar J (2021) 20:348 Page 3 of 9

Fig. 1 Flow chart showing the selection of articles included in this topical review

one dose of IPTp-SP had a prevalence of malaria at for placental malaria and associated adverse pregnancy 0.6% and prevalence of LBW of 6.5%. Women with outcomes. Use of ≥ 2 doses of IPTp-SP during preg- malaria infection had 11 times increased risk of LBW nancy was not associated with decreased risk of pla- compared to those who did not have malaria infection cental malaria) (p = 0.08) or LBW (p = 0.73). Tis study (p = 0.04). Women who used ≥ 3 doses of IPTp-SP had thus concluded that two doses of IPTp-SP are inefec- 83% decreased risk of LBW compared to those who did tive in preventing and treating placental malaria and not use IPTp-SP (p = 0.05). adverse pregnancy outcomes. Mosha et al. [14] investigated the efectiveness of Ndyomugyenyi et al. [16] investigated the efcacy of IPTp-SP (one or two doses) during pregnancy on pla- malaria prevention during pregnancy in an area of low cental malaria, maternal anaemia and birth weight in and unstable malaria transmission in Kabale highlands, areas with diferent malaria transmission intensity in South-Western Uganda. Te study was an individually Tanzania. IPTp-SP was associated with a signifcant randomized placebo-controlled trial, where they used decreased risk of placental malaria. Tis efect was only two doses of IPTp-SP and insecticide-treated nets. Tey pronounced in areas with high malaria transmission examined the efect of these two treatment options as (p = 0.02) and not in areas with low malaria transmis- well as a combination of the two, on LBW. Te preva- sion (p = 0.48). IPTp-SP use was not signifcantly asso- lence of LBW was 6.5%. Tere was no signifcant difer- ciated with reduced risk of LBW. ence between the three study groups in the prevalence In a hospital-based cross-sectional study in Rufji, of LBW. Tanzania, Ndeserua et al. [15] investigated risk factors Bakken and Iversen Malar J (2021) 20:348 Page 4 of 9 Birth f 0.03) < of 54 g = 0.802) f —> 83% = 0.73) d BW = 0.04) = 0.05) associated with associated infection was infection a = 0.004) compared no signifcant infu - no signifcant b —> = 0.11) c Insecticide-treated nets, e 3 doses of IPTp-SP ference between the three between the three ference in the intervention groups of LBWprevalence (p a mean increased ­ a mean increased (p BWwith a mean increased of 128 g (p with mothers who had not used IPTp 6.5%. Malaria women positive risk of had 11 times increased those who LBW to compared (p negative were with the new delivery system with health units (p vs. ence on the presence of P.ence on the presence infection falciparum signifcantly associated with associated signifcantly ­ LBW was insignifcantly associated associated was insignifcantly with risk of LBW (p between IPTp use and between IPTp risk of LBWreduced decreased risk of LBWdecreased com - those who did not to pared (p use IPTp-SP ≥ 2 doses > associated IPTp- ≥ There was no signifcant dif - was no signifcant There 1 dose IPTp—>

The prevalence of LBW prevalence The was Lower prevalence of LBW prevalence (6%) Lower IPTp P. falciparum P. Results/comment Two doses SP during pregnancy Two No signifcant association No signifcant blood smear blood smear headache, joint pain, gen - headache, eral weakness) parasite DNA parasite blood smear parasite DNA parasite Quantifcation of parasites in Quantifcation of parasites Quantifcation of parasites in Quantifcation of parasites Rapid antigen-based test Self-reported (based on fever, Self-reported (based on fever, Polymerase chain reaction of chain reaction Polymerase Method for determining determining Method for malaria infection Quantifcation of parasites in Quantifcation of parasites Polymerase chain reaction of chain reaction Polymerase + placebo

+ IPTp e with every ANC visit with every ANC visit with every ANC visit 3rd trimester 3rd with every ANC visit and one in 3rd trimester and one in 3rd monthly or ITN or IPTp; then Start in 2nd trimester, IPTp, SP; IPTp, then Start in 2nd trimester, IPTp, SP; IPTp, then Start in 2nd trimester, IPTp, SP; IPTp, One dose in 2nd and one IPTp, SP; IPTp, then Start in 2nd trimester, Treatment; frequency Treatment; 2 doses SP; One dose in 2nd 2 doses SP; IPTp; then Start in 2nd trimester, ITN Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine, treatment preventive Intermittent d 889 631 2785 915 Sample size 350 350 5775 2.5 kg) < cross-sectional study (2018) cross-sectional trial (2003–2005) study (2012) (2004–2007) Cohort study (1999–2000) Facility-based observational Facility-based Non-randomized communityNon-randomized Cross-sectional study (2013) Cross-sectional Study design (year) design Study Cross-sectional study (2012) Cross-sectional Prospective observationalProspective Randomized controlled trialRandomized controlled Intermittent preventive treatment during pregnancy, during pregnancy, treatment preventive Intermittent c Kenya Dar-es-Salaam, Tanzania Mukono district, Uganda Western Uganda Western Country Rufji, Tanzania Moshi and Rufji, Tanzania Moshi and Rufji, Kabale, Uganda Low birth Low weight, b Summary during birth of malaria pregnancy on low table of studies examining the efect treatment infants weight Plasmodium falciparum, Plasmodium al. [ 17 ] Eijk et al. Van Mikomangwa13 ] [ et al. al. [ 12 ] et al. Mbonye 1 Table a al. [ 11 ] Braun et al. Authors weight. Note, all papers used the WHO defnition of LBW (birth weight all papers used the Note, weight. al. [ 15 ] Ndeserua et al. 14 ] [ Mosha et al. al. [ 16 ] et al. Ndyomugyenyi Bakken and Iversen Malar J (2021) 20:348 Page 5 of 9 during c LBW was signifcantly associated associated was signifcantly d was not signifcantly associ - was not signifcantly Malaria burden b ated with ­ ated with LBW among malaria- primigravidae infected riskpregnancy—> PM—> of LBW not signifcant) (trends, during - pregnancy—> signif cantly higher risk a LBW of having delivery PM

Results/comment Submicroscopic malaria infection Submicroscopic CXCL9 2.5 kg) < parasite DNA; quantifcation of parasite in blood smear;parasites - histol ogy of placental tissue blood smear; of histology placental tissue parasite DNA; quantifcation of parasite in blood smear;parasites - histol ogy of placental tissue blood- and placental smear Polymerase chain reaction of chain reaction Polymerase Quantifcation of parasites in Quantifcation of parasites Method for determining determining Method for malaria infection Polymerase chain reaction of chain reaction Polymerase Quantifcation of parasites in Quantifcation of parasites ; a every ANC visit every 8th week Start in 2nd trimester, then with Start in 2nd trimester, SP; then given Start in 2nd trimester, Treatment; frequency Treatment; No information given No information SP No information given No information 282 Sample size 174 1115 882 CXC ligand 9. Note, all papers used the WHO defnition of LBW (birth weight all papers used the ligand 9. Note, CXC d Cohort study (2014) Study design (year) design Study Case–control study (2010) Cohort study (2010–2013) Cohort study (2002–2005) Low birth Low weight, c Placental malaria, Placental b Tororo, Uganda Tororo, Country Central Sudan Central Dar-es-Salaam, Tanzania Tanzania Summary table of studies examining placental malaria birth and low infants weight Sulfadoxine-pyrimethamine, Sulfadoxine-pyrimethamine, Kapisi [ 4 ] et al. 2 Table Authors a 19 ] [ Mohammed et al. Kalinjuma [ 18 ] et al. al. [ 20 ] Dong et al. Bakken and Iversen Malar J (2021) 20:348 Page 6 of 9

In a hospital-based study in Western Kenya, Van Eijk cohort-study were divided into three groups to examine et al. [17] investigated the efectiveness of IPTp-SP for the associations between the frequency of malaria infec- control of malaria in pregnancy. Te prevalence of pla- tion during pregnancy and placental malaria. Tese three cental malaria was 13.8% and the prevalence of LBW study groups were defned as follows: (i) “none” = women was 12.2%. Tere was a trend towards decreasing preva- who had no episodes of symptomatic malaria or asymp- lence of LBW with increasing number of IPTp-SP doses tomatic malaria during pregnancy; (ii) “low” = women (p = 0.02). Compared with birth weight of infants of who had 0–1 episode of symptomatic malaria; and (iii) mothers who had not used intermittent preventive treat- “high” = women who had ≥ 2 episodes of symptomatic ment, one dose of IPTp-SP was non-signifcantly associ- malaria during pregnancy. Tis study concluded that ated with an adjusted mean increase in body weight of higher malaria burden during pregnancy was associated 54 g (p = 0.11). Two or more doses of IPT-SP were sig- with placental malaria, and placental malaria was associ- nifcantly associated with an adjusted mean birth weight ated with increased risk for adverse birth outcomes like increase of 128 g (p = 0.004). Moreover, the trend test LBW, but there was no signifcant association between showed a signifcant association between an adjusted placental malaria and risk of LBW. mean increase in birth weight of 61 g for each increase in Dong et al. [20] investigated whether CXC ligand 9 number of IPT-SP doses. (CXCL9) response to malaria infection during pregnancy was associated with LBW infants. CXCL9 is a small Placental malaria and low birth weight cytokine that is signifcantly upregulated and negatively Table 2 summarizes the studies that examined the efect correlated with birth weight. CXCL9 also plays a role in of placental malaria, malaria burden during pregnancy, inducing chemotaxis, cause extravasation and promote and submicroscopic malaria infection. diferentiation and multiplication of leukocytes. Placen- Kalinjuma et al. [18] did a cohort-study in Dar-es- tal malaria was associated with decreasing birth weight Salaam, Tanzania among HIV-negative pregnant women in all study groups (p < 0.001). Tey also found a signif- to identify factors associated with submicroscopic pla- cant association between CXCL9 and reduction in birth cental malaria and its association with LBW. Women weight. Interestingly, CXCL9 was signifcantly associated who did not use bed nets, fumigation or mosquito coils, with decreased birth weight in placenta malaria positive had higher risk (75% increased risk) of submicroscopic primigravidae, but not among infants born to placenta placental malaria (odds ratio = 1.75; p = 0.03) com- malaria positive secundigravidae or multigravidae. pared with those who used malaria prevention. Tis study found no signifcant association between placental Discussion malaria and LBW. Eleven original articles comprising 14,148 pregnant A case–control study by Mohammed et al. [19] inves- women were included in this topical review. Notably, tigated submicroscopic P. falciparum infection and LBW with the current stringent search strategy, studies from in Central Sudan, an area with unstable malaria transmis- only four of the 11 countries located in East Africa were sion. Cases were women who had LBW deliveries and the retrieved. Seven studies investigated the efect of IPTp-SP controls were women without LBW deliveries. Te prev- [11–17], whereas the remaining four investigated adverse alence of submicroscopic malaria infection was higher pregnancy outcomes associated with submicroscopic pla- in the cases compared with the controls: 27.6% versus cental malaria [18, 19], infection with P. falciparum and 7% (p < 0.001). By using multivariate analysis, this study measures of placental malaria [4] and CXCL9 response to showed that malaria infection in the placenta was not malaria during pregnancy [20]. Only three studies found signifcantly associated with LBW, while submicroscopic a signifcant reduction in the prevalence of LBW with P. falciparum infection (p = 0.001) or a combination of IPTp-SP [12, 13, 17]. submicroscopic infections and histologically determined Kapisi et al. [4] divided the women into three groups infections (p = 0.012), were signifcantly associated with and found that high malaria burden during pregnancy led LBW. to signifcantly increased risk of placental malaria com- Kapisi et al. [4] did a cohort-study based on data from pared with the other two groups with a lower malaria a randomized controlled trial of intermittent preven- burden. Even though increasing malaria burden was sig- tive treatment during pregnancy among 300 Ugandan nifcantly associated with placental malaria, there were participants. In the parental randomized controlled trial trends, but not signifcant, of an association between pla- they investigated placental malaria and delivery out- cental malaria and LBW [4, 18, 19]. Another study found comes. SP was given every 8 weeks versus dihydroarte- a signifcant association between placental malaria and misinin-piperaquine (DP) given every 8 weeks versus LBW by investigating placental CXCL9 [20]. In contrast, DP given every 4 weeks. Te available 282 women in the the case–control study from Central Sudan showed that Bakken and Iversen Malar J (2021) 20:348 Page 7 of 9

women who had LBW deliveries had signifcantly higher has been reported as an important predictor of placen- prevalence of submicroscopic malaria infection com- tal malaria, but Ndeserua et al. [15] could not diferenti- pared to those who did not have LBW deliveries [19]. In ate between confrmed malarial illness and non-malarial other words, it appears that placental malaria may not be fever during the pregnancy. Te study had a small sam- signifcantly associated with LBW, but submicroscopic ple size as well, and as a result of that they only studied P. falciparum infection may [4, 19]. However, due to the one district, so the fndings cannot be generalized to the limited evidence, a frm conclusion on this cannot be larger Tanzanian population. drawn. Tere has been a signifcant progress in reducing the Most studies in this review investigated the efect prevalence of P.falciparum over the past decade, espe- of one to three doses of IPTp-SP [11–17]. A systematic cially in Africa. A review by Rijken et al. [24] investigated review and meta-analysis by Kayentao et al. [21] inves- malaria in pregnancy in the Asia–Pacifc region. Tey tigated intermittent preventive treatment for malaria in found that malaria in pregnancy in this region contrasts pregnancy using two versus three or more doses of SP with that in Africa because many women are at risk in and its association to LBW in Africa. Te reason they highly heterogeneous transmission settings. Most of the chose to study the diference between two and three or pregnant women had little or no background immunity more doses is that two doses may not provide protection to malaria, so each infection is potentially fatal to the during the last four to ten weeks of pregnancy, which is women and their . Moreover, they found that the an essential period for fetal weight gain. Tey found that prevalence of reduced birth weight of newborns was sim- among pregnant women in sub-Saharan Africa, IPTp-SP ilar to that recorded in Africa, but efects of symptomatic with three or more doses was associated with a higher malaria during pregnancy seemed to be more prominent birth weight and a decreased risk of LBW compared with in the Asia–Pacifc region compared to Africa. Most the standard 2-dose regimen. Tese data provide support pregnant women who live in the Asia–Pacifc region are for the recommendations from WHO to provide at least at risk for infection with Plasmodium vivax, but preven- three doses of IPTp-SP [7, 21]. Mikomangwa et al. [13] tion of malaria during pregnancy is not emphasized in found that ≥ 3 doses of IPTp-SP led to an 83% decreased national guidelines in the Asia–Pacifc region as it is in risk of LBW compared to those who did not use IPTp-SP. sub-Saharan Africa. In line with this, the WHO recom- Tese results support the study of Kayentao et al. [21]. mendation for interventions for the control of malaria A systematic review and meta-analysis from 2015 of during pregnancy are mostly based on fndings from randomized and quasi-randomized trials investigated sub-Saharan Africa. Based on this, several studies should anti-malarial drugs for preventing malaria during preg- examine malaria during pregnancy and make strategies nancy and the risk of LBW [22]. Tis review found that to prevent malaria infection during the pregnancy for the all combined anti-malarial drugs were associated with a Asia–Pacifc region as well. 27% decreased risk of LBW compared with no use. Te Te aim was to summarize data collected during the authors concluded that SP may no longer protect against past 20 years (i.e. in the period after the WHO recom- the risk of LBW in areas of high-level drug resistance in mended to use IPTp-SP) on the relationship between Africa. A recent meta-analysis investigated the efect of P. pregnancy and malaria with focus on LBW infants in falciparum SP resistance on the efectiveness for malaria Eastern Africa in the form of a topical review to provide in pregnancy in Africa [23]. Te results showed that and facilitate such information to relevant stake-holders IPTp-SP increased the prevalence of molecular markers (e.g. the pregnant women, health-staf and policy-mak- of SP resistance and it was correlated with a decrease in ers). Tere are some limitation to this approach, e.g. the efectiveness of SP to prevent malaria infections and there are several challenges in measuring the prevalence LBW. Based on these fndings it was suggested that mon- of LBW because many infants in LMICs are not weighed itoring of SP resistance could be a policy tool to guide the at birth, some are misclassifed and the quality of data- use of IPTp-SP [23]. reporting varies [5]. In addition, estimates of LBW in Te study from Central Sudan found that among LMICs are mainly based on data compiled from health women who had LBW deliveries, the prevalence of sub- facilities, but these may be under-estimates because microscopic malaria infection was signifcantly higher some newborns are delivered at home, in particular compared with the controls [19]. A limitation in this those of poor households [25]. Moreover, any heteroge- study is the low sample size. In line with this, the study neity among the selected studies was not quantifed, or failed to obtain enough submicroscopic malaria infec- of any confounding factors. Furthermore, there might be tions to enable parasite genotyping. Hence, a cross-sec- diferences among the studies regarding the diagnosis of tional study with a larger sample size is needed. In areas malaria in pregnancy. Te possible impact on seasonal with stable malaria transmission, fever during pregnancy variations, e.g. related to climate, was not included. Bakken and Iversen Malar J (2021) 20:348 Page 8 of 9

Conclusion References 1. WHO. World malaria report 2020. Geneva: World Health Organiza- Tis topical review reports that among pregnant women tion; 2020. https://​www.​who.​int/​publi​catio​ns/i/​item/​97892​40015​791. in sub-Saharan Africa, three or more doses IPTp-SP were Accessed 29 May 2021. associated with a decreased risk of LBW and an increased 2. McClure EM, Goldenberg RL, Dent AE, Meshnick SR. A systematic review of the impact of malaria prevention in pregnancy on low birth weight birth weight compared to the standard 2-dose regimen. and maternal anemia. Int J Gynaecol Obstet. 2013;121:103–9. Tese studies provide support for the current WHO rec- 3. WHO. Reducing the burden of malaria in pregnancy. Geneva: World ommendation to provide at least three doses of IPTp- Health Organization, 2003. https://​www.​who.​int/​malar​ia/​publi​catio​ns/​ atoz/​meraj​an2003.​pdf. Accessed 29 May 2021. SP during pregnancy. Some studies concluded that SP 4. 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Malar J. 2014;13:274. adoxine-pyrimethamine; LMICs: Low- and middle-income countries; DP: 9. WHO. Malaria terminology. Geneva: World Health Organization, 2016. Dihydroartemisinin-piperaquine; CXCL9: CXC ligand 9. https://​apps.​who.​int/​iris/​bitst​ream/​handle/​10665/​208815/​WHO_​HTM_​ GMP_​2016.6_​eng.​pdf. Accessed 29 May 2021. Acknowledgements 10. Sharma L, Shukla G. Placental malaria: a new insight into the pathophysi- We appreciate the valuable inputs on the manuscript from Dr. Richard ology. Front Med. 2017;4:117. Mwaiswelo. 11. Braun V, Rempis E, Schnack A, Decker S, Rubaihayo J, Tumwesigye NM, et al. Lack of efect of intermittent preventive treatment for malaria in Authors’ contributions pregnancy and intense drug resistance in western Uganda. Malar J. LB and POI conceived the study; LB and POI designed the study protocol; LB 2015;14:372. carried out the analysis of the individual studies; LB and POI carried out the 12. Mbonye AK, Bygbjerg IC, Magnussen P. Intermittent preventive treatment analysis and interpretation of these data. LB drafted the manuscript; LB and of malaria in pregnancy: a new delivery system and its efect on maternal POI critically revised the manuscript for intellectual content. Both authors read health and pregnancy outcomes in Uganda. Bull World Health Organiza- and approved the fnal manuscript. tion. 2008;86:93–100. 13. Mikomangwa WP, Oms M, Aklillu E, Kamuhabwa AAR. Adverse birth Funding outcomes among mothers who received intermittent preventive treat- None. ment with sulphadoxine-pyrimethamine in the low malaria transmission region. BMC Pregnancy Childbirth. 2019;19:236. Availability of data and materials 14. Mosha D, Chilongola J, Ndeserua R, Mwingira F, Genton B. Efectiveness of Available on request. intermittent preventive treatment with sulfadoxine–pyrimethamine dur- ing pregnancy on placental malaria, maternal anaemia and birthweight in areas with high and low malaria transmission intensity in Tanzania. Declarations Trop Med Int Health. 2014;19:1048–56. 15. Ndeserua R, Juma A, Mosha D, Chilongola J. Risk factors for placental Ethical approval and consent to participate malaria and associated adverse pregnancy outcomes in Rufji, Tanzania: a Not required. hospital based cross sectional study. Afr Health Sci. 2015;15:810–8. 16. Ndyomugyenyi R, Clarke SE, Hutchison CL, Hansen KS, Magnussen P. Consent for publication Efcacy of malaria prevention during pregnancy in an area of low and Not applicable. unstable transmission: an individually-randomised placebo-controlled trial using intermittent preventive treatment and insecticide-treated nets Competing interests in the Kabale Highlands, southwestern Uganda. Trans R Soc Trop Med The authors declare that they have no competing interests. Hyg. 2011;105:607–16. 17. van Eijk AM, Ayisi JG, Kuile FO, Otieno JA, Misore AO, Odondi JO, et al. Author details Efectiveness of intermittent preventive treatment with sulphadoxine- 1 Department of Nutrition, University of Oslo, Oslo, Norway. 2 Department pyrimethamine for control of malaria in pregnancy in western Kenya: a of and Haematology, Muhimbili University of Health hospital-based study. Trop Med Int Health. 2004;9:351–60. and Allied Sciences, Dar‑es‑Salaam, Tanzania. 18. Kalinjuma AV, Darling AM, Mugusi FM, Abioye AI, Okumu FO, Aboud S, et al. Factors associated with sub-microscopic placental malaria and its Received: 17 June 2021 Accepted: 16 August 2021 association with adverse pregnancy outcomes among HIV-negative women in Dar es Salaam, Tanzania: a cohort study. BMC Infect Dis. 2020;20:796. 19. Mohammed AH, Salih MM, Elhassan EM, Mohmmed AA, Elzaki SE, El- Sayed BB, et al. Submicroscopic Plasmodium falciparum malaria and low Bakken and Iversen Malar J (2021) 20:348 Page 9 of 9

birth weight in an area of unstable malaria transmission in Central Sudan. in pregnancy in Africa: a systematic review and meta-analysis. Lancet Malar J. 2013;12:172. Infect Dis. 2019;19:546–56. 20. Dong S, Jonathan DK, Sunthorn P-T, Kabyemela E, Dufy PE, Fried M. CXC 24. Rijken MJ, McGready R, Boel ME, Poespoprodjo R, Singh N, Syafruddin D, ligand 9 response to malaria during pregnancy is associated with low- et al. Malaria in pregnancy in the Asia-Pacifc region. Lancet Infect Dis. birth-weight deliveries. Infect Immun. 2012;80:3034–8. 2012;12:75–88. 21. Kayentao K, Garner P, van Eijk AM, Naidoo I, Roper C, Mulokozi A, et al. 25. Kasaye HK, Endale ZM, Gudayu TW, Desta MS. Home delivery among Intermittent preventive therapy for malaria during pregnancy using antenatal care booked women in their last pregnancy and associ- 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low ated factors: community-based cross sectional study in Debremarkos birth weight in Africa: systematic review and meta-analysis. JAMA. town, North West Ethiopia, January 2016. BMC Pregnancy Childbirth. 2013;309:594–604. 2017;17:225. 22. Muanda FT, Chaabane S, Boukhris T, Santos F, Sheehy O, Perreault S, et al. Antimalarial drugs for preventing malaria during pregnancy and the risk of low birth weight: a systematic review and meta-analysis of randomized Publisher’s Note and quasi-randomized trials. BMC Med. 2015;13:193. Springer Nature remains neutral with regard to jurisdictional claims in pub- 23. van Eijk AM, Larsen DA, Kayentao K, Koshy G, Slaughter DEC, Roper C, lished maps and institutional afliations. et al. Efect of Plasmodium falciparum sulfadoxine-pyrimethamine resist- ance on the efectiveness of intermittent preventive therapy for malaria

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