research on malaria in pregnancy

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Article contents

Introduction, prevalence trends, associations with prevalence of malaria, meta regression, quality assessment, data availability statement, author contribution, funding statement, competing interest, ethical standard, malaria in pregnancy: meta-analyses of prevalence and associated complications.

Published online by Cambridge University Press:  13 February 2024

• Supplementary materials

This review aims to assess the prevalence of malaria in pregnancy during antenatal visits and delivery, species-specific burden together with regional variation in the burden of disease. It also aims to estimate the proportions of adverse pregnancy outcomes in malaria-positive women. Based on the PRISMA guidelines, a thorough and systematic search was conducted in July 2023 across two electronic databases (including PubMed and CENTRAL). Forest plots were constructed for each outcome of interest highlighting the effect measure, confidence interval, sample size, and its associated weightage. All the statistical meta-analysis were conducted using R-Studio version 2022.07. Sensitivity analyses, publication bias assessment, and meta-regression analyses were also performed to ensure robustness of the review. According to the pooled estimates of 253 studies, the overall prevalence of malaria was 18.95% (95% CI: 16.95–21.11), during antenatal visits was 20.09% (95% CI: 17.43–23.06), and at delivery was 17.32% (95% CI: 14.47–20.61). The highest proportion of malarial infection was observed in Africa approximating 21.50% (95% CI: 18.52–24.81) during ANC and 20.41% (95% CI: 17.04–24.24) at the time of delivery. Our analysis also revealed that the odds of having anaemia were 2.40 times (95% CI: 1.87–3.06), having low birthweight were 1.99 times (95% CI: 1.60–2.48), having preterm birth were 1.65 times (95% CI: 1.29–2.10), and having stillbirths were 1.40 times (95% CI: 1.15–1.71) in pregnant women with malaria.

Malaria during pregnancy is a significant source of concern in public health because of the negative repercussions it can have, not only on the mother but also on the developing foetus [ Reference Adam, Ibrahim and Elhardello 1 ]. According to the World Malaria Report by World Health Organization (WHO), there were 241 million cases of malaria in the year 2020 in 85 malaria endemic countries, an increase from the 227 million cases in 2019 [ Reference Aleem and Bhutta 2 ]). Concurrently, around 33.8 million pregnancies occurred during the same duration, with 34 percent of women accounting to 11.6 million being exposed to malaria infection during pregnancy [ Reference Aleem and Bhutta 2 ]).

According to literature, there are two types of malaria that can occur during pregnancy: placental malaria (PM) and gestational malaria (GM), both of which are diagnosed by demonstrating the presence of Plasmodium spp. in the placenta or the mother’s peripheral blood using a thick blood smear (TBS), polymerase chain reaction (PCR), or rapid diagnostic tests [ Reference Almaw 3 ]. Simple, quick, and more convenient, rapid diagnostic techniques have great potential in malaria detection. They may be of great utility as helpful instruments in the global delivery of health services by improving overall diagnosis of malaria infections. However, the testing procedure must be improved further to overcome the shortcomings of the present implementation. In spite of its drawbacks, such as time and expense, PCR remains the gold standard for identification of malaria parasites [ Reference Balduzzi, Rücker and Schwarzer 4 ].

Several unfavourable effects have been reported to occur after parasite sequestration, including maternal anaemia, foetal growth restriction, abortion or stillbirth, premature delivery, and low birthweight (LBW) [ Reference Cardona-Arias and Carmona-Fonseca 5 ]. Malaria contributes to up to 26% of cases of severe anaemia during pregnancy in endemic regions, and it is responsible for between 0.5 and 23% of all maternal fatalities caused by malaria [ Reference De Beaudrap 6 ]. In sub-Saharan Africa, malaria during pregnancy is responsible for up to 20% of LBW, or 35% of all avoidable LBW [ Reference Dellicour 7 , Reference Desai 8 ]. Successful malaria preventive measures during pregnancy have been shown to reduce perinatal death by 27% [ Reference Dellicour 7 ].

In malaria-endemic regions, pregnancy and the disease have been shown to worsen each other, especially for first-time mothers and individuals who were previously resistant to malaria. Though it has been previously reported that multigravida bear the heaviest burden of malaria in pregnancy both in terms of prevalence and outcome, it is now widely acknowledged that women with greater gravidities, even in areas of low transmission, are also susceptible [ Reference Dellicour 7 ].

About 125 million pregnant women worldwide are at risk of contracting malaria caused by either Plasmodium falciparum or Plasmodium vivax each year [ Reference Dosoo 9 ]. While Plasmodium falciparum malaria is responsible for most of the malaria-related morbidity, Plasmodium vivax may also play a crucial role in certain regions of South America and Southeast Asia [ Reference Falade 10 ]. A systematic review of sub-Saharan Africa concluded that the prevalence of Plasmodium falciparum was (22.1%, 95% CI: 17.1–27.2 %), followed by Plasmodium vivax 3% (95%CI: 0–5%), Plasmodium malariae 0.8% (95%CI: 0.3–0.13%), and Plasmodium ovale 0.2% (95%CI: −0.01–0.5) [ Reference Furuya-Kanamori, Barendregt and Doi 11 ]. Similarly, another meta-analysis has shown a significant incidence of malaria in pregnancy in Colombia, which emphasizes the urgent need for researchers, research funding organizations, government agencies, and health authorities to pay more attention to its research and intervention [ Reference Guyatt and Snow 12 ].

Based on the significant burden of malaria on the pregnancy outcomes and the health of pregnant women, marked variation in the available evidence is recorded due to diagnostic technique variability, heterogeneity in the enormity of disease, low sample size in some studies, lack of solid meta-analysis of relevant literature, and a substantial lack of understanding on the prevalence of malaria associated in pregnancy, which highlights the significance of a systematic review to quantify the prevalence of disease and understand the underpinnings pertaining to the causality and the burden of outcomes associated. Thus, the current review aims to assess the overall prevalence of malaria in pregnancy along with time-specific burden, that is, during antenatal visits and during delivery and to deduce the specie-specific and regional prevalence of infection. Secondarily, the review also aims to estimate the proportions of adverse pregnancy outcomes and its association with the presence of malarial infection.

Study design

Using the guidelines provided by ‘Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)’, a systematic review was conducted. Comprising of a 27-component checklist, the PRISMA guidelines aids in producing a transparent and coherent review which can be easily understood and interpretated globally [ Reference Guyatt and Snow 13 ].

Data source and searches

To find relevant articles, a thorough and systematic search was conducted on 31 July 2023 across two electronic databases (including PubMed and CENTRAL) using precise and accurate search strategies. Publications from the year 2000 to 2023 were searched using database specific strategies. To ensure completeness and entirety, manual searches were also conducted in addition to cross-referencing of source articles to avoid missing out any important source of evidence.

Search strategies

Based on the MeSH terminologies specific to the objectives and aims of the study, the following search strategy was developed to retrieve studies from databases.

(“Malaria”[Mesh] OR “Malaria, Vivax”[Mesh] OR “Malaria, Falciparum”[Mesh] OR “P. vivax malaria” OR “P. falciparum” OR “maternal malarial” OR “congenital malaria” OR “foetal malaria” OR “malaria in pregnancy” OR “malaria in pregnant”) AND ("Pregnancy"[Mesh:NoExp] OR pregnancy OR pregnant OR “malaria in pregnancy” OR pregnant women OR pregnant woman) AND (parasite densities OR diagnostic test* OR diagnostic* OR endemicity OR Intermittent Preventive Treatment OR IPT OR Intermittent Preventive Therapy OR Insecticide Treated Nets OR drug therapies)

Eligibility criteria

All the studies quantifying the burden of malaria in pregnancy along with the impact of Plasmodium falciparum and vivax on maternal and child adverse outcomes were taken into consideration. The studies considered eligible were those that were published after the year 2000, were in English language, and catered human subjects only.

The exclusion criteria involved: (1) Clinical trials in which the randomization was done on a predefined criterion; (2) Cohort studies in which the exposure of interest was malaria cases; (3) Case control studies in which the cases were malaria patients as this would not enumerate the burden; (4) Study designs including case reports, case series, commentaries, editorials, narrative reviews, and systematic reviews; (5) Studies using data from previous publications of the author.

To avoid double-counting/the same data being pooled more than once, data reported from different studies, such as those by the same authors, were checked to ensure patient cohorts were non-overlapping.

Study selection and data extraction

Articles retrieved from the databases were screened by two independent reviewers at a title and abstract level. Articles not immediately ruled out as irrelevant were then reviewed in a similar manner on a full-text basis. Where the relevance of an article was deemed ambiguous, or reviewer decisions conflicted, consensus was reached amongst the authors. Data were then extracted from each included article by a reviewer.

Extracted parameters included author names, publication year, location of study, diagnostic test used for malaria, malaria case count, strain of organism involved, time point in pregnancy at which diagnosis was made, sample size, and calculated prevalence. Additionally, where reported, data were extracted on complications and adverse outcomes for the pregnant women and their foetuses/offspring, for both test-positive and test-negative pregnant women. These data were used to perform secondary analyses to evaluate the association between malaria and maternal and infant morbidity.

Some studies reported adjusted odds ratios but not dichotomized data. Due to the non-uniformity in the method by which these odds ratios were computed, pooling them was deemed invalid and they were not extracted for meta-analysis.

Studies using multiple diagnostic modalities

Certain included studies tested the same subjects at the time time point for malaria using multiple diagnostic tools. Based on the evidence, a hierarchy of selection was determined to prefer PCR data, followed by microscopy, and then rapid diagnostic tests [ Reference Guyatt and Snow 13 , Reference Kaforau 14 ]. In this manner, the most reliable data for a cohort at a given time point were pooled in the analysis without double or triple counting.

Studies reporting prevalence of multiple strains or at multiple time points

Some included studies did not explicitly state an overall prevalence of malaria but reported prevalence in a strain-wise fashion. In these cases, it was evaluated if the reported patient positive for different strains of malaria were non-overlapping groups. Where this condition was met, the groups were combined, and the overall prevalence was calculated and utilized in the analysis.

Similarly, some studies reported prevalence data for a cohort during ANC and then again during delivery. Given that these estimates were taken at distinct points in time, they were considered separate datapoints and pooled in overall estimates of prevalence.

Peripheral and placental malaria

Where studies clearly reported overall prevalence data, the data were extracted and analysed simply. However, some studies reported results having tested participants for both peripheral and placental malaria. In such cases, data on peripheral infection were pooled and analysed and placental infection data were only used if that on peripheral infection was not reported.

Data analysis

The proportions of pregnant women who tested positive for malaria using any diagnostic technique were tabulated. Similarly, the proportions of pregnant women with adverse pregnancy outcomes were also recorded for both test-positive and test-negative women.

Along with confidence intervals of 95%, the following quantitative assessments of malaria were deduced:

1. Overall prevalence of malaria in pregnancy irrespective of the diagnostic test used, period of pregnancy and organism involved.

2. Prevalence of infection during antenatal care and at delivery.

3. Regional disparities of malaria proportions according to UNICEF regions.

4. Association of malaria with adverse pregnancy outcomes.

Due to heterogeneity caused by experimental differences between the included articles, all reported results were computed using a random-effects model meta-analysis. Point estimates and 95% confidence intervals are reported, while heterogeneity was evaluated using the Tau-squared and I-squared metrics, which represent the variance of the distribution of estimates reported by included studies and the percentage of that variation not attributable to sampling error, respectively. Forest plots were constructed for each outcome of interest highlighting the effect measure, confidence interval, sample size, and its associated weightage. Both pooled estimates and sub-groups estimates were illustrated using effective plots.

Publication biases were assessed using DOI plots and LFK index [ Reference Kaforau 14 ]. The sensitivity analysis was conducted through the leave-one-out method. This method recalculates the effect sizes and heterogeneity by removing one study each time [ Reference Kattenberg 15 ]. Additionally, meta regression analyses were conducted to evaluate differences in proportions within subgroups of region, species, and diagnostic test.

R-Studio version 2022.07.1 was used to carry out the meta-analysis using the package ‘meta’ (version 6.1.0) [ Reference Lawn 16 ], and a p -value of less than 0.05 was taken as benchmark of significance.

Each study included in the systematic review underwent a quality assessment to evaluate the research methodology employed in each study to ensure the reliability and validity of its findings. The Joanna Briggs Institute (JBI) critical appraisal tools, widely acknowledged and reliable for quality assessment, were used to investigate each study [ Reference Mabrouk 17 ]. It covers variations of study designs including analytical cross-sectional analysis, case–control, and cohort studies which were used to report the quality of studies in this systematic review. This tool aims to understand the extent to which the study has considered the potential bias in its design and implementation. An overview of the results has been provided in the tables.

Figure 1 below depicts the selection process of the studies included in the review. Initially, 7824 studies were retrieved out of which only 253 qualified for the final inclusion.

Figure 1. PRISMA diagram of included studies.

The characteristics of the included studies including the author and the year, title, study design, region, sample size, point of pregnancy at which the data were recorded, and diagnostic test used are summarized in Table 1 below.

Table 1. Characteristics of included studies

Supplementary Figure 2 shows overall trends of prevalence of malaria in an ascending order of years, estimated from 253 studies. As evident, the proportions have remained relatively persistent with the passing years and no significant reduction has been observed from the year 2000 to year 2023.

According to the pooled estimates, the prevalence of malaria was 18.95% (95% CI: 16.95–21.11, n=375,792) based on random-effects model. Similarly, when bifurcated on the time of reporting, the prevalence of malaria during antenatal visits was 20.09% (95% CI: 17.43–23.06, n =282,169, studies = 182) and during delivery was 17.32% (95% CI: 14.47–20.61, n = 93,623, studies = 121) using the same random-effects model. The heterogeneity was deduced using I-squared test, which was reported to be 99% in each model. Sensitivity analysis showed no change in the heterogeneity ( Supplementary Appendix Figure 1a ). The DOI plot was symmetrical indicating no publication bias ( Supplementary Appendix Figure 1b ).

Specie-specific prevalence

During the antenatal period, the prevalence of malaria caused by Plasmodium falciparum alone was 17.76% (95% CI: 15.04–20.85, n = 269,537, studies = 166) using random-effects model. This was followed by Plasmodium vivax caused infections accounting to 4.41% (95% CI: 2.80–6.89, n = 164,008, studies = 26) prevalence. In about 1.69% (95% CI: 0.80–3.52, n = 109,497, studies = 16) pregnant women, traces of both Plasmodium falciparum and vivax species were found as shown in Supplementary Figure 3a and Figures 2 and 3 .

Figure 2. Forest Plot depicting Plasmodium vivax pooled estimates of prevalence of malaria with 95% CIs.

Figure 3. Forest Plot depicting Plasmodium falciparum and vivax pooled estimates of prevalence of malaria with 95% CIs.

A similar pattern of infection was observed during delivery. Approximately 16.55% (95% CI: 13.57–20.04, n= 73,417, studies = 113) pregnant women were infected by Plasmodium falciparum and 5.18% (95% CI: 3.10–8.54, n= 21,928 studies = 17) by Plasmodium vivax, and 0.73% (95% CI: 0.19–2.75, n = 8149, studies = 7) were infected by both Plasmodium falciparum and vivax. The sensitivity analysis showed no change in heterogeneity ( Supplementary Appendix Figure 3a–c ). The DOI plots showed no asymmetry for Plasmodium falciparum but for Plasmodium vivax alone and combined vivax and falciparum thus concluding positive publication bias ( Supplementary Appendix Figure 2a–c ).

Regional distribution of malarial infection

The meta-analysis revealed that the highest proportion of malarial infection during ANC was observed in Africa approximating 21.50% (95% CI: 18.52–24.81, n = 110,012, studies = 143). This was followed East Asia and Pacific region accounting to 17.28% (95% CI: 9.29–29.86, n = 157,986, studies = 18). The lowest prevalence was observed in South Asia 8.66% (95% CI: 3.06–22.17, n = 8,513, studies = 9) followed by Latin America and Caribbean region 14.20% (95% CI: 6.31–28.91, n = 3,929, studies = 7) as shown in Supplementary Figure 4a . Sensitivity analysis revealed no significant difference. A symmetrical DOI plot was also indicative of no publication bias ( Supplementary Appendix Figures 4a and 5a ).

A similar random-effects meta-analysis at the time of delivery revealed that the prevalence of malaria in Africa was 20.41% (95% CI: 17.04–24.24, n = 46,925, studies = 95), in East Asia in Pacific Region was 16.33% (95% CI: 8.46–29.19, n = 22,214, studies =12), in Latin America and Caribbean region was 5.28% (95% CI: 2.68–10.12, n = 4,834, studies = 7), and in South Asia was 4.14% (95% CI: 1.52–10.80, n = 19,071, studies = 6) as shown in Supplementary Figure 4b . Sensitivity analysis revealed no significant difference. On the other hand, DOI for delivery showed minor asymmetry favouring positive publication bias ( Supplementary Appendix Figure 5b ).

Adverse pregnancy outcomes have shown mild-to-moderate associations with the prevalence of malarial infection in pregnancy.

A statistically significant association was observed between anaemia and malaria presence in 62 studies as shown in Figure 4 . The odds of having anaemia were 2.40 times (95% CI: 1.87–3.06) in malaria-positive women as compared to malaria-negative women. The heterogeneity of the studies as calculated with I-squared value was 86%. Sensitivity analysis revealed that the effect size of meta-analysis was deviating significantly due to two studies; hence, they were excluded ( Supplementary Appendix Figure 6 ). The DOI plot showed minor asymmetry thus depicting minimal publication bias ( Supplementary Appendix Figure 7 ).

Figure 4. Forest plot confirming association of malaria in pregnancy and anaemia.

Low birthweight

A significant association of low birthweight of the babies and malaria-positive women was also observed after pooling estimates from 42 studies as shown in Figure 5 . The overall odds ratio deduced was 1.99 (95% CI: 1.60–2.48). Sensitivity analyses revealed that two studies were responsible for major deviation in the effect size; hence, they were excluded. Absence of publication bias was confirmed by symmetrical DOI plot ( Supplementary Appendix Figure 9 ).

Figure 5. Forest plot confirming association of malaria in pregnancy and LBW.

Pre-term birth

A positive relation between malaria in pregnancy and preterm births was observed in 24 studies with an overall odds ratio of 1.65 (95% CI: 1.29–2.10) as shown in Figure 6 . The random-effects model took into consideration the heterogeneity of 49% as calculated by I-squared value. Sensitivity analysis revealed that the effect size of meta-analysis was deviating significantly due to one study; hence, it was excluded. The DOI plot showed major asymmetry, thus indicating positive publication bias ( Supplementary Appendix Figure 11 ).

Figure 6. (a) Forest plot confirming association of malaria in pregnancy and preterm births. (b) Forest plot confirming association of malaria in pregnancy and stillbirths. (c) Forest plot confirming association of malaria in pregnancy and SGA.

A statistically significant association was observed between stillbirths amongst malaria test-positive pregnant women with and odds ratio of 1.40 (95% CI: 1.15–1.71) based on ten studies as shown in Figure 6b . Sensitivity analyses revealed that one study was responsible for major deviation in the effect size; hence, it was excluded. The DOI plot showed major asymmetry, thus indicating positive publication bias ( Supplementary Appendix Figure 13 ).

Small for gestational age (SGA)

A significant association has been observed between SGA and pregnancy malaria with an overall odds ratio of 1.50 (95% CI: 1.42–1.59) 1.39 (95% CI: 0.99–1.96) using estimates of six studies as shown in Figure 6c . Sensitivity analysis revealed that the effect size of meta-analysis was deviating significantly due to one study; hence, it was excluded. The DOI plot shows minor asymmetry, thus depicting minimal publication bias ( Supplementary Appendix Figure 15 ).

An insignificant statistical association was observed in abortion and malaria in pregnancy with an odds ratio of 0.85 (95% CI: 0.21–3.48) using estimates from five studies ( Supplementary Appendix Figure 16 ). Sensitivity analyses revealed that two studies were responsible for major deviation in the effect size; hence, they were excluded. The DOI plot showed major asymmetry, thus confirming negative publication bias ( Supplementary Appendix Figure 17 ).

Preeclampsia

A statistically insignificant association was seen with pre-eclampsia using the estimates from three studies with an odds ratio of 0.82 (95% CI: 0.16–4.34). Sensitivity analyses revealed that one study was responsible for major deviation in the effect size; hence, it was excluded ( Supplementary Appendix Figure 18 ). The DOI showed no asymmetry, thus confirming absence of publication bias ( Supplementary Appendix Figure 19 ).

Growth restriction

A statistically insignificant association was seen with growth restriction using the estimates from two studies with an odds ratio of 1.21 (95% CI: 0.04–35.52, n= 508). There was no change in effect observed during sensitivity analysis ( Supplementary Appendix Figure 20 ). The DOI showed major asymmetry, thus confirming negative publication bias ( Supplementary Appendix Figure 21 ).

Results of meta regression analyses for region, diagnostic test, and specie variables are displayed in Table 2 Test of moderators were found significant in both region ( p < 0.001) and specie ( p -value < 0.01), indicating a significant influence on the effect sizes. The R-squared for region showed that 10.45% of the difference in the true effect sizes can be explained by the region, and 3.67% by the specie, and 1.22% by the diagnostic variable.

Table 2. Meta regression analysis of effect size with respect to region, diagnostic tests, and specie

For meta-regression analysis by region, South America had the highest effect sizes when compared with South Asia (b=1.92, p < 0.001) which was followed by Africa (b=1.35, p < 0.001). Conversely, the effect sizes for the East Asia and Pacific were relatively lower (b=1.07, p < 0.01).

None of the diagnostic tests showed a significant difference in effect sizes when compared with histopathology, as evident. With respect to specie, Plasmodium falciparum was the only specie with significantly higher effect size when compared to Plasmodium vivax in the meta regression analysis by specie.

All studies were included in the review after quality assessment. The JBI checklists for case–control, cohort, and cross-sectional studies were used according to the study designs ( Table 3 ). Each study was scored out of the number of questions included in the checklist. The highest score was 10 for case–control studies, 11 for cohort studies, and 8 for cross-sectional studies.

Table 3. JBI appraisal checklist for included studies

Abbreviations: Y, Yes; N, No; U, Unclear; N/A, Not Applicable.

Out of the 8 case–control studies, three studies scored 10/10, one study scored 8/10, and four studies scored 7/10. Of the 71 cohort studies, one study scored 11/11, twenty-two studies scored 10/11, seventeen studies scored 8/11, nineteen studies scored 7/11, one study scored 6/11, and two studies scored 5/11. Of the 174 cross-sectional studies, seventy-one studies scored 8/8, fifteen studies scored 7/8, sixty-three studies scored 6/8, nineteen studies scored 5/8, five studies scored 4/8, and one study scored 3/8.

The most common problems that came across overall were the identification of confounding factors and strategies to deal with confounding factors were not mentioned clearly. In the cohort studies, the most common problem was that the subjects were not free of the outcome at the start of the study and strategies to deal with incomplete follow-up were not clearly mentioned.

Malaria in pregnancy is a cause of extensive morbidity and mortality globally, both among infectious diseases and overall. While numerous studies have estimated the rate of infection in different regions, this meta-analysis synthesizes an immense volume of data to describe the overall prevalence and distribution of the disease. The findings of our study highlight that prevalence of malaria varies geographically, temporally, and species specifically. Amongst the many virulent species, Plasmodium falciparum has been the cause of highest incidence of infection. Similarly, African region has shown highest regional prevalence amongst the other regions. In addition, prevalence was higher during the antenatal visits as opposed to at delivery.

In addition, we have secondarily analysed and demonstrated that several morbid disease states and outcomes, such as anaemia, low birthweight, preterm birth, and stillbirth, may be significantly associated with malaria during pregnancy. These detrimental factors to the well-being and survival of mothers and their infants may influence maldevelopment and poor health in individuals throughout the life-course if left unaddressed.

As estimated by our study, Africa presents with the highest burden of malaria in pregnancy. This is in line with studies conducted earlier in the region and the report presented by the World Health Organization [ Reference Aleem and Bhutta 2 , Reference Matteelli 18 – Reference Moya-Alvarez, Abellana and Cot 20 ]. This may be due to malarial endemicity of the region as it is considered as the most tropical continent, coupled with higher transmissibility of the infection. This endemicity is the product of a complex interplay of environmental, biological, and socio-economic factors. Tropical climates with appropriate temperature, humidity, and rainfall conditions encourage endemicity of the disease as they are conducive to the reproduction of the parasite within the anopheles’ mosquito, which is itself native to these environments [ Reference Mabrouk 17 ].

However, this natural localization of malaria is compounded by a lack of robust and resilient health systems in many of the affected countries, where poverty, conflict, and natural disasters often further limit the impact of concerted public health efforts to tackle the disease [ Reference Kaforau 14 , Reference Kattenberg 15 ]. To counter, preventive measures and immunogenicity of the population play a very significant role in combatting the pathogenesis of disease in any geographical region. Thus, the prevalence has reduced within Africa but is still the highest amongst other regions [ Reference Munn 21 ]. Even though the studies of Africa have shown a significant reduction in the prevalence of malaria, it is worth noting that these measures have not accounted for all the countries in the region, hence limiting its generalizability [ Reference Furuya-Kanamori, Barendregt and Doi 11 ].

In this study, we also observed that Plasmodium falciparum was responsible for the pathogenicity of the majority of infections. Several systematic reviews have confirmed that P. falciparum is the highest inhabited organism in pregnancy to cause the infection [ Reference Dellicour 7 , Reference Ndifreke Edem, Okon Mbong and Hussain 22 ]. Our study’s findings of a disproportionately high prevalence of this organism of malaria underscore the importance of taking strong measures to prevent and manage the disease, especially among pregnant women. While the WHO malaria 2016 report found that over 99% of malaria cases were attributable to P. falciparum, our analysis found a smaller proportion of P. falciparum-causing illnesses [ Reference Otten 23 ]). Extreme seasonal, interannual, and geographical fluctuation may be responsible for these shifts. Possible causes include dissimilarities in development and housing patterns, population migration, as well as climatic (temperature, precipitation, and relative humidity) factors.

The study assessment also revealed that malaria-positive women were more prone to encounter anaemia. Several meta-analyses support our findings as the overall odds of malaria of anaemia are higher amongst pregnant women with malaria [ Reference Page, McKenzie, Bossuyt, Boutron, Hoffmann, Mulrow, Shamseer, Tetzlaff, Akl, Brennan, Chou, Glanville, Grimshaw, Hróbjartsson, Lalu, Li, Loder, Mayo-Wilson, McDonald, McGuinness, Stewart, Thomas, Tricco, Welch, Whiting and Moher 24 ]. According to a review, malaria is responsible for an estimated 26% of the severe anaemia experienced by pregnant women of all gravities (population attributable fraction) [ Reference Dellicour 7 ]. Anaemia is strongly linked to malaria, although the underlying pathophysiology is poorly understood. Nonetheless, illness-related inadequate food intake, haemolysis, and a lack of micronutrients are all viable justifications for anaemia and malaria.

Association of low birthweight with the presence of maternal malaria was amongst the deductions from our study. This is validated by other reviews conducted that suggest the same statistically significant association between malaria in pregnancy and low birthweight of the baby [ Reference Rayco-Solon, Fulford and Prentice 25 ]. Around 19% of LBWs and 6% of LBW-related infant fatalities are attributed to malaria in regions where the disease is endemic. According to these estimates, over 100,000 infants die each year in parts of Africa where malaria is common because to LBW [ Reference Rogerson and Unger 26 ].

Augmenting with the findings of our study related to preterm babies and malaria exposure, several reviews have reported malaria to be the primary infection in pregnancy that can be associated with the PTB [ Reference Willis and Riley 27 ]. Moreover, PTB seasonality patterns were also observed in some studies to be paralleling those of malaria infection, with its peak occurring with periods of high malaria infection [ 28 ].

Our study also revealed that proportions of stillbirths were higher with women with malaria in pregnancy. This has been validated by other reviews conducted earlier that have reported a widespread effect of malaria and risk of stillbirths [ Reference Falade 10 , 29 ]. Amongst the major modifiable risk factors of stillbirths, risk attributed to malaria is approximately 8% which can be prevented if exposure minimized [ Reference Yimam, Nateghpour, Mohebali and Afshar 30 ].

Amongst the major strengths of the review, the inclusion of 253 studies determining the burden of malaria in pregnancy creates a substantial mark. It gives us a holistic global standpoint of prevalence of the disease and its association with adverse pregnancy outcomes on both the maternal and neonatal health. To further strengthen the robustness of the review, sensitivity analyses were performed which refined the effect sizes of the meta-analyses eliminating the influential studies. In addition, assessment of publication bias was also undertaken to identify the presence of biases via relevant plots.

The limitations of the review include the non-uniformity of diagnostic test used. Multiple approaches, varying in sensitivity and specificity, were used to detect malaria during pregnancy. Not all studies utilize PCR for logistical reasons, and microscopy and rapid diagnostic tests are vulnerable to errors depending on reagents, personnel, mutant strains, and other factors. It is also pertinent to note that we lacked access to individual patient data from the studies that yielded adjusted estimates; thus, we were unable to account for this variation. Since the factors adjusted were not uniform in all studies, dichotomous data were preferred as a measure of reported and studies that failed to report dichotomous data were excluded. Further, confounding was also not taken into consideration when deducing associations with adverse outcomes and we also could not conduct the association analysis by strain due to paucity and diversity of data, which did not allow us to do a sub-group analysis.

Despite significant work being done to control the spread of the disease, the burden of malaria persists. A substantial impact of unfavourable pregnancy outcome also adds up to the seriousness of the issue and requires urgent attention and concern. Large-scale interventional studies are the need of the time to address this public health issue along with global level policy formulations to target the vulnerable populations living with such elevated burden of disease.

Supplementary material

The supplementary material for this article can be found at http://doi.org/10.1017/S0950268824000177 .

Data are available upon reasonable request. All data relevant to the study is included in the article.

Conceptualization: S.L., J.K.D., S.K., Z.A.P., M.A.B.; Data curation: S.L., F.S., J.K.D., S.K.N., Z.R.; Formal analysis: S.L.; Investigation: S.L., F.S., J.K.D., Z.A.P., Z.R., M.A.B.; Methodology: S.L., F.S., J.K.D., A.R.R., Z.A.P.; Project administration: S.L., J.K.D., Z.A.P., M.A.B.; Writing – original draft: S.L., H.J., O.M.; Writing – review & editing: S.L., H.A.N., J.K.D., S.K., Z.A.P., M.A.B.; Supervision: J.K.D., Z.A.P., M.A.B.; Validation: J.K.D., S.K., M.A.B.; Resources: A.R.R.; Software: A.R.R.

There was no funding available for the review.

There is no competing interest declared.

Ethical approvals were acquired from the Ethics Review Committee of the Aga Khan University Hospital and the Institution Review Board of the Jinnah Postgraduate Medical Center. Patient privacy and confidentiality were maintained at every stage of the study.

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• Jai K. Das (a1) , Sohail Lakhani (a2) , Abdu R. Rahman (a1) , Faareha Siddiqui (a1) , Zahra Ali Padhani (a3) , Zainab Rashid (a1) , Omar Mahmud (a4) , Syeda Kanza Naqvi (a1) , Hamna Amir Naseem (a1) , Hamzah Jehanzeb (a4) , Suresh Kumar (a5) and Mohammad Asim Beg (a6)
• DOI: https://doi.org/10.1017/S0950268824000177

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REVIEW article

Malaria in pregnancy: from placental infection to its abnormal development and damage.

• 1 School of Biosciences, Taylor’s University, Subang Jaya, Malaysia
• 2 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
• 3 Department of Medicine, Monash University, Victoria, VIC, Australia
• 4 National Center for Infectious Diseases, Singapore, Singapore
• 5 Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore
• 6 Department of Medicine at Royal Melbourne Hospital, Peter Doherty Institute, University of Melbourne, Melbourne, VIC, Australia

Malaria remains a global health burden with Plasmodium falciparum accounting for the highest mortality and morbidity. Malaria in pregnancy can lead to the development of placental malaria, where P. falciparum -infected erythrocytes adhere to placental receptors, triggering placental inflammation and subsequent damage, causing harm to both mother and her infant. Histopathological studies of P. falciparum -infected placentas revealed various placental abnormalities such as excessive perivillous fibrinoid deposits, breakdown of syncytiotrophoblast integrity, trophoblast basal lamina thickening, increased syncytial knotting, and accumulation of mononuclear immune cells within intervillous spaces. These events in turn, are likely to impair placental development and function, ultimately causing placental insufficiency, intrauterine growth restriction, preterm delivery and low birth weight. Hence, a better understanding of the mechanisms behind placental alterations and damage during placental malaria is needed for the design of effective interventions. In this review, using evidence from human studies and murine models, an integrated view on the potential mechanisms underlying placental pathologies in malaria in pregnancy is provided. The molecular, immunological and metabolic changes in infected placentas that reflect their responses to the parasitic infection and injury are discussed. Finally, potential models that can be used by researchers to improve our understanding on the pathogenesis of malaria in pregnancy and placental pathologies are presented.

Introduction

Malaria is a blood-borne disease caused by Plasmodium spp., with Plasmodium falciparum ( P. falciparum ) being the most deadly species ( World Health Organization [WHO], 2020 ). Pregnant women, especially first-time mothers, are at high risk of severe malaria due to P. falciparum , hence P. falciparum- related malaria in pregnancy (MiP) will be the focus of this review. Long-term childhood exposure to the parasites can result in the development of protective antibodies; however, first-time pregnant mothers become susceptible again ( Teo et al., 2016 ). Their susceptibility can be attributed to the P. falciparum erythrocyte membrane protein-1 (PfEMP1), a major variant surface antigen displayed on the surface of P. falciparum -infected erythrocytes (IEs) that serves as an adhesin ( Lennartz et al., 2019 ; Wang et al., 2021 ). Each parasite has up to 60 var genes that encode the PfEMP1 molecules, and only a single variant is expressed at any one time ( Smith et al., 2001 ). Switching of this var gene expression enables P. falciparum to evade host immunity. Consequently, IEs can sequester in organs and avoid splenic clearance, which then promotes inflammation and/or microvasculature obstruction ( Biggs et al., 1991 ; Dondorp et al., 2008 ; Chua et al., 2021b ). VAR2CSA is a PfEMP1 molecule that is expressed during MiP, and it mediates the binding of IEs to placental receptors such as chondroitin sulfate A found on placental syncytiotrophoblast (SCT) ( Salanti et al., 2003 ; Tuikue Ndam et al., 2005 ). As a result, IEs accumulate within the placenta, triggering an inflammation in the placental intervillous spaces; the infected and inflamed placenta is commonly termed as placental malaria (PM). PM is particularly common amongst first-time pregnant women, due to their lack of immunity against placental-binding IEs, and this is likely to adversely impact the placenta, leading to poor outcomes in MiP ( Fried et al., 1998 ; Staalsoe et al., 2001 ; Tran et al., 2020 ). However, our understanding on the physical and physiological changes to the infected placentas during PM is still rather limited, mainly due to the invasive nature of studying placental tissues during pregnancy and the limitations associated with existing animal models of MiP.

In this review, we will first provide a general overview of a successful pregnancy, followed by a detailed discussion on MiP and its deleterious impact on the placenta. The different immunological, molecular and metabolic changes in the infected placentas following parasitic infection, which are subsequently linked to placental injury and its dysregulated physiology, will be reviewed. We will include findings from several established rodent models of MiP which have enhanced our understanding on the topic, albeit there are differences between humans and rodents, as described in Table 1 . Lastly, we discuss potential models that can be used by researchers to better understand the pathogenesis of MiP and the mechanisms underlying placental damage and injury in this disease.

Table 1. Comparison between humans and rodent models of malaria in pregnancy.

A Successful Pregnancy

A successful pregnancy requires proper development of the placenta and its sustenance throughout pregnancy. In the first trimester, T h 1 pro-inflammatory responses promote proper tissue remodeling and angiogenesis; dysregulated immune responses have been associated with increased risk of early pregnancy failures ( Wang et al., 2020 ). Subsequent shift toward a T h 2 environment during the second trimester, characterized by increased anti-inflammatory cytokine levels and expansion of regulatory T cells, allows for rapid fetal growth and prevents fetal rejection ( Aluvihare et al., 2004 ; Wang et al., 2020 ). At the end of pregnancy, there is a shift back to the pro-inflammatory environment with increased IL-1β, IL-6, and IL-8 expression, which are essential for parturition ( Christiaens et al., 2008 ; Rinaldi et al., 2017 ). However, elevated T h 1-type responses in the third trimester can increase the risk of pre-term birth ( Romero et al., 2014 ; Fried et al., 2017 ).

Various immune tolerance mechanisms in the placenta play crucial roles to prevent fetal rejection. For example, placental trophoblasts do not express the classical major histocompatibility complex (MHC) molecules, which can otherwise trigger a pro-inflammatory immune cascade. Instead, they widely express the non-classical human leukocyte antigen (HLA)-G and HLA-E molecules that protect the placenta from CD8 + T cell and decidual natural killer cell cytotoxicity ( Tersigni et al., 2020 ; Xu et al., 2020 ). The placenta can also secrete exosomes with immuno-regulatory functions, such as inducing the differentiation of macrophages to display characteristics of decidual cells that play important roles at the maternal-fetal interface ( Bai et al., 2021 ). In addition, Hofbauer cells, which are fetal-derived placental macrophages in the chorionic villi, display M2 phenotype and express IL-10 ( Yang et al., 2017 ). IL-10 is an anti-inflammatory cytokine expressed throughout pregnancy, with higher expression levels detected during first and second trimesters, and the lack of this cytokine was associated with poor pregnancy outcomes such as growth restriction and preterm birth ( Cheng and Sharma, 2015 ). However, clinical studies and rodent models, increased IL-10 levels at delivery have been associated with poor birth outcomes, suggesting possible impairment in parasite clearance that may contribute to poor outcomes ( Megnekou et al., 2013 , 2015a ). Overall, the dysregulation of either T h 1 or T h 2 responses during pregnancy may contribute to adverse outcomes and maintaining a balance between pro- and anti-inflammatory immune responses is crucial for a healthy pregnancy.

The Development of the Human Placenta

The placenta is a highly specialized organ that regulates the exchange of metabolites between fetal blood in the chorionic villi and maternal blood within the intervillous spaces. Defective placental development can lead to placental insufficiency, contributing to fetal growth restriction (FGR), miscarriage and stillbirth ( Brosens et al., 2011 ). Critically, placental development is a complex and yet delicate process. In the first trimester, the trophoblast, a specialized group of cells, differentiates to form blastocyst, and the outer layer termed trophectoderm fuses to the uterine endometrium to form the primary syncytium. The primary syncytium then further divides and differentiates into the cytotrophoblasts (inner core) and SCT (outer layer). Around 6–8 weeks after implantation, the SCT rapidly expands, forming branching villous trees that invade maternal intervillous spaces and endometrial glands, subsequently allowing the perfusion of intervillous spaces with maternal blood. Toward the second trimester, the cytotrophoblasts continue to expand, giving rise to extravillous trophoblasts that will further invade the decidua and maternal uterine spiral arteries ( Figure 1 ). The uterine spiral arteries then undergo extracellular remodeling through degradation and rebuilding, a process which is critical for ensuring adequate blood supply to the placenta during pregnancy. This complex process involves various immunological cells such as decidual macrophages, regulatory T cells and uterine natural killer cells ( Staff et al., 2020 ), as well as angiogenic, vascular, and placental growth factors ( Hanna et al., 2006 ; Lash et al., 2006 ).

Figure 1. Schematic representation of a healthy functional unit of the human placenta. The placenta is a specialized organ that is primarily involved in the exchange of metabolites between the mother and her fetus. In the early trimester, the trophoblast differentiates to form primary syncytium that further divides into the cytotrophoblast and syncytiotrophoblast. The syncytiotrophoblast will then expand to form a continuous layer of tree-like villous that are in contact with maternal blood in the intervillous spaces. These villous trees greatly increase the surface areas available for the exchange of metabolites. Cytotrophoblasts can further differentiate into extravillous trophoblasts that invade the decidua, which is the maternal uterine tissue, to promote immune tolerance between the mother and her fetus. The extravillous trophoblasts also migrate up the maternal spiral arteries and promote spiral artery remodeling, to form large vessels of low resistance that is required to sustain a healthy pregnancy.

Placental Pathologies During Malaria in Pregnancy

Dysregulated placental vascularization and angiogenesis.

Bilateral uterine artery notching and concomitant vascular resistance are signs of disruption to the utero-placental hemodynamics and these have been observed in P. falciparum -infected placentas ( Dorman et al., 2002 ). Placental vascularization begins as early as eight gestational weeks (GW) ( Leijnse et al., 2018 ), hence infection during and after this period may affect the development of placental vasculature and its blood flow. In placentas from Tanzanian women, MiP before 15 GW was associated with decreased volume of transport villi and increased diffusion distance in diffusion vessels, suggesting impairment of placental vascular development ( Moeller et al., 2019 ). Furthermore, Doppler ultrasound studies showed that infection before 20 GW in primigravids was associated with increased umbilical artery resistance, an indirect measurement of resistance flow within the placenta ( Griffin et al., 2012 ; Ome-Kaius et al., 2017 ). A study on a cohort of Malawian pregnant women revealed that MiP infection between 13 and 23 GW was associated with dysregulation of various angiogenic factors and metabolic hormones, which play vital roles in placental vascularization ( Elphinstone et al., 2019 ). Impaired trophoblast differentiation, represented by shallow trophoblast invasion and narrow spiral arteries formation, may contribute to increased umbilical artery resistance and poor placental perfusion, leading to preeclampsia ( Roland et al., 2016 ; Obiri et al., 2020 ). MiP before 18 GW was associated with reduced trophoblast invasion and migration in vitro , suggesting possible reduction in placental blood circulation that might contribute to later pregnancy complications ( Abrahams et al., 2005 ; Umbers et al., 2013 ). Interestingly, MiP infection in later pregnancy, 32–35 GW, was also associated with increased uterine artery resistance ( Dorman et al., 2002 ). Given that the invasion of trophoblasts is usually complete around 19–20 GW, this pathology is more likely to be due to damaged trophoblasts and/or their impaired function in producing angiogenic factors to sustain exponential fetal growth in the third trimester ( Pollheimer et al., 2018 ). Additionally, in one study, women with PM were reported to be four times more likely to have low placental weight, which is a risk factor for FGR ( Singoei et al., 2021 ). This may be related to the dysregulation of angiopoietins, where women with higher levels of Angiopoietin-2 (Ang-2) were at higher risk of having low placental weight, and in PM, increased levels of Ang-2 in both peripheral and placental blood at delivery have been reported ( Silver et al., 2010 ; McDonald et al., 2016 ; Singh et al., 2020 ).

Irreversible Damage and Abnormal Placental Structure

Irreversible placental damage and abnormal placental structure have been reported in MiP, regardless of the timing of infection. Placentas from women who were infected in their first trimester showed signs of damage at delivery, including reduced transport villi, increased syncytial knotting and increased placental lesions ( Crocker et al., 2004 ; Elphinstone et al., 2019 ; Moeller et al., 2019 ). Active infection at delivery was associated with reduced villous area and vascularity, increased basal membrane thickening, syncytial damage, increased syncytial knotting, and fibrinoid necrosis ( Crocker et al., 2004 ; Chaikitgosiyakul et al., 2014 ). Collectively, the accumulation of fibrin in the intervillous spaces coupled with dysregulation of angiogenesis in placenta can result in inadequate perfusion to the placenta, causing necrosis ( Burton and Jauniaux, 2018 ). Necrotic cell death has been observed in infected placentas, with extensive syncytial breaks in some cases of active PM leading to denudation of the villi, vacuolation, and complete destruction of villous integrity ( Crocker et al., 2004 ). Chronic placental infection at delivery is characterized by increased accumulation of phagocytes in the intervillous spaces and sparse villi numbers, which are likely to reduce nutrient and protein transport across the placenta ( Figure 2 ; Lybbert et al., 2016 ; Chua et al., 2021a ).

Figure 2. Plasmodium parasite infection in the placenta that cause abnormal placental development and damage. Placental malaria is an infection in the placenta by Plasmodium spp., commonly P. falciparum . Emerging evidence suggests that pregnant women are at the highest risk of PM in the first trimester, which coincides with the period of placental growth and development. Abnormalities in the placenta during PM include permanent damage to placental structures such as broken syncytiotrophoblast, thickening of basement membrane, increased syncytial knotting, increased areas of fibrinoid necrosis and dysregulated apoptosis of trophoblasts. This can result in placental insufficiency that contributes to the increased risk of fetal growth restriction, low birth weight and pre-eclampsia. The pathology is mainly associated with the activation of a local inflammatory response, characterized by the accumulation of activated maternal mononuclear cells within the intervillous spaces. The subsequent pathways leading to placental pathologies include the increased production of pro-inflammatory cytokines, chemokines, and complement proteins, as well as reduced levels of important angiogenic and placental growth factors. Together, these factors may disrupt the development of placenta if infection takes place early in pregnancy, leading to shallow spiral artery development and increased intrauterine arterial resistance.

Hemozoin, the insoluble product of Plasmodium parasites, is commonly observed in the intervillous spaces, either trapped in fibrin or within maternal macrophages ( McGready et al., 2002 ). The presence of hemozoin in infected placentas can further cause placental damage through its immunomodulatory properties. For instance, hemozoin may fuel placental inflammation by reducing parasite clearance, as phagocytes that have ingested hemozoin were shown to have reduced phagocytic capacity and increased cytokine secretion ( Tyberghein et al., 2014 ). Furthermore, an in vitro study reported that hemozoin can activate SCT to produce cytokines and chemokines such as Tumor necrosis factor (TNF)-α, IL-8, CCL3, and CCL4; consequently, this may sustain an inflammatory response that contributes to increased inflammatory cell infiltration and fibrinoid deposits in the placenta ( Lucchi et al., 2008 ).

Apoptosis in the Placenta

Apoptosis is a physiological response that is involved in normal placental growth and development. The apoptosis of placental villi is observed throughout pregnancy, with increasing percentage of apoptosis being reported as the pregnancy progresses to third trimester ( Smith et al., 1997b ). High rates of apoptosis in the placenta have been associated with several pathological conditions including spontaneous abortion, intrauterine growth restriction, and preeclampsia ( Smith et al., 1997a ; He et al., 2013 ). Interestingly, active parasitemia at delivery was not associated with increased placental apoptosis despite being associated with significantly lower birth weights compared to healthy placentas ( Crocker et al., 2004 ). Instead, the study reported reduced apoptosis in placentas with past infections. In contrast, another study showed that apoptotic gene expressions were increased in women with past infections and increased oxidative insults may trigger apoptosis in the placenta ( Kawahara et al., 2019 ). The discrepancies could be because the latter study was based on a larger sample size and the authors performed molecular studies instead of histological analysis to detect apoptosis. In a mouse model of PM, increased oxidative stress, determined by increased levels of malondialdehyde (MDA) and reduced levels of antioxidant enzyme catalase, were associated with enhanced apoptosis in the placentas of mice with active infection ( Sharma et al., 2012 ). Similarly, apoptosis markers were observed in maternal blood and junctional zone trophoblasts in P. chabaudi- infected pregnant mice ( Sarr et al., 2015 ). Of note, the junctional zone trophoblasts are cells that are only found in mice placentas; it is unknown if specific types of human trophoblasts similarly undergo apoptosis during infection. In women with PM, similar findings of increased MDA and reduced antioxidant enzyme levels were also reported in placental tissues, suggesting that oxidative stress may contribute to pathophysiology of the placenta; however, whether or not this was mediated through placental apoptosis is unclear ( Megnekou et al., 2015b ). Further investigations are required to understand the mechanisms of apoptosis and its impact on placental function and outcomes at delivery in MiP.

Mechanisms Underlying Placental Pathologies in Malaria in Pregnancy

Disruption to placental blood vessels formation.

Decreased villous area and vascularity were observed in active P. falciparum infected-placentas compared to both healthy and previously treated malaria cases ( Chaikitgosiyakul et al., 2014 ). While the underlying mechanism has yet to be fully understood, it is hypothesized that activated maternal complement system during infection may play a role. C5a levels assayed from placental blood correlated negatively to Ang-1 levels, and positively to Ang-2, vascular endothelial growth factor (VEGF) (required for early vessel formation) and sFLt-1 (inhibits angiogenesis by binding to VEGF), suggesting that alterations in angiogenic factor expression may contribute to poor birth outcomes ( Conroy et al., 2013 ; Singh et al., 2020 ). Increase in the Ang-2:Ang-1 ratio in women with a positive episode of parasitemia during pregnancy has been reported and sustained Ang-2 levels during pregnancy may result in the formation of new blood vessels instead of vessel maturation; this may explain the excessive fetal vessels observed in infected placentas ( Leke et al., 2004 ; Silver et al., 2010 ). Importantly, in healthy pregnancies, a gradual increase and decrease in Ang-1 and Ang-2 levels, respectively, across pregnancy, enables the initial branching and subsequent maturation of blood vessels to promote normal placental vascular development ( Geva et al., 2002 ). Altered L-arginine level was also proposed as a contributor to dysregulated placental angiogenesis. L-arginine is a precursor of nitric oxide (NO), which plays a central role in promoting endothelial growth, regulating the expression of placental growth factors and angiopoietins ( Krause et al., 2011 ). In Malawi, MiP before 28 GW was associated with lower L-arginine levels and increased levels of NO inhibitors; these in turn, were associated with small for gestational age babies ( McDonald et al., 2018 ). In a mouse model of MiP, supplementation of L-arginine reduced C5 protein and Ang-2 expression, while Ang-1 level was upregulated ( McDonald et al., 2018 ). Furthermore, L-arginine supplementations led to an increase in total number of placental vessel segments and small-diameter vessels (<50 μm) compared to infected controls without supplementation, and this correlated with improved birth weight ( McDonald et al., 2018 ). Of note, these small-diameter vessels are important in vascular remodeling during pregnancy ( Geva et al., 2002 ). Overall, these findings suggest a potential intervention in improving vascularization in the placenta, but whether L-arginine supplementation is useful in pregnant women remains to be investigated.

Disruption to Placental Development and Utero-Placental Hemodynamics

The role of cytokines.

The production of pro-inflammatory cytokines during pregnancy is a double-edged sword. While timely production of these inflammatory mediators assists placental remodeling and growth, dysregulated production may cause irreversible damage to its structure and function. For example, although IFN-γ plays an important role in the remodeling of uterine spiral artery, excessive levels of the cytokine may be detrimental for fetal growth ( Ashkar et al., 2000 ; Suguitan et al., 2003a ). In a mouse model of PM, increased IFN-γ levels, and IFN-γ receptor 1 signaling were linked to reduced numbers of vascular branches in the labyrinth of the placentas compared to IFN-γ receptor 1 knocked-out (KO) mice ( Niikura et al., 2017 ). In normal pregnancy, TNF-α expression in the placenta was detectable across all trimesters but was highest in the second trimester ( Basu et al., 2016 ). In MiP, the levels of TNF-α were further elevated and often associated with poor birth outcomes ( Rogerson et al., 2003a ). Previous in vitro studies reported that TNF-α can exert various effects on the placenta such as inhibiting extravillous trophoblast invasion through promoting apoptosis and downregulating human chorionic gonadotropin (hCG) expression by cytotrophoblasts to cause suppressed trophoblast growth and increased apoptosis ( Leisser et al., 2006 ; Otun et al., 2011 ). These mechanisms could ultimately result in the inhibition of extravillous trophoblast invasion; however, they have yet to be proven in MiP models. Additionally, in a mouse model of PM, increased expression of TNF-α in the placenta was found to induce the expression of tissue factor, which correlated to hemorrhage, fibrin and thrombi formation in the placenta; interestingly, placental architecture can be preserved in mice treated with anti-TNF antibodies ( Poovassery et al., 2009 ).

In P. falciparum -infected placentas, increased inflammasome activation was also associated with increase in necrotic areas, fibrioid necrosis and syncytial aggregates ( Reis et al., 2020 ). In the same study, using murine PM model, it was revealed that inflammasome activation led to downstream increase in IL-1β signaling, which contributed to decreased expression of nutrient transporters including SNAT1, SNAT2, and GLUT1 gene expression in P. berghei -infected placentas ( Reis et al., 2020 ). In PM, decreased activities of amino acid and glucose transporters have been reported, but it is unclear whether these are similarly mediated through inflammasome activation ( Boeuf et al., 2013 ; Chandrasiri et al., 2014 ). Furthermore, in mice treated with an IL-1 receptor antagonist or in IL-1β KO mice, nutrient transporter expression was comparable to uninfected controls, suggesting that targeting the IL-1 pathway could be a possible therapeutic approach in MiP ( Reis et al., 2020 ).

The Role of Placental Hormones and Chemokines

A complex network of placental hormones ensures a functional placenta. Insulin-like growth factor (IGFs) are produced by placental cells and play pivotal roles in placental survival and promoting fetal development ( Han et al., 1996 ). Lack of IGFs was associated with decreased proliferation and poor survival of placental fibroblasts, which can predispose to FGR ( Miller et al., 2005 ; Forbes et al., 2008 ). In PM, pregnant women were reported to have reduced levels IGF-1, IGF-2, and IL-8, and increased levels of invasion-inhibitory factors including hCG and IL-10 in peripheral blood samples; these factors can inhibit trophoblast invasion and migration ( Jovanović et al., 2010 ; Umbers et al., 2013 ). In addition, the levels of fetal insulin-like growth factor-binding protein-1 (IGFBP-1) were elevated in PM; this molecule negatively regulates IGFs expression and is associated with placental insufficiency ( Shibuya et al., 2011 ; Umbers et al., 2011 ; Nawathe et al., 2016 ). Hypothetically, the dysregulated levels of these growth factors during early trimesters MiP may reduce trophoblast invasion and migration, subsequently affecting the transformation of maternal spiral arteries leading to FGR ( Lyall et al., 2013 ). Healthy placental development also requires chemokines that will recruit immune cells into the decidua during early stage of pregnancy; different chemokines may be needed at different stages of placental development ( Ramhorst et al., 2016 ). However, PM is known to cause elevated levels of chemokines within the intervillous spaces. CCL2 (MCP-1), CCL3 (MIP- 1α), CCL4, CXCL8, CXCL9, CXCL13, and CXCL16 have been observed in the placentas of women with PM, and CXCL9, CXCL13, and CCL4 were associated with adverse pregnancy outcomes such as low birth weight ( Ioannidis et al., 2014 ; Fried et al., 2017 ). In addition, increased levels of chemokines produced by maternal cells during infection is likely to result in the accumulation of phagocytic cells within the placenta ( Suguitan et al., 2003b ; Megnekou et al., 2015a ). Together, the recruitment of immune cells to the placenta due to infection rather than for the purpose of promoting placental growth, is likely to overdrive inflammation, thus adversely impact on the development of the organ.

The Role of Complement Proteins

The placenta’s ability to synthesize both complement proteins and their relevant inhibitors suggest that a tightly regulated complement system is essential for a successful pregnancy ( Bulla et al., 2009 ; Lokki et al., 2014 ). For example, in murine pregnancy model, C1q is synthesized by migrating extravillous trophoblasts to promote trophoblast migration and adhesion, whereas C1q deficiency was associated with impaired labyrinth development ( Agostinis et al., 2010 ). Dysregulated C5a levels may have pathological consequence, as increased C5a expression has been observed in the trophoblasts of pre-eclamptic placentas and C5a-stimulated trophoblasts demonstrated an anti-angiogenic phenotype in vitro ( Ma et al., 2018 ). In PM, increased peripheral and placental levels of C5a have been associated with poor birth outcomes in women from all gravidities ( Conroy et al., 2009 , 2013 ). In a mouse model of PM, increased C5a and C5a receptor (C5aR) expressions were observed. Interaction between C5a and C5aR was found to impair vascular remodeling necessary to compensate for the placental insult and C5aR blockade improved vasculature development, further highlighting the impact of complement on placental vascularization ( Conroy et al., 2013 ). Of note, these studies were conducted at delivery; hence future studies investigating infection at earlier trimesters are required to further improve understanding on the impact of complement system activation in placental development.

The Role of Activated Coagulation Cascade

Several studies have shown that MiP induces a pro-coagulative state in the placenta, characterized by perivillous fibrin deposits, elevated biomarkers of coagulation such as tissue factor and D-Dimer, as well as reduced levels of fibrinolysis biomarkers including protein-C, antithrombin-III, and tissue factor pathway inhibitor ( Avery et al., 2012 ; Mostafa et al., 2015 ). Tissue factor is primarily expressed by macrophages that are found in abundance in P. falciparum -infected placentas, particularly those with chronic PM, and may be the reason for increased fibrin deposition in these placentas ( Hohensinner et al., 2021 ). High levels of plasminogen activator inhibitor-1 (PAI-1) can suppress fibrinolysis, leading to increased fibrin deposition and pathological effects on tissues. Interestingly, pregnant women with submicroscopic infections, presumably due to having lower parasite density, had increased levels of PAI-1 but not fibrin deposition; PAI-1 levels were comparable to that of PM detected by microscopy ( Avery et al., 2012 ). The authors also found low levels of inflammation in the submicroscopic cases, suggesting that fibrin deposition/coagulation is likely to be triggered only in chronic infection. Indeed, increase in fibrin deposits was more common in placentas from primigravids, who are usually unable to effectively clear infection due to lack of immunity ( Rogerson et al., 2003b ). Given that coagulation may play a role in placental pathology, therapeutics that target the inflammatory-coagulation pathways may be useful in preventing placental injury. In vivo , the treatment of P. chabaudi -infected pregnant mice with low molecular heparin (an anticoagulant), showed absence of placental hemorrhage, tissue necrosis and large fibrin deposit in placentas ( Avery et al., 2012 ). More studies are required to determine if similar effects can be achieved in humans.

Dysregulated Autophagy and Heat Shock Proteins in Rescue Mechanisms

Autophagy is an important mechanism in normal pregnancy as it plays an important role in embryogenesis, implantation and placentation ( Nakashima et al., 2019 ). Autophagy is activated in extravillous trophoblasts during the invasion and vascular remodeling process early in pregnancy. In addition, it appears to be a protective mechanism against cellular senescence in trophoblasts ( Burton et al., 2017 ). However, increased autophagic activities in the villous trophoblasts have been associated with FGR and preterm labor ( Nakashima et al., 2019 ). In placental biopsies, PM with intervillositis increased autophagosome (an upstream pathway of autophagy) formation but not autophagy, and the density of autophagosome formation correlated negatively with amino acid uptake, suggesting that impaired autophagy may reduce transplacental amino acid transport ( Dimasuay et al., 2017b ). In another study, mRNA expression of autophagic genes were reduced in women with PM and was associated with low birth weight delivery ( Lima et al., 2019 ). The triggers of autophagic responses in MiP remains unclear, although hypoxia or inflammation are likely candidates ( Oh and Roh, 2017 ). The effect of MiP on autophagy in earlier stages of pregnancy is also unknown, as current studies employed the use of term placentas.

Heat shock proteins (HSPs) are produced by cells to promote recovery from an injury or stress. HSPs 27, 60, 70, and 90 are also found to be in abundance in the endometrial and uterine cells especially in the first trimester, suggesting that they may be involved in placental development ( Jee et al., 2021 ). Their roles in pregnancy may include maintaining the integrity of decidual cells, promote syncytialization and provide protection from preterm deliveries ( Jee et al., 2021 ). On the other hand, elevated levels of certain HSPs have been associated with adverse pregnancy outcomes including FGR and preterm deliveries, suggesting that abnormally high levels of HSPs may indicate excessive tissue damage ( Tan et al., 2007 ). In P. berghei PM model, levels of HSP 90, 70, 60, and 25 were increased in the placenta during infection, and levels of HSPs 70, 60, 25 but not HSP 90 decreased gradually with increasing disease severity ( Sharma et al., 2014 ). The decrease in HSPs 70, 60, and 25 was proposed to be responsible for placental necrosis, while increased HSP 90 appears to be a compensatory mechanism to repair damaged placental cells ( Sharma et al., 2012 , 2014 ). The mechanisms leading to altered HSP levels and how the repair mechanisms of these proteins are affected in MiP require further attention.

In vitro and in vivo Models to Delineate Pathways in the Placenta During Malaria in Pregnancy

Models that can recapitulate features of MiP are required for studying mechanisms underlying placental pathologies, as well as for testing potential therapies. Monolayer cell lines including primary human trophoblast, Swan 71 and BeWo cells have been used in MiP research, and some findings from these 2D models were successfully translated to in vivo findings ( Boeuf et al., 2013 ; Umbers et al., 2013 ; Dimasuay et al., 2017a ). However, there are still major limitations associated with these models; continuous cell lines have chromosomal abnormalities and single-cell model lacks the immunological stimuli that are usually present in the placentas during PM. Pehrson et al. (2016) reported that a novel ex vivo placental perfusion model can be used to investigate receptor-ligand interactions and they demonstrated the accumulation of parasites in the placenta. This may be a useful model to study real-time pathological changes in the placental tissues at later stage in pregnancy, albeit with some limitations such as requiring highly skilled personnel and specialized equipment. In vivo rodent models have been used to study PM, but their transferability to humans remains an issue. Mouse models were able to replicate certain consequences of PM including dysregulated immunological factors, imbalanced angiogenesis and vasculogenesis factors, and poor outcomes in offsprings ( Megnekou et al., 2013 ; Doritchamou et al., 2017 ; McDonald et al., 2018 ). Additionally, structural similarities and presence of analogous placental cell types between rodents and humans make them an attractive model for MiP ( Georgiades et al., 2002 ). However, there are differences in their placental structures, and certain features of placental inflammation such as monocytes/macrophages accumulation were not seen ( Poovassery and Moore, 2006 ; Sharma et al., 2016 ). In addition, the lack of hemozoin accumulation in mouse placentas suggests that the model may be suitable for studying acute rather than past and/or chronic infection ( Boareto et al., 2019 ). There are other limitations associated with rodent models including the absence of pre-existing immunity in mice which is not reflective of the conditions of pregnant women living in malarious regions, as well as difference in the degree of parasite sequestration and mode of infection between rodents and humans ( Table 1 ). On the other hand, while non-human primate models are more similar to humans in terms of physiology, high cost and sustainability issues arises. The suitability of animal models in MiP has been extensively discussed in many recent reviews, thus will not be further discussed here ( Doritchamou et al., 2017 ; Barateiro et al., 2019 ).

MiP in the first trimester can cause suboptimal development and irreversible damage to the placenta, hence it is crucial to study the effects of MiP during early pregnancy ( Chaikitgosiyakul et al., 2014 ; Moeller et al., 2019 ; Obiri et al., 2020 ). However, this proves to be a huge challenge, as existing models fail to replicate infection during early trimester. In recent years, newer models such as placental organoids have been used to study the placenta. Organoids are miniaturized in vitro tissue construct that are isolated from stem cells and the in vitro culture is usually representative of the organ in vivo . Placental organoids can be isolated from first-trimester trophoblasts and with appropriate growth factors and conditions, they can differentiate into SCT and extravillous trophoblasts that closely resemble first trimester placentas ( Haider et al., 2018 ; Okae et al., 2018 ; Turco et al., 2018 ). This would provide vast experimental opportunities on two major trophoblast layers that are involved in early placental development. For example, a recent study was able to establish innate immune signaling pathways during Zika infection using maternal-derived organoids and key roles of antiviral immunity at the maternal-fetal interface can be elucidated ( Yang et al., 2021 ). The use of trophoblast organoids to study early impact of MiP would allow real-time precise identification of placental responses during infection. Experimental design that includes a co-culture system of the organoids with immune cells can provide a better representation of the placental response, and specific cell populations that are responsible for placental damage or impaired placental development can be identified. This model can also be considered for the study of cytotoxicity and efficacy of potential therapeutics for early trimester MiP.

MiP remains a huge threat to the well-being of pregnant women and their developing fetus in malaria-endemic regions. Pregnant women are at the highest risk of MiP in the first trimester, which often results in poor placental development and irreversible placental structure damages that contribute to poor birth outcomes. Dysregulated levels of various soluble mediators have been associated with placental pathologies, including cytokines, chemokines, complement proteins, and growth factors. However, our current understanding of the pathogenetic mechanisms in the placenta relies either on a single time point during pregnancy, usually at delivery, or on animal models, which have their own limitations. Hence, there is a need to develop better models of the placenta to obtain a more comprehensive understanding of the pathogenesis of MiP during early pregnancy and follow through the disease progression. These efforts will ultimately enable the design of targeted strategies to aid placenta recovery and minimize the impact of MiP.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

CLLC received support from Ministry of Education (MOE) Fundamental Research Grant Scheme of Malaysia: FRGS/1/2020/SKK0/TAYLOR/02/1. AT was supported by the Nanyang Technological University Research Scholarship Block Fellowship of Singapore and Lee Kong Chian School of Medicine start up grant. TWY was supported by Lee Kong Chian School of Medicine Singapore, Start-up grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords : low birth weight, preterm birth, malaria, pregnancy, Plasmodium falciparum , syncytiotrophoblast, placental insufficiency, fetal growth restriction

Citation: Chua CLL, Khoo SKM, Ong JLE, Ramireddi GK, Yeo TW and Teo A (2021) Malaria in Pregnancy: From Placental Infection to Its Abnormal Development and Damage. Front. Microbiol. 12:777343. doi: 10.3389/fmicb.2021.777343

Received: 15 September 2021; Accepted: 20 October 2021; Published: 11 November 2021.

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Copyright © 2021 Chua, Khoo, Ong, Ramireddi, Yeo and Teo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Caroline Lin Lin Chua, [email protected] ; Andrew Teo, [email protected]

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• Open access
• Published: 11 March 2024

Prevention of malaria in pregnancy through health education intervention programs on insecticide-treated nets use: a systematic review

• Opara Monica Onyinyechi 1 ,
• Suriani Ismail 1 &
• Ahmad Iqmer Nashriq Mohd Nazan 1  

BMC Public Health volume  24 , Article number:  755 ( 2024 ) Cite this article

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Malaria is a widespread and prevalent disease that affects human population globally, particularly in tropical countries. Malaria is a major health issue in sub-Saharan Africa and it contributes to morbidity and mortality among individuals in Africa. Pregnant women have been also reported as high risk of people been infected with malaria. This review attempted to evaluate the various methods used for health education programs and the effectiveness of the programs in improving ITNs among pregnant women.

Methods  The search involved various databases; EBCOHOST, MEDLINE, CINAHL, Cochrane library, ScienceDirect, PubMed, SAGE, Sringer link, Web of Science and Wiley Online Library. It was limited to full text research articles that report intervention studies, written in English Language, published between 2003 to 2022. The key words were “malaria”, “malaria prevention”, “health education”, “insecticide-treated nets”, “utilization”, “pregnant women”.

Results  A total of eleven articles met the inclusion criteria and included in the review. Six studies reported randomized controlled trials (RCTs) while five reported non-randomized controlled trials (NRCT).

Conclusions  There are evidences from the results which showed that health education programs were improved among pregnant women due to the use of ITNs and LLINS utilization. Furthermore, additional interventions directed at significant others need to be implemented, considering their important role in determining pregnant women’s use of ITNs.

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Introduction

Malaria is a widespread and persistent disease that affects humans’ inhabitants globally, particularly in tropical countries. It is among the major health problems in sub-Saharan Africa and it contributes to morbidity and mortality among individuals in Africa [ 1 ]. According to what was well-described previously, the incidence of malaria decreased steadily from about 2000 to 2015, with delaying of progress since that time. There were 241 million cases of malaria in 2020 and an increase of 6% from 227 million in 2019 which WHO estimated for at latest (which, notably, include changes in estimates for past years) [ 2 ]. The distribution of mortality in young children markedly raised an estimates of malaria deaths that included a change for the past years. In 2020, deaths attributed to malaria increased to 627,000 as compared with 558,000 in 2019, 562,000 in 2015, and 896,000 in 2000. With the new baseline, it is estimated that 47,000 of the 69,000 increased deaths, compared with those in the previous year. In 2020, the results of service were disrupted due to the Covid-19 pandemic [ 2 ]. The problem has recently been worsened by the challenges of the pandemic and it made the progress against malaria to be stalled. The malaria problem has been greatest in Africa through recent times, but the imbalance between Africa and the rest of the world has been growing. Recently, many countries outside African have seen a remarkable malaria profits with so many moving towards elimination. In 2021, WHO certified China free from malaria. Meanwhile in 2020, sub-Saharan Africa accounted for 95% of the malaria burden [ 3 ]. Six countries in Africa accounted for 55% of cases and the countries included were Nigeria, Democratic Republic of the Congo, Uganda, Mozambique, Angola, and Burkina Faso. Malaria can be appreciated as primarily an African problem as the burden is overwhelmingly from Plasmodium falciparum; Plasmodium vivax, which is little seen in most of Africa, now makes up only 2% of total global cases even though the problem keeps persisting in a large part of the tropics [ 2 ]. Most of the global population lives in areas were malaria is endemic, pregnant women and young children below five years are vulnerable group for malaria infection [ 4 ]. A total of 10,000 pregnant women and 200,000 children die due to the complications of malaria annually [ 5 ]. An estimated of 207 million cases had led to around 627,000 mortality in 2012 [ 6 ]. In malaria endemic areas more than half of pregnant women are predictable to be asymptomatic carriers of parasitaemia [ 7 ]. Pregnant women have been also reported as high risk of people been infected with malaria. Malaria during pregnancy is associated with numerous health issues, this include decreases level of haemoglobin, miscarriage and premature delivery [ 8 , 9 , 10 ].

The WHO recommended three approach to malaria control during pregnancy which consist of the use of insecticide-treated nets (ITNs), intermittent preventive treatment (IPT), and case management treatment [ 11 ] and the pregnant women are encouraged to take preventive treatment monthly. Sleeping under an ITN each night and taking two doses of IPTp with sulfadoxine-pyrimethamine (SP) in pregnancy have been confirmed to reduce malaria infection risk and its complications in pregnancy [ 12 , 13 , 14 ].

Although trials have established that ITNs are effective malaria control approach. Within the period of 2019–2020, about 590 million ITNs were delivered to communities in sub-Saharan Africa, where most ITNs are distributed. However, the estimated percentage of the population with access to an ITN within their household and the percentage of the population sleeping under an ITN was 54% and 47%, respectively in 2021 which owned to several reasons.

[ 15 ]. In some parts of Africa, it has been previously reported that lack of access to ITNs and poor knowledge and perception on ITNs and malaria is a great important barrier to the use [ 16 ]. Though, access does not always result in usage due to sociocultural and logistical reasons [ 17 , 18 ] reported that over 90% of its respondents found ITNs to be uncomfortable to use, especially during pregnancy. The persistence of malaria challenges is predominantly felt in Africa, largely attributed to the setbacks caused by the disruptions of the COVID-19 pandemic. These disruptions have hampered the strides made in the efforts to eliminate the disease. Even with much studies on ITNs use, pregnant women still get infected with malaria during pregnancy. Use of insecticide treated nets in pregnancy has remained poor in spite of increased health education and awareness campaign by government agencies (Ezeama et al., 2014) (study gap). Thus, this paper reviews literature in order to understand the impact of health education intervention on the effects of ITNs in malaria prevention among pregnant women. Challenges of malaria burden still remain mostly in Africa due to the disruption related to COVID-19 pandemic which has set back all the progress that has been put in eradicating the disease. However, research on malaria still remains very much active by leading to the most important new tools to control the hardest hit areas which will make us to move towards eliminating the disease in many countries. There is an increased worldwide attention on the control of infectious diseases. We hope in a coming year, this attention will outgrowth will improve the efforts to eliminate and control malaria.

The purpose of this review is to evaluate the various methods used for health education programs and its effectiveness in improving the use of ITNs among pregnant women.

Materials and methods

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was used to report this review Fig.  1 (Boutron, Moher, Altman, Schulz & Ravaud). Inclusion criteria in this review were restricted to Health education intervention studies on insecticide-treated nets utilization among pregnant women, for example, randomized control trials (RCTs) and non-randomized controlled study (NRS) assessing the effects of health education interventions for pregnant women. Age limits of participants from 18 years and above. The intervention includes educational programs involving teaching, discussion, practical and demonstration. Exclusion criteria were articles that are Non-experimental studies, review papers, pharmacological trials, studies that focus on other chronic diseases were excluded. Articles that are not published in English language and articles published before 2003. Health education interventions studies that did not focus on malaria prevention in pregnancy, and studies that malaria prevention education are not sole intervention were excluded. The search involved various databases; EBCOHOST, MEDLINE, CINAHL, Cochrane library, ScienceDirect, PubMed, SAGE, Sringer link, Web of Science and Wiley Online Library. It was limited to full text research articles that reported only intervention studies that were written in English Language and it was published between the year 2003 to 2022. The key words used in the search were “malaria”, “malaria prevention”, “health education”, “insecticide-treated nets”, “utilization”, “pregnant women”.

PRISMA flow Diagram

Reference lists were checked and search for important studies, in order to detect additional related publications. Independently two authors reviewed the full-text articles to check if inclusion criteria were in accordance and compared results at each stage. All article retrieved during the search was assessed independently by two authors of the team. Each article titles and abstracts were screened subsequently and the full text screening was reviewed by two authors.

Search outcome

Studies on educational programs to improve insecticide-treated nets utilization for prevention of malaria among pregnant women were searched. A total of 2260 studies were identified through electronic searching using key words. Each article title and abstract were initially reviewed and assessed to know if they correspond with inclusion criteria to review the full text, published review paper, abstract, conference paper, dissertation and thesis were excluded from this review. Only 38 articles were included to review in full text. Only articles on Randomized Control Trails (RCTs) and Non-Randomized Studies (NRS) designs were included. Among the 38 articles, a total of 27 articles were excluded because of these reasons: articles are not intervention study and articles that are protocol development. The studies reviewed were based ITNs use in malaria prevention, pregnant women, health education programs and follow-up.

"The Consolidated Standards of Reporting Trials (CONSORT) statement for assessing non-pharmacologic treatments checklist was used as a reporting guideline to evaluate the articles" [ 19 , 20 ] Table  1 . The CONSORT components covered are title, abstract, introduction, methodology, results and discussion.

Abstracts was reviewed and screened by one author for inclusion criteria. Second set of reviewers assessed the retrieved articles for uncertainty. Articles that met the inclusion criteria were included to review full-text to confirm if inclusion criteria were met. Cochrane Risk of Bias Tool was applied by the authors to assess risk of bias, Table  2 shows summary of risk of bias (Cochrane Statistical Methods Group and the Cochrane Bias Methods Group). Based on the tool, assessing risk of bias in studies were as follows: "random sequence generation allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, short-term outcomes (2–6 weeks), incomplete outcome data, long-term outcomes (> 6 weeks) and selective reporting [ 30 ].

In this systematic review, a total of 463 records were retrieved from the databases based on our search strategy, 11 studies were reviewed (Table  1 ). The revived studies reported the sample size and it is from 25 to 495 patients. All studies stated respondents age and the age ranged from 18 years and above. Based on our risk assessment, (Table  2 ) summarized the risk of bias for the reviewed studies. Among the reviewed studies, the risk of bias was not clear however, two studies reported methodologically low risk of bias [ 21 , 31 ]. For both studies, the education interventions improved insecticide-treated nets utilization among pregnant women. The possible risk of bias is an evidence selection bias such as: random sequence generation, allocation, performance etc. (kindly check Table  2 for easy understanding).

Types of intervention studies

Six studies reported randomized controlled trial (RCTs) [ 21 , 22 , 23 , 24 , 31 , 32 ] and Five studies reported non-randomized controlled trial (NRCT) [ 25 , 26 , 27 , 28 , 29 ].

Most studies focus on education programmes on insecticide-treated nets utilization and its effectiveness over other prevention technique. Education programmes in all the studies was taught by trained personnel that has knowledge of research and they are either medical or health science graduates. Among the reviewed articles, studies were carried out either in health facility or at participant’s house. Some studies reported that there was no control group in their studies. Regarding the study location, eight studies were carried out in health facilities [ 21 , 23 , 24 , 25 , 26 , 27 , 31 , 32 ].

One study was conducted in household [ 28 ]. One study was conducted in Research Centre [ 22 ]. The educational approach included one-to-one or group approaches, groups discussion, teaching delivery method, demonstration on use of ITN posters and manuals.

A study reported that the intervention group received a four-hour health education intervention on ITN use, while the control group received a similar designed health education on breastfeeding [ 31 ]. Another study mentioned that pregnant women in the intervention group received health education sessions on malaria for 12 weeks, while those in the control group received routine information from health workers. Pre- and post-intervention assessment was on knowledge regarding malaria and use of insecticide bed nets [ 25 ]. In another study, the intervention group received health education on malaria, while the control group received health education on breastfeeding by the same facilitator [ 21 ]. Another study reported that health education and training was given to intervention group and control group on how to use and hang the bed net [ 22 ]. Meanwhile five studies did not mention what was given to the control group [ 23 , 26 , 27 , 28 , 32 ]. However, one study did not mention what was given to the intervention group and the control group [ 24 ]. Follow-up time differs in various studies, some was assessed at baseline. There was an observed time interval difference from baseline to end of the research in the reviewed studies. The longest evaluation time of two years follow‑up. One study follow-up at patients’ home [ 24 ].

Outcome measures

In the reviewed studies, outcomes measured were total knowledge, motivation and behavioural skills scores among pregnant women. Perceptions and practices regarding malaria and to improve ITNs use, ensure usage of ITNs among pregnant women. The reduction in severe anaemia at delivery, the reduction in low birth weight. The level of knowledge about malaria, malaria prevention among pregnant women; specific targets were increasing ITN use, and increasing access to intermittent preventive treatment (IPTp) in the form of two doses of sulphadoxine-pyrimethamine (SP) during pregnancy.

In the studies reviewed, a study pointed out that the intervention had significantly improved ITN use for the intervention group and also IPTp uptake at second follow up increased in the intervention group [ 31 ]. Moreover, a study improved in scores of knowledge and increase in use of LLINs scores in the intervention group compared to control after the intervention which was significant, and this shows that the intervention program had a positive effect [ 25 ]. Another study showed improvement in knowledge of ITN use, motivation, and behavioural skills scores respectively, for the intervention group over the control group [ 21 ]. Another study reported that the significant increase in the proportion of households who used LLINs the previous night compared with untreated nets participant. The study also reported that the educational program increased respondent’s knowledge regarding malaria transmission in intervention and control group. Also, respondent’s knowledge regarding mosquitoes breeding places improved in both intervention and control group. Knowledge regarding critical time to hang the net also increased over time in both intervention and control group but it remained quite low [ 26 ]. A study reported that there were improvements for ITN use for both intervention group and control group, however there was increases use of ITN in intervention group compared to control group. The education intervention program also improved adherence of IPTp and also increased the fraction of pregnant women that took minimum of two SP doses during pregnancy [ 27 ]. A study shows improvement in utilization of ITN in the control group when compared to the intervention group [ 22 ]. Another study shows improvement in ITN’s use for both the intervention and control groups for more than 90% of the participants improved in ITN’s use [ 23 ]. A study revealed that a significant increase also was seen in the proportion of households who used ITNs the previous night compared with untreated nets. Educational status was an important predictor of ITNs use. Regular use of ITN among the respondents were considered higher than the targeted coverage (80%) which was recommended by World Health Organization (29). In another study, the intervention group got improved due to the use of ITNs and household ownership of ITNs increased significantly over the study period with a significantly higher increase in the intervention group as compared to control group between the baseline and follow-up (24). A study revealed that in intense malaria transmission areas, ITN decrease adverse effect of malaria during pregnancies [ 24 ].

This review reported 11 studies on education of malaria preventive measures among the pregnant women from different kinds of intervention including RCTs and NRSs. Discussion method was based on the reviewed articles, the NRSs has high risk of bias, although the studies are relevant and have information on health education programme. Malaria prevent education among pregnant women which comprises of ITNs, LLINs IPTp, SP during pregnancy, written or spoken instructions on malaria prevention, group discussions on malaria prevention and also counselling that focused on promoting ITNs, aiming at preventing malaria in pregnancy.

WHO currently recommends that pregnant women in Africa malaria endemic region should use both IPTp-SP and ITNs for malaria prevention, the trials assessed the effect of ITNs and IPTp-SP simultaneously, the results showed that ITNs provided benefits in primigravidae if used alone [ 33 , 34 ]. The result of the reviewed studies shows that all education programs applied by the previous researchers’ shows improvement on ITNs, LLINs, IPTp, SP, knowledge of malaria transmission in intervention and control group. Also, respondent’s knowledge regarding mosquitoes breeding places among the pregnant women. Among the review articles, trained personnel in research field delivered educational programs and this will prevent observer bias.

Some studies were carried out in health facility and some at participants house based on the reviewed articles. With regards to the methods of educational programs, different intervention studies used different methods and approaches. The education programs were carried out in group session or one on one method, this include discussions, counselling, demonstrations. Discussions method is more effective because it helps to express, clarify participants knowledge, experiences and feelings. Discussion method helps the participants to apply and interchange ideas within the group. However, the challenges in discussion method is that it is time consuming, this is as a result of allocated time for the participants to ask questions after the discussion. Discussion method is not expensive unlike other methods example is demonstration method which requires materials to teach the respondents.

Among the eleven articles in this review only two studies were low risk of bias [ 21 , 31 ]. Both studies reported that the education interventions improved ITN use for the intervention group and also IPTp uptake at second follow up increased in the intervention group, also for the intervention group, there was improvement in knowledge of ITN use, motivation, and behavioural skills scores respectively.

In evaluating program effectiveness, Randomized Controlled Trials (RCTs) emerge as a superior design, offering a direct exploration of cause-and-effect relationships with minimal bias [ 35 ]. The straightforward nature of RCTs facilitates the investigation of program impact compared to observational studies, with the added advantage of easy blinding/masking (Jones, 2018). This characteristic enhances the reliability of findings, contributing to the validity of the study.

Moreover, the analysis of RCT results is streamlined through the utilization of well-established statistical packages, enhancing the robustness of the conclusions drawn [ 36 ]. Clearly defined populations of participating individuals in RCTs contribute to the transparency of the study, allowing for precise identification of contributing factors [ 37 ].

In light of these strengths, the authors of this paper advocate for the consideration of RCTs in future studies, particularly for long-term follow-ups [ 38 ]. Emphasizing patient-centered interventions, powered samples, strategic randomization approaches, and meticulous concealment and reporting of sample information are crucial for the success of future RCTs [ 39 ].

Furthermore, the authors recommend focusing on research that evaluates educational programs effective in improving Insecticide-Treated Nets (ITNs) and Long-Lasting Insecticidal Nets (LLINs) use among pregnant women. This emphasis on high-quality RCT design is paramount, as it ensures the generation of robust recommendations for healthcare practitioners and clinicians regarding optimal educational interventions to prevent malaria [ 40 ]. The impact of such interventions can potentially be transformative, contributing significantly to public health efforts in malaria prevention.

Strength and limitations of the study

This review reports the finding from studies that focus on effectiveness of health education intervention programs to improve ITNs, LLINs use among pregnant women. The selected articles were original research only, written in English language from year 2003 to 2022. Selection bias may occur during data extraction, due to only full text articles were searched. This review adherence with proper systematic review methodology, however because of limited time, resources and methodological issues in some of the reviewed studies, the authors could not proceed to meta-analysis.

From the 11 reviewed studies, there was a higher knowledge and practice of insecticide treated use among the intervention group during the intervention and the final follow-up visits. We can conclude in this review that the intervention program was effective in improving the study outcomes. The use of ITNs and LLINs is important and will also help for decision-making in the national malaria control program campaigns. Due to the ease of its implementation at scale, it can also improve maternal morbidity and mortality which could not only be beneficial in preventing malaria and reducing its burden of disease. Furthermore, additional interventions directed at significant others need to be implemented, considering the important role they play in determining pregnant women’s use of insecticide treated nets.

Availability of data and materials

This is purely a review paper, there was no data/analysis. The discussions and conclusions are purely based on the papers reviewed. Anyone that wishes to get the study data should contact the “Corresponding author”.

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Onyinyechi, O.M., Ismail, S. & Nashriq Mohd Nazan, A.I. Prevention of malaria in pregnancy through health education intervention programs on insecticide-treated nets use: a systematic review. BMC Public Health 24 , 755 (2024). https://doi.org/10.1186/s12889-024-17650-7

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Prevalence and associated factors of malaria among pregnant women in Sherkole district, Benishangul Gumuz regional state, West Ethiopia

• Girma Bekele Gontie 1 ,
• Haileab Fekadu Wolde 2 &
• Adhanom Gebreegziabher Baraki 2  

BMC Infectious Diseases volume  20 , Article number:  573 ( 2020 ) Cite this article

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Malaria during pregnancy leads to serious adverse effects on mothers and the fetus. Approximately 25 million pregnant women in sub-Saharan Africa live at risk of malaria. This study would help to achieve Sustainable Development Goals (SDGs) by improving programs that deal with the prevention of malaria. Therefore, this study aimed to assess the prevalence and associated factors of malaria among pregnant women.

A community-based cross-sectional study was conducted from July to August 2018 in Sherkole district, West Ethiopia. A multi-stage sampling technique was used to select 504 pregnant women. The interviewer-administered semi-structured questionnaire was used for data collection. Malaria was also diagnosed using a rapid diagnostic test. The data was entered using EPI info version 7.2.2.2 and transferred to SPSS version 20 for analysis. Descriptive statistics were done using frequency and percentages. Both bivariable and multivariable logistic regression models were employed. Variables having p -value < 0.2 were included in the final multivariable model. Variables having p -values < 0.05 from the multivariable model were considered to be significantly associated with the dependent variable. The adjusted odds ratio with its 95% confidence interval (CI) was used as a measure of association.

Of the total 498 pregnant women who participated in this study, 51(10.2, 95% CI: 7.72–13.24) were found to have malaria. Of these, 46 (90.2%) and 5 (9.8%) were caused by Plasmodium falciparum and Plasmodium vivax, respectively. Decreasing Age (Adjusted Odds Ratio (AOR) 0.78; 95% CI 0.67–0.911), not using insecticide-treated bed net (ITN) (AOR 12.5; 95% CI 4.86–32.21), lack of consultation and health education about malaria prevention (AOR 7.18; 95% CI 2.74–18.81), being on second-trimester pregnancy (AOR 7.58; 95% CI 2.84–20.2), gravidae II (AOR 5.99; 95% CI 1.68–21.44) were found to be significantly associated with malaria during pregnancy.

Malaria is still a public health problem among pregnant women in the Sherkole district. Age, ITN use, gravidity, gestational age, and health education had a significant association with malaria. Screening pregnant women for asymptomatic malaria infection and educating and consulting on the appropriate malaria preventive methods shall be provided.

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Malaria is caused by parasites of the genus Plasmodium and transmitted by female Anopheles mosquitoes. There are five different human malaria species such as P. falciparum , P. vivax , P. malariae, P. knowlesi and P. ovale . In 2016, an estimated 216 million cases of malaria and 445,000 deaths occurred worldwide [ 1 ]. Most, (90%), malaria cases and 91% of all malaria death in 2015 and 2016 were reported from the WHO African Region. Of the 91 countries reporting indigenous malaria cases worldwide, around 80% of the total cases were from sub-Saharan African countries [ 1 , 2 ].

Malaria during pregnancy is a serious public health problem in sub-Saharan Africa. It is estimated that each year approximately 25 million pregnant women in sub-Saharan Africa live at risk of P. falciparum malaria infection [ 3 ]. Two institution-based studies done among pregnant women attending antenatal care (ANC) in Nigeria showed the prevalence of malaria to be 41.6% [ 4 ] and 7.7% [ 5 ]. Another institution based study in Eastern Sudan showed 13.7% of pregnant women were infected with P. falciparum [ 6 ]. Studies conducted in Burkina Faso [ 7 ], and Malawi [ 8 ] also showed the prevalence to be 18.1%, and 19.% respectively. Besides, two institution and one community-based studies conducted in different parts of Ethiopia also showed the prevalence of malaria among pregnant women to be between 2.83 and 16.3% [ 9 , 10 , 11 ].

Malaria infection during pregnancy causes an enormous risk to the mother, fetus, and neonates [ 12 ]. Indeed although malaria during pregnancy might be asymptomatic due to a high level of acquired immunity in mothers residing in high transmission areas, it is still associated with an increased risk of maternal anemia, spontaneous abortion, stillbirth, prematurity, and low birth weight [ 3 , 13 , 14 ]. Moreover, severe maternal anemia increases the mother’s risk of death. Malaria-related anemia is estimated to cause as many as 10,000 maternal deaths each year in Africa [ 15 ].

Different risk factors for malaria among pregnant women were identified by previous studies. These include educational status [ 7 , 16 ], age [ 5 , 17 ], ANC visit, gestational age [ 18 ], parity [ 7 , 18 ], gravidity, and ITN utilization [ 11 ].

In Benishangul Gumuz regional state, almost all districts (98%) of the landmass are malarious areas and 97% of the population are at risk for malaria infection. Despite the high risk of malaria transmission in the area, there is limited evidence about the burden and risk factors of malaria among pregnant women which can be used for reducing maternal and child mortality due to the disease. Therefore, this study aimed to assess the prevalence of malaria and its associated factors among pregnant women in Sherkole District, Benishangul Gumuz regional state, West Ethiopia.

Study area and period

The study was conducted in Sherkole district, Benishangul Gumuz Regional state (BGRS) from July 20 to August 30, 2018. Sherkole district is one of the 21 BGRS administration districts which is found 756 km to the West of Addis Ababa, the capital city of the country, and 96 km far away from region city, Assosa. The district is found at a latitude of 13.169308 and longitude of 39.987117 and the altitude of the district is 680–800 m above sea level. The climatic condition of the district is hot and the annual temperature is estimated to be between 25 °C and 41 °C. The Annual range of rainfall in the district is 900–1200 mm. In this district, all kebeles are malarious with 39,373 populations at risk of the disease. In 2016/2017, the annual malaria incidence rate in the district was 263 cases per 1000 population. There were 1243 pregnant women, 1196 under 1 year, and 6370 under 5 years old of children in the district (Fig.  1 ).

Location of the study area

Study design and population

A community-based cross-sectional study was conducted. The source population for this study was all pregnant women at any gestational age living in the district. The study population was those pregnant women in the selected kebeles and who were available during the data collection period. Pregnant women with mental illness and severely debilitating diseases were excluded from the study.

Sample size determination and sampling procedure

The sample size was determined using a single proportion formula using a 50% prevalence of malaria among pregnant women, 95% confidence level, 5% margin of error, and design effect of 2. To compensate for the non-response rate, 10% of the determined sample size was added. Finally, finite population correction was done to adjust the final sample size which gives a total sample size of 504. A multi-stage sampling technique was used to select the determined sample size. At the first stage, from a total of 20 kebeles in the district, 8 kebeles with a a total of 1243 pregnant women were selected by using a simple random sampling technique. In the second stage, the sample size was distributed proportionally for the 8 kebeles based on the number of pregnant women in the kebeles with a range of 41 to 79 housholds for each kebele and then households were selected using a simple random sampling technique. Finally, pregnant women in the household were taken and in the presence of more than one eligible woman in a single household, a lottery method was used to select one.

Variable measurement and data collection procedure

The outcome variable for this study was malaria infection which was assessed using RDT and pregnant mother with any type of Plasmodium species from the test were considered as having malaria infection. The independent variables include socio-demographic factors (age, marital status, educational status, and occupational status); obstetric factors (gravidity, parity, trimester of pregnancy, history of abortion); malaria prevention measures (ITN ownership, indoor residual spraying (IRS) use, personal protective measures, and ITN utilization); health service use (accessibility of ANC, gestational age at the first visit, number of ANC visit, place of delivery for the previous child, previous history of malaria infection during pregnancy, and health education about malaria prevention methods during ANC follow up).

The interviewer-administered Semi-structured questionnaire was used to collect the required information. For those pregnant women who were on ANC followup, the data collector reviewed their antenatal followup cards to cross-check the information given by them. Card information checked includes; gravidity, parity, and gestational age at first ANC visit. Following the interviews, blood was obtained from the third finger of women’s left hand. First, the tip of the finger was wiped with a piece of cotton wool lightly soaked in alcohol. Then piercing with sterile lancet was done and the blood allowed to flow freely without squeezing the finger. Then, 5 μl (μl) blood was collected and a single small drop was added on the CareStart RDT to examine the presence or absence of malaria and to differentiate its species. The RDT read and determine the species qualitatively after 15–20 min of putting the blood to the kit. Ten percent of the randomly selected negative slides were rechecked and reread. Eight trained diploma nurses and midwives collected the data and they were supervised by two health professionals with a qualification of BSc degree. The questioner was pretested and one-day training was given for supervisors and data collectors on the basic technique of the data collection.

Data processing and analysis

The data were entered using EPI-Info 7.2.2 and then transferred to SPSS version 20 statistical package for further analysis. Data cleaning and management were done. Descriptive statistics (frequencies, mean, SD, and percentage) were done to explain the study population in relation to relevant variables. The Chi-square assumption was checked for all categorical independent variables and multicollinearity was also checked using the Variance inflation factor (VIF). Both bi-variable and multi-variable logistic regressions were used to assess the association between outcome and explanatory variables. Factors with p -value ≤0.2 from the bi-variable model were included in the final model. Variables having a p -value < 0.05 from the multivariable model were considered as having a statistically significant association with the outcome. Adjusted Odds ratio with 95% CI was used as a measure of association. The model goodness of fit was assessed using the Hosmer lemisho test.

Socio-demographic characteristics, obstetric characteristics, and malaria prevention methods adopted by pregnant women

A total of 498 pregnant women participated in this study with a response rate of 98.8%. The majority, 208(41.8%), of the pregnant women were in the age group of 25–29 years. Concerning the educational status, more than three fourth, 384(77.1%), of the mothers had no formal education. Almost all, 482 (96.8%), study participants were farmers and traditional gold miners. About 478 (96%) of respondents owned at least one mosquito bed net, and 405 (81.3%) of them sleep under mosquito nets in the previous night. Almost all, 485 (97.8%), of the households had Indoor Residual Spray (IRS) in the last 12 months. All women 431 (86.5%) who had ANC follow-up were given health education about the prevention methods of malaria infection during their ANC follow-up. The majority, 323 (64.9%), of the study participants were multi-gravida, and more than half, 292 (58.6%), of the study participants were in their third trimester of pregnancy (Table  1 ).

Prevalence of malaria infection among pregnant women

In our study, the prevalence of malaria was found to be 10.2% (95% CI: 7.72–13.24). Of these, 46(90.2%) were P. falciparum cases and 5 (9.8%) were P. vivax cases. From the total confirmed cases, the majority, 35 (68.8%) were asymptomatic.

Factors affecting malaria infection among pregnant women

From the bi-variable logistic regression, malaria was significantly associated with all of the variables at a significance level of 0.2. However, from the multivariable logistic regression model only age, ITN utilization, consultation about malaria prevention methods during ANC, trimester of pregnancy, and gravidity were significantly associated with malaria infection during pregnancy. For 1 year increase in the age of the pregnant women, the odds of malaria infection was decreased by 22%(AOR = 0.78, 95% CI: 0.67, 0.91). The odds of malaria infection was 14.98 times higher among pregnant women who did not utilize ITN compared to their counterparts (AOR = 14.98, 95% CI: 5.24, 42.27). Pregnant women who had no education about malaria prevention methods during their ANC follow up had 7.15 times increased odds of malaria infection compared to their counterparts (AOR = 7.15, 95% CI: 2.44, 20.96). Women who were in their first trimester of pregnancy had 23.33 times increased odds of having malaria infection compared to mothers on their third trimester (AOR = 23.33, 95% CI: 1.90, 28.20). Women who are in their second trimester of pregnancy also had 7.78 times increased odds of having malaria infection compared to mothers on their third trimester (AOR = 7.78, 95% CI:2.77, 21.87). The odds of malaria infection was 5.87 times higher among women who had their second pregnancy compared to multi gravid women (AOR = 5.87, 95% CI: 1.61, 21.37) (Table  2 ).

This study assessed the prevalence of malaria infection and associated factors among pregnant women in Sherkole district, Benishangul Gumuz regional state, West Ethiopia. Different studies reported different factors that affect the rate of malaria infection among pregnant women. Our study also assessed socio-demographic, obstetric, and ITN ownership and utilization factors. As a result, Age the woman, ITN utilization, health education about prevention methods during pregnancy, gestational age, and gravidity were found to be significantly associated with malaria infection.

In this study, the prevalence of malaria was found to be 10.2%. This result was higher than studies conducted in Felege Hiwot referral hospital and Addis Zemen health center, Ethiopia (2.83%) [ 9 ], rural district surrounding Arbaminch town, Ethiopia (9.1%) [ 11 ], coastal Ghana (5%) [ 19 ], South-West Nigeria (7.7%) [ 5 ], Southern Laos (8.3%) [ 20 ] and India (5.4%) [ 21 ]. This difference might be attributed to the difference in geographical location among the study areas. For instance, our study was conducted in a malaria-endemic area with a high rate of transmission. Therefore, individuals living in malaria-endemic areas have a greater chance of developing asymptomatic malaria, while those living in low transmission areas have a low chance of being infected, which can lead to a low prevalence of the diseases in such areas. Another reason for the difference could be the inclusion criteria used by the studies because our study included both symptomatic and asymptomatic pregnant women which might increase the prevalence but most of the other studies included only asymptomatic pregnant women. On the other hand, the prevalence in our study was found to be lower than studies conducted in Pawe hospital, Ethiopia (16.3%) [ 10 ], Sudan (13.7%) [ 6 ], Nigeria (41.6%) [ 4 ], Malawi (19.6%) [ 8 ] Burkinafaso (18.1%) [ 7 ] and a systematic review and meta-analysis in Ethiopia 12.7% [ 22 ]. It is also found to be much lower than the findings from two studies conducted in Nigeria which showed the prevalence to be 58% [ 23 ] and 59.9% [ 24 ]. This difference may be due to better implementation of improved malaria interventions including increased coverage in the distribution of Long Lasting Insecticide Treated Nets (LLINs), and indoor residual spraying in our study area which showed 96 and 81.3% of respondents own and utilize ITN, respectively. Almost all (98%) of participants in our study area also lived in residual sprayed households. Therefore, these interventions might reduce the malaria burden in the study area. Another possible reason for the low prevalence in our study could be, the study was done during the low malaria transmission season (July – August). However, the major transmission for malaria occurs between September and December.

In this study, 90.2% of the cases were caused by P.falciparum species. This result was in line with the study conducted in tropical Africa which showed 80–95% of malaria infections are caused by P. falciparum [ 19 ]. However, our result was higher than the national prevalence reports of the species which was 60–70% [ 25 ]. This high proportion of this malaria species in our study is a clear implication that there is a need for aggressive prevention and control of the diseases, especially among pregnant women. Because P. falciparum causes the most severe form of the disease and it can cause devastating complications not only for the mother but also for the fetus. This result also implies that there is a need for early screening of pregnant women for early detection and treatment of the cases to prevent possible complications. On the other hand, the proportion of malaria cases caused by P.falciparum in our study was lower than the WHO malaria 2017 report which revealed over 99% of malaria cases were due to P.falciparum [ 1 ]. The possible reason for these variations might be due to marked seasonal, inter-annual, and spatial variability. It may also be due to large differences in climate (temperature, rainfall, and relative humidity), human settlement, and population movement patterns.

In this study mothers with an increased age were found to have lower odds of developing malaria infection. This is in line with studies conducted in different tropical African countries [ 5 , 17 ] which reported pregnant women of young age are at the greatest risk of malaria infection, as well as having the highest parasite densities. This may be attributed to mothers with increased age have better exposure to health services and gain a good awareness about the disease and the ways of prevention. Also, due to previous frequent malaria exposures, older aged mothers might develop immunity to malaria. However, according to the studies conducted in rural surroundings of Arbaminch Town, Ethiopia [ 11 ], and Sudan [ 6 ], age had no significant association with malaria infection.

According to our study, pregnant women who were in the second trimester of pregnancy were at increased odds of developing malaria infection compared to mothers in the third trimester. Besides, and women who were gravidae II have increased odds of malaria infection compared to the multi gravid. Similar results were found from studies done in sub-Saharan Africa countries [ 7 , 11 , 18 ], which showed a higher risk of malaria infection among primigravidae and gravida two than multigravidae. Low risk of malaria among multigravidae mothers may be associated with the development of pre-immunity to malaria with increased gravidity and previous exposures. It might be also linked to infection-specific immunological factors. Some Plasmodium -infected erythrocytes sequester/arrest in the maternal placenta by producing surface antigens mainly variant surface antigens that adhere to chondroitin sulphate-A (CSA) receptors expressed by syncytiotrophoblasts in the placenta. These antibodies are associated with protection against placental infection. Therefore, primigravidae and secundigravidae mothers lack these anti-adhesion antibodies against CSA binding parasites, which develop only after successive pregnancies and this makes them more susceptible to infection [ 26 ].

In our study, getting a consultation and health education about malaria preventive methods during ANC follow up significantly decreased the odds of developing malaria infection during pregnancy. A similar association was found in studies conducted different parts of Ethiopia [ 27 , 28 ]. Health education and consultation specifically on prevention and control program of malaria during pregnancy ensures the use of antimalarials and other intervention measures effectively.

In this study, not using ITN increases the odds of developing malaria infection during pregnancy. Indeed, WHO, MoH, and presidents malaria initiatives (PMI) have advocated for a three-pronged approach to tackle malaria and one of the strategies is the use of ITN [ 1 , 25 , 29 ]. This study’s finding was also in agreement with the study conducted in Malawi [ 8 ], Nigeria [ 30 ], and Arbaminch, Ethiopia [ 11 ], which showed that the use of bed nets has a significant impact on decreasing malaria infection. The possible explanation for this association could be ITNs effectively reduce human-mosquito contact which can prevent diseases.

Since our study used a cross-sectional study design, it does not show a direct temporal relationship. Though using PCR and blood film microscopy may have higher sensitivity, we could not do these tests because the study is done in rural areas and there is no electricity in the area. Therefore, the result of this study could be affected by the inherent performance of the RDT utilized.

The prevalence of malaria infection among pregnant women was relatively low in Sherkole district and P. falciparum is the most predominant Plasmodium species in the area. Age of respondents, ITN use, gravidity, gestational age, and health education about malaria prevention methods during ANC had a significant association with malaria infection. Health professionals should give health education about malaria prevention methods during ANC and they should also give special attention to those pregnant women with the identified risk factors. Besides, further research is recommended by using more sensitive diagnostic methods like PCR and blood film microscopy for the diagnosis of malaria.

Availability of data and materials

The data upon which the result based could be accessed a reasonable request.

Abbreviations

Adjusted Odds Ratio

Antenatal Care

Benishangul Gumuz Regional state

Chondroitin Sulphate-A

Confidence Interval

Insecticide Treated Net

Long Lasting Insecticide Treated Nets

Ministry of Health

Presidents Malaria Initiatives

Rapid Diagnostic Test

World Health Organization

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Acknowledgments

We would like to express our deepest thanks to the University of Gondar College of Medicine and Health Sciences and Health Officer Department, for facilitating the research work. We also want to thank all pregnant women who participated in this study for their contribution.

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Ethical clearance was obtained from the Ethical review board of the University of Gondar and the permission letter was also obtained from Benishangul Gumuz regional state administration Health Bureau. Then this letter was delivered to Sherkole district Health office and the respected villages. The purpose and importance of the study were explained to the participants and since the majority of our study participants cannot read and write, verbal consent was obtained from each participant above the age of 18. Assent was also obtained for participants below the age of 18 from their parents or guardian. Pregnant women who tested positive were linked to the nearby health center for treatment. Confidentiality of the information was maintained by omitting their names and personal identification.

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Gontie, G.B., Wolde, H.F. & Baraki, A.G. Prevalence and associated factors of malaria among pregnant women in Sherkole district, Benishangul Gumuz regional state, West Ethiopia. BMC Infect Dis 20 , 573 (2020). https://doi.org/10.1186/s12879-020-05289-9

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Drug treatment and prevention of malaria in pregnancy: a critical review of the guidelines

• Khalid A. J. Al Khaja   ORCID: orcid.org/0000-0001-6591-7686 1 &
• Reginald P. Sequeira 1  

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Malaria caused by Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae. This review evaluated the adherence of the national guidelines drawn from World Health Organization (WHO) regions, Africa, Eastern Mediterranean, Southeast Asia, and Western Pacific, to the WHO recommendations on drug treatment and prevention of chloroquine-resistant falciparum malaria in pregnant women.

Thirty-five updated national guidelines and the President’s Malaria Initiative (PMI), available in English language, were reviewed. The primary outcome measures were the first-line anti-malarial treatment protocols adopted by national guidelines for uncomplicated and complicated falciparum malaria infections in early (first) and late (second and third) trimesters of pregnancy. The strategy of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) was also addressed.

This review evaluated the treatment and prevention of falciparum malaria in pregnancy in 35 national guidelines/PMI-Malaria Operational Plans (MOP) reports out of 95 malaria-endemic countries. Of the 35 national guidelines, 10 (28.6%) recommend oral quinine plus clindamycin as first-line treatment for uncomplicated malaria in the first trimester. As the first-line option, artemether–lumefantrine, an artemisinin-based combination therapy, is adopted by 26 (74.3%) of the guidelines for treating uncomplicated or complicated malaria in the second and third trimesters. Intravenous artesunate is approved by 18 (51.4%) and 31 (88.6%) guidelines for treating complicated malaria during early and late pregnancy, respectively. Of the 23 national guidelines that recommend IPTp-SP strategy, 8 (34.8%) are not explicit about directly observed therapy requirements, and three-quarters, 17 (73.9%), do not specify contra-indication of SP in human immunodeficiency virus (HIV)-infected pregnant women receiving cotrimoxazole prophylaxis. Most of the guidelines (18/23; 78.3%) state the recommended folic acid dose.

Several national guidelines and PMI reports require update revisions to harmonize with international guidelines and emergent trends in managing falciparum malaria in pregnancy. National guidelines and those of donor agencies should comply with those of WHO guideline recommendations although local conditions and delayed guideline updates may call for deviations from WHO evidence-based guidelines.

Malaria caused by Plasmodium falciparum in pregnancy can result in adverse maternal and fetal sequelae [ 1 ]. Pregnant women are at increased risk of maternal anaemia, placental malaria and death [ 1 , 2 , 3 ]. However, stillbirth, premature birth, intra-uterine growth restriction, and low birth weight (LBW) are poor fetal/newborn pregnancy outcomes [ 1 , 2 , 3 ]. Placental malaria results from the sequestration of infected red blood cells (RBCs) in the intervillous spaces of the placenta and binding of parasites to surface chondroitin sulfate-A (CSA). Furthermore, the recruitment of macrophages and pro-inflammatory cytokines in response to parasite-infected RBCs contributes to the thickening of the placental basement membrane, which interferes with the maternal and fetal exchange mechanisms, leading to poor outcomes [ 4 , 5 ]. Immunity to placental malaria is acquired during the first and subsequent pregnancies as women develop antibodies against parasite-binding sites to CSA: it blocks P. falciparum sequestration into intervillous spaces, and enhances the opsonic clearance of parasitized erythrocytes [ 4 , 5 , 6 , 7 ].

The symptoms and sequelae of malaria in pregnancy vary according to the severity of transmission of malaria and levels of immunity acquired by individuals [ 1 ]. For areas with moderate-to-high (stable) malaria transmission (areas characterized by steady prevalence pattern, with little variation from 1 year to another and affected population often has high levels of immunity), pregnant women appear to have high acquired immunity; thus, they are paucisymptomatic during infection [ 1 , 6 ]. Prompt diagnosis and treatment of malaria infection, whether symptomatic or paucisymptomatic, are required to prevent maternal anaemia and LBW of the newborn [ 1 , 6 ]. Moreover, malaria prevention and treatment are essential components of antenatal care, especially in regions where the malaria parasite is endemic, as in sub-Saharan Africa (SSA) [ 1 , 4 ]. The World Health Organization (WHO) has recommended the intermittent preventive treatment in pregnancy (IPTp) strategy in which a single dose of three tablets of single-pill combination (SPC) of sulfadoxine-pyrimethamine (SP) is administered integral to antenatal care service [ 8 , 9 ]. This strategy mitigates or prevents malaria-related adverse maternal and fetal outcomes. The IPTp-SP is implemented in pregnant women starting as early as possible in the second trimester, with SP administered at monthly intervals up to the time of delivery. IPTp-SP should be administered under directly observed therapy (DOT) along with folic acid dose reduction (400 µg daily), usually with iron for prevention of maternal anaemia. IPTp-SP strategy is contra-indicated in pregnant women who are human immunodeficiency virus (HIV)-positive, receiving cotrimoxazole prophylaxis in malaria-endemic regions of Africa.

In areas with low (unstable) malaria transmission (areas characterized by considerable variation in incidence pattern from 1 year to another and the population usually has little immunity), pregnant women appear to have low antibody-mediated immunity to malaria infection: they are more likely to develop severe malaria syndrome with cerebral malaria, hypoglycaemia and respiratory distress [ 1 , 10 ]. In such regions, malaria is associated with a greater risk of spontaneous abortion, stillbirth, prematurity, and LBW [ 1 , 6 , 7 ]. Both primigravidae and multigravidae are equally susceptible [ 10 ]. IPTp-SP strategy cannot be implemented in low malaria transmission areas in the Greater Mekong Sub-region (GMS) and some African countries because of high drug resistance [ 1 ].

The rational use of anti-malarial drugs for treating of falciparum malaria in pregnancy in each country is determined by several variables that include therapeutic efficacy of drugs against P. falciparum , maternal and fetal adverse events, safety concerns, and treatment cost-effectiveness [ 1 ]. Only anti-malarials with a proven safety profile supported by robust clinical evidence are used to treat malaria during pregnancy [ 1 ]. Physiological changes associated with pregnancy and their potential effects on anti-malarial pharmacokinetics are important considerations [ 11 ]. WHO-recommended, evidence-based, malaria treatment protocols that can be safely used in pregnancy [ 1 ] are presented in Table  1 . Anti-malarials, such as primaquine, tafenoquine (for management of recurrent vivax/ovale malaria), and tetracyclines, are contra-indicated in pregnancy.

Malaria caused by Plasmodium vivax in Asia–Pacific regions is, although considered benign, associated with adverse pregnancy outcomes and requires prompt and effective management with parenteral artesunate as for severe falciparum malaria [ 1 , 12 ]. Following parenteral artesunate, treatment can be completed with the full treatment course of oral artemisinin-based combination therapy (ACT) (in countries with chloroquine-resistant P. vivax ) or chloroquine (in countries where chloroquine is the treatment of choice) [ 1 ]. The eradication of hepatic-stage parasites with primaquine or tafenoquine is deferred until after delivery. Malaria caused by Plasmodium knowlesi appears to be more severe than infections by other non-falciparum species and is treated as for falciparum infection [ 13 ].

This review aims to evaluate critically the degree to which national guidelines comply with WHO recommendations [ 1 ] to treat and prevent chloroquine-resistant P. falciparum in pregnancy, specifically to include:

uncomplicated malaria in the first trimester;

uncomplicated and complicated malaria in the second and third trimesters;

complicated malaria during all trimesters;

chemoprophylaxis of malaria in pregnancy in moderate-to-high transmission areas.

In this review, the focus is on falciparum malaria and not on other species common in some of the countries reviewed in view of the magnitude of the problem due to implications on perinatal morbidity and mortality, emergent anti-malarial resistance and updates on drug therapy recommendations.

Literature survey

National and international malaria treatment guidelines were retrieved using PubMed Medical Subject Heading terms: “guidelines” and “malaria”. The Worldwide Web via Google was used with the following phrases: malaria treatment guidelines followed by the country name (e.g., Angola, Thailand) or organizations such as WHO, US Centers for Disease Control and Prevention (US CDC) and President’s Malaria Initiatives (PMI)-Malaria Operational Plans (MOP). The data analysis was limited to publications, literature and reports from December 2012 onwards about 2 years after the release of the second edition of WHO Guidelines for Treatment of Malaria [ 14 ]. It was assumed that 2 years would suffice for guideline dissemination and for countries to adopt WHO Guidelines.

Inclusion and exclusion criteria

Updated national guidelines emerged 2012 onwards and PMI-MOP reports for 2018–2019 published in English were included. Based on WHO regional classification [ 15 ], countries from Africa, Eastern Mediterranean, Southeast Asia, and Western Pacific regions known to have the highest estimated malaria prevalence were included. National guidelines/PMI-MOP reports written in languages other than English, guidelines published before 2012, and Pan-American Health Organization (PAHO) countries were excluded.

Except for malaria chemoprevention in pregnancy, there was no significant difference between the 3rd [ 1 ] and 2nd [ 14 ]. WHO Guidelines recommendations reported with regard to first-line treatment in uncomplicated and complicated falciparum malaria in all trimesters of pregnancy (Table  2 ). Since national guidelines in Malaysia (2013) and national guidelines in both India and Sri Lanka (2014) were published 1–2 years ahead of the 2015 WHO Guidelines [ 1 ] and 3–4 years after publication of the 2010 WHO Guidelines [ 14 ], both WHO Guidelines editions were used in this review (Table  2 ).

Outcome measures

According to WHO recommendations on treatment of chloroquine-resistant falciparum malaria in pregnant women, the primary outcome measures evaluated were: (1) first-line drugs for treating either uncomplicated or complicated (severe) malaria infection during any trimesters of pregnancy; (2) IPTp-strategy with SP combination, guidance on folic acid supplementation and concomitant IPTp-SP with cotrimoxazole in HIV-positive pregnant women.

Validity assessment

The authors independently carried out an assessment of outcome measures in a non-blinded standardized manner. Any discrepancy was resolved in consultation with another clinical pharmacologist.

PMI definition

PMI is a US Government initiative, one of the largest international sources of funding to control and eradicate malaria in PMI-supported countries. PMI works in partnership with host-country governments in SSA and GMS to: (a) provide effective therapeutic and prophylactic intervention to those at risk of malaria; (b) develop annual MOPs; and, (c) complement and expand malaria monitoring and evaluation strategies [ 16 ].

A total of 38 international and national guidelines and updated PMI-MOP reports fulfilled the inclusion criteria. WHO region-wide breakdown of the 35 national guidelines/reports was as follows: SSA: 25, Eastern Mediterranean: 3, Southeast Asia: 5, Western Pacific region: 2.

Uncomplicated falciparum malaria in first trimester

Contrary to WHO recommendations [ 1 ], oral quinine monotherapy instead of quinine plus clindamycin regimen was adopted by 23/35 (65.7%) guidelines/reports as first-line treatment for uncomplicated falciparum malaria in the first semester of pregnancy (Table  2 ).

Uncomplicated and complicated falciparum malaria in second and third trimesters

As first-line treatment, artemether-lumefantrine (AL), an SPC, was the most common artemisinin-based combination recommended by 26/35 (74.3%) guidelines for treating uncomplicated malaria in second and third trimesters, and as the preferred option for completing treatment following parenteral artesunate/quinine for complicated malaria in second and third trimesters. The proportion of national guidelines/PMI reports that adopted oral quinine or quinine plus clindamycin for completing of initial parenteral quinine for complicated malaria in first trimester was 12/35 (34.3%) and 3/35 (8.6%), respectively (Table  2 ).

Complicated falciparum malaria during all trimesters

Intravenous artesunate has been approved by 18/35 (51.4%) and 31/35 (88.6%) of guidelines/reports for treating severe malaria in early (first trimester) and late (second and third trimesters) of pregnancy, respectively (Table  2 ).

Malaria chemoprophylaxis in pregnancy in moderate-to-severe areas

Of the 23 guidelines/PMI reports to implement IPTp-SP strategy, emphasis on DOT was overlooked by 8 (34.8%). The standard dose of folic acid (400 µg daily) recommended by WHO Guidelines was adopted by 18/23 (78.3%) of SSA countries that implemented IPTp-SP strategy (Table  2 ). Of note, 17/23 (73.9%) did not include an explicit warning of adverse events potential if concomitant cotrimoxazole prophylaxis is used in HIV-positive pregnant women.

This review evaluated the treatment and prevention of falciparum malaria in pregnancy in 35 national guidelines/PMI-MOP reports out of 95 malaria-endemic countries as compared to WHO Guideline recommendation [ 1 ].

Uncomplicated malaria in first trimester

The national guidelines and PMI reports of several representative SSA and GMS countries recommend quinine monotherapy for 7 days as the preferred regimen, administered under full supervision, for treating uncomplicated malaria during first trimester (Table  2 ). The use of quinine alone is contrary to WHO Guidelines, which strongly recommend quinine in combination with clindamycin for 7 days [ 1 ]. Although quinine at the recommended dose is considered safe in first trimester [ 1 ], quinine use in pregnant women is associated with drawbacks [ 17 , 18 ]. The clearance of quinine is increased in pregnant women compared to non-pregnant women [ 19 , 20 ]. Meta-analysis findings of five randomized trials in pregnant women revealed that a 7-day course of quinine monotherapy was linked with a slower rate of malaria parasite clearance and higher rate of gametocyte carrier emergence risk compared to ACT [ 21 ] or quinine plus clindamycin regimens [ 17 , 22 , 23 ].

The gametocidal activity of quinine against falciparum malaria has been reported to be sub-optimal to prevent transmission in endemic areas [ 18 , 24 ]. Nausea and vomiting often associated with quinine may exacerbate morning sickness [ 25 ]. A 7-day course of oral quinine should be administered under full supervision because of poor tolerability that may compromise patient compliance resulting in treatment failure [ 17 , 26 , 27 , 28 , 29 ]. Nonetheless, the reviewed data suggest a trend towards quinine monotherapy by two-thirds of national guidelines, although robust evidence supports the need to combine quinine with clindamycin. In real-world settings, a combination of oral quinine plus clindamycin for a 7-day treatment course has been reported to improve the therapeutic efficacy against multidrug-resistant P. falciparum in first trimester of pregnancy and to reduce the risk of therapeutic failure [ 22 , 23 , 26 ].

Moreover, this combined regimen is considered important in children and pregnant women in whom the use of doxycycline, the slow-acting partner schizonticide, is contra-indicated [ 26 ]. The explanation for quinine plus clindamycin regimen under-use is most likely the cost in endemic areas with resource constraints [ 22 , 26 ]. Using International Medical Products Price Guide [ 30 ], the estimated current average cost of quinine plus clindamycin regimen (administered twice daily for 7 days) was equal to $4.05–5.95 (Table  3 ) in contrast to $18.5 for combined regimen [ 22 ] and $15.0 for clindamycin alone [ 26 ], reported two decades ago. These cost differences are because the estimated treatment cost was based on the supplier/buyer average price of generic clindamycin. In contrast, the treatment cost reported in previous studies [ 22 , 26 ] was based on the price of proprietary clindamycin (Dalacin C). A meta-analysis of seven randomized controlled trials has affirmed that the quinine plus clindamycin regimen was safe and rarely associated with severe adverse events [ 23 ]. Perhaps neither the cost of such regimen nor adverse effects are the reasons for not recommending them by some guidelines/PMI reports. Treatment regimen complexity, including the duration, frequency of dosing, number of pills prescribed (Table  3 ), and poor tolerability by pregnant women with uncomplicated malaria who may require full supervision, are more likely barriers to universal endorsement of quinine plus clindamycin regimen. This controversy can be resolved by revising WHO Guidelines to include ACT as a first-line treatment option for uncomplicated malaria in first trimester as recommended by the WHO Malaria Policy Advisory Committee [ 31 ] based on growing evidence on artemisinin safety [ 32 , 33 , 34 , 35 ]. US-CDC updated recommendation in 2018 states that during first trimester of pregnancy falciparum malaria should be treated with the currently available options of either mefloquine or quinine plus clindamycin. However, when neither of these options is available, AL should be considered for treatment [ 36 ].

Uncomplicated and complicated malaria in second and third trimesters

In 2006, WHO [ 37 ] recommended the use of ACT, including AL, artesunate–amodiaquine (AS–AQ), and artesunate–mefloquine (AS–MQ), to treat uncomplicated falciparum malaria in second and third trimesters, but not during first trimester, until safety data becomes available. Except for dihydroartemisinin–piperaquine (DHA–PPQ) combination, ACT was considered first-line treatment in second and third trimesters [ 14 ]. In 2015, WHO recommended the use of ACT, including DHA–PPQ, as first-line treatment in second and third trimesters [ 1 ]. More recent data from SSA and many GMS countries confirm that exposure to ACT (AL or artemisinin derivatives) were not associated with adverse pregnancy outcomes during first trimester [ 32 , 33 , 34 , 35 , 36 , 38 ] as well as in second and third trimesters [ 25 , 32 , 36 , 38 , 39 , 40 , 41 ]. Adverse effects of AL, such as asthenia, poor appetite, dizziness, nausea, and vomiting, occur significantly less often with AL compared to other ACT [ 42 ]. In addition to WHO recommendations [ 1 ], several guidelines of non-endemic-malaria countries have adopted AL as the preferred treatment option for falciparum malaria in second and third trimesters [ 36 , 43 , 44 , 45 , 46 ].

Among artemisinin-based combinations recommended by the WHO [ 1 ], AL as first-line choice has been widely recommended by approximately three-quarters of guidelines/PMI reports for treatment of uncomplicated and complicated falciparum malaria in second and third trimesters, both in endemic and non-endemic regions (Table  2 ). This finding harmonizes with the recent World Malaria Report for treating uncomplicated confirmed falciparum malaria in the general population [ 15 ]. As first-line treatment, AL is recommended in 24 of 46 (52%) SSA countries and 11 of 20 (55%) Southeast Asian and Western Pacific countries, respectively [ 15 ]. The extensive use of AL is due to efficacy, safety, moderate cost (compared to other ACT; Table  3 ); availability as a flavoured, dispersible, paediatric formulation is a distinct advantage for infants, toddlers and preschool children [ 47 ]. However, in countries, such as Cambodia where ACT resistance is a problem, national guidelines for first-line therapy need to be updated regularly because of emergent AS–MQ resistance and treatment failure. A recent randomized clinical trial carried out in Bangladesh, Cambodia, Laos, Burma, and the Democratic Republic of Congo has affirmed the safety of triple ACT, such as DHA–PPQ plus mefloquine versus AL plus amodiaquine, might provide effective treatment and delay emergence of multidrug anti-malarial resistance [ 48 ].

Sub-optimal exposure to lumefantrine, the partner component of artemether in AL (SPC) that may compromise therapeutic efficacy, is a concern with a 3-day course of AL in treating malaria during late pregnancy [ 49 , 50 ]. The plasma concentrations of lumefantrine treatment were approximately 20% less in pregnant than in non-pregnant women [ 50 ], due to pregnancy-related physiological changes in drug absorption, and biotransformation (primarily due to altered hepatic cytochrome P450 isoenzymes), and increased apparent volume of drug distribution [ 11 ]. Prolonging AL treatment duration from the recommended twice daily for 3-days regimen to the extended 5-days regimen (twice daily for 5 days) was associated with acceptable tolerability and adequate safety. It enhanced overall lumefantrine exposure during late trimesters of pregnancy [ 49 , 50 ] and among the general population in artemisinin resistance-emergent regions [ 51 ]. Further clinical trials evaluating the 5-days extended AL regimen for malaria treatment are awaited [ 50 ].

The oral bioavailability of lumefantrine, a lipophilic drug, is enhanced if it is administered along with milk or fat-rich meal [ 1 ]. Fat-rich food increased the bioavailability of artemether and lumefantrine by threefold and sixfold, respectively [ 52 ]. The therapeutic concentration of lumefantrine must be sustained for four 48-h asexual life cycles of P. falciparum and to be at least twice the minimum parasiticidal concentration on day 7 after the start of treatment in order to optimize the cure rates and to reduce the emergence of resistance and early stages of gametocyte development [ 53 ]. Ingestion of a fat-rich diet to enhance AL oral bioavailability has received little attention by most of the national guidelines/PMI reports (Table  2 ). Except for Ethiopia [ 54 ], Saudi Arabia [ 45 ], South Africa [ 46 ], and Sri Lanka [ 55 ], the vast majority of national guidelines have not addressed this crucial issue, an essential factor for ensuring lumefantrine plasma concentrations up to day 7 of treatment.

Complicated malaria during any trimesters of pregnancy

Severe malaria in pregnancy needs a fast-acting and very effective treatment to save the mother’s life so that the risk/benefit equation overcomes any concerns about the safety of parenteral AS. Artesunate is first-line anti-malarial drug recommended for treatment of complicated (severe) malaria in all trimesters of pregnancy by international guidelines [ 1 , 56 ], based on evidence from various studies [ 17 , 18 , 28 ]. In contrast to quinine, artesunate had shorter parasite clearance time and lower gametocyte carriage rate in falciparum malaria [ 57 ]. Artesunate is well tolerated [ 58 ] and has a better safety profile on the risk of miscarriage [ 33 , 58 ] or significant congenital malformations [ 33 ] if administered during pregnancy compared to quinine. Unlike quinine, artesunate does not require an initial loading dose in severe malaria [ 1 ]. Moreover, quinine is associated with a higher risk of hypoglycaemia compared to artesunate, particularly in second and third trimesters, which may be refractory to intravenous glucose and may even be fatal [ 18 , 28 ].

Whereas 18 of 35 (51.4%) of the reviewed guidelines/PMI reports have adhered to international guidelines regarding intravenous artesunate as a first-line option for treating complicated malaria in first trimester of pregnancy [ 1 , 56 ], almost all guidelines have adopted intravenous artesunate for treating complicated malaria in the second and third trimesters. The guidelines for Benin [ 54 ] and Sudan [ 59 ] recommend either parenteral quinine or artesunate whereas in Cote d’Ivoire [ 54 ] parenteral quinine is recommended to treat complicated malaria during second and third trimesters. Paradoxically, however, in Cote d’Ivoire [ 54 ] parenteral artesunate is recommended for complicated malaria in general population. However, severe and refractory quinine-induced hypoglycaemia is more likely to occur in late than early trimesters [ 1 ], unless parenteral quinine is administered concomitantly along with glucose. The reluctance of some guidelines to recommend artesunate for treating complicated malaria in the first trimester can be attributed to safety risk controversy over artesunate; quinine during early trimester is associated with potentially less hypoglycaemic risk than during late trimesters [ 1 ]. Moreover, drug cost seems to be a deterrent for not recommending artesunate, since intravenous artesunate per treatment course costs $22.92 compared to $5.04 for intravenous quinine (Table  3 ). High drug cost is an impediment, especially in countries with limited healthcare budgets.

Malaria chemoprevention in pregnancy

Based on robust evidence, WHO [ 8 , 9 ] has proposed the IPTp strategy to mitigate adverse effects of malaria on maternal and fetal outcomes. IPTp should be implemented in malaria-endemic regions with high (stable) transmission as in Africa, where falciparum malaria is more prevalent. The IPTp policy requires that SP is administered to pregnant women (regardless of whether malaria parasites are identified in peripheral blood film or otherwise) at each scheduled antenatal visits starting as early as possible at the beginning of the second trimester around 13th week of gestation. Subsequent doses are to be administered at monthly intervals until delivery. The IPTp-SP strategy should be implemented as DOT of three SPC tablets (each tablet containing 500 mg/25 mg SP) [ 1 , 8 ], administered by attending healthcare personnel as an integral component of antenatal care. DOT requirement of IPTp-SP policy is a vital strategy to ensure that the full preventive dose (i.e., three SPC of SP) is indeed ingested. Among 23 African countries that are required to implement IPTp-SP, the DOT requirement has not been explicitly stated in 8 (37.8%) national guidelines/reports, including that of Angola [ 54 ], Benin [ 54 ], Ghana [ 54 ], Liberia [ 54 ], Madagascar [ 54 ], Sierra Leone [ 54 ], Zambia [ 54 ], and Somalia [ 60 ] (Table  2 ). Although several guidelines adopt the DOT approach, its implementation in real-world practice is uncertain. Recently, poor adherence to DOT has been reported in Kenya, Nigeria and Tanzania, although DOT has been explicit in malaria guidelines of these countries [ 61 ]. National malaria plans of Ethiopia [ 54 ], South Africa [ 46 ] and Sudan [ 59 ] do not include IPTp-SP strategy as a part of their national malaria plans because of the relatively low intensity of malaria transmission in these countries, and in Rwanda due to increased parasite resistance to SP [ 54 ]. Antenatal healthcare providers should carefully adhere to the recommended DOT policy to ensure that the IPTp-SP strategy is effectively implemented. It is worth noting that WHO has not recommended IPTp strategy in countries with low transmission or high SP resistance, which is a gap in care for pregnant women, and involves other strategies, such as frequent testing and treating.

The requirement to administer daily dose of folic acid in the IPTp-SP strategy merits further attention. The recommended dose of folic acid in early pregnancy (400 µg daily) along with iron is for prevention of maternal anaemia. However, women with high risk or family history of neural tube defects should receive 5000 µg (5 mg) daily instead, to prevent neural tube defects, ideally administered before pregnancy, but if in first trimester when it would not conflict with IPTp since it is not recommended in the first trimester. The therapeutic dilemma over folic acid is among those women who have severe anaemia, especially associated with risk of severe malaria, who may require iron and higher dose of folic acid in excess of the usual recommended dose; WHO Guidelines are not clear on how this should be managed. According to WHO recommendations [ 8 ], folic acid supplement at a dose of 400 µg daily should be administered to pregnant women on IPTp-SP since it assures desired benefits without compromising IPTp-SP effectiveness. However, dose ≥ 5000 µg per day should be avoided because it antagonizes the anti-malarial efficacy of folate antagonists (SP) by pharmacodynamic antagonism [ 8 , 62 ]. Almost all guidelines/PMI reports that adopted IPTp-SP strategy in their national guidelines have adhered to the WHO-recommended dose of folic acid, except for Angola [ 54 ], Cameroon [ 54 ] and Mozambique [ 54 ] PMI reports, which advocate ≥ 1000 µg daily. The guidelines need to be clear on moderate and severe anaemia, which is common in pregnant women especially in Asia where higher doses of folic acid may be justified along with other interventions, such as de-worming and vitamin A supplementation.

Falciparum malaria in pregnancy causes several harmful severe effects on maternal and fetal outcomes. WHO IPTp-SP strategy is recommended to prevent or mitigate malaria-related outcomes [ 8 ]. In pregnant women, HIV infection is associated with a significant increase in the prevalence of malaria [ 63 , 64 ]. In HIV-positive pregnant women, cotrimoxazole prophylaxis is required to prevent Pneumocystis jirovecii opportunistic infection [ 65 ]. Of note, IPTp-SP strategy is inappropriate in HIV-infected pregnant women who are already on cotrimoxazole prophylaxis to avoid the exacerbation risk of sulfonamide-related adverse effects, especially severe cutaneous reaction [ 66 ]. WHO IPTp-SP strategy remains valid even in areas where quintuple mutations linked to SP resistance are prevalent in P. falciparum [ 9 ]. However, a recent meta-analysis showed that IPTp-SP might not be effective in areas where the prevalence of sextuple mutation is common, and alternative strategies to replace IPTp-SP is a pressing research priority to control malaria in pregnancy [ 67 ]. Therefore, it may be arguable whether WHO IPTp-SP strategy remains valid. DHA–PPQ is a valuable alternative to replace SP in IPTp [ 68 ], and more recent meta-analysis data have confirmed that previous concerns about repolarization-related cardiotoxicity need not limit its use for the prevention and treatment of malaria [ 69 ]. However, concurrent use of cotrimoxazole and DHA–PPQ is best avoided. Moreover, cotrimoxazole prophylaxis has been demonstrated to be non-inferior to WHO IPTp-SP strategy in pregnant women with HIV regarding infant mortality, LBW, placental malaria, maternal death, and treatment-limiting adverse events [ 70 ]. Despite the clinical importance of IPTp-SP contra-indication in such patients, this therapeutic issue has received scant attention in several guidelines. Seventeen of 23 (73.9%) PMI reports stating IPTp-SP policy, do not provide guidance on adverse consequences of drug–drug interactions between SP and cotrimoxazole (Table  2 ). Although more than one million HIV-positive women at risk of contracting malaria become pregnant every year in SSA countries, such as Kenya, Malawi, Mozambique, Tanzania, and Zambia [ 71 ], the national guidelines of these countries have overlooked and never addressed this important public health issue (Table  2 ).

Limitations of this review

First, non-inclusion of several national guidelines of Eastern Mediterranean and Asian countries known to be endemic with malaria such as Yemen, Syria, Iran, Iraq, Pakistan, and Afghanistan; second, non-inclusion of Francophone countries in North Africa, and Hispanophone and Lusophone countries of PAHO in Central and South America eliminated the national guidelines of many countries with high malaria prevalence.

This review revealed that most of the revised national guidelines/PMI-MOP reports are non-compliant to WHO Guidelines recommendations. Two-third of the revised guidelines have adopted oral quinine monotherapy to treat uncomplicated malaria during first trimester, instead of quinine plus clindamycin combination recommended by WHO Guidelines. Among ACT, three-quarters of guidelines for uncomplicated and complicated malaria recommend AL during second and third trimesters. A few of the guidelines continue to recommend intravenous quinine instead of artesunate for treating complicated malaria infections in late pregnancy in spite of potential high risk of refractory and fatal hypoglycaemia. Some countries have been slow to adopt parenteral artesunate at all, unrelated to specific concerns around safety in pregnancy.

Contrary to WHO recommendations, half of the guidelines recommend intravenous quinine instead of artesunate for treating complicated malaria in first trimester, most likely due to drug cost considerations. As a component of IPTp-SP strategy, DOT has been overlooked by one-third of the guidelines that recommend IPTp-SP policy. Three-quarters of the revised guidelines have overlooked the contra-indication of IPTp-SP implementation in HIV-co-infected pregnant women receiving cotrimoxazole prophylaxis. These lacunae in the guidelines of several countries must be addressed by policymakers to comply with current evidence-based international guidelines.

Availability of data and materials

Not applicable.

Abbreviations

Artemisinin-based combination therapy

Artemether–lumefantrine

Artesunate–amodiaquine

Artesunate–mefloquine

Chondroitin sulfate-A

Dihydroartemisinin–piperaquine

Directly observed therapy

Greater Mekong Sub-region

Human immunodeficiency virus

Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine

Low birth weight

Malaria Operational Plans

Pan-American Health Organization

President’s Malaria Initiatives

Red blood cells

Sulfadoxine-pyrimethamine

Single-pill combination

Sub-Saharan Africa

US Centers for Disease Control and Prevention

World Health Organization

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Al Khaja, K.A.J., Sequeira, R.P. Drug treatment and prevention of malaria in pregnancy: a critical review of the guidelines. Malar J 20 , 62 (2021). https://doi.org/10.1186/s12936-020-03565-2

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The Diagnosis and Treatment of Malaria in Pregnancy (Green-top Guideline No. 54b)

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Summary: Malaria is the most important parasitic infection in humans and is the tropical disease most commonly imported into the UK, with approximately 1500 cases reported each year and rising, apart from 2008. Immigrants and second- and third-generation relatives returning home assuming they are immune from malaria are by far the highest-risk group. They may take no prophylaxis or may be deterred by the cost, may not adhere to advice, may receive poor advice or some combination of these factors. 

In the UK, the prevalence of imported malaria in pregnancy is unknown. A review of the burden of malaria in pregnancy estimated that about one in four women in sub-Saharan Africa in areas of stable transmission has malaria at the time of birth. Online and telephone enquiries with the  Health Protection Agency  and  Eurosurveillance archives  and reviews of published reports failed to uncover a report of maternal death from malaria in UK for the past 10 years. Maternal deaths from malaria are unlikely to be reported when they occur in endemic countries.

The aim of this guideline is to provide clinicians with up-to-date, evidence-based information on the diagnosis and treatment of malaria in pregnancy, in situations that are likely to be encountered in UK medical practice. Initial rapid assessment and management is covered in Appendix 1. Prevention of malaria is covered in  Green-top Guideline No. 54A: The prevention of malaria in pregnancy .

COVID disclaimer: This guideline was developed as part of the regular programme of Green-top Guidelines, as outlined in our document  Developing a Green-top Guideline: Guidance for developers (PDF) , and prior to the emergence of COVID-19.

Version history: This is the first edition of this guideline.

The  Advisory committee on malaria prevention  have agreed to take over and update this guideline. This version will remain valid until the publication of the new guidance.

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Management of malaria in pregnancy

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• 1 Department of Medicine at the Doherty Institute, The University of Melbourne, Melbourne, Australia.
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• PMCID: PMC5793466
• DOI: 10.4103/ijmr.IJMR_1304_17

Pregnant women are especially susceptible to malaria infection. Without existing immunity, severe malaria can develop requiring emergency treatment, and pregnancy loss is common. In semi-immune women, consequences of malaria for the mother include anaemia while stillbirth, premature delivery and foetal growth restriction affect the developing foetus. Preventive measures include insecticide-treated nets and (in some African settings) intermittent preventive treatment. Prompt management of maternal infection is key, using parenteral artemisinins for severe malaria, and artemisinin combination treatments (ACTs) in the second and third trimesters of pregnancy. ACTs may soon also be recommended as an alternative to quinine as a treatment in the first trimester of pregnancy. Monitoring the safety of antimalarials and understanding their pharmacokinetics is particularly important in pregnancy with the altered maternal physiology and the risks to the developing foetus. As increasing numbers of countries embrace malaria elimination as a goal, the special needs of the vulnerable group of pregnant women and their infants should not be overlooked.

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Malaria Vaccine Candidate Could Prevent Infection During Pregnancy

An experimental malaria vaccine could offer protection during pregnancy for up to 2 years without a booster dose, according to a randomized clinical trial conducted in Mali. The 3-dose vaccine, known as Plasmodium falciparum sporozoite (PfSPZ) vaccine, had previously been tested successfully in adults in other parts of Africa.

This was the first clinical trial to test the vaccine’s safety and efficacy among people who were planning to become pregnant after immunization, according to the researchers. Approximately 300 healthy adults in Mali aged 18 to 38 years received a treatment to remove malaria parasites, then 3 injections of either a placebo or the PfSPZ vaccine, at higher or lower doses.

In the 55 people who became pregnant after the final vaccine dose, the vaccine was 65% effective at the lower dose and 86% effective at the higher dose. Among the 155 women who became pregnant over the course of the 2-year study, vaccine efficacy was 57% at the lower dose and 49% at the higher dose. Most adverse reactions were mild.

“Existing measures are not protecting women from malaria in pregnancy…and our results indicate that PfSPZ vaccine might be a suitable candidate,” the researchers wrote in The Lancet .

Published Online: September 13, 2024. doi:10.1001/jama.2024.18197

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Anderer S. Malaria Vaccine Candidate Could Prevent Infection During Pregnancy. JAMA. Published online September 13, 2024. doi:10.1001/jama.2024.18197

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Malaria and Pregnancy: A Global Health Perspective

Julianna schantz-dunn.

* Brigham and Women’s Hospital, Division of Global Obstetrics and Gynecology, Harvard Medical School, Boston, MA

Nawal M Nour

† Department of Maternal-Fetal Medicine, Brigham and Women’s Hospital, Division of Global Obstetrics and Gynecology, Harvard Medical School, Boston, MA

Malaria, a parasitic infection transmitted by mosquitoes, is one of the most devastating infectious diseases, killing more than 1 million people annually. Pregnant women, children, and immunocompromised individuals have the highest morbidity and mortality, and Africa bears the heaviest burden. The World Health Organization defines malaria as a disease of poverty caused by poverty. Pregnant women infected with malaria usually have more severe symptoms and outcomes, with higher rates of miscarriage, intrauterine demise, premature delivery, low-birth-weight neonates, and neonatal death. They are also at a higher risk for severe anemia and maternal death. Malaria can be prevented with appropriate drugs, bed nets treated with insecticide, and effective educational outreach programs.

Malaria is the second most common cause of infectious disease-related death in the world, after tuberculosis. It is estimated to affect between 350 to 500 million people annually and accounts for 1 to 3 million deaths per year. 1 , 2 Sub-Saharan Africa has the largest burden of malarial disease, with over 90% of the world’s malaria-related deaths occurring in this region. Twenty-five million pregnant women are currently at risk for malaria, and, according to the World Health Organization (WHO), malaria accounts for over 10,000 maternal and 200,000 neonatal deaths per year. 3

These figures may underestimate the impact malaria has in maternal morbidity and mortality. A recent study from Mozambique that assigned cause of maternal death via autopsy examination found that up to 10% of maternal deaths were directly attributed to malarial infection and 13% were secondary to human immunodeficiency virus (HIV)/AIDS, which can be exacerbated by coexisting malarial infection. 4 This suggests that in parts of the world where malaria is endemic, it may directly contribute to almost 25% of all maternal deaths.

Malaria in pregnancy also contributes to significant perinatal morbidity and mortality. Infection is known to cause higher rates of miscarriage, intrauterine demise, premature delivery, low-birth-weight neonates, and neonatal death. As funding increases to combat both malaria and maternal mortality, understanding how malaria specifically affects pregnant women is crucial in our efforts to improve maternal and perinatal health and curb the spread of this preventable infectious disease.

Epidemiology

Malaria is a parasitic infection caused by the 4 species of Plasmodium that infect humans: vivax, ovale, malariae , and falciparum . Of these, Plasmodium falciparum is the most deadly. The infection is transmitted by the female anopheline mosquito; therefore factors that influence mosquito breeding, such as temperature, humidity, and rainfall, affect malaria incidence. 2 In the United States, malaria was eradicated in the 1940s after widespread spraying of dichlorodiphenyltrichloroethane (DDT) in the South. 5 Other areas of the world, including Europe and parts of Central and South America, have also had success in eradicating malaria, whereas Sub-Saharan Africa continues to bear the burden of disease, as illustrated in Figure 1 .

(A) World territories. The size of each territory shows the relative proportion of the world’s population. (B) Worldwide distribution of malaria cases. The size of each territory shows the proportion of all people living with malaria. (C) Worldwide distribution of malaria deaths. The size of each territory shows the proportion of worldwide deaths from malaria that occur there. © 2006 SASI Group (University of Sheffield) and Mark Newman (University of Michigan). Reproduced with permission.

Pathophysiology

Malaria is transmitted when an infected mosquito takes a human blood meal and the Plasmodium sporozoites are transferred from the saliva of the mosquito into the capillary bed of the host. Within hours, the parasite will migrate to the liver, where it undergoes further cycling and replication before being released back into the host’s bloodstream ( Figure 2 ). 6

Life cycle of malaria infection. Reproduced with permission from Jones MK, Good MF. Malaria parasites up close. Nat Med. 2006;12:170–171 .

The incubation period, from the time of mosquito bite until clinical symptoms appear, is typically 7 to 30 days. Symptoms include fever, headache, nausea, vomiting, and myalgias. Due to the cycling parasitemia in the bloodstream, patients will often experience symptoms every 2 to 3 days, depending on the type of Plasmodium with which they are infected.

In the human, plasmodial infection is a complicated reproductive life cycle involving hepatic and erythrocytic infection. Once the sporozoite enters the liver, it multiplies and exits into the bloodstream in the merozoite form. The merozoite then invades erythrocytes, leading to phagocytosis of infected blood cells by the spleen. Malarial symptoms are caused mainly by the red blood cell invasion and the body’s inflammatory response. 7 Malarial infection causes marked immunoglobulin synthesis and, in the case of P falciparum , creates immunoglobulin complexes and increased production of tumor necrosis factor. The ability of P falciparum to cause cytoadherence of erythrocytes to vascular walls leads to sequestration of infected cells in small blood vessels, causing end organ damage via hemorrhage or infarct. 6 , 7 Phagocytosis of infected blood cells in the spleen helps clear infection, but also contributes to profound anemia and folic acid deficiency.

It has been established that repeated malarial infections lead to some immunity. In fact, in areas where malaria incidence is episodic rather than endemic, patients will present with more severe forms of the disease, as their previously “learned immunity” appears to fade over time. It is not surprising, therefore, that malaria-naive and immunocompromised patients are prone to more severe infection. This puts pregnant women, children, travelers to endemic regions, and persons with coexisting HIV infection at highest risk for morbidity and mortality secondary to malarial infection.

Clinically, malaria is categorized into 2 types: uncomplicated and severe. Uncomplicated malaria is characterized by a cold stage , consisting of cold sensation and shivering, and a hot stage , with fever, headache, sweating, and occasionally seizures. Symptoms generally last for 6 to 10 hours and occur every 2 to 3 days, depending on the infecting species. Severe malaria, the second subtype, is generally caused by P falciparum infection and is characterized clinically by organ damage or blood abnormalities, including cerebral malaria, hemolysis and severe anemia, pulmonary edema, acute respiratory distress syndrome, thrombocytopenia, renal failure, and cardiovascular collapse. Microscopically, it is characterized by a parasitemia level of greater than 5%. Severe anemia is a medical emergency. 1 , 7

Historically, diagnosis of malaria has relied on clinical history or microscopic identification of the asexual stages of the parasite on a blood smear fixed with Giemsa stain. More recent advances in diagnosis have been made with the introduction of rapid diagnostic tests (RDTs), immunochromatographic dipstick assays that act in a similar fashion to a home pregnancy test. Most of the RDTs report sensitivities above 90% for detection of malaria, with increasing sensitivity as the level of parasitemia increases. It is hypothesized that malarial antigen detection via RDTs may be a better diagnostic tool for use in pregnant women, as much of P falciparum sequesters in the placenta and therefore may not be visible on a standard smear, producing false-negative results if diagnosis is based on microscopy and clinical symptoms alone. 8

Malaria in Pregnancy

Pregnant women are 3 times more likely to suffer from severe disease as a result of malarial infection compared with their nonpregnant counterparts, and have a mortality rate from severe disease that approaches 50%. 6 , 9 In areas endemic for malaria, it is estimated that at least 25% of pregnant women are infected with malaria, with the highest risk for infection and morbidity in primigravidas, adolescents, and those coinfected with HIV. 10 The second trimester appears to bring the highest rate of infection, supporting the need for antepartum care as part of malarial prevention and treatment efforts.

It is hypothesized that the majority of sequelae in pregnancy results from 2 main factors: the immunocompromised state of pregnancy and placental sequestration of infected erythrocytes.

As discussed previously, adults who live in malaria-endemic regions generally have some acquired immunity to malaria infection as a result of immunoglobulin production during prior infections in childhood. This immunity diminishes significantly in pregnancy, particularly in primigravidas. A recent study of 300 women delivering in rural Ghana showed higher rates of anemia, clinical malaria, and placental burden of infection among primigravidas compared with multigravidas. The study also noted that babies born to mothers with placental malaria infection were more than twice as likely to be underweight at birth. 11

Splenic sequestration of malariainfected erythrocytes leads to folic acid deficiency and microcytic anemia in adults. In pregnant women, additional sequestration of malariainfected erythrocytes occurs in the placenta. Pregnant women therefore suffer disproportionately from severe anemia as a result of infection. In Africa, it has been estimated that malaria is responsible for 25% of severe anemia during pregnancy (defined as hemoglobin less than 7 gm/dL). 10 Women with severe anemia are at higher risk for morbidities such as congestive heart failure, fetal demise, and mortality associated with hemorrhage at the time of delivery ( Figure 3 ).

Severe anemia in the third trimester of pregnancy (hemocrit, 13%). Photo courtesy of J. Schantz-Dunn (Belladere, Haiti, 2008).

Interestingly, the greatest degree of placental infestation is seen in women who have the highest level of immunity, leading to milder maternal symptoms and a disproportionate increase in fetal complications. 6 It could be hypothesized, therefore, that although primigravidas may develop the clinical symptoms of malaria, women with higher immunity may not demonstrate symptoms, will not receive treatment, and will build a higher placental parasite burden. Fetal complications result from this placental inflammation, as well as maternal anemia, and manifest as stillbirth, intrauterine growth restriction, and low-birth-weight neonates. Low-birth-weight neonates, in turn, are at higher risk for neonatal and newborn death. Congenital malaria is a relatively rare complication in areas with endemic malaria; however, newborn parasitemia may present 2 to 3 months after delivery when maternal antibodies wear off.

It is also thought that infected erythrocytes collected in the placenta stimulate pancreatic β-cell production of insulin, leading to hyperinsulinemia and hypoglycemia during infection. This contributes to the severity of disease during pregnancy. Other maternal effects of malarial infection result from the “stickiness” of the infected erythrocytes that become trapped in small vessels, resulting in cerebral malaria, renal failure, and thrombocytopenia. Case reports confusing malaria infection with HELLP syndrome demonstrate the overlap in clinical and laboratory findings between the 2 diseases and the importance of proper diagnosis. 12

Malaria and HIV

Each year, approximately 50 million women become pregnant in malariaendemic regions. Among these women, 1 million are estimated to be infected with both malaria and HIV, both of which are preventable, treatable, and responsible for significant maternal and neonatal morbidity. 3 As a result of the impaired immune state, HIV infection increases the pregnant woman’s susceptibility to malaria and the morbidity associated with malaria, resulting in higher incidences of severe anemia and low-birth-weight neonates in coinfected women. 13 Malarial infection in HIV-positive women is associated with higher levels of parasitemia, leading to a greater risk of severe anemia. Likewise, HIV viral load is increased, creating opportunity for infection and more severe disease. 14

Current prevention of malarial disease in pregnancy relies on 2 main strategies: providing pregnant women with insecticide-treated bed nets (ITN) and intermittent presumptive treatment (IPT) with antimalarial medications. IPT refers to the administration of 2 or more doses of chemoprophylaxis after 20 weeks of gestation in an attempt to reduce subclinical malarial load.

In a Cochrane Review comparing malarial chemoprophylaxis with no prophylaxis during pregnancy, Garner and Gülmezoglu found a significant reduction in maternal anemia, parasitemia, and perinatal death, and a higher mean birth weight in the groups given IPT. 15 More recent studies in Nigeria that examined specific IPT regimens found significant reductions in maternal anemia with the use of sulfadoxine-pyrimethamine as compared with chloroquine, pyrimethamine, or no prophylaxis. 16 , 17 Sulfadoxine-pyrimethamine has been found safe in pregnancy when used intermittently as part of IPT. 18

Although the WHO currently recommends that all pregnant women living in malaria-endemic regions use insecticide-treated bed nets and IPTp-SP (intermittent presumptive treatment in pregnancy with at least 2 doses of sulfadoxine-pyrimethamine), studies show poor uptake of both preventative efforts among pregnant women. A recent survey among postpartum women in rural Uganda, in which 88% had made more than 1 prenatal visit, found that only 31% of women used a bed net during pregnancy and only 36% had received 2 doses of IPTp- SP. 19 This indicates that as access to and utilization of antepartum care increase, there is still a role for improved administration of IPTp-SP and education regarding bed net use.

Additional constraints appear when there is concurrent use of IPT with antiretroviral medications for the treatment of HIV and prevention of vertical transmission secondary to limited knowledge surrounding the drug-drug interactions. In particular, review of the literature suggests increased risk of cutaneous and hepatic toxicity when IPT is used in conjunction with nevirapine, and increased risk of bone marrow suppression when used in conjunction with zidovudine, leading to unintended morbidity associated with treatment of the 2 diseases. 13

Treatment of uncomplicated malaria in pregnancy is a balance between potential fetal adverse effects from drug toxicity and improved clinical status with clearance of the parasite. In 2006, the WHO recommended a combination of quinine and clindamycin for treatment of uncomplicated malaria in pregnancy; however, there is a risk of hypoglycemia with quinine use, as well as increasingly drug-resistant P falciparum . More data currently support the use of artemisinin-based combination therapy, which appears safe and effective in pregnancy. 20

For severe malaria in pregnancy, the WHO currently recommends treatment with either intravenous (IV) quinine or artesunate, or IV artesunate in the second and third trimesters. Not only should IV quinine be avoided in the second and third trimesters as it is associated with recurrent hypoglycemia, but evidence supports the superiority of artesunate over quinine in the nonpregnant patient. In epidemic situations, if IV or intramuscular medication is unavailable, patients should receive artesunate suppositories and be transferred to a higherlevel facility. 9

Malaria has become one of the most challenging infectious diseases to eradicate in Africa. The overall disease burden is devastating youth, women, and health systems. Malaria accounts for 40% of public health expenditure, 30% to 50% of inpatient admission, and up to 50% of outpatient visits in endemic regions. It has affected Africa’s human resources and directly lowered its annual economic growth. It not only debilitates the workforce, but keeps children from going to school, prevents pregnant mothers from effectively caring for their families, and decreases the likelihood of a healthy pregnancy outcome. Governments and donors have recognized this extraordinary toll and have increased their commitment toward prevention, treatment, and eradication. More successful programs have included reducing tariffs on ITNs to make them more affordable, incorporating infectious disease in reproductive health programs, and intermittent preventive treatment. With sustained governmental commitment and financial resources, the eradication of malaria can succeed.

Main Points

• The United States, Europe, and parts of Central and South America have had success in eradicating malaria, whereas sub-Saharan Africa continues to bear the burden of disease.
• Recent advances in diagnosis include immunochromotographic dipstick assays that report sensitivity above 90% and may be a better diagnostic tool for use in pregnant women.
• Pregnant women are 3 times more likely to suffer from severe disease as compared with their nonpregnant counterparts and have a mortality rate from severe malarial infection that approaches 50%.
• Pregnant women suffer disproportionately from severe anemia as a result of malarial infection. Women with severe anemia are at higher risk for congestive heart failure, fetal demise, and mortality associated with hemorrhage at the time of delivery.
• Current prevention of malarial disease in pregnancy relies on providing women with insecticide-treated bed nets and intermittent presumptive treatment.