Prevalence of Molecular Markers of Resistance to Antimalarial Drugs Three Years After Perennial Malaria Chemoprevention in Sierra Leone

Delivery effectiveness of and adherence to intermittent preventive treatment for malaria in pregnancy with dihydroartemisinin–piperaquine with or without targeted information transfer or sulfadoxine–pyrimethamine in western Kenya: a three-armed, pragmatic, open-label, cluster-randomised trial

Editorial Commentary: Intermittent Preventive Treatment in Pregnancy With Sulfadoxine-Pyrimethamine: The Controversy Continues

Malaria during pregnancy remains a major public health problem in Sub-Saharan Africa. Current strategies to prevent malaria in pregnancy and promote health include the use of insecticide-treated bed nets and intermittent preventive treatment in pregnancy (IPTp). Despite the availability of IPTp service in all health clinics in Zambia, Lufwanyama district has continued recording low utilisation of this service. The purpose of this study was to determine factors associated with the low utilisation of IPT of malaria among pregnant women attending antenatal (ANC) clinics in Lufwanyama. A cross-sectional study interviewed 382 pregnant women attending ANC clinics in Lufwanyama using simple random sampling. Data was entered and analyzed using SPSS version 20.0 after all variables were coded. Validation of findings was set at 95% CI with a p-value <0.05. This study revealed that the following variables were significantly associated with low IPTp utilisation or completion of the three IPTp doses: knowledge levels about IPTp; number of antenatal visits made; gestational age of pregnancy at first antenatal visit; gestational age of pregnancy; timing of first dose of fansidar; use of traditional medicine; health workers behaviour towards pregnant women; wait times; and perception of fansidar. These factors perpetuated low attendance to ANC schedules and non-adherence towards completion of the three recommended IPTp doses. Healthcare workers should intensify sensitization on IPTp service and benefits through training on effective health promotion strategies. Keywords: Malaria, Pregnant women, Intermittent Preventive Treatments in pregnancy (IPTp), Antenatal care, Insecticide Treated Nets, Sulphadoxine-Pyrimethamine, Health Promotion

Malaria remains one of the most preventable causes of adverse birth outcomes. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine is used to prevent malaria, but resistance to this drug combination has decreased its efficacy and new alternatives are needed. In Africa, a meta-analysis showed three-course or monthly IPTp with sulfadoxine-pyrimethamine to be safe and more effective than the original two-course sulfadoxine-pyrimethamine strategy, prompting WHO to update its policy in 2012. Although resistance to sulfadoxine-pyrimethamine reduces the parasitological efficacy of IPTp, this drug combination remains associated with reduced incidence of low birthweight in areas where prevalence of parasites with quintuple Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthetase (Pfdhps) mutations is greater than 90%. Nevertheless, its effectiveness is compromised in women infected with sextuple mutant parasites. Six trials of IPTp showed that neither amodiaquine, mefloquine, nor chloroquine-azithromycin are suitable replacements for sulfadoxine-pyrimethamine because of poor tolerability. Furthermore, four trials showed that intermittent screening and treatment with the current generation of malaria rapid diagnostic tests was not a suitable alternative strategy to IPTp with sulfadoxine-pyrimethamine, even in areas with high prevalence of quintuple mutations. Two trials showed that IPTp with dihydroartemisinin-piperaquine was well tolerated, effective, and acceptable for IPTp, with monthly regimens being the most effective. Coverage of IPTp and insecticide-treated nets continues to lag behind targets. The key barriers to uptake are well documented, and many are open to intervention. Outside of Africa, a single trial suggests a potential role for integrated approaches that combine sulfadoxine-pyrimethamine with azithromycin for IPTp in areas of Papua New Guinea where malaria transmission is high. Modelling analysis suggests the importance of the prevention of malaria early in pregnancy and the need to protect pregnant women declines more slowly than the rate at which transmission declines. Improved funding has led to an increase in the number of prevention trials in the past decade, showing the value of more sustained protection with monthly IPTp regimens. There is a need for confirmatory trials of the safety, efficacy, and feasibility of IPTp with dihydroartemisinin-piperaquine, for studies of intermittent screening and treatment with more sensitive rapid diagnostic tests, for studies of integrated strategies for malaria and other co-infections, and for studies of prevention strategies for malaria in pregnant women who are HIV-positive and living outside of Africa. Additional research is required on how to improve uptake of WHO's updated policy on IPTp with sulfadoxine-pyrimethamine and insecticide-treated nets.

Introduction: Malaria remains a major public health threat in sub-Saharan Africa. In Cameroon, where malaria is endemic, pregnant women are especially vulnerable due to reduced immunity and placental sequestration of infected erythrocytes. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization (WHO) to prevent malaria-related complications. However, national coverage remains below the 80% target. This study aimed to assess IPTp uptake and its associated factors among pregnant women in five diverse regions of Cameroon.Methods: A cross-sectional study was conducted between 2020 and 2022 in five health areas, using two-stage cluster sampling. A total of 259 pregnant women aged 15-49 were interviewed using a structured questionnaire. Data collected included sociodemographic characteristics, antenatal care (ANC) attendance, knowledge of malaria and IPTp, and prevention practices. Malaria infection was assessed using rapid diagnostic tests (RDTs). Logistic regression analysis was used to identify factors associated with the uptake of at least three doses of IPTp.Results: Among participants, 62.55% (CI95%: 56.31% to 68.40%) had received at least three doses of IPTp. Age was a significant predictor: women aged between 25 and 30 years had higher odds of optimal uptake (adjusted odds ratio (aOR): 4.87; 95% CI: 2.15-11.51), and those over 30 had even greater odds (aOR: 7.93; 95% CI: 3.08-21.71) compared to those aged between 21 and 25 years. Marital status also influenced uptake: married women (aOR: 9.52; 95% CI: 4.29-23.27) and cohabiting women (aOR: 2.85; 95% CI: 1.50-5.56) were more likely to receive three doses than single women. Parity was associated with higher adherence, with primiparous (aOR: 8.25; 95% CI: 3.02-26.69) and multiparous women (aOR: 7.26; 95% CI: 2.17-27.74) more likely to complete IPTp than nulliparous women. ANC attendance was a key determinant: women with more than two visits were significantly more likely to complete IPTp (aOR: 2.41; 95% CI: 1.17-4.96). Good malaria knowledge (aOR: 1.99; 95% CI: 1.12-3.58) and good IPTp knowledge (aOR: 2.19; 95% CI: 1.10-4.38) were also positively associated. Testing positive for malaria was associated with lower IPTp adherence (aOR: 0.53; 95% CI: 0.31-0.92).Conclusion: Despite improvements compared to national statistics, IPTp uptake remains below WHO recommendations. Key factors influencing adherence include age, marital status, parity, ANC frequency, and knowledge levels. Higher IPTp uptake was associated with lower malaria prevalence, which suggests but does not confirm a protective effect given the cross-sectional design. Public health strategies should focus on promoting early and regular ANC attendance, improving education on malaria prevention, and encouraging male involvement to boost IPTp coverage and improve maternal outcomes.

BackgroundMalaria during pregnancy is associated with poor maternal and pregnancy outcome and the World Health Organization recommends the administration of intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) and distribution of insecticide-treated mosquito nets (ITNs) to all pregnant women attending antenatal care (ANC) services. This study was conducted with the aim to assess the uptake of IPTp and ITNs in pregnant women attending ANC services and correlate with ANC attendance and frequency of stock-outs in 22 health facilities Mozambique.MethodsA cross-sectional study was conducted between July and December 2011 in 22 health units in 11 districts situated in 11 provinces in Mozambique. Two health facilities were selected per district (one urban and one rural). Data were collected by reviewing logbooks of antenatal consultations as well as from monthly district reports.ResultsDuring the period under investigation, a total of 23,524 pregnant women attended their 1st antenatal care visits, of which 12,775 (54.3%) and 7581 (32.2%) received one and two doses of IPTp, respectively. In regard to ITNs, a total of 16,436 (69.9%) pregnant women received ITNs. Uptake of IPTp and ITNs by pregnant women at ANC services was higher in southern Mozambique and lower in districts situated in the northern part of the country. Stock-outs of SP and ITNs were reported in 50.0% (11/22) and 54.5% (12/22) of the health facilities, respectively. Coverage of IPTp and ITN in health facilities with stock-outs of SP and ITNs was much lower as compared to health facilities with no stock-outs.ConclusionsAltogether, data from this study shows that coverage of the 2nd dose of IPTp, as well as ITNs, was low in pregnant women attending ANC services in Mozambique. In addition, this data also shows that stock-outs of SP and ITNs were frequent and led to lower coverage of IPTp and ITN, representing a serious barrier for the accomplishment of targets. In conclusion, this study recommends that efforts should be made to improve the supply chains of SP and ITNs.

BackgroundMalaria in pregnancy (MiP) remains a major public health challenge in areas of high malaria transmission. Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended to prevent the adverse consequences of MiP. The effectiveness of SP for IPTp may be reduced in areas where the dhps581 mutation (a key marker of high level SP resistance) is found; this mutation was previously reported to be common in the Tanga Region of northern Tanzania, but there are limited data from other areas. The frequency of molecular markers of SP resistance was investigated in malaria parasites from febrile patients at health centres (HC) in seven regions comprising the Lake and Southern Zones of mainland Tanzania as part of the ongoing efforts to generate national-wide data of SP resistance.MethodsA cross-sectional survey was conducted in the outpatient departments of 14 HCs in seven regions from April to June, 2015. 1750 dried blood spot (DBS) samples were collected (117 to 160 per facility) from consenting patients with positive rapid diagnostic tests for malaria, and no recent (within past 2 months) exposure to SP or related drugs. DNA was extracted from the DBS, pooled by HC, and underwent pooled targeted amplicon deep sequencing to yield estimates of mutated parasite allele frequency at each locus of interest.ResultsThe dhps540 mutation was common across all 14 sites, ranging from 55 to 98.4% of sequences obtained. Frequency of the dhps581 mutation ranged from 0 to 2.4%, except at Kayanga HC (Kagera Region, Lake Zone) where 24.9% of sequences obtained were mutated. The dhfr164 mutation was detected only at Kanyanga HC (0.06%).ConclusionBy pooling DNA extracts, the allele frequency of mutations in 14 sites could be directly determined on a single deep-sequencing run. The dhps540 mutant was very common at all locations. Surprisingly, the dhps581 was common at one health center, but rare in all the others, suggesting that there is geographic micro-heterogeneity in mutant distribution and that accurate surveillance requires inclusion of multiple sites. A better understanding of the effect of the dhps581 mutant on the efficacy of IPTp-SP is needed.

Prevention of malaria in pregnancy

Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ) is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women. A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1) SP, (2) single dose MQ (15 mg/kg), and (3) split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome) between groups (360/2,778 [13.0%]) for MQ group and 177/1,398 (12.7%) for SP group; risk ratio [RR], 1.02 (95% CI 0.86-1.22; p=0.80 in the ITT analysis). Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51-0.96]; p=0.03) and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85-0.99]; p=0.03), and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52-0.88]; p=0.004) and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78-0.95]; p=0.003). There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP. The most frequently reported related adverse events were dizziness (ranging from 33.9% to 35.5% after dose 1; and 16.0% to 20.8% after dose 2) and vomiting (30.2% to 31.7%, after dose 1 and 15.3% to 17.4% after dose 2) with similar proportions in the full and split MQ arms. The open-label design is a limitation of the study that affects mainly the safety assessment. Women taking MQ IPTp (15 mg/kg) in the context of long lasting insecticide treated nets had similar prevalence rates of low birth weight as those taking SP IPTp. MQ recipients had less clinical malaria than SP recipients, and the pregnancy outcomes and safety profile were similar. MQ had poorer tolerability even when splitting the dose over two days. These results do not support a change in the current IPTp policy. ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001429343 Please see later in the article for the Editors' Summary.

The use of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment in pregnancy (IPTp) is threatened by the spread of resistance to SP. Therefore, we studied the efficacy, safety, and tolerance of amodiaquine (AQ) or the combination of AQ and SP (SPAQ) as possible alternative treatments. The study was performed in Ghana from June 2004 through February 2007. Women were individually randomized to receive IPTp with SP (n=1328), AQ (n= 986), or SPAQ (n=1328). Incidences of anemia, peripheral anemia, and placental parasitemia at delivery were assessed for paucigravidae, as were the birth weights of their infants. Delivery outcomes and the incidence of adverse events were investigated for all women. The prevalences of anemia (as defined by a hemoglobin concentration of <11.0 g/dL) at delivery were comparable between the SP and AQ groups and between the SP and SPAQ groups. Similarly, there was no significant difference between the SP and AQ groups or between the SP and SPAQ groups with regard to the incidences of low birth weight (LBW). Women who received AQ or SPAQ were more likely to report adverse events than were those who received SP. The effects of IPTp with AQ or SPAQ on maternal anemia and LBW were comparable to the effects of IPTp with SP; however, IPTp regimens that contain AQ are unlikely to be useful as an alternative to IPTp with SP in Ghana, because of a high frequency of associated adverse events. Clinicaltrials.gov identifier: NCT00146783 .

BackgroundDespite decades of prevention efforts, the burden of malaria in pregnancy (MiP) remains a great public health concern. Sulfadoxine-pyrimethamine (SP), used as intermittent preventive treatment in pregnancy (IPTp-SP) is an important component of the malaria prevention strategy implemented in Africa. However, IPTp-SP is under constant threat from parasite resistance, thus requires regular evaluation to inform decision-making bodies.MethodsIn two malaria endemic communities in the Volta region (Adidome and Battor), a cross-sectional hospital-based study was conducted in pregnant women recruited at their first antenatal care (ANC) visit and at delivery. Basic clinical and demographic information were documented and their antenatal records were reviewed to confirm IPTp-SP adherence. Peripheral and placental blood were assayed for the presence of Plasmodium falciparum parasites by quantitative polymerase chain reaction (qPCR). One hundred and twenty (120) positive samples were genotyped for mutations associated with SP resistance.ResultsAt first ANC visit, P. falciparum prevalence was 28.8% in Adidome and 18.2% in Battor. At delivery, this decreased to 14.2% and 8.2%, respectively. At delivery, 66.2% of the women had taken at least the recommended 3 or more doses of IPTp-SP and there was no difference between the two communities. Taking at least 3 IPTp-SP doses was associated with an average birth weight increase of more than 360 g at both study sites compared to women who did not take treatment (p = 0.003). The Pfdhfr/Pfdhps quintuple mutant IRNI-A/FGKAA was the most prevalent (46.7%) haplotype found and the nonsynonymous Pfdhps mutation at codon A581G was higher at delivery among post-SP treatment isolates (40.6%) compared to those of first ANC (10.22%). There was also an increase in the A581G mutation in isolates from women who took 3 or more IPTp-SP.ConclusionsThis study confirms a positive impact following the implementation of the new IPTp-SP policy in Ghana in increasing the birth weight of newborns. However, the selection pressure exerted by the recommended 3 or more doses of IPTp-SP results in the emergence of parasites carrying the non-synonymous mutation on codon A581G. This constant selective pressure calls into question the time remaining for the clinical utility of IPTp-SP treatment during pregnancy in Africa.

Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.

BackgroundMalaria in pregnancy is responsible for various adverse maternal and birth outcomes. The emerging resistance to sulfadoxine–pyrimethamine (SP) raises important concerns about its use for intermittent preventive treatment in pregnancy (IPTp) in Africa. This trial aimed to assess the efficacy and safety of IPTp with dihydroartemisinin–piperaquine (DP) as an alternative to IPTp with SP.ResultsThe double-blind, randomized, and controlled superiority trial was conducted between July 2020 and June 2021. A total of 250 women were enrolled and randomly assigned to receive SP (n = 125) or DP (n = 125). Two hundred and six (82.4%) participants that contributed to the outcomes were included in the modified intention-to-treat (ITT) analysis, while 84 participants that completed the three courses of the study drugs were included in the per protocol (PP) analysis. The ITT analysis results showed that the incidence of histopathologically confirmed placental malaria was nonsignificantly higher in the DP group compared with the SP group (62.5% vs. 51.1%, P = 0.098). After adjusting for confounders, the risk of histopathologically confirmed placental malaria was also nonsignificantly higher in the DP group (Adjusted Relative Risk [RR] = 1.27, 95% CI 0.94–1.71) compared with the SP group. In contrast, the risk of a low APGAR score was significantly lower in the DP group (RR = 0.45, 95% CI 0.38–0.52) compared with the SP group. Also, the risk of a composite adverse birth outcome (low birth weight or preterm delivery or neonates small for the gestational age) was nonsignificantly lower in the DP group (Adjusted RR = 0.82, 95% CI 0.55–1.21) compared with the SP group. Both drugs were well tolerated, although nausea and vomiting occurred in a significant number of participants in the SP group.ConclusionsA three-course IPTp with DP was safe and was not found to be superior to IPTp with SP in the prevention of placental malaria. Although IPTp with DP was associated with a significant lower risk of low APGAR score and nonsignificant lower risks of other adverse birth outcomes compared with IPTp with SP.Trial registrationPACTR, PACTR202002644579177. Registered 20 February 2020, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9753.

BackgroundIn 2006, the first-line anti-malarial drug treatment in Tanzania was changed from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu), an artemisinin-based combination (ACT), since when the use of SP has been restricted for intermittent preventive treatment in pregnancy (IPTp). A number of Plasmodium falciparum mutations are known to be associated with resistance to SP, but it is not known if the prevalence of these mutations is increasing or decreasing under the conditions of reduced levels of SP use. This study reports on the current SP resistant quintuple Pfdhfr-Pfdhps mutations in six regions of Tanzania.MethodsFinger-prick blood on filter paper and rapid diagnostic test strips from P. falciparum-positive individuals of all age groups attending health facilities in six regions of Tanzania between June 2010 and August 2011 were obtained. Using chelex-100 extracted DNA, genotyping was done for mutations on codons 51, 59 and 108 of Pfdhfr and 437 and 540 of Pfdhps genes using PCR-RFLP technique.ResultsA total of 802 malaria-positive samples were screened and genotyped. The prevalence of Pfdhfr 51I, Pfdhps 437G and 540E varied between the regions (p < 0.001) whereas Pfdhfr 59R (FE 10.79, p = 0.225) and 108 N (FE 10.61, p = 0.239) did not vary between the regions. The Pfdhfr triple mutant was above 84% and close to fixation levels in all regions, whereas the Pfdhps double mutation ranged from 43.8 to 97% between the regions. The quintuple mutant (IRNGE) was the most prevalent in all regions and it varied significantly from 37.5 to 90.2% (χ2 = 1.11, p <0.001).ConclusionsThere is evidence of persistent high levels of SP resistance markers in Tanzania with evidence of quintuple mutations that are likely to become fixed in the population. This threatens the future of SP not only in IPTp programmes, but as a combination drug for ACT. Continuous monitoring of SP-IPTp efficacy should be encouraged subsequent to searching for alternative drugs for IPTp in East Africa.

BackgroundStudies on uptake of first dose of intermittent preventive treatment in pregnancy (IPTp) are lacking, despite it being a predictor of subsequent doses. This study aimed at assessing the determinants of uptake of first dose of IPTp among pregnant women at the State Specialist Hospital, Maiduguri.MethodsA cross-sectional study was conducted, in which respondents were selected using a systematic random sampling method, and structured questionnaires were used to obtain information from them. Chi-squared test was used to determine factors associated with uptake of first IPTp dose, while a further multivariate logistic regression was performed to determine its predictors.ResultsThree hundred and eighty respondents answered the survey, whose ages ranged from 15 to 45 years, and 86.8% were multigravid. Sixty five percent of them were aware of IPTp, and 34.7% believed that IPTp could be harmful to their pregnancies. Over a half of the respondents (52.9%) believed that taking all their IPTp medicines was very good for their pregnancies, while 45.0% felt that taking their IPTp medicines was very pleasant. Only two respondents (0.5%) stated that it was very untrue that their significant others thought that they should take all their IPTp medicines. Half of the respondents said it was very easy for them to take all their IPTp medicines even if they were experiencing mild discomforts while taking them. Less than a half (42.37%) had received their first dose of IPTp. In bivariate as well as multivariate analysis, only higher level of knowledge was significantly associated with uptake of first IPTp dose. Those with better knowledge of IPTp were about twice more likely to have taken their first dose of IPTp, compared to those with lower knowledge of IPTp (AOR = 1.85; 95% CI: 1.17–2.92).ConclusionsKnowledge of IPTp as well as its uptake, were sub-optimal in this study. Since knowledge of IPTp significantly predicts uptake of the first dose of IPTp, there is the need to implement health education campaigns to raise the awareness of pregnant women and their families on the need to receive and comply with it.