Does Iron Increase the Risk of Malaria in Pregnancy?
ABSTRACT: Background. Pregnancy-associated malaria (PAM) remains a significant health concern in sub-Saharan Africa. Cross-sectional studies report that iron might be associated with increased malaria morbidity, raising fears that current iron supplementation policies will cause harm in the present context of increasing resistance against intermittent preventive treatment in pregnancy (IPTp). Therefore, it is necessary to assess the relation of iron levels with malaria risk during the entire pregnancy. Methods. To investigate the association of maternal iron levels on malaria risk in the context of an IPTp clinical trial, 1005 human immunodeficiency virus-negative, pregnant Beninese women were monitored throughout their pregnancy between January 2010 and May 2011. Multilevel models with random intercept at the individual levels and random slope for gestational age were used to analyze the factors associated with increased risk of a positive blood smear and increased Plasmodium falciparum density. Results. During the follow-up, 29% of the women had at least 1 episode of malaria. On average, women had 0.52 positive smears (95% confidence interval [CI], 0.44-0.60). High iron levels (measured by the log10 of ferritin corrected on inflammation) were significantly associated with increased risk of a positive blood smear (adjusted odds ratio = 1.75; 95% CI, 1.46-2.11; P < .001) and high P falciparum density (beta estimate = 0.22; 95% CI, 0.18-0.27; P < .001) during the follow-up period adjusted on pregnancy parameters, comorbidities, environmental and socioeconomic indicators, and IPTp regime. Furthermore, iron-deficient women were significantly less likely to have a positive blood smear and high P falciparum density (P < .001 in both cases). Conclusions. Iron levels were positively associated with increased PAM during pregnancy in the context of IPTp. Supplementary interventional studies are needed to determine the benefits and risks of differently dosed iron and folate supplements in malaria-endemic regions.
Project description:<h4>Background</h4>Antenatal intermittent preventive therapy with 2 doses of sulfadoxine-pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads.<h4>Methods</h4>We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes.<h4>Results</h4>The prevalence of parasites with highly SP-resistant haplotypes increased from 17% to 100% (P < .001), and the proportion of women receiving full IPTp (?2 doses) increased from 25% to 82% (P < .001). Women who received full IPTp with SP had lower peripheral (P = .018) and placental (P < .001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity.<h4>Conclusions</h4>In this longitudinal study of malaria at delivery, the receipt of SP as IPTp did not potentiate PAM morbidity despite the increasing prevalence and fixation of SP-resistant P. falciparum haplotypes. Even when there is substantial resistance, SP may be used in modified IPTp regimens as a component of comprehensive antenatal care.
Project description:BACKGROUND: Malaria during pregnancy remains a serious public health problem. The aim of this study was to determine the prevalence and possible risk factors for malaria in pregnant women attending antenatal clinic at two primary health facilities in Bobo-Dioulasso. METHODS: We conducted a cross sectional study from September to December 2010 in two primary health facilities located in the periurban area of Bobo-Dioulasso. Pregnant women attending antenatal clinic (ANC) were included in the study after signing informed consent. For each participant, the social-demographic profile, malaria and obstetric histories were investigated through a questionnaire. Peripheral blood was collected and thick and thin blood smears were prepared to check Plasmodium falciparum parasitaemia. Hemoglobin concentration was measured. The associations between age, parity, gestational age, schooling, number of ANC visits, use of IPTp-SP, use of insecticide-treated nets (ITN) and anemia with the occurrence of P. falciparum malaria infection during pregnancy were analyzed through logistic regression. RESULTS: During the period of study, 105 (18.1%) out of 579 pregnant women were infected by P. falciparum. The hemoglobin concentration mean was 10.5?±?1.7/dL and was significantly lower in pregnant women with malaria infection (9.8 g/dL ±1.6) than in those who had no malaria infection (10.6 g/dL ±1.7) (P?<?0.001). Multivariate analysis indicated that, education (AOR 1.9, 95% CI?=?[1.2-3.2]), parity [primigravidae (AOR 5.0, 95% CI?=?[2.5-9.8]) and secundigravidae (AOR 2.1, 95% CI?=?[1.2-3.8])], and anaemia (AOR 2.1, 95% CI?=?[1.3-3.5]) were significantly associated with P. falciparum malaria infection. The use of IPTp-SP was not associated with P. falciparum malaria infection. CONCLUSIONS: P. falciparum malaria infection is common in pregnant women attending antenatal clinic and anaemia is an important complication. The results show that the use of IPTp-SP does not reduce the risk of malaria incidence during pregnancy.
Project description:Background:Dihydroartemisinin-piperaquine (DHA-PQ) is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine (PQ) exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies. Methods:Human immunodeficiency virus-uninfected pregnant women (n = 300) were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks' gestation and randomized to sulfadoxine-pyrimethamine every 8 weeks, DHA-PQ every 8 weeks, or DHA-PQ every 4 weeks during pregnancy. Pharmacokinetic sampling for PQ was performed every 4 weeks, and an intensive pharmacokinetic substudy was performed in 30 women at 28 weeks' gestation. Concentration-effect relationships were assessed between exposure to PQ; the prevalence of Plasmodium falciparum infection during pregnancy; outcomes at delivery including placental malaria, low birth weight, and preterm birth; and risks for toxicity. Simulations of new dosing scenarios were performed. Results:Model-defined PQ target venous plasma concentrations of 13.9 ng/mL provided 99% protection from P. falciparum infection during pregnancy. Each 10-day increase in time above target PQ concentrations was associated with reduced odds of placental parasitemia, preterm birth, and low birth weight, though increases in PQ concentrations were associated with QT interval prolongation. Modeling suggests that daily or weekly administration of lower dosages of PQ, compared to standard dosing, will maintain PQ trough levels above target concentrations with reduced PQ peak levels, potentially limiting toxicity. Conclusions:The protective efficacy of IPTp with DHA-PQ was strongly associated with higher drug exposure. Studies of the efficacy and safety of alternative DHA-PQ IPTp dosing strategies are warranted. Clinical Trials Registration:NCT02163447.
Project description:BACKGROUND:Placental malaria is a major cause of adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of parasitemia during pregnancy and placental malaria. METHODS:Data came from 637 women enrolled in a randomized controlled trial of intermittent preventive treatment of malaria in pregnancy (IPTp) from Uganda. Plasmodium falciparum parasitemia was assessed using microscopy and ultrasensitive quantitative PCR at intervals of 28 days from 12 to 20 weeks gestation through delivery. Multivariate analysis was used to measure associations between characteristics of parasitemia during pregnancy and the risk of placental malaria based on histopathology. RESULTS:Overall risk of placental malaria was 44.6%. None of the 34 women without parasitemia detected during pregnancy had evidence of placental malaria. Increasing proportion of interval assessments with parasitemia and higher parasite densities were independently associated with an increased risk of placental malaria. Higher gravidity and more effective IPTp were associated with a decreased risk of placental malaria. Women with parasitemia only detected before the third trimester still had an increased risk of placental malaria. CONCLUSIONS:The frequency, density, and timing of parasitemia are all important risk factors for placental malaria. Interventions should target the prevention of all levels of parasitemia throughout pregnancy.
Project description:Zanzibar has transitioned from malaria control to the pre-elimination phase, and the continued need for intermittent preventive treatment during pregnancy (IPTp) has been questioned. We conducted a prospective observational study to estimate placental malaria positivity rate among women who did not receive IPTp with sulfadoxine-pyrimethamine. A convenience sample of pregnant women was enrolled from six clinics on the day of delivery from August of 2011 to September of 2012. Dried placental blood spot specimens were analyzed by polymerase chain reaction (PCR); 9 of 1,349 specimens (0.7%; precision estimate = 0.2-1.1%) were PCR-positive for Plasmodium falciparum. Placental infection was detected on both Pemba (N = 3) and Unguja (N = 6). Placental malaria positivity in Zanzibar was low, even in the absence of IPTp. It may be reasonable for the Ministry of Health to consider discontinuing IPTp, intensifying surveillance efforts, and promoting insecticide-treated nets and effective case management of malaria in pregnancy.
Project description:Pregnant women are a high-risk group for Plasmodium falciparum infections, which may result in maternal anaemia and low birth weight newborns, among other adverse birth outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy (IPTp-SP) is widely implemented to prevent these negative effects of malaria. However, resistance against SP by P. falciparum may decrease efficacy of IPTp-SP. Combinations of point mutations in the dhps (codons A437, K540) and dhfr genes (codons N51, C59, S108) of P. falciparum are associated with SP resistance. In this study the prevalence of SP resistance mutations was determined among P. falciparum found in pregnant women and the general population (GP) from Nanoro, Burkina Faso and the association of IPTp-SP dosing and other variables with mutations was studied.Blood spots on filter papers were collected from pregnant women at their first antenatal care visit (ANC booking) and at delivery, from an ongoing trial and from the GP in a cross-sectional survey. The dhps and dhfr genes were amplified by nested PCR and products were sequenced to identify mutations conferring resistance (ANC booking, n = 400; delivery, n = 223; GP, n = 400). Prevalence was estimated with generalized estimating equations and for multivariate analyses mixed effects logistic regression was used.The prevalence of the triple dhfr mutation was high, and significantly higher in the GP and at delivery than at ANC booking, but it did not affect birth weight. Furthermore, quintuple mutations (triple dhfr and double dhps mutations) were found for the first time in Burkina Faso. IPTp-SP did not significantly affect the occurrence of any of the mutations, but high transmission season was associated with increased mutation prevalence in delivery samples. It is unclear why the prevalence of mutations was higher in the GP than in pregnant women at ANC booking.The high number of mutants and the presence of quintuple mutants in Burkina Faso confirm concerns about the efficacy of IPTp-SP in the near future. Other drug combinations to tackle malaria in pregnancy should, therefore, be explored. An increase in mutation prevalence due to IPTp-SP dosing could not be confirmed.
Project description:BACKGROUND:Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) significantly reduces the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (SP), the current standard of care, but its impact on the incidence of malaria during infancy is unknown. METHODS:We conducted a double-blind randomized trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomized to monthly IPTp with either DP or SP. Infants were followed for all their medical care in a dedicated study clinic, and routine assessments were conducted every 4?weeks. At all visits, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was malaria incidence during the first 12?months of life. All analyses were done by modified intention to treat. RESULTS:Of the 782 women enrolled, 687 were followed through delivery from December 9, 2016, to December 5, 2017, resulting in 678 live births: 339 born to mothers randomized to SP and 339 born to those randomized to DP. Of these, 581 infants (85.7%) were followed up to 12?months of age. Overall, the incidence of malaria was lower among infants born to mothers randomized to DP compared to SP, but the difference was not statistically significant (1.71 vs 1.98 episodes per person-year, incidence rate ratio (IRR) 0.87, 95% confidence interval (CI) 0.73-1.03, p?=?0.11). Stratifying by infant sex, IPTp with DP was associated with a lower incidence of malaria among male infants (IRR 0.75, 95% CI 0.58-0.98, p?=?0.03) but not female infants (IRR 0.99, 95% CI 0.79-1.24, p?=?0.93). CONCLUSION:Despite the superiority of DP for IPTp, there was no evidence of a difference in malaria incidence during infancy in infants born to mothers who received DP compared to those born to mothers who received SP. Only male infants appeared to benefit from IPTp-DP suggesting that IPTp-DP may provide additional benefits beyond birth. Further research is needed to further explore the benefits of DP versus SP for IPTp on the health outcomes of infants. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02793622 . Registered on June 8, 2016.
Project description:BACKGROUND:The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) alongside long-lasting insecticide-treated nets (LLIN) and case management for reducing the risks associated with malaria in pregnancy in areas of moderate-to-high transmission in sub-Saharan Africa. Due to increasing Plasmodium falciparum resistance to SP, the search for alternative drugs or strategies to control malaria in pregnancy is a priority. We assessed the acceptability among pregnant women and health providers of intermittent screening and treatment (ISTp) and IPTp with dihydroartemisinin-piperaquine (DP) as alternative strategies in the context of an un-blinded clinical trial. METHODS:Qualitative data were collected through ten focus group discussions with women participating in a randomized controlled trial to evaluate ISTp or IPTp with DP (multi-day regimen) versus IPTp with SP (single dose) in western Kenya. Individual in-depth interviews were conducted with 26 health providers working in the trial facilities and trial staff. RESULTS:Women appreciated the advantages of being tested with a rapid diagnostic test (RDT) at every ANC visit (although a few women disliked finger pricks) and accepted that they would not receive any antimalarial when tested RDT-negative. There were differences in women's experiences of the efficacy of antimalarials between the trial arms, with more women in the IPTp-SP arm reporting they had experienced malaria episodes. Side effects were experienced among women taking DP and SP. Although women and trial staff reported adherence to the full DP regimen within the trial, health providers were not confident that women would adhere to multi-day regimens in non-trial settings. Health providers recognized the advantages of ISTp in reducing unnecessary exposure to drugs, but lacked confidence in the reliability of RDTs compared to microscopy. CONCLUSIONS:Our findings indicate that, within a trial context, ISTp-DP and IPTp-DP were generally acceptable among both users and providers and were regarded as potentially valuable alternatives to IPTp-SP. Several challenges were identified the most important of which was concerns with achieving adherence to DP in non-trial settings, requiring operational feasibility studies in routine health systems. Policy adoption of ISTp with RDTs would require a major shift in thinking among health providers due to lack of confidence in RDTs.
Project description:BACKGROUND:Non-Plasmodium falciparum malaria infections are found in many parts of sub-Saharan Africa but little is known about their importance in pregnancy. METHODS:Blood samples were collected at first antenatal clinic attendance from 2526 women enrolled in a trial of intermittent screening and treatment of malaria in pregnancy (ISTp) versus intermittent preventive treatment (IPTp) conducted in Burkina Faso, The Gambia, Ghana and Mali. DNA was extracted from blood spots and tested for P. falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale using a nested PCR test. Risk factors for a non-falciparum malaria infection were investigated and the influence of these infections on the outcome of pregnancy was determined. RESULTS:P. falciparum infection was detected frequently (overall prevalence by PCR: 38.8 %, [95 % CI 37.0, 40.8]), with a prevalence ranging from 10.8 % in The Gambia to 56.1 % in Ghana. Non-falciparum malaria infections were found only rarely (overall prevalence 1.39 % [95 % CI 1.00, 1.92]), ranging from 0.17 % in the Gambia to 3.81 % in Mali. Ten non-falciparum mono-infections and 25 mixed falciparum and non-falciparum infections were found. P. malariae was the most frequent non-falciparum infection identified; P. vivax was detected only in Mali. Only four of the non-falciparum mono-infections were detected by microscopy or rapid diagnostic test. Recruitment during the late rainy season and low socio-economic status were associated with an increased risk of non-falciparum malaria as well as falciparum malaria. The outcome of pregnancy did not differ between women with a non-falciparum malaria infection and those who were not infected with malaria at first ANC attendance. CONCLUSIONS:Non-falciparum infections were infrequent in the populations studied, rarely detected when present as a mono-infection and unlikely to have had an important impact on the outcome of pregnancy in the communities studied due to the small number of women infected with non-falciparum parasites.
Project description:Plasmodium falciparum infected red blood cells (iRBC) express variant surface antigens (VSA) of which VAR2CSA is involved in placental sequestration and causes pregnancy-associated malaria (PAM). Primigravidae are most susceptible to PAM whereas antibodies associated with protection are often present at higher levels in multigravid women. However, HIV co-infection with malaria has been shown to alter this parity-dependent acquisition of immunity, with more severe symptoms as well as more malaria episodes in HIV positive women versus HIV negative women of a similar parity.Using VAR2CSA DBL-domains expressed on the surface of CHO-745 cells we quantified levels of DBL-domain specific IgG in sera from pregnant Malawian women by flow cytometry. Dissociations constants of DBL5epsilon specific antibodies were determined using a surface plasmon resonance technique, as an indication of antibody affinities.VAR2CSA DBL5epsilon was recognized in a gender and parity-dependent manner with anti-DBL5epsilon IgG correlating significantly with IgG levels to VSA-PAM on the iRBC surface. HIV positive women had lower levels of anti-DBL5epsilon IgG than HIV negative women of similar parity. In primigravidae, antibodies in HIV positive women also showed significantly lower affinity to VAR2CSA DBL5epsilon.Pregnant women from a malaria-endemic area had increased levels of anti-DBL5epsilon IgG by parity, indicating this domain of VAR2CSA to be a promising vaccine candidate against PAM. However, it is important to consider co-infection with HIV, as this seems to change the properties of antibody response against malaria. Understanding the characteristics of antibody response against VAR2CSA is undoubtedly imperative in order to design a functional and efficient vaccine against PAM.