The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis

Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24–0.97, I² = 0%, 3 studies); 0.58 (95% CI 0.31–1.16, I² = 0%, 6 studies); and 1.00 (95% CI 0.27–3.75, I² = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77–1.66, I² = 86.7%, 3 studies); 1.10 (95% CI 0.79–1.54, I² = 0%, 4 studies); and 0.79 (95% CI 0.37–1.67, I² = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2^nd and 3^rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews conducted by the WHO in 2002 and 2006 and supports the current WHO malaria treatment guidelines malaria in pregnancy.     

Malaria in Pregnancy Is a Predictor of Infant Haemoglobin Concentrations during the First Year of Life in Benin,West Africa

Background

Anaemia is an increasingly recognized health problem in Africa, particularly in infants and pregnant women. Although malaria is known to be the main risk factor of anaemia in both groups, the consequences of maternal factors, particularly malaria in pregnancy (MiP), on infant haemoglobin (Hb) concentrations during the first months of life are still unclear.

Methods

We followed-up a cohort of 1005 Beninese pregnant women from the beginning of pregnancy until delivery. A subsample composed of the first 400 offspring of these women were selected at birth and followed until the first year of life. Placental histology and blood smear at 1^st clinical antenatal visit (ANC), 2^nd ANC and delivery were used to assess malaria during pregnancy. Infant Hb concentrations were measured at birth, 6, 9 and 12 months of age. A mixed multi-level model was used to assess the association between MiP and infant Hb variations during the first 12 months of life.

Results

Placental malaria (difference mean [dm] = - 2.8 g/L, 95% CI [-5.3, -0.3], P = 0.03) and maternal peripheral parasitaemia at delivery (dm = - 4.6 g/L, 95% CI [-7.9, -1.3], P = 0.007) were the main maternal factors significantly associated with infant Hb concentrations during the first year of life. Poor maternal nutritional status and malaria infection during infancy were also significantly associated with a decrease in infant Hb.

Conclusion

Antimalarial control and nutritional interventions before and during pregnancy should be reinforced to reduce specifically the incidence of infant anaemia, particularly in Sub-Saharan countries.     

Impact of Placental Plasmodium falciparum Malaria on the Profile of Some Oxidative Stress Biomarkers in Women Living in Yaoundé, Cameroon

Background

Impact of the pathophysiology of Plasmodium falciparum placental malaria (PM) on the profile of some oxidative stress biomarkers and their relationship with poor pregnancy outcomes in women remain unknown.

Methods

Between 2013 and 2014, peripheral blood and placenta tissue from 120 Cameroonian women at delivery were assessed for maternal haemoglobin and, parasitaemia respectively. Parasite accumulation in the placenta was investigated histologically. The levels of oxidative stress biomarkers Malondialdehyde (MDA), Nitric Oxide (NO), Superoxide dismutase (SOD), Catalase (CAT) and Gluthatione (GSH) in the supernatant of teased placenta tissues were determined by Colorimetric enzymatic assays.

Results

Parasitaemia was inversely related to haemoglobin levels and birth weight (P <0.001 and 0.012, respectively). The level of lipid peroxide product (MDA) was significantly higher in the malaria infected (P = 0.0047) and anaemic (P = 0.024) women compared to their non-infected and non-anaemic counterparts, respectively. A similar trend was observed with SOD levels, though not significant. The levels of MDA also correlated positively with parasitaemia (P = 0.0024) but negatively with haemoglobin levels (P = 0.002). There was no association between parasitaemia, haemoglobin level and the other oxidative stress biomarkers. From histological studies, levels of MDA associated positively and significantly with placenta malaria infection and the presence of malaria pigments. The levels of SOD, NO and CAT increased with decreasing leukocyte accumulation in the intervillous space. Baby birth weight increased significantly with SOD and CAT levels, but decreased with levels of GSH.

Conclusions

Placental P. falciparum infection may cause oxidative stress of the placenta tissue with MDA as a potential biomarker of PM, which alongside GSH could lead to poor pregnancy outcomes (anaemia and low birth weight). This finding contributes to the understanding of the pathophysiology of P. falciparum placental malaria in women.     

Induction of labour at 41 weeks or expectant management until 42 weeks: A systematic review and an individual participant data meta-analysis of randomised trials

BackgroundThe risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant data meta-analysis (IPD-MA) on this subject.Methods and findingsWe searched PubMed, Excerpta Medica dataBASE (Embase), The Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO on February 21, 2020 for RCTs comparing IOL at 41 weeks with expectant management until 42 weeks in women with uncomplicated pregnancies. Individual participant data (IPD) were sought from eligible RCTs. Primary outcome was a composite of severe adverse perinatal outcomes: mortality and severe neonatal morbidity. Additional outcomes included neonatal admission, mode of delivery, perineal lacerations, and postpartum haemorrhage. Prespecified subgroup analyses were conducted for parity (nulliparous/multiparous), maternal age (<35/≥35 years), and body mass index (BMI) (<30/≥30). Aggregate data meta-analysis (MA) was performed to include data from RCTs for which IPD was not available.From 89 full-text articles, we identified three eligible RCTs (n = 5,161), and two contributed with IPD (n = 4,561). Baseline characteristics were similar between the groups regarding age, parity, BMI, and higher level of education. IOL resulted overall in a decrease of severe adverse perinatal outcome (0.4% [10/2,281] versus 1.0% [23/2,280]; relative risk [RR] 0.43 [95% confidence interval [CI] 0.21 to 0.91], p-value 0.027, risk difference [RD] −57/10,000 [95% CI −106/10,000 to −8/10,000], I² 0%). The number needed to treat (NNT) was 175 (95% CI 94 to 1,267).Perinatal deaths occurred in one (<0.1%) versus eight (0.4%) pregnancies (Peto odds ratio [OR] 0.21 [95% CI 0.06 to 0.78], p-value 0.019, RD −31/10,000, [95% CI −56/10,000 to −5/10,000], I² 0%, NNT 326, [95% CI 177 to 2,014]) and admission to a neonatal care unit ≥4 days occurred in 1.1% (24/2,280) versus 1.9% (46/2,273), (RR 0.52 [95% CI 0.32 to 0.85], p-value 0.009, RD −97/10,000 [95% CI −169/10,000 to −26/10,000], I² 0%, NNT 103 [95% CI 59 to 385]). There was no difference in the rate of cesarean delivery (10.5% versus 10.7%; RR 0.98, [95% CI 0.83 to 1.16], p-value 0.81) nor in other important perinatal, delivery, and maternal outcomes. MA on aggregate data showed similar results.Prespecified subgroup analyses for the primary outcome showed a significant difference in the treatment effect (p = 0.01 for interaction) for parity, but not for maternal age or BMI. The risk of severe adverse perinatal outcome was decreased for nulliparous women in the IOL group (0.3% [4/1,219] versus 1.6% [20/1,264]; RR 0.20 [95% CI 0.07 to 0.60], p-value 0.004, RD −127/10,000, [95% CI −204/10,000 to −50/10,000], I² 0%, NNT 79 [95% CI 49 to 201]) but not for multiparous women (0.6% [6/1,219] versus 0.3% [3/1,264]; RR 1.59 [95% CI 0.15 to 17.30], p-value 0.35, RD 27/10,000, [95% CI −29/10,000 to 84/10,000], I² 55%).A limitation of this IPD-MA was the risk of overestimation of the effect on perinatal mortality due to early stopping of the largest included trial for safety reasons after the advice of the Data and Safety Monitoring Board. Furthermore, only two RCTs were eligible for the IPD-MA; thus, the possibility to assess severe adverse neonatal outcomes with few events was limited.ConclusionsIn this study, we found that, overall, IOL at 41 weeks improved perinatal outcome compared with expectant management until 42 weeks without increasing the cesarean delivery rate. This benefit is shown only in nulliparous women, whereas for multiparous women, the incidence of mortality and morbidity was too low to demonstrate any effect. The magnitude of risk reduction of perinatal mortality remains uncertain. Women with pregnancies approaching 41 weeks should be informed on the risk differences according to parity so that they are able to make an informed choice for IOL at 41 weeks or expectant management until 42 weeks.Study Registration: PROSPERO CRD42020163174

Mårten Alkmark and co-workers report on a meta-analysis of randomized trials of labour induction at 41 weeks'' gestation as compared with expectant management until 42 weeks.     

Malaria prevalence among pregnant women in two districts with differing endemicity in Chhattisgarh, India

ABSTRACT: BACKGROUND: In India, malaria is not uniformly distributed. Chhattisgarh is a highly malarious state where both Plasmodium falciparum and Plasmodium vivax are prevalent with a preponderance of P. falciparum. Malaria in pregnancy (MIP), especially when caused by P. falciparum, poses substantial risk to the mother and foetus by increasing the risk of foetal death, prematurity, low birth weight (LBW), and maternal anaemia. These risks vary between areas with stable and unstable transmission. The specific objectives of this study were to determine the prevalence of malaria, its association with maternal and birth outcomes, and use of antimalarial preventive measures for development of evidence based interventions to reduce the burden of MIP. METHODS: A cross-sectional study of pregnant women presenting to antenatal clinics (ANC) or delivery units (DU), or hospitalized for non-obstetric illness was conducted over 12 months in high (Bastar) and low (Rajnandgaon) transmission districts in Chhattisgarh state. Intensity of transmission was defined on the basis of slide positivity rates with a high proportion due to P. falciparum. In each district, a rural and an urban health facility was selected. RESULTS: Prevalence of peripheral parasitaemia was low: 1.3% (35/2696) among women at ANCs and 1.9% at DUs (19/1025). Peripheral parasitaemia was significantly more common in Bastar (2.8%) than in Rajnandgaon (0.1%) (p < 0.0001). On multivariate analysis of ANC participants, residence in Bastar district (stable malaria transmission) was strongly associated with peripheral parasitaemia (adjusted OR [aOR] 43.4; 95% CI, 5.6-335.2). Additional covariates associated with parasitaemia were moderate anaemia (aOR 3.7; 95% CI 1.8-7.7), fever within the past week (aOR 3.2; 95% CI 1.2-8.6), and lack of formal education (aOR 4.6; 95% CI 2.0-10.7). Similarly, analysis of DU participants revealed that moderate anaemia (aOR 2.5; 95% CI 1.1-5.4) and fever within the past week (aOR 5.8; 95% CI 2.4-13.9) were strongly associated with peripheral and/or placental parasitaemia. Malaria-related admissions were more frequent among pregnant women in Bastar, the district with greater malaria prevalence (51% vs. 11%, p < 0.0001). CONCLUSIONS: Given the overall low prevalence of malaria, a strategy of enhanced anti-vector measures coupled with intermittent screening and targeted treatment during pregnancy should be considered for preventing malaria-associated morbidity in central India.     

Simple flow cytometric detection of haemozoin containing leukocytes and erythrocytes for research on diagnosis, immunology and drug sensitivity testing

Background

Plasmodium falciparum malaria remains endemic in sub-Saharan Africa including Ghana. The epidemiology of malaria in special areas, such as mining areas needs to be monitored and controlled. Newmont Ghana Gold Limited is conducting mining activities in the Brong Ahafo Region of Ghana that may have an impact on the diseases such as malaria in the mining area.

Methods

Prior to the start of mining activities, a cross-sectional survey was conducted in 2006/2007 to determine malaria epidemiology, including malaria parasitaemia and anaemia among children < 5 years and monthly malaria transmission in a mining area of Ghana.

Results

A total of 1,671 households with a child less than five years were selected. About 50% of the household heads were males. The prevalence of any malaria parasitaemia was 22.8% (95% CI 20.8 - 24.9). Plasmodium falciparum represented 98.1% (95% CI 96.2 - 99.2) of parasitaemia. The geometric mean P. falciparum asexual parasite count was 1,602 (95% CI 1,140 - 2,252) and 1,195 (95% CI 985 - 1,449) among children < 24 months and ≥ 24 months respectively. Health insurance membership (OR 0.60, 95% CI 0.45 - 0.80, p = 0.001) and the least poor (OR 0.57, 95% CI 0.37 - 0.90, p = 0.001) were protected against malaria parasitaemia. The prevalence of anaemia was high among children < 24 months compared to children ≥ 24 months (44.1% (95% CI 40.0 - 48.3) and 23.8% (95% CI 21.2 - 26.5) respectively. About 69% (95% CI 66.3 - 70.9) of households own at least one ITN. The highest EIRs were record in May 2007 (669 ib/p/m) and June 2007 (826 ib/p/m). The EIR of Anopheles gambiae were generally higher than Anopheles funestus.

Conclusion

The baseline malaria epidemiology suggests a high malaria transmission in the mining area prior to the start of mining activities. Efforts at controlling malaria in this mining area have been intensified but could be enhanced with increased resources and partnerships between the government and the private sector.     

Factors associated with the prevalence of HIV,HSV-2, pregnancy,and reported sexual activity among adolescent girls in rural western Kenya: A cross-sectional analysis of baseline data in a cluster randomized controlled trial

BackgroundAdolescence is a sensitive time for girls’ sexual and reproductive health (SRH), as biological changes occur concurrently with heightening pressures for sexual activity. In western Kenya, adolescent girls are vulnerable to acquiring sexually transmitted infections (STIs), such as HIV and herpes simplex virus type 2 (HSV-2), and to becoming pregnant prior to reaching adulthood. This study examines associations between individual, household, and partner-related risk factors and the prevalence of sex, adolescent pregnancy, HIV, and HSV-2.Methods and findingsWe report baseline findings among 4,138 girls attending secondary school who were enrolled between 2017 and 2018 in the Cups or Cash for Girls (CCG) cluster randomized controlled trial in Siaya County, rural western Kenya. Laboratory confirmed biomarkers and survey data were utilized to assess the effects of girls’ individual, household, and partner characteristics on the main outcome measures (adolescent reported sex, prior pregnancy, HIV, and HSV-2) through generalized linear model (GLM) analysis. Complete data were available for 3,998 girls (97%) with median age 17.1 years (interquartile range [IQR] 16.3 to 18.0 years); 17.2% were HSV-2 seropositive (n = 686) and 1.7% tested positive for HIV (n = 66). Sexual activity was reported by 27.3% girls (n = 1,090), of whom 12.2% had been pregnant (n = 133). After adjustment, orphanhood (adjusted risk ratio [aRR] 2.81, 95% confidence interval [CI] 1.18 to 6.71, p-value [p] = 0.020), low body mass index (BMI) (aRR 2.07; CI: 1.00 to 4.30, p = 0.051), and age (aRR 1.34, 1.18 to 1.53, p < 0.001) were all associated with HIV infection. Girls reporting light menstrual bleeding (aRR 2.42, 1.22 to 4.79, p = 0.012) for fewer than 3 days (aRR 2.81, 1.16 to 6.82, p = 0.023) were over twice as likely to have HIV. Early menarche (aRR 2.05, 1.33 to 3.17, p = 0.001) was associated with adolescent pregnancy and HSV-2–seropositive girls reported higher rates of pregnancy (aRR 1.62, CI: 1.16 to 2.27, p = 0.005). High BMI was associated with HSV-2 (aRR 1.24, 1.05 to 1.46, p = 0.010) and sexual activity (aRR 1.14, 1.02 to 1.28, p = 0.016). High levels of harassment were detected in the cohort (41.2%); being touched indecently conveyed the strongest association related to reported sexual activity (aRR 2.52, 2.26 to 2.81, p < 0.001). Study limitations include the cross-sectional design of the study, which informs on the SRH burdens found in this population but limits causal interpretation of associations, and the self-reported exposure ascertainment, which may have led to possible underreporting of risk factors, most notably prior sexual activity.ConclusionsOur findings indicate that adolescent girls attending school in Kenya face frequent harassment for sex and are at high risk of pregnancy and HSV-2, with girls experiencing early menarche particularly vulnerable. Targeted interventions, such as earlier sexual education programs, are warranted to address their vulnerability to SRH harms.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03051789","term_id":"NCT03051789"}}NCT03051789.

In a cross sectional analysis, Garazi Zulaika and colleagues study associations between risk factors and prevalence of sexual activity, pregnancy, and HIV and HSV-2 infections among adolescent girls in rural Kenya.     

Performance characteristics of combinations of host biomarkers to identify women with occult placental malaria: a case-control study from Malawi

Background

Because of its propensity to sequester in the placental intervillous space, Plasmodium falciparum can evade detection by peripheral smear in women with placental malaria (PM). We evaluated host biomarkers as potential indicators of occult PM infections.

Methods and Findings

Using a case-control design, we evaluated the ability of biomarkers to identify PM in the absence of circulating peripheral parasites (n = 24) compared to placental smear-negative controls (n = 326). We measured levels of biomarkers (C3a, C5a, CRP, angiopoietin-1, angiopoietin-2, sTie-2, sEndoglin, VEGF, sFlt-1, tissue factor, and leptin) in maternal peripheral plasma at delivery. Using ROC curve analysis, we assessed the ability of clinical parameters and biomarkers to accurately detect PM infections identified by placental smear. We show that decreases in sFlt-1 and leptin and increases in CRP were associated with occult PM infections (p<0.01) and correlated with placental parasitaemia (p<0.01). Individually, all markers had moderate ability to diagnose occult PM infections with areas under the ROC between 0.62 and 0.72. In order to improve diagnostic performance, we generated simple scoring systems to identify PM infections using either a clinical score (0–2), a biomarker score (0–3) or a clinical plus biomarker score (0–5). The combinatorial model that incorporated both clinical parameters and biomarkers had an area under curve (AUC) of 0.85 (95% CI, 0.81-0.89), which was significantly better at identifying occult PM infections than the clinical score alone (p = 0.001).

Conclusion

These data suggest that host biomarkers in the maternal peripheral blood may improve the detection of PM in the absence of peripheral parasitaemia.     

Plasmodium falciparum parasitaemia in the first half of pregnancy, uterine and umbilical artery blood flow, and foetal growth: a longitudinal Doppler ultrasound study

ABSTRACT: BACKGROUND: During early pregnancy, the placenta develops to meet the metabolic demands of the foetus. The objective of this analysis was to examine the effect of malaria parasitaemia prior to 20 weeks' gestation on subsequent changes in uterine and umbilical artery blood flow and intrauterine growth restriction. METHODS: Data were analysed from 548 antenatal visits after 20 weeks' gestation of 128 women, which included foetal biometric measures and interrogation of uterine and umbilical artery blood flow. Linear mixed effect models estimated the effect of early pregnancy malaria parasitaemia on uterine and umbilical artery resistance indices. Log-binomial models with generalized estimating equations estimated the effect of early pregnancy malaria parasitaemia on the risk of intrauterine growth restriction. RESULTS: There were differential effects of early pregnancy malaria parasitaemia on uterine artery resistance by nutritional status, with decreased uterine artery resistance among nourished women with early pregnancy malaria and increased uterine artery resistance among undernourished women with early pregnancy malaria. Among primigravidae, early pregnancy malaria parasitaemia decreased umbilical artery resistance in the late third trimester, likely reflecting adaptive villous angiogenesis. In fully adjusted models, primigravidae with early pregnancy malaria parasitaemia had 3.6 times the risk of subsequent intrauterine growth restriction (95% CI: 2.1, 6.2) compared to the referent group of multigravidae with no early pregnancy malaria parasitaemia. CONCLUSIONS: Early pregnancy malaria parasitaemia affects uterine and umbilical artery blood flow, possibly due to alterations in placentation and angiogenesis, respectively. Among primigravidae, early pregnancy malaria parasitaemia increases the risk of intrauterine growth restriction. The findings support the initiation of malaria parasitaemia prevention and control efforts earlier in pregnancy.     

Prevalence and risk factors for Plasmodium falciparum malaria in pregnant women of eastern Sudan

Background

Pregnant women are more susceptible to malaria, which is associated with serious adverse effects on pregnancy. The presentation of malaria during pregnancy varies according to the level of transmission in the area. Our study aimed to demonstrate the prevalence and risk factors for malaria (age, parity and gestational age) among pregnant women of eastern Sudan, which is characterized by unstable malaria transmission.

Methods

The prevalence and possible risk factors for Plasmodium falciparum malaria were investigated in 744 pregnant Sudanese women attending the antenatal clinic of New Haifa Teaching Hospital, eastern Sudan, during October 2003-April 2004.

Results

A total 102 (13.7%) had P. falciparum malaria, 18(17.6%) of these were severe cases (jaundice and severe anaemia). Univariate and multivariate analysis showed that, age and parity were not associated with malaria. Women who attended the antenatal clinic in the third trimester were at highest risk for malaria (OR = 1.58, 95% CI = 1.02–2.4; P < 0.05). Women with malaria had significantly lower mean haemoglobin (9.4 g/dl, 95% CI 9.1–9.7 versus 10.7, CI 10.6–10.8, P < 0.05). A significantly lower haemoglobin was observed in those with severe falciparum malaria compared to non-severe form (8.3 g/dl, 95% CI 7.6–9.1 versus 9.4, 95% CI 9.1–9.7, P = < 0.05).

Conclusion

The results suggest that P. falciparum malaria is common in pregnant women attending antenatal care and that anaemia is an important complication. Preventive measures (chemoprophylaxis and insecticide-treated bednets) may be beneficial in this area for all women irrespective of age or parity.     

Impact of Pregnancy-Associated Malaria on Infant Malaria Infection in Southern Benin

Background

Infants of mothers with placental Plasmodium falciparum infections at delivery are themselves more susceptible to malaria attacks or to infection in early life.

Methodology/ Principal Findings

To assess the impact of either the timing or the number of pregnancy-associated malaria (PAM) infections on the incidence of parasitemia or malaria attacks in infancy, we followed 218 mothers through pregnancy (monthly visits) up to delivery and their infants from birth to 12 months of age (fortnightly visits), collecting detailed clinical and parasitological data. After adjustment on location, mother’s age, birth season, bed net use, and placental malaria, infants born to a mother with PAM during the third trimester of pregnancy had a significantly increased risk of infection (OR [95% CI]: 4.2 [1.6; 10.5], p = 0.003) or of malaria attack (4.6 [1.7; 12.5], p = 0.003). PAM during the first and second trimesters had no such impact. Similarly significant results were found for the effect of the overall number of PAM episodes on the time to first parasitemia and first malaria attack (HR [95% CI]: 2.95 [1.58; 5.50], p = 0.001 and 3.19 [1.59; 6.38], p = 0.001) respectively.

Conclusions/ Significance

This study highlights the importance of protecting newborns by preventing repeated episodes of PAM in their mothers.     

Is Plasmodium vivax Malaria a Severe Malaria?: A Systematic Review and Meta-Analysis

Background

Plasmodium vivax is one of the major species of malaria infecting humans. Although emphasis on P. falciparum is appropriate, the burden of vivax malaria should be given due attention. This study aimed to synthesize the evidence on severe malaria in P. vivax infection compared with that in P. falciparum infection.

Methods/Principal Findings

We searched relevant studies in electronic databases. The main outcomes required for inclusion in the review were mortality, severe malaria (SM) and severe anaemia (SA). The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Overall, 26 studies were included. The main meta-analysis was restricted to the high quality studies. Eight studies (n = 27490) compared the incidence of SM between P. vivax infection and P. falciparum mono-infection; a comparable incidence was found in infants (OR: 0.45, 95% CI:0.04–5.68, I ²:98%), under 5 year age group (OR: 2.06, 95% CI: 0.83–5.1, I ²:83%), the 5–15 year-age group (OR: 0.6, 95% CI: 0.31–1.16, I ²:81%) and adults (OR: 0.83, 95% CI: 0.67–1.03, I ²:25%). Six studies reported the incidences of SA in P. vivax infection and P. falciparum mono-infection; a comparable incidence of SA was found among infants (OR: 3.47, 95%:0.64–18.94, I ²: 92%), the 5–15 year-age group (OR:0.71, 95% CI: 0.06–8.57, I ²:82%). This was significantly lower in adults (OR:0.75, 95% CI: 0.62–0.92, I ²:0%). Five studies (n = 71079) compared the mortality rate between vivax malaria and falciparum malaria. A lower rate of mortality was found in infants with vivax malaria (OR:0.61, 95% CI:0.5–0.76, I ²:0%), while this was comparable in the 5–15 year- age group (OR: 0.43, 95% CI:0.06–2.91, I ²:84%) and the children of unspecified-age group (OR: 0.77, 95% CI:0.59–1.01, I ²:0%).

Conclusion

Overall, the present analysis identified that the incidence of SM in patients infected with P. vivax was considerable, indicating that P. vivax is a major cause of SM. Awareness of the clinical manifestations of vivax malaria should prompt early detection. Subsequent treatment and monitoring of complications can be life-saving.     

Malaria in Pregnancy Interacts with and Alters the Angiogenic Profiles of the Placenta

Malaria in pregnancy remains a substantial public health problem in malaria-endemic areas with detrimental outcomes for both the mother and the foetus. The placental changes that lead to some of these detrimental outcomes have been studied, but the mechanisms that lead to these changes are still not fully elucidated. There is some indication that imbalances in cytokine cascades, complement activation and angiogenic dysregulation might be involved in the placental changes observed. Nevertheless, the majority of studies on malaria in pregnancy (MiP) have come from areas where malaria transmission is high and usually restricted to Plasmodium falciparum, the most pathogenic of the malaria parasite species. We conducted a cross-sectional study in Cruzeiro do Sul, Acre state, Brazil, an area of low transmission and where both P. vivax and P. falciparum circulate. We collected peripheral and placental blood and placental biopsies, at delivery from 137 primigravid women and measured levels of the angiogenic factors angiopoietin (Ang)-1, Ang-2, their receptor Tie-2, and several cytokines and chemokines. We measured 4 placental parameters (placental weight, syncytial knots, placental barrier thickness and mononuclear cells) and associated these with the levels of angiogenic factors and cytokines. In this study, MiP was not associated with severe outcomes. An increased ratio of peripheral Tie-2:Ang-1 was associated with the occurrence of MiP. Both Ang-1 and Ang-2 had similar magnitudes but inverse associations with placental barrier thickness. Malaria in pregnancy is an effect modifier of the association between Ang-1 and placental barrier thickness.     

Spatio-temporal analysis of malaria incidence and its risk factors in North Namibia

Though anecdotal evidence suggests that smoke from HAP has a repellent effect on mosquitoes, very little work has been done to assess the effect of biomass smoke on malaria infection. The study, therefore, sought to investigate the hypothesis that interventions to reduce household biomass smoke may have an unintended consequence of increasing placental malaria or increase malaria infection in the first year of life. This provides evidence from a randomized controlled trial among 1414 maternal-infant pairs in the Kintampo North and Kintampo South administrative areas of Ghana. Logistic regression was used to assess the association between study intervention assignment (LPG, Biolite or control) and placental malaria. Finally, an extended Cox model was used to assess the association between study interventions and all episodes of malaria parasitaemia in the first year of infant’s life. The prevalence of placental malaria was 24.6%. Out of this, 20.8% were acute infections, 18.7% chronic infections and 60.5% past infections. The study found no statistical significant association between the study interventions and all types of placental malaria (OR = 0.88; 95% CI 0.59–1.30). Of the 1165 infants, 44.6% experienced at least one episode of malaria parasitaemia in the first year of life. The incidence of first and/or only episode of malaria parasitaemia was however found to be similar among the study arms. The findings suggest that cookstove interventions for pregnant women and infants, when combined with additional malaria prevention strategies, do not lead to an increased risk of malaria among pregnant women and infants.     

Predictors of asymptomatic malaria in pregnancy

A number of studies have described malaria parasitaemia in pregnancy as mostly an asymptomatic condition, however information about predictors of asymptomatic malaria is largely lacking. We investigated the prevalence of symptoms and potential predictors of asymptomatic malaria in pregnant women attending Ante-Natal Clinic (ANC) of two public maternity hospitals in Ibadan, Southwest-Nigeria. Demographic data, history of previous and present pregnancy were obtained from the subjects and blood smears were examined for malaria diagnosis by light microscopy. Seventy - seven parasitaemic pregnant women attending antenatal clinic were evaluated for presence or absence of symptoms that may be associated with malaria. Thirty-seven women (48%) were asymptomatic whereas 40 (52%) presented with symptoms such as weakness, headache and general body ache and fever. Parasite density was significantly higher in symptomatic patients (P = 0.042), while asymptomatic patients had low level parasitaemia but significantly higher gametocyte carriage (P = 0.035). In conclusion, parasitaemic pregnant women resident in hyper- or holo-endemic malaria region are likely to be symptomatic with increasing density of the parasitaemia.     

Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon

BackgroundMalaria in Brazil represents one of the highest percentages of Latin America cases, where approximately 84% of infections are attributed to Plasmodium (P.) vivax. Despite the high incidence, many aspects of gestational malaria resulting from P. vivax infections remain poorly studied. As such, we aimed to evaluate the consequences of P. vivax infections during gestation on the health of mothers and their neonates in an endemic area of the Amazon.Methods and findingsWe have conducted an observational cohort study in Brazilian Amazon between January 2013 and April 2015. 600 pregnant women were enrolled and followed until delivery. After applying exclusion criteria, 329 mother-child pairs were included in the analysis. Clinical data regarding maternal infection, newborn’s anthropometric measures, placental histopathological characteristics, and angiogenic and inflammatory factors were evaluated. The presence of plasma IgG against the P. vivax (Pv) MSP1₁₉ protein was used as marker of exposure and possible associations with pregnancy outcomes were analyzed. Multivariate logistic regression analysis revealed that P. vivax infections during the first trimester of pregnancy are associated with adverse gestational outcomes such as premature birth (adjusted odds ratio [aOR] 8.12, 95% confidence interval [95%CI] 2.69–24.54, p < 0.0001) and reduced head circumference (aOR 3.58, 95%CI 1.29–9.97, p = 0.01). Histopathology analysis showed marked differences between placentas from P. vivax-infected and non-infected pregnant women, especially regarding placental monocytes infiltrate. Placental levels of vasomodulatory factors such as angiopoietin-2 (ANG-2) and complement proteins such as C5a were also altered at delivery. Plasma levels of anti-PvMSP1₁₉ IgG in infected pregnant women were shown to be a reliable exposure marker; yet, with no association with improved pregnancy outcomes.ConclusionsThis study indicates that P. vivax malaria during the first trimester of pregnancy represents a higher likelihood of subsequent poor pregnancy outcomes associated with marked placental histologic modification and angiogenic/inflammatory imbalance. Additionally, our findings support the idea that antibodies against PvMSP1₁₉ are not protective against poor pregnancy outcomes induced by P. vivax infections.     

Association between Cryptosporidium infection and cancer: A systematic review and meta-analysis

The link between cryptosporidiosis and cancer has been suggested by some epidemiological studies. This systematic review and meta-analysis was conducted to further understand this relationship. In the current study, six electronic databases were reviewed for Cryptosporidium infection in cancer patients. We used random effects model and 95% confidence intervals (CI) to determine the overall odds ratio (OR). Heterogeneity was calculated with Cochran's Q test and I²statistic. In total, 19 studies involving 3562 individuals with case-control (nine) and cross-sectional (ten) designs were included in our project. The pooled overall random effect favored a statistically significant increased risk of Cryptosporidium infection in cancer patients compared with non-cancer individuals [OR = 3.3; 95% CI: 2.18–4.98]. The overall heterogeneity was medium (χ² = 25.77; I² = 30.2%, P = .11). The pooled ORs in case-control and cross-sectional studies were [OR = 5.60; 95% CI: 3.43–9.13; χ² = 5.51; I² = 0.00%, P = .70] and [OR = 2.08; 95% CI: 1.18–3.67; χ² = 13.69; I² = 34.3, P = .13], respectively. T-value and P-value were 0.54 and 0.57 based on the results of Harbord's modified's regression test. In summary, this meta-analysis demonstrates that Cryptosporidium infection is associated with cancer. Also, it found that study design and year of publication are the specific sources of heterogeneity. Further studies should be carried out to investigate the impact of Cryptosporidium infection in the onset or development of cancer in the future.     

Plasmodium vivax Malaria in Pregnant Women in the Brazilian Amazon and the Risk Factors Associated with Prematurity and Low Birth Weight: A Descriptive Study

Introduction

Plasmodium vivax is the most prevalent malaria species in the American region. Brazil accounts for the higher number of the malaria cases reported in pregnant women in the Americas. This study aims to describe the characteristics of pregnant women with malaria in an endemic area of the Brazilian Amazon and the risk factors associated with prematurity and low birth weight (LBW).

Methods/Principal Findings

Between December 2005 and March 2008, 503 pregnant women with malaria that attended a tertiary health centre were enrolled and followed up until delivery and reported a total of 1016 malaria episodes. More than half of study women (54%) were between 20–29 years old, and almost a third were adolescents. The prevalence of anaemia at enrolment was 59%. Most women (286/503) reported more than one malaria episode and most malaria episodes (84.5%, 846/1001) were due to P. vivax infection. Among women with only P. vivax malaria, the risk of preterm birth and low birth weight decreased in multigravidae (OR, 0.36 [95% CI, 0.16–0.82]; p = 0.015 and OR 0.24 [95% CI, 0.10–0.58]; p = 0.001, respectively). The risk of preterm birth decreased with higher maternal age (OR 0.43 [95% CI, 0.19–0.95]; p = 0.037) and among those women who reported higher antenatal care (ANC) attendance (OR, 0.32 [95% CI, 0.15–0.70]; p = 0.005).

Conclusion

This study shows that P. vivax is the prevailing species among pregnant women with malaria in the region and shows that vivax clinical malaria may represent harmful consequences for the health of the mother and their offsprings particularly on specific groups such as adolescents, primigravidae and those women with lower ANC attendance.     

Assessment of Markers of Antimalarial Drug Resistance in Plasmodium falciparum Isolates from Pregnant Women in Lagos,Nigeria

Background

The use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP) is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ) and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1) and type 1 antifolate antimalarial medicines (Pfdhfr).

Methods

Plasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72–76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt) gene by real time polymerase chain reaction (PCR) using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1) gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene.

Results

Two haplotypes of Pfcrt (n = 54) were observed: CVMNK 13(24.2%) and CVIET 41 (75.9%) of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28) haplotypes were NYSND 15(53.6%), YYSND 5(17.9%), NFSND 6(21.4%) and YFSND 2(7.1%). The Pfdhfr (n = 15) were ACNCSVI 4(26.7%), and ACICNSVI 1(6.7%) and ACIRNVI 10 (66.7%). The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Yand184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024) while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006). The median parasitaemia were similar (P>0.05) in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and presence of mutations in the Pfcrt, Pfmdr1 or Pfdhfr genes (P>0.05).

Conclusion

Markers of resistance to chloroquine and pyrimethamine were high, whereas cycloguanil-resistance marker was not present in the studied population. The low level of mutations in the Pfmdr1gene indicates likely efficacy of amodiaquine against malaria in pregnancy.     

Effect of traditional Chinese medicine on gut microbiota in adults with type 2 diabetes: A systematic review and meta-analysis

BackgroundDespite advances in research on type 2 diabetes mellitus (T2DM) with the development of science and technology, the pathogenesis and treatment response of T2DM remain unclear. Recent studies have revealed a significant role of the microbiomein the development of T2DM, and studies have found that the gut microbiota may explain the therapeutic effect of traditional Chinese medicine (TCM), a primary branch of alternative and complementary medicine, in the treatment of T2DM. The aim of this study was to systematically review all randomized controlled trials (RCTs) on TCM for gut microbiota to assess the effectiveness and safety of TCM in T2DM patients.MethodsAll RCTs investigating the effects of TCM interventions on modulating gut microbiota and improving glucose metabolism in the treatment of T2DM adults were included. Meta-analyses were conducted when sufficient data were available, other results were reported narratively. The study protocol was pre-specified, documented, and published in PROSPERO (registration no. CRD42020188043).ResultsFive studies met the eligibility criteria ofthe systematic review. All five studies reported the effects of TCM interventions on the gut microbiota modulation and blood glucose control. There were statistically significant improvements in HbA1c (mean difference [MD]: -0.69%; [95% CI −0.24, −0.14]; p = 0.01, I² = 86%), fasting blood glucose (MD: −0.87 mmol/l; [95% CI -1.26, -0.49]; p < 0.00001, I² = 75%) and 2-h postprandial blood glucose(MD: -0.83mmol/l; [95% CI: -1.01, -0.65]; p < 0.00001, I² = 0%). In addition, there were also statistically significant improvements in homeostasis model assessment of insulin resistance (HOMA-IR) (standardized mean difference [SMD]: −0.99, [95% CI −1.25 to -0.73]; p < 0.00001, I² = 0%) and homeostasis model assessment of β-cell function (HOMA-β) (SMD: 0.54, [95% CI 0.21 to 0.87]; p = 0.001, I² = 0%).There was a significant change in the relative abundance of bacteria in the genera Bacteroides (standardized mean difference [SMD] 0.87%; [95% CI 0.58, 1.16], however, the change in Enterococcus abundance was not statistically significant (SMD: -1.71%; [95% CI: -3.64, 0.23]; p = 0.08) when comparing TCM supplementaltreatment with comparator groups. Other changes in the gut microbiota, including changes in the relative abundances of some probiotics and opportunistic pathogens at various taxon levels, and changes in diversity matrices (α and β), were significant by narrative analysis. However, insufficient evidences were found to support that TCM intervention had an effect on inflammation.ConclusionTCM had the effect of modulating gut microbiota and improving glucose metabolisms in T2DM patients. Although the results of the included studies are encouraging, further well-conducted studies on TCM interventions targeting the gut microbiota are needed.