Interactions between antenatal sulfadoxine-pyrimethamine, drug-resistant Plasmodium falciparum parasites and delivery outcomes in Malawi.

BACKGROUND Sulfadoxine-pyrimethamine (SP) is used as intermittent preventive therapy in pregnancy (IPTp) for malaria in sub-Saharan Africa. The resistance marker dhps A581G has been associated with reduced IPTp-SP efficacy and enhanced morbidity in SP-recipients. METHODS We measured SP-resistance allele frequencies in Malawian women participating in a trial (www.isrctn.com/ISRCTN69800930) comparing IPTp with SP against intermittent screening by rapid diagnostic tests (ISTp). We genotyped PCR-detected parasites using deep sequencing of SP-resistance alleles. RESULTS Among 125 placental infections, A581G-bearing parasites were associated with reduced birthweight (mean difference[MD]:252g, 95% CI:46,457, p=0.017). Relative to ISTp, IPTp-SP was associated with higher birthweights in women with wildtype parasites (MD:116g, 95% CI:-40,272; p=0.142) and lower birthweights in women with A581G-bearing parasites (MD:192g, 95% CI:-264,648; p=0.385) (pinteraction=0.033). Similar associations were noted on gestational age (pinteraction=0.075). Amongst only IPTp-SP recipients, relative to women who last received SP >4 weeks before delivery, recent SP receipt was associated with lower birthweight in women with wildtype parasites (MD:118g, 95% CI:-376,139; p=0.361) and higher birthweight in women with A581G-bearing parasites (MD:783g, 95% CI:-20,1586; p=0.054) (pinteraction=0.005). CONCLUSIONS The effectiveness on birthweight of IPTp-SP is compromised by A581G-bearing parasites, but there was no evidence that the adverse effects of these parasites are exacerbated by antenatal SP

Sequential disruptions to inflammatory and angiogenic pathways and risk of spontaneous preterm birth in Malawian women

Preterm birth is a leading cause of death in children under five years of age. We hypothesized that sequential disruptions to inflammatory and angiogenic pathways during pregnancy increase the risk of placental insufficiency and spontaneous preterm labour and delivery. We conducted a secondary analysis of inflammatory and angiogenic analytes measured in plasma samples collected across pregnancy from 1462 Malawian women. Women with concentrations of the inflammatory markers sTNFR2, CHI3L1, and IL18BP in the highest quartile before 24 weeks gestation and women with anti-angiogenic factors sEndoglin and sFlt-1/PlGF ratio in the highest quartile at 28-33 weeks gestation, had an increased relative risk of preterm birth. Mediation analysis further supported a potential causal link between early inflammation, subsequent angiogenic dysregulation detrimnental to placental vascular development, and earlier gestational age at delivery. Interventions designed to reduce the burden of preterm birth may need to be implemented before 24 weeks of gestation

Intestinal barrier disruption with Plasmodium falciparum infection in pregnancy and risk of preterm birth: a cohort study

Malaria in early pregnancy is a risk factor for preterm birth and is associated with sustained inflammation and dysregulated angiogenesis across gestation. This study investigated whether malaria is associated with increased gut leak and whether this contributes to systemic inflammation, altered angiogenesis, and preterm birth. We quantified plasma concentrations of gut leak markers, soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) from 1339 HIV-negative pregnant Malawians at <24 weeks gestational age. We assessed the relationship of sCD14 and LBP concentrations with markers of inflammation, angiogenesis, and L-arginine bioavailability and compared them between participants with and without malaria, and with and without preterm birth. Plasma concentrations of sCD14 and LBP were significantly higher in participants with malaria and were associated with parasite burden (p <0.0001, both analyses and analytes). The odds ratio for preterm birth associated with one log sCD14 was 2.67 (1.33 to 5.35, p = 0.006) and 1.63 (1.07-2.47, p = 0.023) for LBP. Both gut leak analytes were positively associated with increases in proinflammatory cytokines CRP, sTNFR2, IL18-BP, CHI3L1 and Angptl3 (p <0.05, all analytes) and sCD14 was significantly associated with angiogenic proteins Angpt-2, sENG and the sFLT:PlGF ratio (p <0.05, all analytes). sCD14 was negatively associated with L-arginine bioavailability (p <0.001). Malaria in early pregnancy is associated with intestinal barrier dysfunction, which is linked to an increased risk of preterm birth. Open Philanthropy, Canadian Institutes of Health Research, Canada Research Chair program, European and Developing Countries Clinical Trials Partnership, Bill & Melinda Gates Foundation

Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study

BACKGROUND Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. METHODS AND FINDINGS Between April 2014 and April 2015, we followed 421 Malawian mother-baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur-Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], -7.53 [-13.04, -2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], -8.57 [-13.09, -4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. CONCLUSIONS This mother-baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children

The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy

BACKGROUND Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes. METHODS Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1 mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes. FINDINGS Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1), to worsen birth outcomes by impeding vascular remodeling required for placental function. INTERPRETATION Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes. FUNDING This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies

Intermittent screening and treatment with artemisinin-combination therapy versus intermittent preventive treatment with sulphadoxine-pyrimethamine for malaria in pregnancy: a systematic review and individual participant data meta-analysis of randomised clinical trials.

BACKGROUND: In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections. METHODS: We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789. FINDINGS: Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I2=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I2=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I2=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I2=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57). INTERPRETATION: ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections. FUNDING: Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network

Intermittent preventive therapy in pregnancy and incidence of low birth weight in malaria-endemic countries

Objectives. To estimate the impact of hypothetical antimalarial and nutritional interventions (which reduce the prevalence of low midupper arm circumference [MUAC]) on the incidence of low birth weight (LBW). Methods. We analyzed data from 14 633 pregnancies from 13 studies conducted across Africa and the Western Pacific from 1996 to 2015. We calculated population intervention effects for increasing intermittent preventive therapy in pregnancy (IPTp), full coverage with bed nets, reduction in malaria infection at delivery, and reductions in the prevalence of low MUAC. Results. We estimated that, compared with observed IPTp use, administering 3 or more doses of IPTp to all women would decrease the incidence of LBW from 9.9% to 6.9% (risk difference = 3.0%; 95% confidence interval = 1.7%, 4.0%). The intervention effects for eliminating malaria at delivery, increasing bed net ownership, and decreasing low MUAC prevalence were all modest. Conclusions. Increasing IPTp uptake to at least 3 doses could decrease the incidence of LBW in malaria-endemic countries. The impact of IPTp on LBW was greater than the effect of prevention of malaria, consistent with a nonmalarial effect of IPTp, measurement error, or selection bias

The epidemiology of trypanosomiasis in Rumphi district, Malawi: a ten year retrospective study

Background Human African Trypanosomiasis (HAT) is caused by two species of the tsetse fly vectored protozoan hemoflagellates belonging to Trypanosma brucei, namely T.b gambiense which predominates in Western Africa and follows a chronic disease course and T.b rhodensiense which is more prevalent in Southern and Eastern Africa, Malawi included, and follows a more acute and aggressive disease course. Previous studies in the Democratic Republic of Congo, Angola, Uganda and Sudan have demonstrated that the prevalence rates of T.b rhodensiense infection have reached epidemic proportions. Objectives To describe the epidemiology of Trypanosomiasis in Rumphi District over the past ten years. Methodology A total of 163 records from January 2000 to December 2006 were retrospectively studied. Results There were more males than females (121 vs. 40) with the 20 – 29 years age bracket having the highest number of cases (26.3%, n=160). Stage 2 HAT was the commonest stage at presentation (58.2%, n=158) with the patients in the same being 3.5 times more likely to die than those with stage 1 HAT. Case fatality rates for late and early stage disease were 21.5% (n = 92) and 7.2% (n = 66) respectively with 84.6% having been cured (n=162). Convulsions were associated with fatal disease outcome and the majority of cases (97.2%, n=103) lived within 5 kilometres of the Vwaza game reserve boundary. Conclusion More men have been infected than women, with a high involvement in the 20 – 29 age brackets. A dramatic increase with active case finding indicates a high under-detection of the disease with late stage HAT being predominant at presentation. Though it has been found that cases with late stage disease have an increased likelihood of dying compared to those in early stage HAT, the high proportion of successful treatment indicates that the disease still carries a high degree of favourable outcome with treatment. It has also been demonstrated in this study that more than 95% of trypanosomiasis cases live within 5 km of game reserve boundary. Disease interventions should be implemented in areas within 5km of marshland game reserve boundary as priority areas. Malawi Medical Journal Vol. 21 (1) 2009: pp. 22-2