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Intermittent preventive treatment in pregnancy (IPTp) with azithromycin and monthly sulfadoxine-pyrimethamine increased the mean child weight, mid-upper arm and head circumference at four weeks of age in a rural low-income setting. Now we assess for how long these gains were sustained during 0-5 years of age. We enrolled 1320 pregnant Malawian women in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (control) or monthly sulfadoxine-pyrimethamine as IPTp against malaria, or monthly sulfadoxine-pyrimethamine and two doses of azithromycin (AZI-SP) as IPTp against malaria and reproductive tract infections. Child weight, mid-upper arm circumference, head circumference and weight-for-height Z-score were recorded at one, six, 12, 24, 36, 48, and 60 months. Throughout follow-up, the mean child weight was approximately 100 g higher (difference in means 0.12 kg, 95% CI 0.04-0.20, P = 0.003 at one month; 0.19 kg, 95% CI 0.05-0.33, P = 0.007, at six months), mean head circumference 2 mm larger (0.3 cm, 95% CI 0.1 to 0.5, P = 0.004 at one month) and the cumulative incidence of underweight by five years of age was lower (hazard ratio 0.74, 95% CI 0.60 to 0.90, P = 0.002) in the AZI-SP group than in the control group. The 2 mm difference in the mean mid-upper arm circumference at one month (0.2 cm, 95% CI 0.0 to 0.3, P = 0.007) disappeared after three years of age. There was no difference in mean weight-for-height Z-score at any time point. In Malawi, IPTp with azithromycin and monthly sulfadoxine-pyrimethamine has a modest, 3-5-year positive impact on child weight, mid-upper arm circumference and head circumference, but not on weight-for-height Z-score.

Background New diagnostic tools for malaria are required owing to the changing epidemiology of malaria, particularly among pregnant women in sub-Saharan Africa. Real-time PCR assays targeting Plasmodium falciparum lactate dehydrogenase ( pfldh ) gene may facilitate the identification of a high proportion of pregnant women with a P. falciparum parasitaemia below the threshold of microscopy. These molecular methods will enable further studies on the effects of these submicroscopic infections on maternal health and birth outcomes. Methods The pfldh real-time PCR assay and conventional microscopy were compared for the detection of P. falciparum from dried blood spots and blood smears collected from the peripheral blood of 475 Malawian women at delivery. A cycle threshold (Ct) of the real-time PCR was determined optimizing the sensitivity and specificity of the pfldh PCR assay compared to microscopy. A real-time PCR species-specific assay was applied to identify the contribution to malaria infections of three Plasmodium species ( P. falciparum P. ovale and P. malariae ) in 44 discordant smear and pfldh PCR assay results. Results Of the 475 women, P. falciparum was detected in 11 (2.3%) by microscopy and in 51 (10.7%) by real-time PCR; compared to microscopy, the sensitivity of real-time PCR was 90.9% and the specificity 91.2%. If a Ct value of 38 was used as a cut-off, specificity improved to 94.6% with no change in sensitivity. The real-time PCR species-specific assay detected P. falciparum alone in all but four samples: two samples were mixed infections with P. falciparum and P. malariae , one was a pure P. malariae infection and one was a pfldh PCR assay-positive/species-specific assay-negative sample. Of three P. malariae infections detected by microscopy, only one was confirmed by the species-specific assay. Conclusions Although microscopy remains the most appropriate method for clinical malaria diagnosis in field settings, molecular diagnostics such as real-time PCR offer a more reliable means to detect malaria parasites, particularly at low levels. Determination of the possible contribution of these submicroscopic infections to poor birth outcomes and maternal health is critical. For future studies to investigate these effects, this pfldh real-time PCR assay offers a reliable detection method.

New regimens for intermittent preventive treatment in pregnancy (IPTp) against malaria are needed as the effectiveness of the standard two-dose sulfadoxine-pyrimethamine (SP) regimen is under threat. Previous trials have shown that IPTp with monthly SP benefits HIV-positive primi- and secundigravidae, but there is no conclusive evidence of the possible benefits of this regimen to HIV-negative women, or to a population comprising of both HIV-positive and -negative women of different gravidities. This study analyzed 484 samples collected at delivery as part of a randomized, partially placebo controlled clinical trial, conducted in rural Malawi between 2003 and 2007. The study included pregnant women regardless of their gravidity or HIV-infection status. The participants received SP twice (controls), monthly SP, or monthly SP and two doses of azithromycin (AZI-SP). The main outcome was the prevalence of peripheral Plasmodium falciparum malaria at delivery diagnosed with a real-time polymerase chain reaction (PCR) assay. Overall prevalence of PCR-diagnosed peripheral P. falciparum malaria at delivery was 10.5%. Compared with the controls, participants in the monthly SP group had a risk ratio (95% CI) of 0.33 (0.17 to 0.64, P<0.001) and those in the AZI-SP group 0.23 (0.11 to 0.48, P<0.001) for malaria at delivery. When only HIV-negative participants were analyzed, the corresponding figures were 0.26 (0.12 to 0.57, P<0.001) for women in the monthly SP group, and 0.24 (0.11 to 0.53, P<0.001) for those in the AZI-SP group. Our results suggest that increasing the frequency of SP administration during pregnancy improves the efficacy against malaria at delivery among HIV-negative women, as well as a population consisting of both HIV-positive and -negative pregnant women of all gravidities, in a setting of relatively low but holoendemic malaria transmission, frequent use of bed nets and high SP resistance.

Antibodies towards placental-binding P. falciparum are thought to protect against pregnancy malaria; however, environmental factors may affect antibody development. Using plasma from pregnant Malawian women, we measured IgG against placental-binding P. falciparum parasites by flow cytometry, and related results to intermittent preventive treatment (IPTp) regime, and bed net use. Bed net use was associated with decreased antibody levels at mid-pregnancy but not at 1 month post partum (1 mpp). At 1 mpp a more intensive IPTp regime was associated with decreased antibody levels in primigravidae, but not multigravidae. Results suggest bed nets and IPTp regime influence acquisition of pregnancy-specific P. falciparum immunity.

Background. Plasmodium falciparum parasites that cause malaria in pregnancy express unique variant surface antigens (VSAs). Levels of immunoglobulin G (IgG) antibody to pregnancy-associated VSAs measured at delivery are gravidity dependent, and they have been associated with protection from disease. It is not known how these IgG responses develop in pregnant women receiving intermittent preventive treatment during pregnancy (IPTp) or whether IgG levels in early pregnancy predict pregnancy outcomes. Methods. We performed longitudinal measurements of IgG antibody to VSAs by flow cytometric analysis of serum samples obtained from 549 Malawian women receiving IPTp. We examined fluctuations in IgG levels over time and associated the IgG levels noted at study enrollment with clinical outcomes. Results. Levels of IgG antibody to pregnancy-associated VSAs were gravidity dependent. Overall, levels decreased while women were receiving IPTp, but the levels of the individuals were highly dynamic. Primigravidae developed low levels of pregnancy-specific IgG, which were often boosted during second pregnancies. The prevalence of parasites was low (8.4% at enrollment and 2.4% in late pregnancy). Antibody levels at enrollment did not predict birth weight, duration of gestation at delivery, or the maternal hemoglobin level in late pregnancy. Conclusion. Levels of IgG antibody to pregnancy-specific VSAs decrease during receipt of IPTp. Antibody levels in early pregnancy did not predict clinical outcome. IPTp and decreasing malaria prevalence pose challenges for the evaluation of novel interventions for malaria during pregnancy. Trial registration. Clinicaltrials.gov identifier NCT00131235.

ObjectiveTo assess whether intermittent preventive treatment of pregnant women (IPTp) with sulfadoxine-pyrimethamine (SP) and azithromycin (AZI) in a malaria-endemic area leads to sustained gains in linear growth and development in their offspring.DesignFollow-up study of a randomised trial.SettingMangochi District in rural southern Malawi.Participants1320 pregnant women and their offspring.InterventionsIPTp monthly with SP and twice with AZI (AZI-SP group), monthly with SP but no AZI (monthly SP), or twice with SP (control). No intervention was given to children.Main outcome measuresCognitive performance using Raven’s Coloured Progressive Matrices (CPM) at 13 years of age; mean height and height-for-age Z-score (HAZ), cumulative incidence and prevalence of stunting (HAZ <−2); weight, body mass index, mid-upper-arm circumference and head circumference.ResultsAt approximately 13 years of age, the mean CPM score was 14.3 (SD 3.8, range 6–29, maximum 36), with no differences between groups. Children in the AZI-SP group were on average 0.4 cm (95% CI −0.9 to 1.7, p=0.6) taller than those in the control group. For cumulative incidence of stunting, the HR in the AZI-SP group was 0.72 (95% CI 0.61 to 0.84, p<0.001) compared with the control and 0.76 (95% CI 0.65 to 0.90, p<0.001) compared with the monthly SP groups. There was no intergroup difference in stunting prevalence or anthropometric measurements.ConclusionsIn rural Malawi, maternal intensified infection control during pregnancy reduces offspring’s cumulative incidence of ever being stunted by 13 years of age. In this study, there was no evidence of a positive impact on cognitive performance.Trial registration number NCT00131235.

Resistance of Plasmodium falciparum to sulfadoxine–pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine–pyrimethamine (ITPp-SP) in sub-Saharan Africa. We updated an aggregated-data meta-analysis to assess the associations between sulfadoxine–pyrimethamine resistance and the effectiveness of IPTp-SP to inform policy. We searched databases (Jan 1, 1990, to June 8, 2024) for observational studies or trials reporting data on malaria, low birthweight (<2500 g), anaemia, and other outcomes by IPTp-SP dose and matched these by year and location with studies that reported on molecular markers of sulfadoxine–pyrimethamine resistance. Studies including only women with HIV or combined interventions were excluded. We evaluated how sulfadoxine–pyrimethamine resistance influenced the adjusted risk ratio (aRR) between three and two doses of IPTp-SP for various outcomes using Poisson mixed-effects models that allowed for non-linear relationships. Initially, we performed a threshold analysis, stratified by region, to identify the resistance levels most predictive of altered effect of IPTp-SP doses on malaria parasitaemia at delivery (peripheral or placental parasitaemia by any test), our primary outcome. These resistance strata were then used in all subsequent models for other outcomes. All analyses were adjusted for malaria transmission intensity, HIV infection, percentage of paucigravidae, and insecticide-treated net use. Performance of models was evaluated using cross-validation. The trial was registered with PROSPERO (CRD42021250359). Overall, 122 studies involving 148 693 participants were included. For west and central Africa (69 studies comprising 63 745 participants), very low resistance was categorised as a prevalence of the dihydropteroate synthase (dhps) Lys540Glu mutation in the parasite population of less than 4%, and low resistance as a prevalence of Lys540Glu of 4% or higher. In east and southern Africa (53 studies comprising 84 948 participants), moderate resistance was categorised as a prevalence of the Lys540Glu mutation of less than 60% combined with a prevalence of the Ala581Gly mutation of less than 5%, high resistance as a prevalence of Lys540Glu of 60% or higher combined with a prevalence of Ala581Gly of less than 5%, and very high resistance as a prevalence of the Lys540Glu mutation of 60% or higher combined with a prevalence of Ala581Gly of 5% or higher. There was a marked trend towards lower efficacy of IPTp-SP on reducing malaria infection with increasing resistance levels. In west and central Africa, when comparing three versus two doses, the aRR was 0·71 (95% CI 0·65–0·78) in areas with very low resistance and 0·83 (0·72–0·95) in areas with low resistance (p=0·0144 for the difference between dose–response curves in very low vs low resistance). For east and southern Africa, the same trend was observed: the aRR was 0·63 (95% CI 0·57–0·69) in areas with moderate resistance, 0·89 (0·82–0·96) in areas with high resistance, and 0·93 (0·85–1·01) in areas with very high resistance (p<0·0001 for dose–response curves differences between moderate vs high and moderate vs very high resistance). This pattern was not seen for low birthweight. When comparing three versus two doses in west and central Africa, the aRR was 0·58 (95% CI 0·48–0·68) in areas with very low resistance and 0·56 (0·44–0·68) in areas with low resistance (p=0·72 for dose–response curves very low vs low resistance). For east and southern Africa, the aRR was 0·75 (95% CI 0·52–0·98) in areas with moderate resistance, 0·73 (0·69–0·78) in areas with high resistance, and 0·75 (0·63–0·87) in areas with very high resistance (p=0·80 for dose–response curves moderate vs high resistance; p=0·90 for moderate vs very high resistance). Dose comparisons in some resistance strata were limited by sample size. IPTp-SP antimalarial efficacy is greatly reduced in very high resistance areas. However, it remains effective at reducing low birthweight in these areas, possibly through non-malaria effects on fetal growth. While IPTp-SP use should continue in high SP-resistance areas, alternative malaria preventive strategies are urgently needed in these areas. WHO and WorldWide-Antimalarial-Resistance-Network.

Background: Stunting affects a quarter of the world's children and is associated with increased mortality and developmental delay. We showed earlier that intermittent preventive treatment against malaria and other infections in pregnancy was associated with reduced prevalence of neonatal stunting in Malawi. In this follow-up, we assessed whether these gains were sustained and reflected in the epidemiology of childhood growth, development, and mortality. Methods: We enrolled 1320 women with uncomplicated second- trimester pregnancies in a randomised, partially placebo-controlled, outcome assessor-blinded, three-arm clinical trial in rural Malawi and preventively treated them for malaria and other infections with either two doses of sulfadoxine-pyrimethamine (SP, control), monthly SP, or monthly SP and azithromycin twice (AZISP). Child height/length and mortality were recorded at one, six, 12, 24, 36, 48 and 60 months and child development at 60 months of age. Our primary hypothesis was that the difference in mean length at birth would be retained for five years and reflected in a permanently lower incidence and prevalence of stunting among babies born to women treated with AZI-SP. We also hypothesized that these children would have a higher mean developmental score at the age of five and a lower mortality by five years than children born to women in the control group. Findings. Between December 1, 2003 and October 11, 2006 we enrolled 1320 women to the study and randomised them to the control (n=436), monthly SP (n=441) and AZI-SP group (n=443). There were 3, 2 and 2 twin pregnancies in the control, monthly SP and AZI-SP groups, respectively, resulting in 1327 fetuses for follow-up. Throughout the follow-up mean child length was 0.4-0.7 cm higher (p<0.05 at 1-12 months), prevalence of stunting 6-11% lower (p<0.05 at 12-36 months) and five-year cumulative incidence of stunting 13% lower (hazard ratio 0.70, 95% CI 0.60 to 0.83) in the AZI-SP than control group. Mean developmental score was 108.6, 110.2 and 112.4 (difference in means AZI-SP vs control 3.8, 95% CI 1.1 to 6.4; AZI-SP vs monthly SP 2.2, -0.4 to 4.8) in the control, monthly SP and AZI-SP group, respectively. There were no statistically significant differences between groups in the cumulative five-year mortality (hazard ratio AZI-SP vs control 0.84, 95% CI 0.59 to 1.20; AZI-SP vs monthly SP 0.85, 0.60 to 1.21). Total mortality during pregnancy (abortion/stillbirth) and childhood was 15.3%, 15.1%, and 13.1% (risk ratio AZI-SP vs control 0.86, 95% CI 0.62 to 1.19; AZI-SP vs monthly SP 0.87, 0.62 to 1.20) in the control, monthly SP and AZI-SP group, respectively. For postneonatal mortality (secondary outcome), the proportions were 5.5%, 3.3%, and 1.9%, respectively (risk ratio AZI-SP vs control 0.34, 0.15 to 0.76; AZI-SP vs monthly SP 0.56, 0.24 to 1.32). Interpretation. Provision of AZI-SP rather than two doses of SP during pregnancy reduced the incidence of stunting in childhood in Malawi. AZI-SP during pregnancy also had a positive effect on child development and may have reduced postneonatal mortality.