Birth weight, growth, nutritional status and mortality of infants from Lambaréné and Fougamou in Gabon in their first year of life.

BACKGROUND: Malnutrition and low birth weight (LBW) are two common causes of morbidity and mortality among children in sub-Saharan Africa. Both malnutrition and LBW affect early childhood development with long term consequences that may vary in their degree depending on the geographical setting. This study evaluates growth, nutritional status and mortality of infants from Lambaréné and Fougamou in Gabon from a birth cohort of a malaria in pregnancy clinical trial (NCT00811421). METHOD: A prospective longitudinal birth cohort conducted between 2009 and 2012, included infants that were followed up from birth until their first-year anniversary. The exposure of interest was low birth weight and the outcomes explored were growth represented by weight gain, the nutritional status including stunting, wasting and underweight, and the mortality. Scheduled follow-up visits were at one, nine and 12 months of age. Logistic regression was used to assess the association between low birth weight and growth and nutritional outcomes, and cox regression was used for mortality. RESULT: A total of 907 live-born infants were included in the analysis. The prevalence of LBW was 13% (115). At one month of life, out of 743 infants 10% and 4% presented with stunting and underweight, respectively, while these proportions increased at 12 months of life to 17% and 21%, respectively, out of 530 infants. The proportion of infants with wasting remained constant at 7% throughout the follow-up period. Stunting and underweight were associated with LBW, adjusted odds ratio (aOR): 2.6, 95% confidence interval (95%CI): 1.4-4.9 and aOR: 4.5, 95%CI: 2.5-8.1, respectively. Preterm birth was associated with stunting, aOR: 2.7, 95%CI: 1.2-6.3 and underweight, aOR: 5.4, 95%CI: 1.7-16.1 at one month of life. Infants with LBW were at higher hazard of death during the first year of life, adjusted hazard ratio 4.6, 95%CI: 1.2-17.0. CONCLUSION: Low birthweight infants in Gabon are at higher risks of growth and nutritional deficits and mortality during the first year of life. Tailored interventions aiming at preventing adverse pregnancy outcomes including LBW, early detection and appropriate management of growth, and nutritional deficits in infants are necessary in Gabon.

Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon.

Mefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and the metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated, and potential covariates influencing the pharmacokinetic properties were assessed. A population pharmacokinetic analysis was performed with 264 pregnant women from a randomized controlled trial evaluating a single and a split-dose regimen of two 15-mg/kg mefloquine doses at least 1 month apart versus SP-IPTp. Both enantiomers of mefloquine and its carboxy-metabolite (CMQ), measured in plasma and cord samples, were applied for pharmacokinetic modelling using NONMEM 7.3. Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group, mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated (r2 = 0.84) at delivery. With the dosing regimens investigated, prophylactic levels are not constantly achieved. A modeling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented. This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens; however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as a valuable tool for researchers and clinicians to develop and optimize alternative dosing regimens for IPTp in pregnant women.

Urogenital schistosomiasis during pregnancy is associated with low birth weight delivery: analysis of a prospective cohort of pregnant women and their offspring in Gabon.

An estimated 40 million women of childbearing age suffer from schistosomiasis. Animal models indicate a deleterious effect of maternal schistosomiasis on pregnancy outcomes. To date there is a lack of epidemiological evidence evaluating schistosomiasis-related morbidity in pregnancy. This study was designed to describe the impact of urogenital schistosomiasis on pregnancy outcomes in a highly endemic region of central Africa. Pregnant women attending antenatal clinics in Fougamou and Lambaréné, Gabon, were consecutively screened for the presence of Schistosoma haematobium eggs in diurnal urine samples. Maternal and newborn characteristics assessed at delivery were compared between infected and uninfected mothers. The impact of maternal schistosomiasis on low birth weight and preterm delivery was assessed using logistic regression analysis. Urogenital schistosomiasis was diagnosed in 103 (9%) of 1115 pregnant women. Maternal age was inversely associated with the prevalence of urogenital schistosomiasis, with a higher burden amongst nulliparous women. Low birth weight was more common amongst infants of S. haematobium-infected mothers. This association was unaffected by controlling for demographic characteristics, gestational age and Plasmodium infection status (adjusted Odds Ratio 1.93; 95% confidence interval: 1.08-3.42). Other risk factors associated with low birth weight delivery were underweight mothers (adjusted Odds Ratio 2.34; 95% confidence interval: 1.12-4.92), peripheral or placental Plasmodium falciparum infection (adjusted Odds Ratio 2.04; 95% confidence interval: 1.18-3.53) and preterm birth (adjusted Odds Ratio 3.12; 95% confidence interval: 1.97-4.96). Preterm delivery was not associated with S. haematobium infection (adjusted Odds Ratio 1.07 95% confidence interval: 0.57-1.98). In conclusion, this study indicates that pregnant women with urogenital schistosomiasis are at an increased risk for low birth weight deliveries. Further studies evaluating targeted treatment and prevention programmes for urogenital schistosomiasis in pregnant women and their impact on delivery outcomes are warranted.

Young adolescent girls are at high risk for adverse pregnancy outcomes in sub-Saharan Africa: an observational multicountry study.

OBJECTIVES: One of Africa's most important challenges is to improve maternal and neonatal health. The identification of groups at highest risk for adverse pregnancy outcomes is important for developing and implementing targeted prevention programmes. This study assessed whether young adolescent girls constitute a group at increased risk for adverse birth outcomes among pregnant women in sub-Saharan Africa. SETTING: Data were collected prospectively as part of a large randomised controlled clinical trial evaluating intermittent preventive treatment of malaria in pregnancy (NCT00811421-Clinical Trials.gov), conducted between September 2009 and December 2013 in Benin, Gabon, Mozambique and Tanzania. PARTICIPANTS: Of 4749 participants, pregnancy outcomes were collected for 4388 deliveries with 4183 live births including 83 multiple gestations. Of 4100 mothers with a singleton live birth delivery, 24% (975/4100) were adolescents (≤19 years of age) and 6% (248/4100) were aged ≤16 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes of this predefined analysis were preterm delivery and low birth weight. RESULTS: The overall prevalence of low birthweight infants and preterm delivery was 10% (371/3851) and 4% (159/3862), respectively. Mothers aged ≤16 years showed higher risk for the delivery of a low birthweight infant (OR: 1.96; 95% CI 1.35 to 2.83). Similarly, preterm delivery was associated with young maternal age (≤16 years; OR: 2.62; 95% CI 1.59 to 4.30). In a subanalysis restricted to primiparous women: preterm delivery, OR 4.28; 95% CI 2.05 to 8.93; low birth weight, OR: 1.29; 95% CI 0.82 to 2.01. CONCLUSIONS: Young maternal age increases the risk for adverse pregnancy outcomes and it is a stronger predictor for low birth weight and preterm delivery than other established risk factors in sub-Saharan Africa. This finding highlights the need to improve adolescent reproductive health in sub-Saharan Africa. TRIAL REGISTRATION NUMBER: NCT00811421; Post-results.

Epidemiology of Human Herpes Virus 8 in Pregnant Women and their Newborns--A cross-sectional delivery survey in Central Gabon.

OBJECTIVES: On the background of a high prevalence of HHV-8 infection in pre-pubertal Central African children, this study investigated the potential for in utero transmission of HHV-8. PATIENTS: Gabonese pregnant women were invited to provide peripheral and cord blood samples for serological and PCR diagnostics of HHV-8 infection at delivery for this cross-sectional survey. RESULTS: Out of 344 participants 120 (35%, 95% CI: 30-40%) were serologically positive for HHV-8. 31% (95% CI: 22-40%) of cord blood samples of seropositive women had detectable IgG antibodies. Among all seropositive participants HHV-8 was detected by PCR in one maternal peripheral blood sample at delivery (1%, 95% CI: 0.2-7%) and in none of cord blood samples. There was no association between demographic characteristics and infection status. Similarly, there was no difference in risk for premature delivery, low birth weight, and maternal anaemia in HHV-8 seropositive women. DISCUSSION: These data suggest a high seroprevalence of HHV-8 infection in pregnant women, however viraemia at delivery does not commonly occur in Central Africa. Based on these observations it may be speculated that infection of children may occur more commonly either antepartum or later on in infancy and childhood.

Evaluation of intermittent preventive treatment of malaria against group B Streptococcus colonization in pregnant women: a nested analysis of a randomized controlled clinical trial of sulfadoxine/pyrimethamine versus mefloquine.

OBJECTIVES: Streptococcus agalactiae constitutes an important cause of neonatal infections in sub-Saharan Africa. Sulfadoxine/pyrimethamine-the current intermittent preventive treatment of malaria in pregnancy (IPTp)-has proven in vitro activity against group B Streptococcus (GBS). Because of specific drug resistance to sulfadoxine/pyrimethamine, mefloquine-an antimalarial without in vitro activity against GBS-was evaluated as a potential alternative. This study assessed the potential of sulfadoxine/pyrimethamine-IPTp to reduce the prevalence of GBS colonization in pregnant women in Gabon when compared with the inactive control mefloquine-IPTp. METHODS: Pregnant women participating in a randomized controlled clinical trial evaluating mefloquine-IPTp versus sulfadoxine/pyrimethamine-IPTp were invited to participate and recto-vaginal swabs were collected at delivery for detection of GBS colonization. Prevalence of recto-vaginal GBS colonization was compared between IPTp regimens and risk factor and birth outcome analyses were computed. RESULTS: Among 549 participants, 106 were positive for GBS colonization at delivery (19%; 95% CI = 16%-23%). Prevalence of maternal GBS colonization showed no significant difference between the two IPTp regimens (mefloquine-IPTp: 67 of 366 women = 18%; 95% CI = 14%-22%; sulfadoxine/pyrimethamine-IPTp: 39 of 183 women = 21%; 95% CI = 15%-27%). Risk factor analysis for GBS colonization demonstrated a significant association with illiteracy (adjusted OR = 2.03; 95% CI = 1.25-3.30). GBS colonization had no impact on birth outcome, anaemia at delivery, gestational age and birth weight. CONCLUSIONS: Sulfadoxine/pyrimethamine did not reduce colonization rates when used as the IPTp drug during pregnancy. Illiteracy was associated with GBS colonization.

Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-negative women: a multicentre randomized controlled trial.

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

Efficacy of mefloquine intermittent preventive treatment in pregnancy against Schistosoma haematobium infection in Gabon: a nested randomized controlled assessor-blinded clinical trial.

BACKGROUND: Urogenital schistosomiasis is a major public health problem in sub-Saharan Africa, and routine programs for screening and treatment of pregnant women are not established. Mefloquine-currently evaluated as a potential alternative to sulfadoxine-pyrimethamine as intermittent preventive treatment against malaria in pregnancy (IPTp)-is known to exhibit activity against Schistosoma haematobium. In this study we evaluated the efficacy of mefloquine IPTp against S. haematobium infection in pregnant women. METHODS: Pregnant women with S. haematobium infection presenting at 2 antenatal health care centers in rural Gabon were invited to participate in this nested randomized controlled, assessor-blinded clinical trial comparing sulfadoxine-pyrimethamine with mefloquine IPTp. Study drugs were administered twice during pregnancy with a 1- month interval after completion of the first trimester. RESULTS: Sixty-five pregnant women were included in this study. Schistosoma haematobium egg excretion rates showed a median reduction of 98% (interquartile range [IQR], 70%-100%) in the mefloquine group compared to an increase of 20% (IQR, -186% to 75%) in the comparator group. More than 80% of patients showed at least 50% reduction of egg excretion and overall cure rate was 47% (IQR, 36%-70%) 6 weeks after the second administration of mefloquine IPTp. CONCLUSION: When used as IPTp for the prevention of malaria, mefloquine shows promising activity against concomitant S. haematobium infection leading to an important reduction of egg excretion in pregnant women. Provided that further studies confirm these findings, the use of mefloquine may transform future IPTp programs into a 2-pronged intervention addressing 2 of the most virulent parasitic infections in pregnant women in sub-Saharan Africa. CLINICAL TRIALS REGISTRATION: NCT01132248; ATMR2010020001429343.

Prospective evaluation of artemether-lumefantrine for the treatment of non-falciparum and mixed-species malaria in Gabon.

BACKGROUND: The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence. METHODS: This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon. RESULTS: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n=38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study. CONCLUSIONS: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00725777.

The use of paediatric artemisinin combinations in sub-Saharan Africa: a snapshot questionnaire survey of health care personnel.

BACKGROUND: Paediatric drug formulations for artemisinin combination therapy (P-ACT) have been developed over the past few years and have been shown to improve the therapeutic management of young children with uncomplicated falciparum malaria. This process was however not equally paralleled by a timely adoption of P-ACT in national and international treatment recommendations. National malaria programmes in sub-Saharan Africa have not yet widely embraced this new therapeutic tool. To which extent P-ACT is used in the field in sub-Saharan Africa is not known to date. METHODS: This snapshot questionnaire survey aimed to provide an overview on the current routine practices for the availability and use of P-ACT as anti-malarial treatment for young children in sub-Saharan Africa. Health care personnel in seven countries in West-, Central, and East-Africa were invited to answer a structured questionnaire assessing use and availability of P-ACT. RESULTS: A total of 71 respondents including doctors, nurses and pharmacy personnel responsible for the anti-malarial treatment of young children were interviewed. P-ACT was used by 83% (95% confidence interval: 73-90%; n = 59) as first-line treatment for young children. Use of 15 different P-ACT products was reported among which only two have received WHO prequalification status and approval by a stringent registration authority. Use of a specific P-ACT product was not linked to consumer prices or availability of supporting clinical trial data, but may depend more on the marketing capacity of the manufacturer. Major differences in frequency and dosing of anti-malarial regimens with identical anti-malarial compounds and the marketing of loose combinations were recorded. CONCLUSION: Paediatric ACT is widely used for the treatment of uncomplicated malaria in young children. However, the majority of P-ACT formulations in use do not meet highest international quality standards evoking concerns for patients' safety and the induction of drug resistance. Improving the quality of currently marketed P-ACT should constitute a public health priority besides their adoption into official treatment recommendations.

Pyronaridine-artesunate combination therapy for the treatment of malaria.

PURPOSE OF REVIEW: Pyronaridine-artesunate is among the most promising novel artemisinin combination therapies for the treatment of malaria. A series of clinical phase II and III trials have been conducted for the indications of uncomplicated falciparum and vivax malaria in Africa and Asia. On the basis of these novel data, this review aims to provide an appraisal of current evidence and a perspective for its future role in the antimalarial portfolio. RECENT FINDINGS: Pyronaridine-artesunate demonstrated repeatedly high efficacy in the treatment of vivax and falciparum malaria and noninferiority was established compared to standard comparator regimens. An innovative paediatric drug formulation was developed in parallel to the tablet formulation for the treatment of young children. Pharmacokinetic analysis showed dose linearity, low interindividual variation and absence of a clinically important effect of food on the bioavailability of this drug combination. Overall tolerability and safety data are reassuring; however, further surveillance of safety in special patient populations including young children is warranted. SUMMARY: Pyronaridine-artesunate - currently under evaluation by the European Medicines Agency - may become a preferred choice as first-line therapy in malaria endemic regions based on its low cost, long shelf-life, simplified once-daily dosing regimen, proven efficacy against falciparum and vivax malaria, and the parallel clinical development of a paediatric drug formulation.

Current status of the clinical development and implementation of paediatric artemisinin combination therapies in Sub-Saharan Africa.

Timely treatment of infected children with artemisinin based combination therapies is an essential tool for the effective control and potential elimination of malaria. Until recently only tablet formulations have been available for the treatment of children leading to problems of swallowability, palatability and dosing. In consequence, paediatric drug formulations of artemisinin-based combination therapy (ACT) have been developed, showing a clinically significant improvement of tolerability in young children and of their implementation is an increasingly important public health issue. In this mini-review, we focus on the recent development of paediatric ACTs and their use in practice. Paediatric ACTs are formulated as syrup, powder for suspension, dispersible tablets and granules. Overall, the use of paediatric formulation results in an improved management of clinical malaria in young children. To date, only two paediatric ACTs have been certified with WHO prequalification status as an internationally accepted quality standard. Many more paediatric ACTs are available and in use in sub-Saharan Africa despite a lack of publicly available evidence from stringent clinical development programs. The conduct of effectiveness studies to support the introduction of paediatric ACTs in official treatment recommendations is crucial in the global strategy of malaria elimination and quality assurance of available products is a public health priority.

In vitro activity of antifungal drugs against Plasmodium falciparum field isolates.

The increasing resistance of the malaria parasite Plasmodium falciparum to currently available drugs necessitates a continuous effort to develop new antimalarial agents. We therefore aimed to assess the in vitro activity of the antifungal drugs clotrimazole, fluconazole, ketoconazole, itraconazole, voriconazole, flucytosine, amphotericin B, and caspofungin against field isolates of P. falciparum from Lambaréné, Gabon. Using the histidin-rich protein 2 (HRP-2) assay we determined the drug susceptibility (EC(50), EC(90)) of 16 field isolates obtained from outpatients attending the Albert Schweitzer Hospital in Lambaréné, Gabon. For fluconazole, itraconazole and caspofungin the in vitro growth inhibition of these drugs is reported for the first time. Our data indicate that clotrimazole, fluconazole, itraconazole and caspofungin show median EC(50) values of 3.1 µg/mL, 1.9 µg/mL, 1.1 µg/mL and 1.1 µg/mL respectively. Ketoconazole, voriconazole, flucytosine and amphotercin B showed no relevant growth inhibition within the range of drug concentrations used in this study.

Pyronaridine: a new 'old' drug on the verge of entering the antimalarial armamentarium.

Pyronaridine-artesunate is a promising new artemisinin-based combination therapy for the treatment of uncomplicated falciparum malaria and the first systematically evaluated artemisinin-based combination therapy for vivax malaria. The 3-day regimen proved to be highly efficacious in clinical trials in Africa and Asia and is currently under review by the EMA. Price et al. report data of an in vitro drug-susceptibility study evaluating the activity of pyronaridine against Plasmodium vivax and Plasmodium falciparum field isolates from Papua, Indonesia. The authors demonstrate high in vitro activity of pyronaridine at low nanomolar concentrations that is only paralleled by the artemisinin class of antimalarials. Besides exciting methodological insights into the new field of in vitro drug-susceptibility testing for P. vivax, these data are encouraging evidence for the future implementation of pyronaridine in combination therapy for the fight against malaria.