Malaria in Southeast Asia frequently clusters along international borders. For example, while mos... more Malaria in Southeast Asia frequently clusters along international borders. For example, while most of Thailand is malaria free, the border region shared with Myanmar continues to have endemic malaria. This spatial pattern is the result of complex interactions between landscape, humans, mosquito vectors, and malaria parasites. An understanding of these complex ecological and socio-cultural interactions is important for designing and implementing malaria elimination efforts in the region. This article offers an ecological perspective on the malaria situation along the Thailand-Myanmar border. This border region is long (2000 km), mountainous, and the environment ranges from thick forests to growing urban settlements and wet-rice fields. It is also a biologically diverse region. All five species of malaria known to naturally infect humans are present. At least three mosquito vector species complexes, with widely varying behavioural characteristics, exist in the area. The region is also a hub for ethnic diversity, being home to over ten different ethnolinguistic groups, several of which have been engaged in conflict with the Myanmar government now for over half a century. Given the biological and ethnic diversity, as well as the complex socio-political context, malaria control and elimination in the region is challenging. Despite these complexities, multipronged approaches including collaborations with multiple local organizations, quick access to diagnosis and treatment, prevention of mosquito bites, radical cure of parasites, and mass drug administration appear to be drastically decreasing Plasmodium falciparum infections. Such approaches remain crucial as the region moves toward elimination of P. falciparum and potentially Plasmodium vivax.
Antimicrobial agents and chemotherapy, Jan 3, 2015
Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatm... more Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an EMAX model, both predicted treatment outcomes but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the mod...
Estimating gestational age in resource-limited settings is prone to considerable inaccuracy becau... more Estimating gestational age in resource-limited settings is prone to considerable inaccuracy because crown-rump length measured by ultrasound before 14 weeks gestation, the recommended method for estimating gestational age, is often unavailable. Judgements regarding provision of appropriate obstetric and neonatal care are dependent on accurate estimation of gestational age. We determined the accuracy of the Dubowitz Gestational Age Assessment, a population-specific symphysis-fundal height formula, and ultrasound biometry performed between 16 and 40 weeks gestation in estimating gestational age using pre-existing data from antenatal clinics of the Shoklo Malaria Research Unit on the Thai-Myanmar border, where malaria is endemic. Two cohorts of women who gave birth to live singletons were analysed: 1) 250 women who attended antenatal care between July 2001 and May 2006 and had both ultrasound crown-rump length (reference) and a Dubowitz Gestational Age Assessment; 2) 975 women attendin...
Plasmodium falciparum infections adversely affect pregnancy. Anti-malarial treatment failure is c... more Plasmodium falciparum infections adversely affect pregnancy. Anti-malarial treatment failure is common. The objective of this study was to examine the duration of persistent parasite carriage following anti-malarial treatment in pregnancy. The data presented here are a collation from previous studies carried out since 1994 in the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border and performed using the same unique methodology detailed in the Materials and Methods section. Screening for malaria by microscopy is a routine part of weekly antenatal care (ANC) visits and therapeutic responses to anti-malarials were assessed in P. falciparum malaria cases. Women with microscopy confirmed P. falciparum malaria had a PCR blood spot from a finger-prick sample collected. Parasite DNA was extracted from the blood-spot samples using saponin lysis/Chelex extraction method and genotyped using polymorphic segments of MSP1, MSP2 and GLURP. Recurrent infections were classified by ge...
Published literature from resource limited settings is infrequent, although urinary tract infecti... more Published literature from resource limited settings is infrequent, although urinary tract infections (UTI) are a common cause of outpatient presentation and antibiotic use. Point of care test (POCT) interpretation relates to antibiotic use and antibiotic resistance. We aimed to assess the diagnostic accuracy of POCT and their role in UTI antibiotic stewardship. One year retrospective analysis in three clinics on the Thailand-Myanmar border of non-pregnant adults presenting with urinary symptoms. POCT (urine dipstick and microscopy) were compared to culture with significant growth classified as pure growth of a single organism >10(5) cfu/mL. In 247 patients, 82.6% female, the most common symptoms were dysuria (81.2%), suprapubic pain (67.8%) and urinary frequency (53.7%). After excluding contaminated samples, UTI was diagnosed in 52.4% (97/185); 71.1% (69/97) had a significant growth on culture and >80% of these were Escherichia coli (20.9% produced extended spectrum β-lactamase (ESBL)). Positive urine dipstick (leucocyte esterase ≥1 and/or nitrate positive) compared against positive microscopy (white blood cell >10/HPF, bacteria ≥1/HPF, epithelial cells <5/HPF), had a higher sensitivity (99% vs 57%) but a lower specificity (47% vs 89%), respectively. Combined POCT resulted in the best sensitivity (98%) and specificity (81%). Nearly one in ten patients received an antimicrobial to which the organism was not fully sensitive. One rapid, cost-effective POCT was too inaccurate to be used alone by healthcare workers, impeding antibiotic stewardship in a high ESBL setting. Improved POCT are urgently needed to address increasing global antibiotic resistance. This article is protected by copyright. All rights reserved.
Mental illness is a significant contributor to the global burden of disease, with prevalence high... more Mental illness is a significant contributor to the global burden of disease, with prevalence highest in low- and middle-income countries. Rates are high in women of childbearing age, especially during pregnancy and the first year post-partum. Migrant and refugee populations are at risk of developing mental illness due to the multiple stresses associated with migration. The Thai-Myanmar border area is home to large populations of migrants and refugees as a result of long-standing conflict, poverty and unemployment in Myanmar. This study aims to explore perceptions of mental illness among pregnant migrants and refugees and antenatal clinic staff living and working along the Thai-Myanmar border. Thirteen focus group discussions were conducted with pregnant migrants, pregnant refugees and antenatal clinic staff. Focus groups were held in one large refugee camp and two migrant health clinics along the Thai-Myanmar border. Thematic analysis was used to identify and code themes emerging from the data. A total of 92 pregnant women and 24 antenatal clinic staff participated. Discussions centered around five main themes: symptoms of mental illness; causes of mental illness; suicide; mental illness during pregnancy and the post-partum period; and managing mental illness. Symptoms of mental illness included emotional disturbances, somatic symptoms and socially inappropriate behavior. The main causes were described as current economic and family-related difficulties. Suicide was frequently attributed to shame. Mental illness was thought to be more common during and following pregnancy due to a lack of family support and worries about the future. Talking to family and friends, medication and hospitalization were suggested as means of helping those suffering from mental illness. Mental illness was recognized as a concept by the majority of participants and there was a general willingness to discuss various aspects of it. More formal and systematic training including the development of assessment tools in the local languages would enable better ascertainment and treatment of mental illness in this population.
British journal of clinical pharmacology, Jan 15, 2015
To compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women:... more To compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7. Nonlinear mixed-effects modelling was used to compare plasma concentration-time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied three months after delivery when fully recovered. Non-compartmental results of the same study have been published previously. Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied three months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin a...
Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO ... more Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO recommended use of artemisinin-based combination treatments during the second or third trimesters, but data on efficacy and safety in Africa were scarce. We aimed to assess whether artemether-lumefantrine was at least as efficacious as oral quinine for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy in Mbarara, Uganda. We did an open-label, randomised, non-inferiority trial between October, 2006, and May, 2009, at the antenatal clinics of the Mbarara University of Science and Technology Hospital in Uganda. Pregnant women were randomly assigned (1:1) by computer generated sequence to receive either quinine hydrochloride or artemether-lumefantrine, and were followed up weekly until delivery. Our primary endpoint was cure rate at day 42, confirmed by PCR. The non-inferiority margin was a difference in cure rate of 5%. Analysis of efficacy was for all randomised patients without study deviations that could have affected the efficacy outcome. This study was registered with ClinicalTrials.gov, number NCT00495508. 304 women were randomly assigned, 152 to each treatment group. By day 42, 16 patients were lost to follow-up and 25 were excluded from the analysis. At day 42, 137 (99.3%) of 138 patients taking artemether-lumefantrine and 122 (97.6%) of 125 taking quinine were cured-difference 1.7% (lower limit of 95% CI -0.9). There were 290 adverse events in the quinine group and 141 in the artemether-lumefantrine group. Artemisinin derivatives are not inferior to oral quinine for the treatment of uncomplicated malaria in pregnancy and might be preferable on the basis of safety and efficacy. Médecins Sans Frontières and the European Commission.
The Shoklo Malaria Research Unit has been working on the Thai-Myanmar border for 25 y providing e... more The Shoklo Malaria Research Unit has been working on the Thai-Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria. Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged. We expanded malaria activities through EDT and evaluated the impact over a 12-y period. Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations. Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys. In vivo and in vitro antimalarial drug efficacy were monitored. Over this period, the number of malaria cases detected increased initially, but then declined rapidly. In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76-80) (1,048/1,344 consultations) to 7% (95% CI 6.2-7.1) (767/11,542 consultations), p<0.001. The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3-1.4) to 0.7 (95% CI 0.7-0.8). The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04-0.07]). The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year. The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0-28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8-4.3) (76/2,207 pregnant women), p<0.001. The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20-62]). The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13-45) (8/29 patients) in 2011. Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai-Myanmar border. Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area. Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate. Please see later in the article for the Editors' Summary.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000
The efficacy and safety of the 6-dose regimen of artemether-lumefantrine were assessed in an open... more The efficacy and safety of the 6-dose regimen of artemether-lumefantrine were assessed in an open randomized trial in children and adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand between ...
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000
Since no effective malaria prevention measures have been identified for pregnant women living on ... more Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.
Malaria in Southeast Asia frequently clusters along international borders. For example, while mos... more Malaria in Southeast Asia frequently clusters along international borders. For example, while most of Thailand is malaria free, the border region shared with Myanmar continues to have endemic malaria. This spatial pattern is the result of complex interactions between landscape, humans, mosquito vectors, and malaria parasites. An understanding of these complex ecological and socio-cultural interactions is important for designing and implementing malaria elimination efforts in the region. This article offers an ecological perspective on the malaria situation along the Thailand-Myanmar border. This border region is long (2000 km), mountainous, and the environment ranges from thick forests to growing urban settlements and wet-rice fields. It is also a biologically diverse region. All five species of malaria known to naturally infect humans are present. At least three mosquito vector species complexes, with widely varying behavioural characteristics, exist in the area. The region is also a hub for ethnic diversity, being home to over ten different ethnolinguistic groups, several of which have been engaged in conflict with the Myanmar government now for over half a century. Given the biological and ethnic diversity, as well as the complex socio-political context, malaria control and elimination in the region is challenging. Despite these complexities, multipronged approaches including collaborations with multiple local organizations, quick access to diagnosis and treatment, prevention of mosquito bites, radical cure of parasites, and mass drug administration appear to be drastically decreasing Plasmodium falciparum infections. Such approaches remain crucial as the region moves toward elimination of P. falciparum and potentially Plasmodium vivax.
Antimicrobial agents and chemotherapy, Jan 3, 2015
Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatm... more Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an EMAX model, both predicted treatment outcomes but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the mod...
Estimating gestational age in resource-limited settings is prone to considerable inaccuracy becau... more Estimating gestational age in resource-limited settings is prone to considerable inaccuracy because crown-rump length measured by ultrasound before 14 weeks gestation, the recommended method for estimating gestational age, is often unavailable. Judgements regarding provision of appropriate obstetric and neonatal care are dependent on accurate estimation of gestational age. We determined the accuracy of the Dubowitz Gestational Age Assessment, a population-specific symphysis-fundal height formula, and ultrasound biometry performed between 16 and 40 weeks gestation in estimating gestational age using pre-existing data from antenatal clinics of the Shoklo Malaria Research Unit on the Thai-Myanmar border, where malaria is endemic. Two cohorts of women who gave birth to live singletons were analysed: 1) 250 women who attended antenatal care between July 2001 and May 2006 and had both ultrasound crown-rump length (reference) and a Dubowitz Gestational Age Assessment; 2) 975 women attendin...
Plasmodium falciparum infections adversely affect pregnancy. Anti-malarial treatment failure is c... more Plasmodium falciparum infections adversely affect pregnancy. Anti-malarial treatment failure is common. The objective of this study was to examine the duration of persistent parasite carriage following anti-malarial treatment in pregnancy. The data presented here are a collation from previous studies carried out since 1994 in the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border and performed using the same unique methodology detailed in the Materials and Methods section. Screening for malaria by microscopy is a routine part of weekly antenatal care (ANC) visits and therapeutic responses to anti-malarials were assessed in P. falciparum malaria cases. Women with microscopy confirmed P. falciparum malaria had a PCR blood spot from a finger-prick sample collected. Parasite DNA was extracted from the blood-spot samples using saponin lysis/Chelex extraction method and genotyped using polymorphic segments of MSP1, MSP2 and GLURP. Recurrent infections were classified by ge...
Published literature from resource limited settings is infrequent, although urinary tract infecti... more Published literature from resource limited settings is infrequent, although urinary tract infections (UTI) are a common cause of outpatient presentation and antibiotic use. Point of care test (POCT) interpretation relates to antibiotic use and antibiotic resistance. We aimed to assess the diagnostic accuracy of POCT and their role in UTI antibiotic stewardship. One year retrospective analysis in three clinics on the Thailand-Myanmar border of non-pregnant adults presenting with urinary symptoms. POCT (urine dipstick and microscopy) were compared to culture with significant growth classified as pure growth of a single organism >10(5) cfu/mL. In 247 patients, 82.6% female, the most common symptoms were dysuria (81.2%), suprapubic pain (67.8%) and urinary frequency (53.7%). After excluding contaminated samples, UTI was diagnosed in 52.4% (97/185); 71.1% (69/97) had a significant growth on culture and >80% of these were Escherichia coli (20.9% produced extended spectrum β-lactamase (ESBL)). Positive urine dipstick (leucocyte esterase ≥1 and/or nitrate positive) compared against positive microscopy (white blood cell >10/HPF, bacteria ≥1/HPF, epithelial cells <5/HPF), had a higher sensitivity (99% vs 57%) but a lower specificity (47% vs 89%), respectively. Combined POCT resulted in the best sensitivity (98%) and specificity (81%). Nearly one in ten patients received an antimicrobial to which the organism was not fully sensitive. One rapid, cost-effective POCT was too inaccurate to be used alone by healthcare workers, impeding antibiotic stewardship in a high ESBL setting. Improved POCT are urgently needed to address increasing global antibiotic resistance. This article is protected by copyright. All rights reserved.
Mental illness is a significant contributor to the global burden of disease, with prevalence high... more Mental illness is a significant contributor to the global burden of disease, with prevalence highest in low- and middle-income countries. Rates are high in women of childbearing age, especially during pregnancy and the first year post-partum. Migrant and refugee populations are at risk of developing mental illness due to the multiple stresses associated with migration. The Thai-Myanmar border area is home to large populations of migrants and refugees as a result of long-standing conflict, poverty and unemployment in Myanmar. This study aims to explore perceptions of mental illness among pregnant migrants and refugees and antenatal clinic staff living and working along the Thai-Myanmar border. Thirteen focus group discussions were conducted with pregnant migrants, pregnant refugees and antenatal clinic staff. Focus groups were held in one large refugee camp and two migrant health clinics along the Thai-Myanmar border. Thematic analysis was used to identify and code themes emerging from the data. A total of 92 pregnant women and 24 antenatal clinic staff participated. Discussions centered around five main themes: symptoms of mental illness; causes of mental illness; suicide; mental illness during pregnancy and the post-partum period; and managing mental illness. Symptoms of mental illness included emotional disturbances, somatic symptoms and socially inappropriate behavior. The main causes were described as current economic and family-related difficulties. Suicide was frequently attributed to shame. Mental illness was thought to be more common during and following pregnancy due to a lack of family support and worries about the future. Talking to family and friends, medication and hospitalization were suggested as means of helping those suffering from mental illness. Mental illness was recognized as a concept by the majority of participants and there was a general willingness to discuss various aspects of it. More formal and systematic training including the development of assessment tools in the local languages would enable better ascertainment and treatment of mental illness in this population.
British journal of clinical pharmacology, Jan 15, 2015
To compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women:... more To compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7. Nonlinear mixed-effects modelling was used to compare plasma concentration-time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied three months after delivery when fully recovered. Non-compartmental results of the same study have been published previously. Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied three months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin a...
Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO ... more Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO recommended use of artemisinin-based combination treatments during the second or third trimesters, but data on efficacy and safety in Africa were scarce. We aimed to assess whether artemether-lumefantrine was at least as efficacious as oral quinine for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy in Mbarara, Uganda. We did an open-label, randomised, non-inferiority trial between October, 2006, and May, 2009, at the antenatal clinics of the Mbarara University of Science and Technology Hospital in Uganda. Pregnant women were randomly assigned (1:1) by computer generated sequence to receive either quinine hydrochloride or artemether-lumefantrine, and were followed up weekly until delivery. Our primary endpoint was cure rate at day 42, confirmed by PCR. The non-inferiority margin was a difference in cure rate of 5%. Analysis of efficacy was for all randomised patients without study deviations that could have affected the efficacy outcome. This study was registered with ClinicalTrials.gov, number NCT00495508. 304 women were randomly assigned, 152 to each treatment group. By day 42, 16 patients were lost to follow-up and 25 were excluded from the analysis. At day 42, 137 (99.3%) of 138 patients taking artemether-lumefantrine and 122 (97.6%) of 125 taking quinine were cured-difference 1.7% (lower limit of 95% CI -0.9). There were 290 adverse events in the quinine group and 141 in the artemether-lumefantrine group. Artemisinin derivatives are not inferior to oral quinine for the treatment of uncomplicated malaria in pregnancy and might be preferable on the basis of safety and efficacy. Médecins Sans Frontières and the European Commission.
The Shoklo Malaria Research Unit has been working on the Thai-Myanmar border for 25 y providing e... more The Shoklo Malaria Research Unit has been working on the Thai-Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria. Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged. We expanded malaria activities through EDT and evaluated the impact over a 12-y period. Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations. Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys. In vivo and in vitro antimalarial drug efficacy were monitored. Over this period, the number of malaria cases detected increased initially, but then declined rapidly. In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76-80) (1,048/1,344 consultations) to 7% (95% CI 6.2-7.1) (767/11,542 consultations), p<0.001. The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3-1.4) to 0.7 (95% CI 0.7-0.8). The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04-0.07]). The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year. The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0-28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8-4.3) (76/2,207 pregnant women), p<0.001. The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20-62]). The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13-45) (8/29 patients) in 2011. Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai-Myanmar border. Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area. Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate. Please see later in the article for the Editors' Summary.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000
The efficacy and safety of the 6-dose regimen of artemether-lumefantrine were assessed in an open... more The efficacy and safety of the 6-dose regimen of artemether-lumefantrine were assessed in an open randomized trial in children and adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand between ...
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2000
Since no effective malaria prevention measures have been identified for pregnant women living on ... more Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.
Background: Inherited red blood cell disorders are prevalent in populations living in malaria end... more Background: Inherited red blood cell disorders are prevalent in populations living in malaria endemic areas; G6PD deficiency is associated with oxidant-induced hemolysis and abnormal hemoglobin variants may cause chronic anemia. In pregnant women, microcytic anemia caused by hemoglobinopathies mimics iron deficiency, complicating diagnosis and treatment. Anemia during pregnancy is associated with morbidity and mortality. The aim of this study was to characterize the prevalence of G6PD deficiency, hemoglobinopathies, ABO and Rhesus blood groups among the pregnant population living along the Thailand-Myanmar border. Pregnant women attending antenatal clinics in this area belong to several distinct ethnic groups. Methods: Data was available for 13,520 women attending antenatal care between July 2012 and September 2016. Screening for G6PD deficiency was done by fluorescent spot test routinely. G6PD genotyping and quantitative phenotyping by spectrophotometry were analyzed in a subsample...
Conflict settings and refugee camps can be chaotic places, with large and rapid population moveme... more Conflict settings and refugee camps can be chaotic places, with large and rapid population movements, exacerbated public health problems, and ad hoc health services. Reproductive health care that includes family planning is of heightened importance in such settings, however, funding and resources tend to be constrained and geared towards acute health services such as trauma management and infectious disease containment. Here we report on the complexities and challenges of providing family planning in a post-emergency refugee setting, using the example of the largest refugee camp on the Thai-Myanmar border, in existence now for over 30 years. Data from 2009 demonstrates an upward trend in uptake of all contraceptives, especially long acting reversible contraception (LARC) and permanent methods (e.g. sterilization) over time. Increased uptake occurred during periods of time when there were boosts in funding or when barriers to access were alleviated. For example a surgeon fluent in lo...
Bjog an International Journal of Obstetrics and Gynaecology, Feb 1, 2006
We were encouraged to see the review of malaria in pregnancy by Whitty et al. in the BJOG given t... more We were encouraged to see the review of malaria in pregnancy by Whitty et al. in the BJOG given the huge burden of this disease and the lack of therapeutic and prophylactic options. As stated by the authors the risk of significant morbidity and mortality from withholding a drug for treatment of this condition usually outweighs the risk of toxicity. However we would like to share the following comments. We question the notion that pregnant women with malaria in Africa are asymptomatic: in fact there are no large and detailed longitudinal studies to support this hypothesis and most papers on treatment trials report the presence of symptoms in infected women even in areas of high transmission. It is unlikely that a pregnant woman infected with Plasmodium falciparum will remain completely asymptomatic and more likely that she will have mild symptoms that will not be reported. Maternal mortality attributed to malaria is high in Africa a fact that is hard to reconcile with absence of symptoms. (excerpt)
<p>The file is a SAV type file with all variables used in the analysis available in the dat... more <p>The file is a SAV type file with all variables used in the analysis available in the dataset (syp_hivF1000.sav)</p
Malaria misconceptions We have serious concerns about the content of three letters published on N... more Malaria misconceptions We have serious concerns about the content of three letters published on Nov 13. In the first Arthur Caplan refers to the recently published report of the US Institute of Medicine and writes: “there is concern that the artemisinin derivatives are associated with greatly increased rates of birth defects in pregnant women” quoting one of our publications. This is an error: in the cited study there was only one birth defect among singleton babies and the mother had been treated with quinine. The “international agreement” on the use of artemisinin in pregnancy demanded by Caplan was reached by WHO in 2003. It would be disastrous if artemisinin-based combination therapy (ACT) was compromised by fears of liability based on groundless allegations. (excerpt)
Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are o... more Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are one of the few sources of clinical safety data. Complete safety evaluation is not usually incorporated in efficacy studies due to financial and human resource constraints. This review reports the methods used for the assessment of safety of artemisinin-based and quinine-based treatments in efficacy studies in pregnancy. Methodology of assessment and reporting of safety in efficacy studies of artemisinin-based and quinine-based treatment in pregnancy was reviewed using seven databases and two clinical trial registries. The protocol was registered to PROSPERO (CRD42017054808). Of 48 eligible efficacy studies the method of estimation of gestational age was reported in only 32 studies (67%, 32/48) and ultrasound was used in 18 studies (38%, 18/48). Seventeen studies (35%, 17/48) reported parity, 9 (19%, 9/48) reported gravidity and 13 (27%, 13/48) reported both. Thirty-eight studies (79%, 38/...
Perinatal depression is an important contributor to maternal morbidity and mortality worldwide. M... more Perinatal depression is an important contributor to maternal morbidity and mortality worldwide. Migrant women, particularly those resettling within low- and middle-income settings, are at increased risk of perinatal depression due to multiple stressors experienced before, during and after migration. Evidence on migrant perinatal mental health to date has focused largely on women in high-income destination countries, leaving the voices of displaced women in low-income settings unheard. This study addresses the current evidence gap by exploring the experiences of migrant women living on the Thai-Myanmar border. In-depth interviews were conducted with pregnant and post-partum labour migrant and refugee women on the Thai-Myanmar border who had been diagnosed with severe depression. An interview guide covering women's current and past life experiences, social support and the impact of depression on social and occupational functioning was used as a prompt. Thematic analysis was used t...
Antimicrobial agents and chemotherapy, Jan 23, 2018
Amodiaquine plus artesunate is the recommended antimalarial treatment in many malaria-endemic cou... more Amodiaquine plus artesunate is the recommended antimalarial treatment in many malaria-endemic countries. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over three days. Plasma concentration-time profiles for both parent drug and metabolite were characterized using nonlinear mixed-effects modelling. Amodiaquine pharmacokinetics was adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethyla...
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Mar 24, 2018
Primaquine is the only drug providing radical cure of Plasmodium vivax malaria. It is not recomme... more Primaquine is the only drug providing radical cure of Plasmodium vivax malaria. It is not recommended for breastfeeding women as it causes hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals, and breast milk excretion and thus infant exposure are not known. Healthy G6PD normal breastfeeding women with previous P.vivax infection and their healthy G6PD normal infants between 28 days and 2 years old were enrolled. Mothers took primaquine 0.5 mg/kg/day for 14 days. Primaquine and carboxyprimaquine concentrations were measured in maternal venous plasma, capillary plasma, and breast milk samples and infant capillary plasma samples taken on days 0, 3, 7, and 13. In 20 mother-baby pairs primaquine concentrations were below measurement thresholds in all but one infant capillary plasma sample (that contained primaquine 2.6 ng/mL) and carboxyprimaquine was likewise unmeasurable in the majority of infant samples (maximum value 25.8 ng/mL). The estimated primaquine dose r...
Perinatal depression is a significant contributor to maternal morbidity. Migrant women in resourc... more Perinatal depression is a significant contributor to maternal morbidity. Migrant women in resource-poor settings may be at increased risk, yet little research has been conducted in low-income and middle-income settings. This prospective cohort study of migrant women on the Thai-Myanmar border aims to establish prevalence of perinatal depression, identify risk factors for perinatal depression and examine associations with infant outcomes. Participating women are labour migrants and refugees living on the Thai-Myanmar border. A total of 568 women were recruited in their first trimester of pregnancy and are being followed up to 1-year postpartum. At baseline, women in our study had a median age of 25 years, the predominant ethnicity was Sgaw Karen (48.9%), agriculture was the main employment sector (39.2%) and educational attainment was low with a median of 4 years of education. In the first trimester of pregnancy, a quarter (25.8%; 95% CI 22.3 to 29.5) of all women were depressed as d...
During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing p... more During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. Plasmodium falciparum infections may reduce maternofetal antibody transfer efficiency, but mechanisms remain unclear. Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four P. falciparum antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral P. falciparum infection during pregnancy or placental P. falciparum infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between P. falciparum infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG. Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG c...
Data on the cost effectiveness of hepatitis B virus (HBV) screening and vaccination strategies fo... more Data on the cost effectiveness of hepatitis B virus (HBV) screening and vaccination strategies for prevention of vertical transmission of HBV in resource limited settings is sparse. A decision tree model of HBV prevention strategies utilised data from a cohort of 7071 pregnant women on the Thailand-Myanmar border using a provider perspective. All options included universal HBV vaccination for newborns in three strategies: (1) universal vaccination alone; (2) universal vaccination with screening of women during antenatal visits with rapid diagnostic test (RDT) plus HBV immune globulin (HBIG) administration to newborns of HBV surface antigen positive women; and (3) universal vaccination with screening of women during antenatal visits plus HBIG administration to newborns of women testing HBV e antigen positive by confirmatory test. At the time of the study, the HBIG after confirmatory test strategy was used. The costs in United States Dollars (US$), infections averted and incremental c...
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder in huma... more Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder in humans and appears to be protective against falciparum severe malaria. Controversially, it is also thought that Plasmodium vivax has driven the recent selection of G6PD alleles. We use an experimental approach to determine whether G6PD-MahidolG487A variant, a widespread cause of severe G6PD deficiency in Southeast Asia, provides a barrier against vivax malaria. Our results show that the immature reticulocytes (CD71+) targeted by P. vivax invasion are enzymatically normal even in hemizygous G6PD-Mahidol G487A mutants; thus allowing the normal growth, development and high parasite density in severely deficient samples.
Malaria in pregnancy is preventable and contributes significantly to the estimated 5.5 million st... more Malaria in pregnancy is preventable and contributes significantly to the estimated 5.5 million stillbirths and neonatal deaths that occur annually. The contribution of malaria in pregnancy in areas of low transmission has not been quantified, and the roles of maternal anaemia, small-for-gestational-age status, and preterm birth in mediating the effect of malaria in pregnancy on stillbirth and neonatal death are poorly elucidated. We analysed observational data routinely collected at antenatal clinics on the Thai-Myanmar border (1986-2015). We used Cox regression and sequential mediation analysis to determine the effect of falciparum and vivax malaria in pregnancy on antepartum (death in utero) and intrapartum (death during labour) stillbirth and neonatal mortality as well as mediation through maternal anaemia, preterm birth, and small-for-gestational-age status. Of 61,836 women, 9350 (15%) had malaria in pregnancy, and 526 (0.8%) had stillbirths. In a sub-set of 9090 live born singl...
This study aims to identify risk factors and the neurodevelopmental impact of neonatal hyperbilir... more This study aims to identify risk factors and the neurodevelopmental impact of neonatal hyperbilirubinemia in a limited-resource setting among a refugee and migrant population residing along the Thai-Myanmar border, an area with a high prevalence of glucose-6-phosphate dehydrogenase-deficiency. This is an analytic, observational, prospective birth cohort study including all infants of estimated gestational age equal to or greater than 28 weeks from mothers who followed antenatal care in the Shoklo Malaria Research Unit clinics. At birth, a series of clinical exams and laboratory investigations on cord blood will be carried out. Serum bilirubin will be measured in all infants during their first week of life. All the infants of the cohort will be clinically followed until the age of one year, including monitoring of their neurodevelopment. The strength of this study is the prospective cohort design. It will allow us to collect information about the pregnancy and detect all infants with...
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Publications by Rose McGready