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1.  Treatment of Suspected Hyper-Reactive Malarial Splenomegaly (HMS) in Pregnancy with Mefloquine 
Malaria infections in pregnancy are associated with adverse outcomes for both mother and child. There are few data on hyper-reactive malarial splenomegaly, an aberrant immunological response to chronic or recurrent malaria in pregnancy. This retrospective assessment reviewed the impact of mefloquine treatment on pregnant women with suspected hyper-reactive malarial splenomegaly in an area of low malaria transmission in the 1990s, showing significant reductions in spleen size and anemia and anti-malarial antibody titers without any notable negative effect on treated women or their newborns.
PMCID: PMC3973501  PMID: 24591439
2.  Clinical audit to enhance safe practice of skilled birth attendants for the fetus with nuchal cord: evidence from a refugee and migrant cohort 
Current evidence for optimal management of fetal nuchal cord detected after the head has birthed supports techniques that avoid ligation of the umbilical cord circulation. Routine audit found frequent unsafe management of nuchal cord by skilled birth attendants (SBAs) in migrant and refugee birth centres on the Thai-Burmese border.
The audit cycle was used to enhance safe practice by SBA for the fetus with nuchal cord. In the three birth centres the action phase of the audit cycle was initially carried out by the doctor responsible for the site. Six months later a registered midwife, present six days per week for three months in one birth facility, encouraged SBAs to facilitate birth with an intact umbilical circulation for nuchal cord. Rates of cord ligation before birth were recorded over a 24 month period (1-July-2011 to 30-June-2013) and in-depth interviews and a knowledge survey of the SBAs took place three months after the registered midwife departure.
The proportion of births with nuchal cord ligation declined significantly over the four six monthly quarters from 15.9% (178/1123) before the action phase of the audit cycle; to 11.1% (107/966) during the action phase of the audit cycle with the doctors; to 2.4% (28/1182) with the registered midwife; to 0.9% (9/999) from three to nine months after the departure of the registered midwife, (p < 0.001, linear trend). Significant improvements in safe practice were observed at all three SMRU birth facilities. Knowledge of fetal nuchal cord amongst SBAs was sub-optimal and associated with fear and worry despite improved practice. The support of a registered midwife increased confidence of SBAs.
The audit cycle and registered midwife interprofessional learning for SBAs led to a significant improvement in safe practice for the fetus with nuchal cord. The authors would encourage this type of learning in organizations with birth facilities on the Thai-Burmese border and in other similar resource limited settings with SBAs.
PMCID: PMC3943506  PMID: 24552462
Audit cycle; Interprofessional learning; Nuchal cord; Quality improvement; Registered midwife; Skilled birth attendant
3.  A morphometric and histological study of placental malaria shows significant changes to villous architecture in both Plasmodium falciparum and Plasmodium vivax infection 
Malaria Journal  2014;13:4.
Malaria in pregnancy remains a major health problem. Placental malaria infection may cause pathophysiological changes in pregnancy and result in morphological changes to placental villi. Quantitative histomorphological image analysis of placental biopsies was performed to compare placental villous architecture between active or treated placental malaria cases and controls.
A total of 67 placentas were studied from three clinical groups: control patients who did not have malaria (n = 27), active (n = 14) and treated (n=26) malaria cases, including both Plasmodium falciparum and Plasmodium vivax infections. Image analysis of histological placental sections was performed using ImageJ software to measure the number and size (area) of terminal villi, perimeter measurement per villus and total perimeter per unit area, and number of capillaries per villus (vascularity). Histological features of placental malaria were scored and these results were correlated with malaria status and clinical outcomes.
Villous size correlated with vascularity (p <0.0001) but was inversely correlated with observed villi per unit area, (p = 0.0001). Significantly greater villous area and vascularity was observed in UK controls. Indices of histological malaria infection were significantly greater in active versus treated malaria cases. Active placental malaria cases showed significantly smaller villous area (p <0.0084), vascularity (p <0.0139) and perimeter (p <0.0006) than treated malaria cases or controls, but significantly more villi per unit area (p <0.0001). Villous size in treated malaria cases was significantly larger than active placental malaria cases (p <0.001) and similar to controls. There was a significant relationship between villous number and anaemia at the time of infection (p <0.0034), but not placental weight, birth weight or gestational age at delivery. No differences were found between histology or villous morphology comparing infections with P. falciparum or P. vivax.
These results imply that villous size, perimeter and vascularity are acutely decreased during active placental malaria, decreasing the surface area available for gas exchange per villus. However the increased number of villi per unit area offsets this change and persists after treatment. Histopathological and villous architectural changes may be reversed by early detection and appropriate anti-malarial treatment.
PMCID: PMC3900675  PMID: 24386908
Malaria; Placenta; Pregnancy; Pathophysiology; Morphometry; Image analysis; Villi
4.  Population genetic correlates of declining transmission in a human pathogen 
Molecular ecology  2012;22(2):273-285.
Pathogen control programs provide a valuable, but rarely exploited, opportunity to directly examine the relationship between population decline and population genetics. We investigated the impact of an ~12-fold decline in transmission on the population genetics of Plasmodium falciparum infections (n = 1731) sampled from four clinics on the Thai-Burma border over 10 years, and genotyped using 96 genome-wide SNPs. The most striking associated genetic change was a reduction in the frequency of infections containing multiple parasite genotypes from 63% in 2001 to 14% in 2010 (p = 3×10−15). Two measures of the clonal composition of populations (genotypic richness and the β-parameter of the Pareto distribution) declined over time as more people were infected by parasites with identical multilocus genotypes, consistent with increased selfing and a reduction in the rate at which multilocus genotypes are broken apart by recombination. We predicted that the reduction in transmission, multiple clone carriage, and outbreeding would be mirrored by an increased influence of genetic drift. However, geographical differentiation and expected heterozygosity remained stable across the sampling period. Furthermore, Ne estimates derived from allele frequencies fluctuation between years remained high (582 to ∞) and showed no downward trend. These results demonstrate how genetic data can compliment epidemiological assessments of infectious disease control programs. The temporal changes in a single declining population parallel those seen in comparisons of parasite genetics in regions of differing endemicity, strongly supporting the notion that reduced opportunity for outbreeding is the key driver of these patterns.
PMCID: PMC3537863  PMID: 23121253
5.  A three year descriptive study of early onset neonatal sepsis in a refugee population on the Thailand Myanmar border 
BMC Infectious Diseases  2013;13:601.
Each year an estimated four million neonates die, the majority in the first week of life. One of the major causes of death is sepsis. Proving the incidence and aetiology of neonatal sepsis is difficult, particularly in resource poor settings where the majority of the deaths occur.
We conducted a three year observational study of clinically diagnosed early onset (<7 days of age) neonatal sepsis (EONS) in infants born to mothers following antenatal care at the Shoklo Malaria Research Unit clinic in Maela camp for displaced persons on the Thailand-Myanmar border. Episodes of EONS were identified using a clinical case definition. Conventional and molecular microbiological techniques were employed in order to determine underlying aetiology.
From April 2009 until April 2012, 187 infants had clinical signs of EONS, giving an incidence rate of 44.8 per 1000 live births (95% CI 38.7-51.5). One blood culture was positive for Escherichia coli, E. coli was detected in the cerebrospinal fluid specimen in this infant, and in an additional two infants, by PCR. Therefore, the incidence of bacteriologically proven EONS was 0.7 per 1000 live births (95% CI 0.1 – 2.1). No infants enrolled in study died as a direct result of EONS.
A low incidence of bacteriologically proven EONS was seen in this study, despite a high incidence of clinically diagnosed EONS. The use of molecular diagnostics and nonspecific markers of infection need to be studied in resource poor settings to improve the diagnosis of EONS and rationalise antibiotic use.
PMCID: PMC3879187  PMID: 24359288
6.  Neonatal Intensive Care in a Karen Refugee Camp: A 4 Year Descriptive Study 
PLoS ONE  2013;8(8):e72721.
A third of all deaths in children aged <5 years occur in the neonatal period. Neonatal intensive care is often considered too complex and expensive to be implemented in resource poor settings. Consequently the reductions that have been made in infant mortality in the poorest countries have not been made in the neonatal period. This manuscript describes the activities surrounding the introduction of special care baby unit (SCBU) in a refugee setting and the resulting population impact.
A SCBU was developed in Maela refugee camp on the Thailand-Myanmar border. This unit comprised of a dedicated area, basic equipment, drugs and staff training. Training was built around neonatal guidelines, comprising six clinical steps: recognition, resuscitation, examination, supportive medical care, specialised medical care, and counselling of parents with sick newborns.
From January 2008 until December 2011, 952 infants were admitted to SCBU. The main admission diagnoses were early onset neonatal sepsis, jaundice and prematurity. Early prematurity (<34 weeks) carried the highest risk of mortality (OR 9.5, 95% CI 5.4–16.5, p<0.001). There was a significant decrease in mortality from 19.3% (2008) to 4.8% (2011) among the infants admitted for prematurity (p=0.03). The neonatal mortality in Maela camp as a whole declined by 51% from 21.8 to 10.7 deaths per 1000 live births over the corresponding period (p=0.04). Staff expressed more confidence in their ability to take care of neonates and there was a more positive attitude towards premature infants.
Neonatal mortality can be reduced in a resource poor setting by introduction of a simple low cost unit specialising in care of sick neonates and run by local health workers following adequate training. Training in recognition and provision of simple interventions at a high standard can increase staff confidence and reduce fatalistic attitudes towards premature neonates.
PMCID: PMC3749980  PMID: 23991145
7.  Microsatellite genotyping of Plasmodium vivax infections and their relapses in pregnant and non-pregnant patients on the Thai-Myanmar border 
Malaria Journal  2013;12:275.
Plasmodium vivax infections in pregnancy are associated with low birth weight and anaemia. This parasites species is also characterised by relapses, erythrocytic infections initiated by the activation of the dormant liver stages, the hypnozoites, to mature. Genotyping of P. vivax using microsatellite markers has opened the way to comparative investigations of parasite populations. The aim of the study was to assess whether there were any differences between the parasites found in pregnant and non-pregnant patients, and/or between the admission infections and recurrent episodes during follow-up.
Blood samples were collected from 18 pregnant and 18 non-pregnant patients, who had at least two recurrent episodes during follow-up, that were recruited in two previous trials on the efficacy of chloroquine treatment of P. vivax infections on the Thai-Myanmar border. DNA was purified and the P. vivax populations genotyped with respect to eight polymorphic microsatellite markers. Analyses of the genetic diversity, multiplicity of infection (MOI), and a comparison of the genotypes in the samples from each patient were conducted.
The P. vivax parasites present in the samples exhibited high genetic diversity (6 to 15 distinct allelic variants found for the 8 loci). Similar expected heterozygosity (He) values were obtained for isolates from pregnant (0.837) and non-pregnant patients (0.852). There were modest differences between the MOI values calculated for both admission and recurrence samples from the pregnant patients (2.00 and 2.05, respectively) and the equivalent samples from the non-pregnant patients (1.67 and 1.64, respectively). Furthermore, the mean number of distinct alleles enumerated in the admission samples from the pregnant (6.88) and non-pregnant (7.63) patients were significantly lower than that found in the corresponding recurrent episodes samples (9.25 and 9.63, respectively).
The P. vivax populations circulating in inhabitants along the Thai-Myanmar border, an area of low malaria transmission, displayed high genetic diversity. A subtle increase in the multiplicity of P. vivax infections in pregnant patients suggests a higher susceptibility to infection. The higher allelic diversity in the relapse as compared to the admission samples in both patient groups is consistent with the hypothesis that a febrile episode promotes the activation of hypnozoites.
PMCID: PMC3750759  PMID: 23915022
Genetic diversity; Malaria; Plasmodium vivax; Pregnancy; Relapse
8.  Changes in the body weight of term infants, born in the tropics, during the first seven days of life 
BMC Pediatrics  2013;13:93.
Identifying unwell neonates, particularly in the first week of life, is often subjective. If normal values are known, calculating the weight lost or gained from birth weight can be a useful adjunct in the evaluation of the health of a neonate.
Serial body weights of well, term, breast fed infants who were attending for routine follow up, were recorded at the Shoklo Malaria Research Unit clinic in Maela Camp for displaced persons on the Thailand Myanmar border. Newborn examination was routine. Weight loss, expressed as percent weight lost from birth weight, and weight gain, expressed as a velocity (g/kg/day), was calculated for the first seven days of life. The results from normal birth weight infants, low birth weight infants (<2.5 kg) and small for gestational age infants (SGA) were examined.
In the first week of life there were no significant differences in weight gained or lost across the three study groups. The maximum weight lost was 4.4% (95% CI 4.1 – 4.6%), which occurred on day three. Weight gain ranged from 13 g/kg/day [95% CI 10 – 16] on day four to 18 g/kg/day [95% CI 15 – 20] on days six and seven.
Use of these normal values for weight gain and loss, allows infants falling outside of the expected range (95% CI) to be easily identified and subsequently highlighted as needing further medical review.
PMCID: PMC3686593  PMID: 23768173
Neonate; Weight loss; Weight gain; Weight velocity
9.  Genetic Evaluation of the Performance of Malaria Parasite Clearance Rate Metrics 
The Journal of Infectious Diseases  2013;208(2):346-350.
Accurate measurement of malaria parasite clearance rates (CRs) following artemisinin (ART) treatment is critical for resistance surveillance and research, and various CR metrics are currently used. We measured 13 CR metrics in 1472 ART-treated hyperparasitemia infections for which 6-hour parasite counts and parasite genotypes (93 single nucleotide polymorphisms [SNPs]) were available. We used heritability to evaluate the performance of each metric. Heritability ranged from 0.06 ± 0.06 (SD) for 50% parasite clearance times to 0.67 ± 0.04 (SD) for clearance half-lives estimated from 6-hour parasite counts. These results identify the measures that should be avoided and show that reliable clearance measures can be obtained with abbreviated monitoring protocols.
PMCID: PMC3685230  PMID: 23592863
heritability; clearance rate; half-life; artemisinin; Plasmodium falciparum; single nucleotide polymorphism
10.  Malaria in the Post-Partum Period; a Prospective Cohort Study 
PLoS ONE  2013;8(3):e57890.
Several studies have shown a prolonged or increased susceptibility to malaria in the post-partum period. A matched cohort study was conducted to evaluate prospectively the susceptibility to malaria of post-partum women in an area where P.falciparum and P.vivax are prevalent.
In an area of low seasonal malaria transmission on the Thai-Myanmar border pregnant women attending antenatal clinics were matched to a non-pregnant, non-post-partum control and followed up prospectively until 12 weeks after delivery.
Post-partum women (n = 744) experienced significantly less P.falciparum episodes than controls (hazard ratio (HR) 0.39 (95%CI 0.21–0.72) p = 0.003) but significantly more P.vivax (HR 1.34 (1.05–1.72) p = 0.018). The reduced risk of falciparum malaria was accounted for by reduced exposure, whereas a history of P.vivax infection during pregnancy was a strong risk factor for P.vivax in post-partum women (HR 13.98 (9.13–21.41), p<0.001). After controlling for effect modification by history of P.vivax, post-partum women were not more susceptible to P.vivax than controls (HR: 0.33 (0.21–0.51), p<0.001). Genotyping of pre-and post-partum infections (n⊕ = ⊕10) showed that each post-partum P.falciparum was a newly acquired infection.
In this area of low seasonal malaria transmission post-partum women were less likely to develop falciparum malaria but more likely to develop vivax malaria than controls. This was explained by reduced risk of exposure and increased risk of relapse, respectively. There was no evidence for altered susceptibility to malaria in the post-partum period. The treatment of vivax malaria during and immediately after pregnancy needs to be improved.
PMCID: PMC3596341  PMID: 23516418
11.  Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai–Myanmar Border, 1999–2011: An Observational Study 
PLoS Medicine  2013;10(3):e1001398.
Francois Nosten and colleagues evaluate malaria prevalence and incidence in the mobile population on the Myanmar side of the border with Thailand between 1999 and 2011, and also assess resistance to artemisinin.
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.
Methods and Findings
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
Editors' Summary
According to latest figures, the World Health Organization estimates that there are over 200 million cases of malaria each year, with over three-quarters of a million deaths. Several Plasmodium parasites cause malaria (the most serious being Plasmodium falciparum) and are transmitted to people through the bites of infected night-flying mosquitoes. Malaria transmission can be prevented by using insecticides to control the mosquitoes and by sleeping under insecticide-treated bed nets. However, in Southeast Asia the effectiveness of these measures is limited. Treating infected people with antimalarial drugs, particularly with artemisinin-based combination treatments (ACTs), is a key strategy in reducing the deaths and disability caused by malaria. However, progress is now threatened by the emergence in Southeast Asia of P. falciparum isolates that are resistant to artesunate (a common component of ACT). This development is concerning, as resistance to the artemisinin family of drugs, of which artesunate is a member, could trigger a resurgence in malaria in many parts of the world and compromise the progress made in the treatment of severe malaria.
Why Was This Study Done?
P. falciparum resistance to artemisinin has been confirmed in the area around the border between Thailand and Myanmar. Malaria control in this border area is particularly challenging, as there is a reservoir of malaria in Myanmar (where the disease burden is higher than in Thailand), frequent population movement, and differences in adequate control measures on the two sides of the border. In this study the authors evaluated malaria prevalence and incidence in the mobile population on the Myanmar side of the border between 1 October 1999 and 30 September 2011 to assess whether increasing access to early diagnosis and treatment with ACT was associated with a decline in the malaria burden.
What Did the Researchers Do and Find?
The Shoklo Malaria Research Unit (SMRU) has been working on the Thai–Myanmar border for 25 years providing early diagnosis and treatment of malaria and has extended its services from two to 11 health care facilities (health posts) on the Myanmar side of the border over the past few years. In order to evaluate any changes in the malaria burden since the expansion of services, the researchers recorded the number of consultations in all SMRU clinics and health posts with confirmed malaria diagnosis and tracked changes in the prevalence of malaria in the population on the Myanmar side of the border (via cross-sectional surveys in villages). The researchers also assessed the incidence of malaria in a cohort of pregnant women living on both sides of the border and monitored antimalarial drug efficacy over this time period.
The researchers found that although the mobile population on the Thai side of the border remained constant, the population in villages covered by the clinics and health posts in the border area increased four-fold. Over the time period, the researchers found that the number of confirmed malaria cases (P. falciparum) increased initially, rising from just over 5,000 in 2000 to a peak of 13,764 in 2006, and then declined to just over 3,500 in 2011. A striking finding was the predominance of infections in young adult males (50,316/90,321; 55.7%). Encouragingly, the percentage of consultations due to malaria in children under five years fell from 78% to 7%, and the incidence of malaria declined from 1.1 to 0.1 episodes per pregnant woman-year. In addition, the proportion of patients admitted to hospital with severe disease was stable, and the number of deaths from malaria remained extremely low, with an overall case fatality rate of 0.05%. The researchers also found that the ratio of P. falciparum to P. vivax infections declined from 1.4 to 0.7, and the prevalence of P. falciparum decreased from 24.3% to 3.4%. However, worryingly, in the small number of patients undertaking drug efficacy tests, the drug efficacy of artesunate declined steadily, with the proportion of patients still infected with malaria at day 3 of treatment increasing from 0% in 2000 to 28% in 2011.
What Do These Findings Mean?
These findings indicate that despite the emergence of resistance to artesunate in P. falciparum, and the decline in the efficacy of ACT, the strategy of early diagnosis and treatment with ACTs has been associated with a reduction in malaria in the population living on the Thai–Myanmar border. Furthermore, these findings suggest that an aggressive strategy based on early detection and treatment of cases, combined with vector control and information, could be the way forward to eliminate malaria. Although there were only a small number of patients involved in drug efficacy tests in 2011, this study shows that alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.
Additional Information
Please access these websites via the online version of this summary at
More information about the Shoklo Malaria Research Unit is available
The World Health Organization website has more information about antimalarial drug efficacy and drug resistance
The Bill & Melinda Gates Foundation website tells the malaria resistance story
PMCID: PMC3589269  PMID: 23472056
12.  Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects 
To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.
In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg−1) on the first day and oral ARS (4 mg kg−1) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg−1 day−1) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).
I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml−1 h)/(mg kg−1)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).
This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.
PMCID: PMC3370352  PMID: 21950338
artesunate; dihyroartemisinin; malaria; pharmacokinetics; post partum; pregnancy
14.  Performance of a Histidine-Rich Protein 2 Rapid Diagnostic Test, Paracheck Pf®, for Detection of Malaria Infections in Ugandan Pregnant Women 
Improved laboratory diagnosis is critical to reduce the burden of malaria in pregnancy. Peripheral blood smears appear less sensitive than Plasmodium falciparum histidine-rich protein 2–based rapid diagnostic tests (RDTs) for placental malaria infections in studies conducted at delivery. In this study, 81 women in Uganda in the second or third trimester of pregnancy were followed-up until delivery. At each visit, peripheral blood was tested by blood smear, RDT, and nested species-specific polymerase chain reaction (PCR). Sensitivity and specificity of the tests was calculated with PCR, which detected 22 infections of P. falciparum, as the gold standard. The sensitivity and specificity of blood smears were 36.4% (95% confidence interval [CI] = 18.0–59.2%) and 99.6% (95% CI = 97.7–100%), respectively. The corresponding values for RDT were 31.8% (95% CI = 14.7–54.9%) and 100% (95% CI = 98.3–100%). The RDTs could replace blood smears for diagnosis of malaria in pregnancy by virtue of their relative ease of use. Field-based sensitive tests for malaria in pregnancy are urgently needed.
PMCID: PMC3247114  PMID: 22232456
15.  High initiation and long duration of breastfeeding despite absence of early skin-to-skin contact in Karen refugees on the Thai-Myanmar border: a mixed methods study 
Early skin-to-skin contact (SSC) after birth is recommended as part of the United Nations Children’s Fund (UNICEF) baby friendly health initiative to promote optimum breastfeeding. This paper reports rates of breastfeeding initiation and duration in a low resource environment, where early SSC is not practised, and explores views of pregnant women and midwives surrounding breastfeeding and swaddling.
Data from records from a single hospital on the Thai-Myanmar border where refugee women gave birth during a one-year period (2010) were used to determine breastfeeding initiation rates and the time of the first breastfeed, and duration of breastfeeding of the previous alive child in multigravidae. Focus group discussions (FGD) were conducted to obtain information from pregnant women attending antenatal care about their intended or previous duration of breastfeeding and views on breastfeeding. Interviews with local midwives explored reasons for high rates of breastfeeding in this setting and the practice of newborn swaddling.
Of 1404 live births in 2010 in Maela refugee camp there were 982 evaluable mother-newborn pairs, including 80 infants born before 37 weeks gestation. Initiation of breastfeeding within the first hour after birth and exclusive breastfeeding at discharge in term mother-newborn pairs was 91.2% (823/902) and 99.3% (896/902); and before 37 weeks gestation, 48.8% (39/80) and 98.8% (79/80). Reported duration of previous breastfeeding was 19 (range 2 to 72) months.
During FGD all primigravidae (n = 17) intended to breastfeed and all multigravidae (n = 33) had previously breastfed; expected or previous duration of feeding was for more than one year or longer. The major theme identified during FGD was breastfeeding is “good”. Women stated their intention to breastfeed with certainty. This certainty was echoed during the interviews with midwifery staff. SSC requires a delay in early swaddling that in Karen people, with animistic beliefs, could risk loss of the spirit of the newborn or attract malevolent spirits.
In a population with a strong culture of breastfeeding and robust breastfeeding practices, high rates of initiation and duration of breastfeeding were found despite a lack of early skin-to-skin contact. Local preferences, traditions and practices that protect, support and maintain high rates of breastfeeding should be promoted.
PMCID: PMC3547777  PMID: 23241099
Breastfeeding initiation; Breastfeeding duration; Early skin-to-skin care; Midwifery; Refugee; Resource-poor; Swaddling
17.  Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy 
Antimicrobial Agents and Chemotherapy  2012;56(11):5764-5773.
Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.
PMCID: PMC3486620  PMID: 22926572
18.  Long-term storage limits PCR-based analyses of malaria parasites in archival dried blood spots 
Malaria Journal  2012;11:339.
Blood samples collected in epidemiological and clinical investigations and then stored, often at room temperature, as blood spots dried on a filter paper have become one of the most popular source of material for further molecular analyses of malaria parasites. The dried blood spots are often archived so that they can be used for further retrospective investigations of parasite prevalence, or as new genetic markers come to the fore. However, the suitability of the template obtained from dried blood spots that have been stored for long periods for DNA amplification is not known.
DNA from 267 archived blood spots collected over a period of 12 years from persons with microscopically confirmed Plasmodium falciparum infection was purified by one of two methods, Chelex and Qiagen columns. These templates were subjected to highly sensitive nested PCR amplification targeting three parasite loci that differ in length and/or copy number.
When a 1.6 kb fragment of the parasites’ small subunit ribosomal RNA was targeted (primary amplification), the efficiency of P. falciparum detection decreased in samples archived for more than six years, reaching very low levels for those stored for more than 10 years. Positive amplification was generally obtained more often with Qiagen-extracted templates. P. falciparum could be detected in 32 of the 40 negative Qiagen-extracted templates when a microsatellite of about 180 bp was targeted. The remaining eight samples gave a positive amplification when a small region of 238 bp of the higher copy number (20 to 200) mitochondrial genome was targeted.
The average length of DNA fragments that can be recovered from dried blood spots decreases with storage time. Recovery of the DNA is somewhat improved, especially in older samples, by the use of a commercial DNA purification column, but targets larger than 1.5 kb are unlikely to be present 10 years after the initial blood collection, when the average length of the DNA fragments present is likely to be around a few hundred bp. In conclusion, the utility of archived dried blood spots for molecular analyses decreases with storage time.
PMCID: PMC3507721  PMID: 23043522
Archival blood spots; Plasmodium falciparum; Polymerase chain reaction
19.  A major genome region underlying artemisinin resistance in malaria 
Science (New York, N.y.)  2012;336(6077):79-82.
Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) following treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from Cambodia, Thailand and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chr 13 that shows strong association (P=10-6-10-12) with slow CR, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.
PMCID: PMC3355473  PMID: 22491853
20.  Risky alcohol use among reproductive-age men, not women, in Mae La refugee camp, Thailand, 2009 
Globally, alcohol use contributes to close to 4% of all deaths and is a leading cause of ill health and premature death among men of reproductive age. Problem alcohol use is an unaddressed public health issue among populations displaced by conflict. Assessing the magnitude of the problem and identifying affected groups and risk behaviours is difficult in mobile and unstable populations.
From 15–28 December 2009 we conducted a simple rapid screening test of risky alcohol use using the single item modified Short Assessment Screening Questionnaire (mSASQ) by all women currently enrolled in the antenatal care clinic in Mae La refugee camp, a long standing displaced setting on the Thai Burma border. Women self- reported and gave a secondary report of their male partners. Gender differences in alcohol use were further explored in semi-structured interviews with camp residents on attitudes, behaviours, and beliefs regarding alcohol and analysed thematically.
Of 636 women screened in the antenatal clinic, almost none (0.2%, 95CI 0.0-0.9%) reported risky alcohol use prior to pregnancy, whereas around a quarter (24.4%, 95CI 21.2-27.9%) reported risky alcohol use by their male partners. Interviews with 97 camp residents described strong social controls against women’s alcohol use and men’s drinking to intoxication, despite a dominant perception that the social context of life in displacement promoted alcohol use and that controls are loosening.
As a stigmatised behaviour, alcohol use is difficult to assess, particularly in the context of highly mobile adult male populations: the simple assessment methods here show that it is feasible to obtain adequate data for the purposes of intervention design. The data suggest that risky drinking is common and normalised among men, but that the population may have been partially protected from rapid rises in problem alcohol use observed in nation-wide data from Thailand. The changing social context contains vulnerabilities that might promote problem alcohol use: further investigation, ongoing monitoring, and development of targeted interventions are warranted.
PMCID: PMC3493317  PMID: 22963719
Alcohol; Substance abuse; Refugees; Assessment; Displaced population; Conflict; mSASQ
21.  New Insights into Acquisition, Boosting, and Longevity of Immunity to Malaria in Pregnant Women 
The Journal of Infectious Diseases  2012;206(10):1612-1621.
Background. How antimalarial antibodies are acquired and maintained during pregnancy and boosted after reinfection with Plasmodium falciparum and Plasmodium vivax is unknown.
Methods. A nested case-control study of 467 pregnant women (136 Plasmodium-infected cases and 331 uninfected control subjects) in northwestern Thailand was conducted. Antibody levels to P. falciparum and P. vivax merozoite antigens and the pregnancy-specific PfVAR2CSA antigen were determined at enrollment (median 10 weeks gestation) and throughout pregnancy until delivery.
Results. Antibodies to P. falciparum and P. vivax were highly variable over time, and maintenance of high levels of antimalarial antibodies involved highly dynamic responses resulting from intermittent exposure to infection. There was evidence of boosting with each successive infection for P. falciparum responses, suggesting the presence of immunological memory. However, the half-lives of Plasmodium antibody responses were relatively short, compared with measles (457 years), and much shorter for merozoite responses (0.8–7.6 years), compared with PfVAR2CSA responses (36–157 years). The longer half-life of antibodies to PfVAR2CSA suggests that antibodies acquired in one pregnancy may be maintained to protect subsequent pregnancies.
Conclusions. These findings may have important practical implications for predicting the duration of vaccine-induced responses by candidate antigens and supports the development of malaria vaccines to protect pregnant women.
PMCID: PMC3475637  PMID: 22966126
22.  No Association of Phenotypic ABO Blood Group and Malaria during Pregnancy 
In a few small studies an association between blood group O and placental malaria has been described. The relationship between blood group and malaria in pregnancy (Plasmodium vivax and Plasmodium falciparum) was analyzed in 1,468 women from three longitudinal cohort studies in which weekly malaria screening was done systematically during pregnancy. One-third of women (447 of 1,468) had at least one malaria infection in pregnancy. The ABO blood group phenotype was not associated with the species of infection, frequency of malaria attacks, symptoms of malaria, hematocrit, or parasitemia during pregnancy.
PMCID: PMC3435346  PMID: 22826494
23.  Aeromonas spp. Bacteremia in Pregnant Women, Thailand–Myanmar Border, 2011 
Emerging Infectious Diseases  2012;18(9):1522-1523.
PMCID: PMC3437721  PMID: 22932726
pregnant; miscarriage; bacteremia; Aeromonas; bacteria; Thailand; Myanmar
24.  Is areca innocent? The effect of areca (betel) nut chewing in a population of pregnant women on the Thai–Myanmar border 
International Health  2012;4-172(3):204-209.
Eight manuscripts have specifically examined the effects of areca (betel) nut use in pregnant women, seven of which have documented adverse effects on birth weight, newborn neurological status, gender ratio and pregnancy outcomes such as anaemia and miscarriage following areca nut use during pregnancy. A retrospective cohort analysis of migrant and refugee pregnant women attending antenatal clinics along the Thai–Myanmar border (July 1997 to November 2006) was conducted to examine the adverse effects of areca nut use routinely recorded on enrolment. Of 7685 women, 2284 (29.7%) never used areca or smoked (cheroots), 2484 (32.3%) only used areca, 438 (5.7%) only smoked cheroots and 2479 (32.3%) used both areca and cheroots. Pieces of ripe areca nut in a leaf with lime, without tobacco, were used particularly among older multigravid women. Adverse pregnancy effects were not observed in areca nut users compared with non-users. Smoking, but not areca nut use, had a dose-related effect on miscarriage. Areca nut use in conjunction with smoking reduced the adverse effects of smoking on birth weight, further supporting a lack of effect of areca nut. Areca (betel) nut-related adverse pregnancy outcomes were not observed in this population, whereas smoking was clearly harmful. Differences from previous reports may result from the amount or types of areca nut, or quid content, consumed between countries. Smoking, but not areca nut, reduction is likely to improve pregnancy outcomes on the Thai–Myanmar border.
PMCID: PMC3442179  PMID: 24029401
Areca nut; Smoking; Pregnancy; Maternal outcome; Neonatal outcome
25.  Evaluation of a surgical service in the chronic phase of a refugee camp: an example from the Thai-Myanmar border 
Published literature on surgical care in refugees tends to focus on the acute (‘emergent’) phase of crisis situations. Here we posit that there is a substantial burden of non-acute morbidity amenable to surgical intervention among refugees in the ‘chronic’ phase of crisis situations. We describe surgery for non-acute conditions undertaken at Mae La Refugee Camp, Thailand over a two year period.
Surgery was performed by a general surgeon in a dedicated room of Mae La Refugee Camp over May 2005 to April 2007 with minimal instruments and staff. We obtained the equivalent costs for these procedures if they were done at the local Thai District General Hospital. We also acquired the list (and costs) of acute surgical referrals to the District General Hospital over September 2006 to December 2007.
855 operations were performed on 847 patients in Mae La Refugee Camp (60.1% sterilizations, 13.3% ‘general surgery’, 5.6% ‘gynaecological surgery’, 17.4% ‘mass excisions’, 3.5% ‘other’). These procedures were worth 2,207,500 THB (75,683.33 USD) at costs quoted by the District General Hospital. Total cost encountered for these operations (including staff costs, consumables, anaesthesia and capital costs such as construction) equaled 1,280,000 THB (42,666 USD). Pertaining to acute surgical referrals to District General hospital: we estimate that 356,411.96 THB (11,880.40 USD) worth of operations over 14 months were potentially preventable if these cases had been operated at an earlier, non-acute state in Mae La Refugee Camp.
A considerable burden of non-acute surgical morbidity exists in ‘chronic’ refugee situations. An in-house general surgical service is found to be cost-effective in relieving some of this burden and should be considered by policy makers as a viable intervention.
PMCID: PMC3493322  PMID: 22866971
Basic needs; Protracted; Chronic; Refugee; Surgery; Thai-Myanmar border

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