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Background Artemisinin and artemisinin-based combination therapy (ACT) partner drug resistance in Plasmodium falciparum have spread across the Greater Mekong Subregion compromising antimalarial treatment. The current 3-day artemether-lumefantrine regimen has been associated with high treatment failure rates in pregnant women. Although ACTs are recommended for treating Plasmodium vivax malaria, no clinical trials in pregnancy have been reported. Methods Pregnant women with uncomplicated malaria on the Thailand-Myanmar border participated in an open-label randomized controlled trial comparing dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ) and a 4-day artemether-lumefantrine regimen (AL+). The primary endpoint for P. falciparum infections was the PCR-corrected cure rate and for P. vivax infections was recurrent parasitaemia, before delivery or day 63, whichever was longer, assessed by Kaplan-Meier estimate. Results Between February 2010 and August 2016, 511 pregnant women with malaria (353 P. vivax, 142 P. falciparum, 15 co-infections, 1 Plasmodium malariae) were randomized to either DP (n=170), ASMQ (n=169) or AL+ (n=172) treatments. Successful malaria elimination efforts in the region resulted in premature termination of the trial. The majority of women had recurrent malaria (mainly P. vivax relapses, which are not prevented by these treatments). Recurrence-free proportions (95% confidence interval [95% CI]) for vivax malaria were 20.6% (5.1–43.4) for DP (n=125), 46.0% (30.9–60.0) for ASMQ (n=117) and 28.7% (10.0–50.8) for AL+ (n=126). DP and ASMQ provided longer recurrence-free intervals. PCR-corrected cure rates (95% CI) for falciparum malaria were 93.7% (81.6–97.9) for DP (n=49), 79.6% (66.1–88.1) for AMSQ (n=55) and 87.5% (74.3–94.2) for AL+ (n=50). Overall 65% (85/130) of P. falciparum infections had Pfkelch13 propeller mutations which increased over time and recrudescence occurred almost exclusively in them; risk ratio 9.42 (95% CI 1.30–68.29). Among the women with falciparum malaria, 24.0% (95% CI 16.8–33.6) had P. vivax parasitaemia within 4 months. Nausea, vomiting, dizziness and sleep disturbance were more frequent with ASMQ. Miscarriage, small-for-gestational-age and preterm birth did not differ significantly among the treatment groups, including first trimester exposures (n=46). Conclusions DP was well tolerated and safe, and was the only drug providing satisfactory efficacy for P. falciparum-infected pregnant woman in this area of widespread artemisinin resistance. Vivax malaria recurrences are very common and warrant chloroquine prophylaxis after antimalarial treatment in this area. Trial registration ClinicalTrials.gov identifier NCT01054248, registered on 22 January 2010.

Background: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. Methods: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. Findings: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57–14·54, p Interpretation: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.

Migrant and refugee women are at risk of perinatal depression due to stressors experienced before, during and after migration. This study assesses the associations between social support and perinatal depression among migrant and refugee women on the Thai–Myanmar border. We conducted a cohort study of pregnant and post-partum women. Depression status was assessed using a structured clinical interview. Received support, perceived support and partner support were measured in the third trimester. Logistic regression was used to calculate associations between social support measures and perinatal depression controlling for demographic, socio-economic, migration, obstetric and psychosocial factors. Four hundred and fifty-one women (233 migrants; 218 refugees) were included. The prevalence of perinatal depression was 38.6% in migrants and 47.3% in refugees. Migrants had higher levels of received, perceived and partner support than refugees. After controlling for all other variables, higher levels of received support remained significantly associated with a lower likelihood of perinatal depression in migrants (adjusted odds ratio 0.82; 95% CI 0.68–0.99). In both groups, depression history and trauma were strongly associated with perinatal depression. Our study highlights the importance of received social support to perinatal depression in migrant women on the Thailand–Myanmar border. The perinatal period offers a valuable opportunity to ask women about their support and offer community-level or public policy interventions to nurture support networks in current locations and resettlement destinations.This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.

Background: Hepatitis B is highly endemic in south-east Asia with the most common route of transmission being from mother to child. In rural settings, current preventive strategies with hepatitis B immunoglobulins and vaccinations fail due to costs, need for cold chain, homebirths, and transportation difficulties. A new strategy for prevention of mother to child transmission (PMTCT) could be early ( Methods & Materials: Narrative and visual review of start-up challenges encountered during implementation of a study of TDF for PMTCT before 20 weeks gestation in rural areas on the Thailand-Myanmar border. ClinicalTrials.gov Identifier: NCT02995005. Results: Major challenges of implementation from June 2018 to September 2019 included: gestation of pregnancy at presentation, point-of-care (POC)-testing reliability, tablet storage and handling. Overall, 156 women tested positive for HBsAg by Rapid Diagnostic Test (RDT) POC-testing but late presentation (≥20 weeks) was common: 53% (83/156). In women Conclusion: Improved public awareness of the benefits or early antenatal care, better RDT-tests, and confirmation of TDF bioavailability at higher ambient temperatures, are important in the rural tropics for prevention of mother to child transmission for hepatitis B programs.

I.BackgroundAntenatal care and delivery with skilled attendants substantially improve maternal health outcomes across the pregnancy spectrum, from conception to delivery. The Sustainable Development Goals recognize the need to expand these services to all pregnant women but there is limited data on access for migrants and in post-conflict regions.II.MethodsUsing geographic information systems established for malaria elimination efforts in Kayin state, Myanmar and Tak Province, Thailand, retrospective estimates of travel distances from home villages to maternal health facilities between 2007-2015 were made. Multivariable regressions were used to assess the relationships between distance to healthcare and 1) presentation for early pregnancy care, 2) complications during pregnancy like malaria infections, and 3) eventual outcome of the pregnancy.III.FindingsWomen who delayed antenatal care until the third trimester travelled 46% farther (DR: 1.46; CI: 1.39 – 1.53) compared to women who attended in the first trimester, and those with pregnancies complicated by Plasmodium falciparum malaria travelled 62% farther (DR: 1.62; CI: 1.44 – 1.82) than those without P. falciparum. Women did not deliver with skilled birth services and were lost to follow-up travelled 45% farther (distance ratio (DR): 1.45; CI: 1.40 – 1.51) than those who followed-up to deliver with skilled birth services.IV.InterpretationThis analysis supports substantial global evidence that travel distance disrupts access to care in limited resource regions. This is the first demonstration of empirical distance impacting maternal healthcare from early pregnancy to delivery of migrants living in post-conflict Thailand-Myanmar border regions, and future interventions should provide decentralized maternal healthcare to address these barriers.V.FundingThe Bill & Melinda Gates Foundation and the Wellcome Trust

Background The aim of this manuscript is to highlight challenges in the implementation of maternal tenofovir disoproxil fumarate (tenofovir) for prevention of mother to child transmission (PMTCT) of hepatitis B virus (HBV) in resource limited setting. Current preventive strategies in resource-limited settings fail mainly due to prohibitive costs of hepatitis B immunoglobulin (HBIG) and a high proportion of homebirths, meaning both HBIG and hepatitis B birth dose vaccine are not given. A new strategy for PMTCT without the necessity of HBIG, could be daily tenofovir commenced early in gestation. Implementation challenges to early tenofovir for PMTCT can provide insight to elimination strategies of HBV as the burden of disease is high in resource-limited settings. Methods Challenges encountered during implementation of a study of tenofovir for PMTCT before 20 weeks gestation in rural and resource-limited areas on the Thailand-Myanmar border were identified informally from trial study logbooks and formally from comments from patients and staff at monthly visits. ClinicalTrials.gov Identifier: NCT02995005. Main body During implementation 171 pregnant women were hepatitis B surface antigen (HBsAg) positive by point of-care test over 19 months (May-2018 until Dec-2019). In this resource-limited setting where historically no clinic has provided tenofovir for PMTCT of HBV, information provided by staff resulted in a high uptake of study screening (95.5% (84/88) when offered to pregnant women. False positive point-of-care rapid tests hinder a test and treat policy for HBV and development of improved rapid tests that include HBeAg and/or HBV DNA would increase efficiency. Integrated care of HBV to antenatal care, transport assistance and local agreements to facilitate access, could increase healthcare at this critical stage of the life course. As safe storage of medication in households in resource-limited setting may not be ideal, interactive counseling about this must be a routine part of care. Conclusion Despite challenges, results from the study to date suggest tenofovir can be offered to HBV-infected women in resource-limited settings before 20 weeks gestation with a high uptake of screening, high drug accountability and follow-up, with provision of transportation support. This commentary has highlighted practical implementation issues with suggestions for strategies that support the objective of PMTCT and the World Health Organization goal of HBV elimination by 2030.

Background Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. Methods A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and Results Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p Conclusions The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.

Background Perinatal depression is a significant contributor to maternal morbidity and mortality globally. Migrant women, particularly those living in low- and middle-income settings, represent a particularly vulnerable group due to stressors experienced before, during and after migration. The vast majority of global migration flows occurring within and between low- and middle-income regions, yet existing evidence focuses predominantly on migrants in high-income destinations. This study aimed to redress this significant gap in the evidence by determining the prevalence and determinants of perinatal depression among migrant women on the Thai-Myanmar border. Methods A cohort of labour migrant and refugee women was followed-up from the first trimester of pregnancy to one month post-partum. Depression status was assessed in the first, second and third trimesters of pregnancy and at one month post-partum using the Structured Clinical Interview for the Diagnosis of DSM-IV Disorders. Women diagnosed with depression had immediate access to care. Data on potential demographic, social and clinical associated factors was collected using a questionnaire. Prevalence and incidence of any depressive disorder and moderate-severe depressive disorder was calculated. Univariable and multivariable logistic regression using complete case analysis was used to estimate odds ratios (OR) of association between exposure variables and depression status. Results Five hundred sixty-eight women participated. Period prevalence (from first trimester of pregnancy to one month post-partum) of moderate-severe perinatal depression was 18.5% (95% CI 15.4–21.9%). Overall, 15.4% (95% CI 11.8–19.6%) of women developed new-onset moderate-severe depression during the study period. Forty-two participants received treatment for depression. Risk factors were interpersonal violence (OR 4.5; 95% CI 1.9–11.1); history of trauma (OR 2.4; 95% CI 1.4–4.3); self-reported history of depression (OR 2.3; 95% CI 1.2–4.2); labour migrant status (OR 2.1; 95% CI 1.1–4.0); low social support (OR 2.1; 95% CI 1.1–3.7); and maternal age (OR 1.1 per year; 95% CI 1.0–1.1). Limitations of the study include that culturally specific manifestations of depression may have been missed. Conclusions Perinatal depression represents a significant burden among migrant women on the Thai-Myanmar border. Programmes to address the determinants along with early case identification and effective treatment and referral systems are key to addressing perinatal depression in this low-resource setting.

Background The Sustainable Development Goals (SDG) call for increased gender equity and reduction in malaria-related mortality and morbidity. Plasmodium vivax infections in pregnancy are associated with maternal anaemia and increased adverse perinatal outcomes. Providing radical cure for women with 8-aminoquinolines (e.g., primaquine) is hindered by gender-specific complexities. Case presentation A symptomatic episode of vivax malaria at 18 weeks of gestation in a primigravid woman was associated with maternal anaemia, a recurrent asymptomatic P. vivax episode, severe intra-uterine growth restriction with no other identifiable cause and induction to reduce the risk of stillbirth. At 5 months postpartum a qualitative glucose-6-phosphate dehydrogenase (G6PD) point-of-care test was normal and radical cure with primaquine was prescribed to the mother. A 33% fractional decrease in haematocrit on day 7 of primaquine led to further testing which showed intermediate phenotypic G6PD activity; the G6PD genotype could not be identified. Her infant daughter was well throughout maternal treatment and found to be heterozygous for Mahidol variant. Conclusion Adverse effects of vivax malaria in pregnancy, ineligibility of radical cure for pregnant and postpartum women, and difficulties in diagnosing intermediate levels of G6PD activity multiplied morbidity in this woman. Steps towards meeting the SDG include prevention of malaria in pregnancy, reducing unnecessary exclusion of women from radical cure, and accessible quantitative G6PD screening in P. vivax-endemic settings.

PurposeA successful pregnancy relies on the interplay of various biological systems. Deviations from the norm within a system or intersystemic interactions may result in pregnancy-associated complications and adverse pregnancy outcomes. Systems biology approaches provide an avenue of unbiased, in-depth phenotyping in health and disease. The molecular signature in pregnancy (MSP) cohort was established to characterise longitudinal, cross-omic trajectories in pregnant women from a resource constrained setting. Downstream analysis will focus on characterising physiological perturbations in uneventful pregnancies, pregnancy-associated complications and adverse outcomes.ParticipantsFirst trimester pregnant women of Karen or Burman ethnicity were followed prospectively throughout pregnancy, at delivery and until 3 months post partum. Serial high-frequency sampling to assess whole blood transcriptomics and microbiome composition of the gut, vagina and oral cavity, in conjunction with assessment of gene expression and microbial colonisation of gestational tissue, was done for all cohort participants.Findings to date381 women with live born singletons averaged 16 (IQR 15–18) antenatal visits (13 094 biological samples were collected). At 5% (19/381) the preterm birth rate was low. Other adverse events such as maternal febrile illness 7.1% (27/381), gestational diabetes 13.1% (50/381), maternal anaemia 16.3% (62/381), maternal underweight 19.2% (73/381) and a neonate born small for gestational age 20.2% (77/381) were more often observed than preterm birth.Future plansResults from the MSP cohort will enable in-depth characterisation of cross-omic molecular trajectories in pregnancies from a population in a resource-constrained setting. Moreover, pregnancy-associated complications and unfavourable pregnancy outcomes will be investigated at the same granular level, with a particular focus on population relevant needs such as effect of tropical infections on pregnancy. More detailed knowledge on multiomic perturbations will ideally result in the development of diagnostic tools and ultimately lead to targeted interventions that may disproportionally benefit pregnant women from this resource-limited population.Trial registration numberNCT02797327.

Background Most evidence on the association between malaria in pregnancy and adverse pregnancy outcomes focuses on falciparum malaria detected at birth. We assessed the association between the number and timing of falciparum and vivax malaria episodes during pregnancy on small-for-gestational-age (SGA) and preterm birth. Methods We analysed observational data collected from antenatal clinics on the Thailand-Myanmar border (1986–2015). We assessed the effects of the total number of malaria episodes in pregnancy on SGA and the effects of malaria in pregnancy on SGA, very preterm birth, and late preterm birth, by the gestational age at malaria detection and treatment using logistic regression models with time-dependent malaria variables (monthly intervals). World Health Organisation definitions of very preterm birth (≥28 and

Health literacy is increasingly recognized as an important determinant of health outcomes, but definition, measurement tools, and interventions are lacking. Conceptual frameworks must include both individual and health-systems domains which, in combination, determine an individual’s health literacy. Validated tools lack applicability in marginalized populations with very low educational levels, such as migrant worker communities on the Myanmar-Thailand border. We undertake a comprehensive health literacy assessment following a case study of a recent public health campaign promoting preconceptual folic acid uptake in this community. A mixed-methods design utilized quantitative analysis of the prevalence and predictors of low Health literacy, and focus group discussions to gather qualitative data from women about proposed and actual posters used in the campaign. Health literacy was measured with a locally developed tool that has been used in surveys of the population since 1995. Health literacy was low, with 194/525 (37.0%) of tested women demonstrating adequate health literacy, despite 63.1% (331/525) self-reporting being literate. Only one third of women had completed 4th grade or above and reported grade level attained in school was more predictive of health literacy than self-reported literacy. Focus group discussions revealed that low literacy, preconceived associations, and traditional health beliefs (individual domain) interacted with complex images, subtle concepts, and taboo images on posters (health-systems domain) to cause widespread misunderstandings of the visuals used in the campaign. The final poster still required explanation for clarity. Low health literacy is prevalent among pregnant women from this migrant community and barriers to communication are significant and complex. Public health posters need piloting prior to implementation as unanticipated misperceptions are common and difficult to overcome. Verbal communication remains a key method of messaging with individuals of low health literacy and educational system strengthening and audiovisual messaging are critical for improvement of health outcomes.

Background: This study examines the prevalence and determinants of perinatal depression among migrant women on the Thai-Myanmar border. Methods: A cohort of labour migrant and refugee women was followed-up from the first trimester of pregnancy to one month post-partum. Depression status was assessed in the first, second and third trimesters and at one month post-partum using a structured clinical interview. Outcomes: A sample of 568 women was recruited. Period prevalence of moderate-severe perinatal depression was 18.5% (95% CI 15.4-21.9%). Overall, 15.4% (95% CI 11.8-19.6%) of women developed new-onset moderate-severe depression during the study period. Risk factors were interpersonal violence (OR 4.5; 95% CI 1.9-11.1); history of trauma (OR 2.4; 95% CI 1.4-4.3); self-reported history of depression (OR 2.3; 95% CI 1.2-4.2); labour migrant status (OR 2.1; 95% CI 1.1-4.0); low social support (OR 2.1; 95% CI 1.1-3.7); and maternal age (OR 1.1; 95% CI 1.0-1.1). Interpretation: Perinatal depression represents a significant burden among migrant women on the Thai-Myanmar border. Programmes to address the determinants along with early case identification and effective treatment and referral systems are key to addressing perinatal depression in this low-resource setting. Funding Statement: SMRU is part of the Mahidol Oxford Tropical Medicine Research Unit funded by the Wellcome Trust (WT-106698). Declaration of Interests: All authors declare no conflict of interests. Ethics Approval Statement: Ethical approval was granted by the University of Oxford Tropical Research Ethics Committee (OxTREC 28-15), the Mahidol University Faculty of Tropical Medicine Ethics Committee (TMEC 15-045) and the Tak Border Community Advisory Board (T-CAB 6/2/2015).

Background Adolescent pregnancy remains a global health concern, contributing to 11% of all births worldwide and 23% of the overall burden of disease in girls aged 15–19 years. Premature motherhood can create a negative cycle of adverse health, economic and social outcomes for young women, their babies and families. Refugee and migrant adolescent girls might be particularly at risk due to poverty, poor education and health infrastructure, early marriage, limited access to contraception and traditional beliefs. This study aims to explore adolescents’ perceptions and experiences of pregnancy in refugee and migrant communities on the Thailand-Myanmar border. Methods In June 2016 qualitative data were collected in one refugee camp and one migrant clinic along the Thailand-Myanmar border by conducting 20 individual interviews with pregnant refugee and migrant adolescents and 4 focus group discussions with husbands, adolescent boys and non-pregnant girls and antenatal clinic staff. Inductive thematic analysis was used to identify codes and themes emerging from the data. Results Study participants perceived adolescent pregnancy as a premature life event that could jeopardise their future. Important themes were premarital sex, forced marriage, lack of contraception, school dropout, fear of childbirth, financial insecurity, support structures and domestic violence. Supportive relationships with mothers, husbands and friends could turn this largely negative experience into a more positive one. The main underlying reasons for adolescent pregnancy were associated with traditional views and stigma on sexual and reproductive health issues, resulting in a knowledge gap on contraception and life skills necessary to negotiate sexual and reproductive choices, in particular for unmarried adolescents. Conclusions Adolescents perceive pregnancy as a challenging life event that can be addressed by developing comprehensive adolescent-friendly sexual and reproductive health services and education in refugee and migrant communities on the Thailand-Myanmar border. Creating a more tolerant and less stigmatising environment in these communities and their governing bodies will help to achieve this goal.

Purpose 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. Participants 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. Findings to date 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 diagnosed by the Structured Clinical Interview for the Diagnosis of DSM-IV Disorders. Future plans Follow-up is ongoing and expected to continue until January 2018. The prevalence of depression at later stages of pregnancy and during the first postpartum year will be identified, and associations between depression status and demographic, social, migration-related, medical, obstetric and infant factors will be quantified.

Introduction 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. Methods 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. Results Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log2 units). Placental P. falciparum infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log2 units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed. Discussion Primigravid women may be at risk of impaired maternofetal antibody transport with placental P. falciparum infection. Direct effects of P. falciparum on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.

Background 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. Methods 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. Results Of 61,836 women, 9350 (15%) had malaria in pregnancy, and 526 (0.8%) had stillbirths. In a sub-set of 9090 live born singletons followed from birth there were 153 (1.7%) neonatal deaths. The hazard of antepartum stillbirth increased 2.24-fold [95% confidence interval: 1.47, 3.41] following falciparum malaria (42% mediated through small-for-gestational-age status and anaemia), driven by symptomatic falciparum malaria (hazard ratio, HR: 2.99 [1.83, 4.89]) rather than asymptomatic falciparum malaria (HR: 1.35 [0.61, 2.96]). The hazard of antepartum stillbirth increased 2.21-fold [1.12, 4.33] following symptomatic vivax malaria (24% mediated through small-for-gestational-age status and anaemia) but not asymptomatic vivax malaria (HR: 0.54 [0.20, 1.45]). There was no association between falciparum or vivax malaria in pregnancy and intrapartum stillbirth (falciparum HR: 1.03 [0.58, 1.83]; vivax HR: 1.18 [0.66, 2.11]). Falciparum and vivax malaria in pregnancy increased the hazard of neonatal death 2.55-fold [1.54, 4.22] and 1.98-fold [1.10, 3.57], respectively (40% and 50%, respectively, mediated through small-for-gestational-age status and preterm birth). Conclusions Prevention of malaria in pregnancy, new and existing interventions to prevent small-for-gestational-age status and maternal anaemia, and improved capacity for managing preterm and small-for-gestational-age newborns will reduce the number of malaria-associated stillbirths and neonatal deaths in malaria-endemic areas. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0863-z) contains supplementary material, which is available to authorized users.

Background: Castor oil is one of the most popular drugs for induction of labour in a non-medical setting; however, published data on safety and effectiveness of this compound to induce labour remain sparse. Aim: To assess the safety and effectiveness of castor oil for induction of labour in pregnancies with an ultrasound estimated gestational at birth of more than 40 weeks. Methods: Data were extracted from hospital-based records of all pregnant women who attended antenatal clinics on the Thai–Burmese border and who were more than 40 weeks pregnant. The effectiveness of castor oil to induce labour was expressed as time to birth and analysed with a Cox proportional hazards regression model. Measures associated with safety were fetal distress, meconium-stained amniotic fluid, tachysystole of the uterus, uterine rupture, abnormal maternal blood pressure during labour, Apgar scores, neonatal resuscitation, stillbirth, post-partum haemorrhage, severe diarrhoea and maternal death. Proportions were compared using Fisher's exact test. Results: Of 612 women with a gestation of more than 40 weeks, 205 received castor oil for induction and 407 did not. The time to birth was not significantly different between the two groups (hazard ratio 0.99 (95% confidence interval: 0.81 to 1.20; n = 509)). Castor oil use was not associated with any harmful effects on the mother or fetus. Conclusions: Castor oil for induction of labour had no effect on time to birth nor were there any harmful effects observed in this large series. Our findings leave no justification for recommending castor oil for this purpose.

Background Haematological changes associated with malaria in pregnancy are not well documented, and have focused predominantly on anaemia. Examined here is thrombocytopaenia in pregnant women infected with Plasmodium falciparum or Plasmodium vivax in a low transmission area on the north-western border of Thailand. Methods In this observational study we reviewed the platelet counts from routine complete blood count (CBC) in a cohort of healthy and malaria infected Karen pregnant women attending weekly antenatal clinics. A platelet count of 75,000/μL was the threshold at 2 standard deviations below the mean for healthy pregnant women used to indicate thrombocytopenia. Differences in platelet counts in non-pregnant and pregnant women were compared after matching for age, symptoms, malaria species and parasitaemia. Results In total 974 pregnant women had 1,558 CBC measurements between February 2004 and September 2006. The median platelet counts (/μL) were significantly lower in patients with an episode of falciparum 134,000 [11,000–690,000] (N = 694) or vivax malaria 184,000 [23,000–891,000] (N = 523) compared to healthy pregnant women 256,000 [64,000–781,000] (N = 255), P < 0.05 for both comparisons. Plasmodium falciparum and P. vivax caused a 34% (95% CI 24–47) and 22% (95% CI 8–36) reduction in platelet count, respectively. Pregnant compared to non pregnant women were at higher risk OR = 2.27 (95%CI 1.16–4.4) P = 0.017, for thrombocytopaenia. Platelets counts were higher in first compared with subsequent malaria infections within the same pregnancy. Malaria associated thrombocytopaenia had a median [range] time for recovery of 7 [2–14] days which did not differ by antimalarial treatment (P = 0.86), or species (P = 0.63) and was not associated with active bleeding. Conclusion Pregnant women become more thrombocytopenic than non-pregnant women with acute uncomplicated malaria. Uncomplicated malaria associated thrombocytopaenia is seldom severe. Prompt antimalarial treatment resulted in normalization of platelet counts within a week.

During pregnancy immunolglobulin G (IgG) antibodies are transferred from mother to neonate across the placenta. Studies in high transmission areas have shown transfer of P. falciparum-specific IgG, but the extent and factors influencing maternal-foetal transfer in low transmission areas co-endemic for both P. falciparum and P. vivax are unknown. Pregnant women were screened weekly for Plasmodium infection. Mother-neonate paired serum samples at delivery were tested for IgG to antigens from P. falciparum, P. vivax and other infectious diseases. Antibodies to malarial and non-malarial antigens were highly correlated between maternal and neonatal samples (median [range] spearman ρ = 0.78 [0.57–0.93]), although Plasmodium spp. antibodies tended to be lower in neonates than mothers. Estimated gestational age at last P. falciparum infection, but not P. vivax infection, was positively associated with antibody levels in the neonate (P. falciparum merozoite, spearman ρ median [range] 0.42 [0.33–0.66], PfVAR2CSA 0.69; P. vivax ρ = 0.19 [0.09–0.3]). Maternal-foetal transfer of anti-malarial IgG to Plasmodium spp. antigens occurs in low transmission settings. P. vivax IgG acquisition is not associated with recent exposure unlike P. falciparum IgG, suggesting a difference in acquisition of antibodies. IgG transfer is greatest in the final weeks of pregnancy which has implications for the timing of future malaria vaccination strategies in pregnant women.

Limited microbiology services impede adequate diagnosis and treatment of common infections such as pyelonephritis in resource-limited settings. Febrile pregnant women attending antenatal clinics at Shoklo Malaria Research Unit were offered urine dipstick, sediment microscopy, urine culture, and a 5-mL blood culture. The incidence of pyelonephritis was 11/1,000 deliveries (N = 53 in 4,819 pregnancies) between January 7, 2004 and May 17, 2006. Pyelonephritis accounted for 20.2% (41/203) of fever cases in pregnancy. Escherichia coli was the most commonly isolated pathogen: 87.5% (28/32) of organisms cultured. Susceptibility of E. coli to ampicillin (14%), cotrimoxazole (21%), and amoxicillin-clavulanic acid (48%) was very low. E. coli was susceptible to ceftriaxone and ciprofloxacin. The rate of extended spectrum β-lactamase (4.2%; 95% confidence interval = 0.7-19.5) was low. The rate and causes of pyelonephritis in pregnant refugee and migrant women were comparable with those described in developed countries. Diagnostic innovation in microbiology that permits affordable access is a high priority for resource-poor settings.

Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women ( n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of

The objective was to assess the safety of chloroquine (CQ) as prophylaxis against Plasmodium vivax infection during pregnancy. One thousand pregnant Karen women were enrolled in a randomized double-blind placebo-controlled trial of chemoprophylaxis with chloroquine (500 mg phosphate (or 300 mg base) weekly). Women received a median (range) chloroquine phosphate total dose of 9500 (1500-17 500) mg. The mothers were actively followed from inclusion to delivery and their infants until 12 months of age. Chloroquine prophylaxis completely prevented P. vivax episodes; 10.1% (95% CI: 7.3-14.5) of women in the placebo group experienced at least one episode of vivax malaria but no episode occurred in women in the CQ group. By contrast the numbers of P. falciparum episodes were similar in each group: 7.4% (95% CI: 3.7-11.1) and 5.6% (95% CI: 3.3-7.9) in the placebo and CQ groups respectively (P = 0.56). Chloroquine prophylaxis was well tolerated and there was no difference in the proportions of reported side effects between CQ treated and placebo groups except for the duration of palpitations and sleeping disorders which were more frequent in those who had received CQ. Chloroquine prophylaxis had no impact on maternal anaemia birth weight gestational age development of newborns or on growth neurological development or visual acuity in infants at 1 year of age. Chloroquine is safe and effective as prophylaxis against P. vivax during pregnancy in this population. (authors)

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.

BackgroundThe association between malaria during pregnancy and low birth weight (LBW) is well described. This manuscript aims to quantify the relative contribution of malaria to small-for-gestational-age (SGA) infants and preterm birth (PTB) in pregnancies accurately dated by ultrasound on the Thai-Myanmar border at the Shoklo Malaria Research Unit. Method and findingsFrom 2001 to 2010 in a population cohort of prospectively followed pregnancies, we analyzed all singleton newborns who were live born, normal, weighed in the first hour of life and with a gestational age (GA) between 28+0 and 41+6 weeks. Fractional polynomial regression was used to determine the mean birthweight and standard deviation as functions of GA. Risk differences and factors of LBW and SGA were studied across the range of GA for malaria and non-malaria pregnancies. From 10,264 newborns records, population centiles were created. Women were screened for malaria by microscopy a median of 22 [range 1-38] times and it was detected and treated in 12.6% (1,292) of pregnancies. Malaria was associated with LBW, PTB, and SGA compared to those without malaria. Nearly two-thirds of PTB were classified as LBW (68% (539/789)), most of which 83% (447/539) were not SGA. After GA 39 weeks, 5% (298/5,966) of non-LBW births were identified as SGA. Low body mass index, primigravida, hypertension, smoking and female sex of the newborn were also significantly and independently associated with LBW and SGA consistent with previous publications. ConclusionsTreated malaria in pregnancy was associated with an increased risk for LBW, PTB, and SGA, of which the latter are most important for infant survival. Using LBW as an endpoint without adjusting for GA incorrectly estimated the effects of malaria in pregnancy. Ultrasound should be used for dating pregnancies and birth weights should be expressed as a function (or adjusted for GA) of GA in future malaria in pregnancy studies.

Dihydroartemisinin-piperaquine (DHA-PPQ) is a promising new artemisinin combination treatment. There are no published data on the intentional use of the drug in pregnancy. Between June 2006 and January 2007, 50 Karen pregnant women with recurrent P. falciparum infections, despite 7-day treatments with quinine or artesunate (+/-clindamycin) or both, were treated with DHA-PPQ. This rescue treatment was effective and well tolerated and there was no evidence of toxicity for the mothers or the fetus. The PCR adjusted cure rate by Kaplan Meier analysis at day 63 was 92.2% (95% CI: 76.9-97.4).

BackgroundSeveral 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. MethodsIn 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. ResultsPost-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), pP.vivax, post-partum women were not more susceptible to P.vivax than controls (HR: 0.33 (0.21-0.51), pP.falciparum was a newly acquired infection. ConclusionsIn 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.

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.

Background: The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern. We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai-Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments. Methods: We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010. Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester. The association between malaria and miscarriage was estimated using multivariable logistic regression. Findings: Of 48 426 pregnant women, 17 613 (36%) met the inclusion criteria: 16 668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester. The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04-3·59) and symptomatic malaria (3·99, 3·10-5·13), and were similar for Plasmodium falciparum and Plasmodium vivax. Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness. In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15-11·46) and parasitaemia (1·49, 1·25-1·78 for each ten-fold increase in parasitaemia). Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81-0·91). The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed. Interpretation: A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage. No additional toxic effects associated with artesunate treatment occurred in early pregnancy. Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy. Funding: Wellcome Trust and Bill and Melinda Gates Foundation. © 2012 Elsevier Ltd.

BACKGROUNDIntermittent preventive treatment (IPT), the main strategy to prevent malaria and reduce anaemia and low birthweight, focuses on the second half of pregnancy. However, intrauterine growth restriction may occur earlier in pregnancy. The aim of this study was to measure the effects of malaria in the first half of pregnancy by comparing the fetal biparietal diameter (BPD) of infected and uninfected women whose pregnancies had been accurately dated by crown rump length (CRL) before 14 weeks of gestation. METHODOLOGY/PRINCIPAL FINDINGSIn 3,779 women living on the Thai-Myanmar border who delivered a normal singleton live born baby between 2001-10 and who had gestational age estimated by CRL measurement Plasmodium (P) falciparum and/or P.vivax malaria infections were significantly lower than in non-infected pregnancies; -0.57 (1.13) versus -0.10 (1.17), p CONCLUSIONS/SIGNIFICANCEDespite early treatment in all positive women, one or more (a)symptomatic P.falciparum or P.vivax malaria infections in the first half of pregnancy result in a smaller than expected mid-trimester fetal head diameter. Strategies to prevent malaria in pregnancy should include early pregnancy.

In a prospective infant cohort, 21 infants developed Plasmodium vivax malaria during their first year. Twelve of their mothers also had vivax malaria in the corresponding pregnancies or postpartum period. The genotypes of the maternal and infant infections were all different. Eight of the 12 mothers and 9 of the 21 infants had recurrent infections. Relapse parasite genotypes were different to the initial infection in 13 of 20 (65%) mothers compared with 5 of 24 (21%) infants (P = .02). The first P. vivax relapses of life are usually genetically homologous, whereas relapse in adults may result from activation of heterologous latent hypnozoites acquired from previous inoculations.

IntroductionMaternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas. Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand.Methods and findingsAll medical records from women who attended the Shoklo Malaria Research Unit antenatal clinics from 12(th) May 1986 to 31(st) December 2010 were reviewed, and maternal death records were analyzed for causality. There were 71 pregnancy-related deaths recorded amongst 50,981 women who attended antenatal care at least once. Three were suicide and excluded from the analysis as incidental deaths. The estimated maternal mortality ratio (MMR) overall was 184 (95%CI 150-230) per 100,000 live births. In camps for displaced persons there has been a six-fold decline in the MMR from 499 (95%CI 200-780) in 1986-90 to 79 (40-170) in 2006-10, pConclusionsFrequent antenatal clinic screening allows early detection and treatment of falciparum malaria and substantially reduces maternal mortality from P. falciparum malaria. No significant decline has been observed in deaths from sepsis or other causes in refugee and migrant women on the Thai-Myanmar border.

Background Fever in pregnancy is dangerous for both mother and foetus. In the 1980's malaria was the leading cause of death in pregnant women in refugee camps on the Thai-Burmese border. Artemisinin combination therapy has significantly reduced the incidence of malaria in the population. The remaining causes of fever in pregnancy are not well documented. Methodology Pregnant women attending antenatal care, where weekly screening for malaria is routine, were invited to have a comprehensive clinical and laboratory screen if they had fever. Women were admitted to hospital, treated and followed up weekly until delivery. A convalescent serum was collected on day 21. Delivery outcomes were recorded. Principal Findings Febrile episodes (n = 438) occurred in 5.0% (409/8,117) of pregnant women attending antenatal clinics from 7-Jan-2004 to 17-May-2006. The main cause was malaria in 55.5% (227/409). A cohort of 203 (49.6% of 409) women had detailed fever investigations and follow up. Arthropod-borne (malaria, rickettsial infections, and dengue) and zoonotic disease (leptospirosis) accounted for nearly half of all febrile illnesses, 47.3% (96/203). Coinfection was observed in 3.9% (8/203) of women, mostly malaria and rickettsia. Pyelonephritis, 19.7% (40/203), was also a common cause of fever. Once malaria, pyelonephritis and acute respiratory illness are excluded by microscopy and/or clinical findings, one-third of the remaining febrile infections will be caused by rickettsia or leptospirosis. Scrub and murine typhus were associated with poor pregnancy outcomes including stillbirth and low birth weight. One woman died (no positive laboratory tests). Conclusion/Significance Malaria remains the leading cause of fever in pregnancy on the Thai-Burmese border. Scrub and murine typhus were also important causes of fever associated with poor pregnancy outcomes. Febrile pregnant women on the Thai-Burmese border who do not have malaria, pyelonephritis or respiratory tract infection should be treated with azithromycin, effective for typhus and leptospirosis., Author Summary Fever during pregnancy can be harmful for the mother and the infant. In resource poor settings health workers have very few field-based tests that help them identify the cause of infection. This study examined the causes of fever in pregnant women using laboratory support that is typically unavailable to most women living in the tropics. On the Thai-Burmese border there has been a great reduction in malaria in the last 20 years. However malaria remained the leading cause of fever in pregnancy in this study conducted between 2004 and 2006. Urinary tract infection was also a common cause of fever as it is in resource rich countries. Other diseases transmitted by mosquitoes (dengue), ticks (scrub and murine typhus), or rodents (leptospirosis) were common. Scrub and murine typhus were associated with stillbirth and low birth weight. Microscopy remains the most useful tool in the field for the diagnosis of fever in pregnant women. Leptospirosis, dengue and rickettsial infections require improved field-based diagnostic tools to ensure that women receive appropriate antibiotic therapy.

Background Deworming is recommended by the WHO in girls and pregnant and lactating women to reduce anaemia in areas where hookworm and anaemia are common. There is conflicting evidence on the harm and the benefits of intestinal geohelminth infections on the incidence and severity of malaria, and consequently on the risks and benefits of deworming in malaria affected populations. We examined the association between geohelminths and malaria in pregnancy on the Thai-Burmese border. Methodology Routine antenatal care (ANC) included active detection of malaria (weekly blood smear) and anaemia (second weekly haematocrit) and systematic reporting of birth outcomes. In 1996 stool samples were collected in cross sectional surveys from women attending the ANCs. This was repeated in 2007 when malaria incidence had reduced considerably. The relationship between geohelminth infection and the progress and outcome of pregnancy was assessed. Principal Findings Stool sample examination (339 in 1996, 490 in 2007) detected a high prevalence of geohelminths 70% (578/829), including hookworm (42.8% (355)), A. lumbricoides (34.4% (285)) and T.trichuria (31.4% (250)) alone or in combination. A lower proportion of women (829) had mild (21.8% (181)) or severe (0.2% (2)) anaemia, or malaria 22.4% (186) (P.vivax monoinfection 53.3% (101/186)). A. lumbricoides infection was associated with a significantly decreased risk of malaria (any species) (AOR: 0.43, 95% CI: 0.23–0.84) and P.vivax malaria (AOR: 0.29, 95% CI: 0.11–0.79) whereas hookworm infection was associated with an increased risk of malaria (any species) (AOR: 1.66, 95% CI: 1.06–2.60) and anaemia (AOR: 2.41, 95% CI: 1.18–4.93). Hookworm was also associated with low birth weight (AOR: 1.81, 95% CI: 1.02–3.23). Conclusion/Significance A. lumbricoides and hookworm appear to have contrary associations with malaria in pregnancy., Author Summary Intestinal worms, particularly hookworm and whipworm, can cause anaemia, which is harmful for pregnant women. The WHO recommends deworming in pregnancy in areas where hookworm infections are frequent. Some studies indicate that coinfection with worms and malaria adversely affects pregnancy whereas other studies have shown that coinfection with worms might reduce the severity of malaria. On the Thai-Burmese border malaria in pregnancy has been an important cause of maternal death. We examined the relationship between intestinal helminth infections in pregnant women and their malaria risk in our antenatal care units. In total 70% of pregnant women had worm infections, mostly hookworm, but also roundworm and whipworm; hookworm was associated with mild anaemia although ova counts were not high. Women infected with hookworm had more malaria and their babies had a lower birth weight than women without hookworm. In contrast women with roundworm infections had the lowest rates of malaria in pregnancy. Deworming eliminates all worms. In this area it is unclear whether mass deworming would be beneficial.

Background To date no comparative trials have been done, to our knowledge, of fixed-dose artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria in pregnancy. Evidence on the safety and efficacy of ACTs in pregnancy is needed as these drugs are being used increasingly throughout the malaria-affected world. The objective of this study was to compare the efficacy, tolerability, and safety of artemether-lumefantrine, the most widely used fixed ACT, with 7 d artesunate monotherapy in the second and third trimesters of pregnancy. Methods and Findings An open-label randomised controlled trial comparing directly observed treatment with artemether-lumefantrine 3 d (AL) or artesunate monotherapy 7 d (AS7) was conducted in Karen women in the border area of northwestern Thailand who had uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy. The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life. Blood sampling was performed to characterise the pharmacokinetics of lumefantrine in pregnancy. Both regimens were very well tolerated. The cure rates (95% confidence interval) for the intention to treat (ITT) population were: AS7 89.2% (82.3%–96.1%) and AL 82.0% (74.8%–89.3%), p = 0.054 (ITT); and AS7 89.7% (82.6%–96.8%) and AL 81.2% (73.6%–88.8%), p = 0.031 (per-protocol population). One-third of the PCR-confirmed recrudescent cases occurred after 42 d of follow-up. Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. The pharmacokinetic study indicated that low concentrations of artemether and lumefantrine were the main contributors to the poor efficacy of AL. Conclusion The current standard six-dose artemether-lumefantrine regimen was well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy was inferior to 7 d artesunate monotherapy and was unsatisfactory for general deployment in this geographic area. Reduced efficacy probably results from low drug concentrations in later pregnancy. A longer or more frequent AL dose regimen may be needed to treat pregnant women effectively and should now be evaluated. Parasitological endpoints in clinical trials of any antimalarial drug treatment in pregnancy should be extended to delivery or day 42 if it comes later. Trial Registration: Current Controlled Trials ISRCTN86353884, Rose McGready and colleagues show that an artemether-lumefantrine regimen is well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy is inferior to artesunate, probably because of low drug concentrations in later pregnancy., Editors' Summary Background. Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year. Although most deaths occur among young children, malaria during pregnancy is also an important public-health problem. In areas where malaria transmission is high (stable transmission), women acquire a degree of immunity. Although less symptomatic than women who lack natural protection, their babies are often small and sickly because malaria-related anemia (lack of red blood cells) and parasites in the placenta limit the nutrients supplied to the baby before birth. By contrast, in areas where malaria transmission is low (unstable transmission or sporadic outbreaks), women have little immunity to P. falciparum. If these women become infected during pregnancy, “uncomplicated” malaria (fever, chills, and anemia) can rapidly progress to “severe” malaria (in which vital organs are damaged), which can be fatal to the mother and/or her unborn child unless prompt and effective treatment is given. Why Was This Study Done? Malaria parasites are now resistant to many of the older antimalarial drugs (for example, quinine). So, since 2006, the World Health Organization (WHO) has recommended that uncomplicated malaria during the second and third trimester of pregnancy is treated with short course (3 d) fixed-dose artemisinin combination therapy (ACT; quinine is still used in early pregnancy because it is not known whether ACT damages fetal development, which mainly occurs during the first 3 mo of pregnancy). Artemisinin derivatives are fast-acting antimalarial agents that are used in combination with another antimalarial drug to reduce the chances of P. falciparum becoming resistant to either drug. The most widely used fixed-dose ACT is artemether–lumefantrine (AL) but, although several trials have examined the safety and efficacy of this treatment in non-pregnant women, little is known about how well it works in pregnant women. In this study, the researchers compare the efficacy, tolerability, and safety of AL with a 7-d course of artesunate monotherapy (AS7; another artemisinin derivative) in the treatment of uncomplicated malaria in pregnancy in northwest Thailand, an area with unstable but highly drug resistant malaria transmission. What Did the Researchers Do and Find? The researchers enrolled 253 women with uncomplicated malaria during the second and third trimesters of pregnancy into their open-label trial (a trial in which the patients and their health-care workers know who is receiving which drug regimen). Half the women received each type of treatment. The trial's main outcome was the “PCR-adjusted cure rate” at delivery or 42 d after treatment if this occurred after delivery. This cure rate was assessed by examining blood smears for parasites and then using a technique called PCR to determine which cases of malaria were new infections (classified as treatment successes along with negative blood smears) and which were recurrences of an old infection (classified as treatment failures). The PCR-adjusted cure rates were 89.7% and 81.2% for AS7 and AL, respectively. Both treatments were well tolerated, few side effects were seen with either treatment, and infant health and development at birth and up to 1 y old were similar with both regimens. Finally, an analysis of blood samples taken 7 d after treatment with AL showed that blood levels of lumefantrine were below those previously associated with treatment failure in about a third of the women tested. What Do These Findings Mean? Although these findings indicate that the AL regimen is a well tolerated and safe treatment for uncomplicated malaria in pregnant women living in northwest Thailand, the efficacy of this treatment was lower than that of artesunate monotherapy. In fact, neither treatment reached the 90% cure rate recommended by WHO for ACTs and it is likely that cure rates in a more realistic situation (that is, not in a trial where efforts are made to make sure everyone completes their treatment) would be even lower. The findings also suggest that the reduced efficacy of the AL regimen in pregnant women compared to the efficacy previously seen in non-pregnant women may be caused by lower drug blood levels during pregnancy. Thus, a higher-dose AL regimen (or an alternative ACT) may be needed to successfully treat uncomplicated malaria during pregnancy. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050253. The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish) Information is available from the World Health Organization on malaria (in several languages), and their 2006 Guidelines for the Treatment of Malaria includes specific recommendations for the treatment of pregnant women The US Centers for Disease Control and Prevention provide information on malaria and on malaria during pregnancy (in English and Spanish) Information is available from the Roll Back Malaria Partnership on malaria during pregnancy, on artemisinin-based combination therapies, and on malaria in Thailand