US Immigration Westernizes the Human Gut Microbiome.

Many US immigrant populations develop metabolic diseases post immigration, but the causes are not well understood. Although the microbiome plays a role in metabolic disease, there have been no studies measuring the effects of US immigration on the gut microbiome. We collected stool, dietary recalls, and anthropometrics from 514 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants and 19 Karen individuals sampled before and after immigration, as well as from 36 US-born European American individuals. Using 16S and deep shotgun metagenomic DNA sequencing, we found that migration from a non-Western country to the United States is associated with immediate loss of gut microbiome diversity and function in which US-associated strains and functions displace native strains and functions. These effects increase with duration of US residence and are compounded by obesity and across generations.

Functional and immunological mapping of domains of the reticulocyte binding protein, Plasmodium vivax PvRBP2a.

We previously described a novel Plasmodium vivax invasion mechanism into human reticulocytes via the PvRBP2a-CD98 receptor-ligand pair. We assessed the PvRBP2a epitopes involved in CD98 binding and recognised by antibodies from infected patients using linear epitope mapping. We identified two epitope clusters mediating PvRBP2a-CD98 interaction. One cluster named cluster B (PvRBP2a431-448, TAALKEKGKLLANLYNKL) was the target of antibody responses in P. vivax-infected humans. Peptides from each cluster were able to prevent live parasite invasion of human reticulocytes. These results provide new insights for development of a malaria blood stage vaccine against P. vivax.

Comparison of lumefantrine, mefloquine, and piperaquine concentrations between capillary plasma and venous plasma samples in pregnant women with uncomplicated falciparum and vivax malaria.

Capillary samples offer practical benefits compared with venous samples for the measurement of drug concentrations, but the relationship between the two measures varies between different drugs. We measured the concentrations of lumefantrine, mefloquine, piperaquine in 270 pairs of venous plasma and concurrent capillary plasma samples collected from 270 pregnant women with uncomplicated falciparum or vivax malaria. The median and range of venous plasma concentrations included in this study were 447.5 ng/mL (8.81-3,370) for lumefantrine (day 7, n = 76, median total dose received 96.0 mg/kg), 17.9 ng/mL (1.72-181) for desbutyl-lumefantrine, 1,885 ng/mL (762-4,830) for mefloquine (days 3-21, n = 90, median total dose 24.9 mg/kg), 641 ng/mL (79.9-1,950) for carboxy-mefloquine, and 51.8 ng/mL (3.57-851) for piperaquine (days 3-21, n = 89, median total dose 52.2 mg/kg). Although venous and capillary plasma concentrations showed a high correlation (Pearson's correlation coefficient: 0.90-0.99) for all antimalarials and their primary metabolites, they were not directly interchangeable. Using the concurrent capillary plasma concentrations and other variables, the proportions of venous plasma samples predicted within a ±10% precision range was 34% (26/76) for lumefantrine, 36% (32/89) for desbutyl-lumefantrine, 74% (67/90) for mefloquine, 82% (74/90) for carboxy-mefloquine, and 24% (21/89) for piperaquine. Venous plasma concentrations of mefloquine, but not lumefantrine and piperaquine, could be predicted by capillary plasma samples with an acceptable level of agreement. Capillary plasma samples can be utilized for pharmacokinetic and clinical studies, but caution surrounding cut-off values is required at the individual level.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT01054248.

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Severe Falciparum and Vivax Malaria on the Thailand-Myanmar Border: A Review of 1503 Cases.

BACKGROUND: The northwestern border of Thailand is an area of low seasonal malaria transmission. Until recent successful malaria elimination activities, malaria was a major cause of disease and death. Historically the incidences of symptomatic Plasmodium falciparum and Plasmodium vivax malaria were approximately similar. METHODS: All malaria cases managed in the Shoklo Malaria Research Unit along the Thailand-Myanmar border between 2000 and 2016 were reviewed. RESULTS: There were 80 841 consultations for symptomatic P. vivax and 94 467 for symptomatic P. falciparum malaria. Overall, 4844 (5.1%) patients with P. falciparum malaria were admitted to field hospitals, of whom 66 died, compared with 278 (0.34%) with P. vivax malaria, of whom 4 died (3 had diagnoses of sepsis, so the contribution of malaria to their fatal outcomes is uncertain). Applying the 2015 World Health Organization severe malaria criteria, 68 of 80 841 P. vivax admissions (0.08%) and 1482 of 94 467 P. falciparum admissions (1.6%) were classified as severe. Overall, patients with P. falciparum malaria were 15 (95% confidence interval, 13.2-16.8) times more likely than those with P. vivax malaria to require hospital admission, 19 (14.6-23.8) times more likely to develop severe malaria, and ≥14 (5.1-38.7) times more likely to die. CONCLUSIONS: In this area, both P. falciparum and P. vivax infections were important causes of hospitalization, but life-threatening P. vivax illness was rare.

Severe falciparum malaria in pregnancy in Southeast Asia: a multi-centre retrospective cohort study.

BACKGROUND: Severe malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy. METHODS: A retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality. RESULTS: We included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio [aOR], 7.18, 95% CI 2.01-25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27-98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13-22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit < 20%) only. In the SMRU prospective cohort, in which the pregnant women were followed up until delivery, the risks of foetal loss (23.3% by Kaplan-Meier estimator, 25/117) and small-for-gestational-age (38.3%, 23/60) after severe malaria were high. Maternal death, foetal loss and preterm birth occurred commonly within a week of diagnosis of severe malaria. CONCLUSIONS: Vital organ dysfunction in pregnant women with severe malaria was associated with a very high maternal and foetal mortality whereas severe anaemia or hyperparasitaemia alone were not associated with poor prognosis, which may explain the variation of reported mortality from severe malaria in pregnancy. Access to antenatal care must be promoted to reduce barriers to early diagnosis and treatment of both malaria and anaemia.

Unveiling the dynamics of the breast milk microbiome: impact of lactation stage and gestational age.

BACKGROUND: Breast milk (BM) provides complete nutrition for infants for the first six months of life and is essential for the development of the newborn's immature immune and digestive systems. While BM was conventionally believed to be sterile, recent advanced high throughput technologies have unveiled the presence of diverse microbial communities in BM. These insights into the BM microbiota have mainly originated from uncomplicated pregnancies, possibly not reflecting the circumstances of mothers with pregnancy complications like preterm birth (PTB). METHODS: In this article, we investigated the BM microbial communities in mothers with preterm deliveries (before 37 weeks of gestation). We compared these samples with BM samples from healthy term pregnancies across different lactation stages (colostrum, transitional and mature milk) using 16S rRNA gene sequencing. RESULTS: Our analysis revealed that the microbial communities became increasingly diverse and compositionally distinct as the BM matured. Specifically, mature BM samples were significantly enriched in Veillonella and lactobacillus (Kruskal Wallis; p < 0.001) compared to colostrum. The comparison of term and preterm BM samples showed that the community structure was significantly different between the two groups (Bray Curtis and unweighted unifrac dissimilarity; p < 0.001). Preterm BM samples exhibited increased species richness with significantly higher abundance of Staphylococcus haemolyticus, Propionibacterium acnes, unclassified Corynebacterium species. Whereas term samples were enriched in Staphylococcus epidermidis, unclassified OD1, and unclassified Veillonella among others. CONCLUSION: Our study underscores the significant influence of pregnancy-related complications, such as preterm birth (before 37 weeks of gestation), on the composition and diversity of BM microbiota. Given the established significance of the maternal microbiome in shaping child health outcomes, this investigation paves the way for identifying modifiable factors that could optimize the composition of BM microbiota, thereby promoting maternal and infant health.

Giving birth on the way to the clinic: undocumented migrant women's perceptions and experiences of maternal healthcare accessibility along the Thailand-Myanmar border.

BACKGROUND: Millions of women give birth annually without the support of a trained birth attendant. Generally and globally, countries provide maternal health services for their citizens but there is a coverage gap for undocumented migrant women who often can't access the same care due to their legal status. The objective of this investigation is to explore undocumented migrants' experiences and perceptions of maternal healthcare accessibility. METHODS: We held focus groups discussions with 64 pregnant women at 3 migrant health clinics on the Thailand-Myanmar border and asked how they learned about the clinic, their health care options, travel and past experiences with birth services. In this context undocumented women could sign up for migrant health insurance at the clinic that would allow them to be referred for tertiary care at government hospitals if needed. RESULTS: Women learned about care options through a network approach often relying on information from community members and trusted care providers. For many, choice of alternate care was limited by lack of antenatal care services close to their homes, limited knowledge of other services and inability to pay fees associated with hospital care. Women travelled up to 4 h to get to the clinic by foot, bicycle, tractor, motorcycle or car, sometimes using multiple modes of transport. Journeys from the Myanmar side of the border were sometimes complicated by nighttime border crossing closures, limited transport and heavy rain. CONCLUSIONS: Undocumented migrant women in our study experienced a type of conditional or variable accessibility where time of day, transport and weather needed to align with the onset of labour to ensure that they could get to the migrant clinic on time to give birth. We anticipate that undocumented migrants in other countries may also experience conditional accessibility to birth care, especially where travel is necessary due to limited local services. Care providers may improve opportunities for undocumented pregnant women to access maternal care by disseminating information on available services through informal networks and addressing travel barriers through mobile services and other travel supports. Trial registration The research project was approved by Research Ethics Committee at the Faculty of Medicine, Chiang Mai University (FAM-2560-05204), and the Department of Community Medicine and Global Health at the University of Oslo-Norwegian Centre for Research Data (58542).

Undocumented pregnant migrants have difficulties and limitations in accessing maternal health care services. Although the governments have tried to provide maternal health care services to all, there is still a gap in coverage among this population. This study explores how undocumented pregnant migrants perceive their ability to access maternal health care and share their experiences when utilizing it. We used focus groups to interview 64 pregnant women at three migrant health clinics on the Thailand­Myanmar border. We asked how they learned about the clinic, their health care options, travel, and past experiences with birth services. The results showed that they usually knew about care options from community members and trusted care providers. The limitations for the choice of alternate care were due to a lack of services close to their homes, limited knowledge of other services, inability to pay hospital fees, and difficulty traveling from their residence to the clinic. Therefore, we anticipate that undocumented migrants in other countries may also experience difficulties in accessibility to birth care, especially where travel is necessary due to limited local services. Care providers may improve opportunities for these migrants to access maternal care by disseminating information on available services through informal networks and addressing travel barriers through mobile services and other travel supports.

Quantification of the dynamics of antibody response to malaria to inform sero-surveillance in pregnant women.

BACKGROUND: Malaria remains a major public health threat and tools sensitive to detect infections in low malaria transmission areas are needed to progress elimination efforts. Pregnant women are particularly vulnerable to malaria infections. Throughout pregnancy they access routine antenatal care, presenting a unique sentinel population to apply novel sero-surveillance tools to measure malaria transmission. The aim of this study was to quantify the dynamic antibody responses to multiple antigens during pregnancy so as to identify a single or multiple antibody response of exposure to malaria in pregnancy. METHODS: This study involved a secondary analysis of antibody responses to six parasite antigens [five commonly studied merozoite antigens and the variant surface antigen 2-chondroitin sulphate A (VAR2CSA), a pregnancy-specific erythrocytic antigen] measured by enzyme-linked immunosorbent assay (ELISA) over the gestation period until delivery (median of 7 measurements/woman) in 250 pregnant women who attended antenatal clinics located at the Thai-Myanmar border. A multivariate mixture linear mixed model was used to cluster the pregnant women into groups that have similar longitudinal antibody responses to all six antigens over the gestational period using a Bayesian approach. The variable-specific entropy was calculated to identify the antibody responses that have the highest influence on the classification of the women into clusters, and subsequent agreement with grouping of women based on exposure to malaria during pregnancy. RESULTS: Of the 250 pregnant women, 135 had a Plasmodium infection detected by light microscopy during pregnancy (39% Plasmodium falciparum only, 33% Plasmodium vivax only and 28% mixed/other species), defined as cases. The antibody responses to all six antigens accurately identified the women who did not have a malaria infection detected during pregnancy (93%, 107/115 controls). Antibody responses to P. falciparum merozoite surface protein 3 (PfMSP3) and P. vivax apical membrane antigen 1 (PvAMA1) were the least dynamic. Antibody responses to the antigens P. falciparum apical membrane antigen 1 (PfAMA1) and PfVAR2CSA were able to identify the majority of the cases more accurately (63%, 85/135). CONCLUSION: These findings suggest that the combination of antibodies, PfAMA1 and PfVAR2CSA, may be useful for sero-surveillance of malaria infections in pregnant women, particularly in low malaria transmission settings. Further investigation of other antibody markers is warranted considering these antibodies combined only detected 63% of the malaria infections during pregnancy.

Who is protected? Determinants of hepatitis B infant vaccination completion among a prospective cohort of migrant workers in Thailand during the COVID-19 pandemic.

BACKGROUND: Hepatitis B causes significant disease and death globally, despite the availability of effective vaccination. Migration likewise affects hundreds of millions of people annually, many of whom are women and children, and increases risks for poor vaccine completion and mother to child transmission of hepatitis B. In the neighbouring countries of Thailand and Myanmar, vaccine campaigns have made progress but little is known about the reach of these programs into migrant worker communities from Myanmar living in Thailand. METHODS: A cohort of 253 postpartum women (53 urban migrants in Chiang Mai and 200 rural migrants in Tak Province) were surveyed about their Hepatitis B knowledge and willingness to vaccinate their children between September 10, 2019 and March 30, 2019. They were subsequently followed to determine vaccine completion. When records of vaccination were unavailable at the birth facility, or visits were late, families were contacted and interviewed about vaccination elsewhere, and reasons for late or missed vaccines. RESULTS: Though women in Tak province displayed better knowledge of Hepatitis B and equal intention to vaccinate, they were 14 times less likely to complete Hepatitis B vaccination for their children compared to migrants in Chiang Mai. Tak women were largely undocumented, had private (non-profit) insurance and had more transient residence. In Chiang Mai migrant women were mostly documented and had full access to the Thai national health services. Though minor individual and facility-level differences may have contributed, the major driver of the disparity seems to be the place of migrants within local socio-political-economic systems. The COVID-19 pandemic further disproportionately affected Tak province migrants who faced severe travel restrictions hampering vaccination. Sixty percent of families who were lost to vaccine follow-up in Tak province could not be contacted by phone or home visit. Chiang Mai migrants, with 86.8% vaccine completion, nearly reached the target of 90%. CONCLUSIONS: Achievement of high levels of hepatitis B vaccination in migrant communities is important and feasible, and requires inclusive policies that integrate migrants into national health and social services. This is more urgent than ever during the COVID-19 era.

Randomized Controlled Trial of the Electrocardiographic Effects of Four Antimalarials for Pregnant Women with Uncomplicated Malaria on the Thailand-Myanmar Border.

Quinoline antimalarials cause drug-induced electrocardiographic QT prolongation, a potential risk factor for torsade de pointes. The effects of currently used antimalarials on the electrocardiogram (ECG) were assessed in pregnant women with malaria. Pregnant women with microscopy-confirmed parasitemia of any malaria species were enrolled in an open-label randomized controlled trial on the Thailand-Myanmar border from 2010 to 2016. Patients were randomized to the standard regimen of dihydroartemisinin-piperaquine (DP) or artesunate-mefloquine (ASMQ) or an extended regimen of artemether-lumefantrine (AL+). Recurrent Plasmodium vivax infections were treated with chloroquine. Standard 12-lead electrocardiograms were assessed on day 0, 4 to 6 h following the last dose, and day 7. QT was corrected for the heart rate by a linear mixed-effects model-derived population-based correction formula (QTcP = QT/RR0.381). A total of 86 AL+, 82 ASMQ, 88 DP, and 21 chloroquine-treated episodes were included. No patients had an uncorrected QT interval nor QTcP of >480 ms at any time. QTcP corresponding to peak drug concentration was longer in the DP group (adjusted predicted mean difference, 17.84 ms; 95% confidence interval [CI], 11.58 to 24.10; P < 0.001) and chloroquine group (18.31 ms; 95% CI, 8.78 to 27.84; P < 0.001) than in the AL+ group, but not different in the ASMQ group (2.45 ms; 95% CI, -4.20 to 9.10; P = 0.47) by the multivariable linear mixed-effects model. There was no difference between DP and chloroquine (P = 0.91). QTc prolongation resulted mainly from widening of the JT interval. In pregnant women, none of the antimalarial drug treatments exceeded conventional thresholds for an increased risk of torsade de pointes.

Falciparum but not vivax malaria increases the risk of hypertensive disorders of pregnancy in women followed prospectively from the first trimester.

BACKGROUND: Malaria and hypertensive disorders of pregnancy (HDoP) affect millions of pregnancies worldwide, particularly those of young, first-time mothers. Small case-control studies suggest a positive association between falciparum malaria and risk of pre-eclampsia but large prospective analyses are lacking. METHODS: We characterized the relationship between malaria in pregnancy and the development of HDoP in a large, prospectively followed cohort. Pregnant women living along the Thailand-Myanmar border, an area of low seasonal malaria transmission, were followed at antenatal clinics between 1986 and 2016. The relationships between falciparum and vivax malaria during pregnancy and the odds of gestational hypertension, pre-eclampsia, or eclampsia were examined using logistic regression amongst all women and then stratified by gravidity. RESULTS: There were 23,262 singleton pregnancies in women who presented during the first trimester and were followed fortnightly. Falciparum malaria was associated with gestational hypertension amongst multigravidae (adjusted odds ratio (AOR) 2.59, 95%CI 1.59-4.23), whereas amongst primigravidae, it was associated with the combined outcome of pre-eclampsia/eclampsia (AOR 2.61, 95%CI 1.01-6.79). In contrast, there was no association between vivax malaria and HDoP. CONCLUSIONS: Falciparum but not vivax malaria during pregnancy is associated with hypertensive disorders of pregnancy.

A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border.

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.

Tenofovir disoproxil fumarate in pregnancy for prevention of mother to child transmission of hepatitis B in a rural setting on the Thailand-Myanmar border: a cost-effectiveness analysis.

BACKGROUND: Hepatitis B Virus (HBV) is transmitted from mother to child which can be prevented via birth dose vaccine combined with three follow up hepatitis B vaccines, hepatitis B immunoglobulins (HBIG), and maternal antiviral treatment with Tenofovir Disoproxil Fumarate (TDF). This study evaluates the cost effectiveness of six strategies to prevent perinatal HBV transmission in a resource limited setting (RLS) on the Thailand-Myanmar border. METHODS: The cost effectiveness of six strategies was tested by a decision tree model in R. All strategies included birth and follow up vaccinations and compared cost per infection averted against two willingness to pay thresholds: one-half and one gross domestic product (GDP) per capita. Strategies were: 1) Vaccine only, 2) HBIG after rapid diagnostic test (RDT): infants born to HBsAg+ are given HBIG, 3) TDF after RDT: HBsAg+ women are given TDF, 4) TDF after HBeAg test: HBeAg+ women are given TDF, 5) TDF after high HBV DNA: women with HBV DNA > 200,000 are given TDF, 6) HBIG & TDF after high HBV DNA: women with HBV DNA > 200,000 are given TDF and their infants are given HBIG. One-way and probabilistic sensitivity analyses were conducted on the cost-effective strategies. RESULTS: Vaccine only was the least costly option with TDF after HBeAg test strategy as the only cost-effective alternative. TDF after HBeAg test had an incremental cost-effectiveness ratio of US$1062; which would not be considered cost-effective with the lower threshold of one-half GDP per capita. The one-way sensitivity analysis demonstrated that the results were reasonably robust to changes in single parameter values. The PSA showed that TDF after HBeAg test had an 84% likelihood of being cost effective at a willingness to pay threshold of one GDP per capita per infection averted. CONCLUSIONS: We found that TDF after HBeAg test has the potential to be cost-effective if TDF proves effective locally to prevent perinatal HBV transmission. The cost of TDF treatment and reliability of the RDT could be barriers to implementing this strategy. While TDF after RDT may be a more feasible strategy to implement in RLS, TDF after HBeAg test is a less costly option.

Outcomes for 298 breastfed neonates whose mothers received ketamine and diazepam for postpartum tubal ligation in a resource-limited setting.

BACKGROUND: Anesthesia in lactating women is frequently indicated for time-sensitive procedures such as postpartum tubal ligation. Ketamine and diazepam are two of the most commonly used anesthetic agents in low resource settings, but their safety profile in lactating women has not been established. METHODS: Medical records of post-partum tubal ligations between 2013 and 2018 at clinics of the Shoklo Malaria Research Unit were reviewed for completeness of key outcome variables. Logistic regression identified presence or absence of associations between drug doses and adverse neonatal outcomes: clinically significant weight loss (≥95th percentile) and neonatal hyperbilirubinemia requiring phototherapy. RESULTS: Of 358 records reviewed, 298 were lactating women with singleton, term neonates. There were no severe outcomes in mothers or neonates. On the first postoperative day 98.0% (290/296) of neonates were reported to be breastfeeding well and 6.4% (19/298) had clinically significant weight loss. Phototherapy was required for 13.8% (41/298) of neonates. There was no association between either of the outcomes and increasing ketamine doses (up to 3.8 mg/kg), preoperative oral diazepam (5 mg), or increasing lidocaine doses (up to 200 mg). Preoperative oral diazepam resulted in lower doses of intraoperative anesthetics. Doses of intravenous diazepam above 0.1 mg/kg were associated with increased risk (adjusted odds ratio per 0.1 mg/kg increase, 95%CI) of weight loss (1.95, 95%CI 1.13-3.35, p = 0.016) and jaundice requiring phototherapy (1.87, 95%CI 1.11-3.13, p = 0.017). CONCLUSIONS: In resource-limited settings ketamine use appears safe in lactating women and uninterrupted breastfeeding should be encouraged and supported. Preoperative oral diazepam may help reduce intraoperative anesthetic doses, but intravenous diazepam should be used with caution and avoided in high doses in lactating women.

Distance matters: barriers to antenatal care and safe childbirth in a migrant population on the Thailand-Myanmar border from 2007 to 2015, a pregnancy cohort study.

BACKGROUND: Antenatal care and skilled childbirth services are important interventions to improve maternal health and lower the risk of poor pregnancy outcomes and mortality. A growing body of literature has shown that geographic distance to clinics can be a disincentive towards seeking care during pregnancy. On the Thailand-Myanmar border antenatal clinics serving migrant populations have found high rates of loss to follow-up of 17.4%, but decades of civil conflict have made the underlying factors difficult to investigate. Here we perform a comprehensive study examining the geographic, demographic, and health-related factors contributing to loss to follow-up. METHODS: Using patient records we conducted a spatial and epidemiological analysis looking for predictors of loss to follow-up and pregnancy outcomes between 2007 and 2015. We used multivariable negative binomial regressions to assess for associations between distance travelled to the clinic and birth outcomes (loss to follow-up, pregnancy complications, and time of first presentation for antenatal care.) RESULTS: We found distance travelled to clinic strongly predicts loss to follow-up, miscarriage, malaria infections in pregnancy, and presentation for antenatal care after the first trimester. People lost to follow-up travelled 50% farther than people who had a normal singleton childbirth (a ratio of distances (DR) 1.5; 95% confidence interval (CI): 1.4 - 1.5). People with pregnancies complicated by miscarriage travelled 20% farther than those who did not have miscarriages (DR: 1.2; CI 1.1-1.3), and those with Plasmodium falciparum malaria in pregnancy travelled 60% farther than those without P. falciparum (DR: 1.6; CI: 1.6 - 1.8). People who delayed antenatal care until the third trimester travelled 50% farther compared to people who attended in the first trimester (DR: 1.5; CI: 1.4 - 1.5). CONCLUSIONS: This analysis provides the first evidence of the complex impact of geography on access to antenatal services and pregnancy outcomes in the rural, remote, and politically complex Thailand-Myanmar border region. These findings can be used to help guide evidence-based interventions to increase uptake of maternal healthcare both in the Thailand-Myanmar region and in other rural, remote, and politically complicated environments.

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

BACKGROUND: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. METHODS AND FINDINGS: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. CONCLUSIONS: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa.

Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability, and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 nonpregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth and 1, 3, 6, and 12 months. Nonlinear mixed-effects modeling was used to characterize the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range], 3.30 h [1.39 to 7.83 h]) than in nonpregnant women (2.43 h [1.05 to 6.00 h]) (P=0.005). Pregnant women had lower exposures to artemether and dihydroartemisinin than nonpregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to nonpregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and nonpregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure and so could be a promising treatment option in pregnancy in areas with lower rates of malaria transmission and/or emerging drug resistance. (This study has been registered at ClinicalTrials.gov under identifier NCT01916954.).

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

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 < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013. 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 < 0.001). 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.

International gestational age-specific centiles for umbilical artery Doppler indices: a longitudinal prospective cohort study of the INTERGROWTH-21st Project.

BACKGROUND: Reference values for umbilical artery Doppler indices are used clinically to assess fetal well-being. However, many studies that have produced reference charts have important methodologic limitations, and these result in significant heterogeneity of reported reference ranges. OBJECTIVES: To produce international gestational age-specific centiles for umbilical artery Doppler indices based on longitudinal data and the same rigorous methodology used in the original Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. STUDY DESIGN: In Phase II of the INTERGROWTH-21st Project (the INTERBIO-21st Study), we prospectively continued enrolling pregnant women according to the same protocol from 3 of the original populations in Pelotas (Brazil), Nairobi (Kenya), and Oxford (United Kingdom) that had participated in the Fetal Growth Longitudinal Study. Women with a singleton pregnancy were recruited at <14 weeks' gestation, confirmed by ultrasound measurement of crown-rump length, and then underwent standardized ultrasound every 5±1 weeks until delivery. From 22 weeks of gestation umbilical artery indices (pulsatility index, resistance index, and systolic/diastolic ratio) were measured in a blinded fashion, using identical equipment and a rigorously standardized protocol. Newborn size at birth was assessed using the international INTERGROWTH-21st Standards, and infants had detailed assessment of growth, nutrition, morbidity, and motor development at 1 and 2 years of age. The appropriateness of pooling data from the 3 study sites was assessed using variance component analysis and standardized site differences. Umbilical artery indices were modeled as functions of the gestational age using an exponential, normal distribution with second-degree fractional polynomial smoothing; goodness of fit for the overall models was assessed. RESULTS: Of the women enrolled at the 3 sites, 1629 were eligible for this study; 431 (27%) met the entry criteria for the construction of normative centiles, similar to the proportion seen in the original fetal growth longitudinal study. They contributed a total of 1243 Doppler measures to the analysis; 74% had 3 measures or more. The healthy low-risk status of the population was confirmed by the low rates of preterm birth (4.9%) and preeclampsia (0.7%). There were no neonatal deaths and satisfactory growth, health, and motor development of the infants at 1 and 2 years of age were documented. Only a very small proportion (2.8%-6.5%) of the variance of Doppler indices was due to between-site differences; in addition, standardized site difference estimates were marginally outside this threshold in only 1 of 27 comparisons, and this supported the decision to pool data from the 3 study sites. All 3 Doppler indices decreased with advancing gestational age. The 3rd, 5th 10th, 50th, 90th, 95th, and 97th centiles according to gestational age for each of the 3 indices are provided, as well as equations to allow calculation of any value as a centile and z scores. The mean pulsatility index according to gestational age = 1.02944 + 77.7456*(gestational age)-2 - 0.000004455*gestational age3. CONCLUSION: We present here international gestational age-specific normative centiles for umbilical artery Doppler indices produced by studying healthy, low-risk pregnant women living in environments with minimal constraints on fetal growth. The centiles complement the existing INTERGROWTH-21st Standards for assessment of fetal well-being.