Estimating Gestational Age in Late Presenters to Antenatal Care in a Resource-Limited Setting on the Thai-Myanmar Border

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The overlap between miscarriage and extreme preterm birth in a limited-resource setting on the Thailand-Myanmar border: a population cohort study [version 3; referees: 1 approved, 3 approved with reservations]

Background : No universal  demarcation of gestational age  distinguishes miscarriage and stillbirth or extreme preterm birth (exPTB). This study provides a synopsis of outcome between 22 to <28 weeks gestation from a low resource setting. Methods : A retrospective record review of a population on the Thailand-Myanmar border was conducted. Outcomes were classified as miscarriage, late expulsion of products between 22 to < 28 weeks gestation with evidence of non-viability (mostly ultrasound absent fetal heart beat) prior to 22 weeks; or  exPTB (stillbirth/live born) between 22 to < 28 weeks gestation when the fetus was viable at ≥22 weeks. Termination of pregnancy and gestational trophoblastic disease were excluded. Results : From 1995-2015, 80.9% (50,046/ 61,829) of registered women had a known pregnancy outcome, of whom 99.8% (49,931) had a known gestational age. Delivery  between 22 to <28 weeks gestation included 0.9% (472/49,931) of pregnancies after removing 18 cases (3.8%) who met an exclusion criteria. Most  pregnancies had an ultrasound: 72.5% (n=329/454);  43.6% (n=197) were classified as  miscarriage and 56.4% (n=257) exPTB.  Individual record review of miscarriages estimated that fetal death had occurred at a median of 16 weeks, despite late expulsion between 22 to <28 weeks. With available data (n=252, 5 missing) the proportion of stillbirth was 47.6% (n=120), congenital abnormality 10.5% (24/228, 29 missing) and neonatal death was 98.5% (128/131, 1 missing). Introduction of ultrasound was associated with a 2-times higher odds of classification of outcome as exPTB rather than miscarriage. Conclusion : In this low resource setting few (<1%) pregnancy outcomes occurred in the 22 to <28 weeks gestational window; four in ten  were miscarriage (late expulsion) and neonatal mortality approached 100%.  In the scale-up to preventable newborns deaths (at least initially) greater benefits will be obtained by focusing on the viable newborns of ≥ 28 weeks gestation

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

BACKGROUND: Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. METHODS AND FINDINGS: Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. CONCLUSIONS: Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. REVIEW REGISTRATION: PROSPERO CRD42015032371

The influence of the gestational age at malaria detection and treatment during pregnancy on adverse outcomes in an area of low endemicity

© 2017 Dr. Kerryn Anne MooreBackground Each year, 125 million women are at risk of malaria in pregnancy (MiP). MiP is associated with several adverse pregnancy outcomes. The safety of artemisinins – the most effective antimalarials available – for the treatment of first-trimester falciparum MiP is a pressing question. Additionally, the influence of the gestational age (GA) when malaria is detected and treated on the effects of MiP is poorly elucidated, particularly in low endemicity areas. I sought to provide a temporal characterisation of the effects of falciparum and vivax MiP on adverse outcomes in a low endemicity area, starting with an assessment of the safety of first-trimester artemisinin treatment. This work will contribute to accurate quantification of the burden of MiP, and the evidence-base for safe treatment, and targeted, context-appropriate interventions for MiP. Methods I analysed observational data collected from antenatal clinics between 1986 and 2015. The clinics were located in refugee camps and migrant communities on the Thai-Myanmar border, where malaria endemicity is low, and were operated by the Shoklo Malaria Research Unit (SMRU). SMRU antenatal care included weekly-to-fortnightly malaria screening. Data on all MiP episodes and pregnancy outcomes were available for analysis. I assessed the association between firsttrimester malaria and miscarriage, and the safety of first-trimester artemisinin treatment. I then assessed associations between MiP and other adverse outcomes [stillbirth, small-for-gestationalage (SGA), and preterm birth] with regards to the GA at malaria detection and treatment. I did a systematic review and meta-analysis to quantify the MiP-stillbirth association, and the influence of endemicity. Finally, I assessed associations between the GA at screening initiation and adverse outcomes in women with and without MiP, and associations between the length of screening absence prior to malaria detection and adverse outcomes in women with MiP. Results Between 6 January 1986 and 31 December 2015, 68919 pregnant women presented to SMRU antenatal clinics. Of these women, 61836 met my minimum inclusion criteria (women living in the migrant communities or refugee camps, with a singleton pregnancy and an estimated GA), and 9350 (15%) women had MiP. First-trimester falciparum and vivax malaria increased miscarriage risk. However, I found no evidence that first-line artemisinin treatment of firsttrimester falciparum malaria, compared to quinine treatment, further increased the risk of miscarriage or of major congenital malformations. Falciparum malaria detected and treated in third trimester was associated with stillbirth, and both vivax and falciparum malaria detected and treated in any trimester was associated with fetal loss (miscarriage or stillbirth). Mediation analyses suggested that the MiP-stillbirth associations were mediated through maternal anaemia and SGA. In a systematic review and meta-analysis, the falciparum MiP-stillbirth association was two-fold greater in low-to-intermediate endemicity settings compared to high endemicity settings. Falciparum malaria detected and treated from 12 weeks’ gestation, and vivax malaria detected and treated from 20 weeks’ gestation, were associated with SGA and/or preterm birth, regardless of symptoms. Delayed initiation of antenatal malaria screening, and longer absences from malaria screening prior to initial malaria detection, were associated with poorer pregnancy outcomes. Conclusion In this area of low malaria endemicity, falciparum and vivax MiP were associated with adverse outcomes, regardless of if and when during pregnancy it is detected and treated. The deleterious effects of MiP were present despite early detection and prompt treatment within the context of an intensive antenatal malaria screening program. MiP interventions should be started as early as possible during pregnancy. Control and elimination efforts in the general population and preconception interventions for women of reproductive age are needed to eliminate MiP and its adverse consequences

The impact of community-delivered models of malaria control and elimination: a systematic review

Background: Community-delivered models have been widely used to reduce the burden of malaria. This review aimed to explore different community-delivered models and their relative effectiveness in terms of coverage and malaria-metric outcomes in order to inform the design and implementation of Community Health Worker (CHW) programmes for malaria control and elimination. Methods: A systematic review of studies investigating the impact of community-delivered models on coverage and malaria-metric (parasitaemia and hyperparasitaemia, malaria case and mortality, anaemia, and fever) outcomes compared to non- community-delivered models was undertaken by searching in five databases of published papers and grey literature databases. Data were extracted from studies meeting inclusion and quality criteria (assessed using relevant tools for the study design) by two independent authors. Meta-analyses were performed where there was sufficient homogeneity in effect and stratified by community-delivered models to assess the impact of each model on coverage and malaria-metric outcomes. Results: 28 studies were included from 7042 records identified. The majority of studies (25/28) were performed in high transmission settings in Africa and there was heterogeneity in the type of, and interventions delivered as part of the community-delivered models. Compared to non- community-delivered models, community-delivered models increased coverage of actual bed net usage (Relative Risk (RR) = 1.64 95% CI 1.39, 1.95), intermittent preventive treatment in pregnancy (RR = 1.36 95% CI 1.29, 1.44) and appropriate and timely treatment of febrile children, and improved malaria-metric outcomes such as malaria mortality (RR = 0.58 95% CI 0.52, 0.65). However, the considerable heterogeneity was found in the impact of community-delivered models in reducing, parasitaemia and hyperparasitaemia prevalence, anaemia incidence, fever prevalence and malaria caseload. Statistical comparisons of different community-delivered models were not undertaken due to the heterogeneity of the included studies in terms of method and interventions provided. Conclusion: Overall, the community-delivered model is effective in improving the coverage of malaria interventions and reducing malaria-associated mortality. The heterogeneity of the community-delivered models and their impact on malaria-metric indices suggests that evidence for context-specific solutions is required. In particular, community-delivered models for malaria elimination, integrated with services for other common primary health problems, are yet to be evaluated

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Quantification of the association between malaria in pregnancy and stillbirth:a systematic review and meta-analysis

Background: 2·6 million stillbirths occur annually worldwide. The association between malaria in pregnancy and stillbirth has yet to be comprehensively quantified. We aimed to quantify the association between malaria in pregnancy and stillbirth, and to assess the influence of malaria endemicity on the association. Methods: We did a systematic review of the association between confirmed malaria in pregnancy and stillbirth. We included population-based cross-sectional, cohort, or case-control studies (in which cases were stillbirths or perinatal deaths), and randomised controlled trials of malaria in pregnancy interventions, identified before Feb 28, 2017. We excluded studies in which malaria in pregnancy was not confirmed by PCR, light microscopy, rapid diagnostic test, or histology. The primary outcome was stillbirth. We pooled estimates of the association between malaria in pregnancy and stillbirth using meta-analysis. We used meta-regression to assess the influence of endemicity. The study protocol is registered with PROSPERO, protocol number CRD42016038742. Findings: We included 59 studies of 995 records identified, consisting of 141 415 women and 3387 stillbirths. Plasmodium falciparum malaria detected at delivery in peripheral samples increased the odds of stillbirth (odds ratio [OR] 1·81 [95% CI 1·42–2·30]; I2=26·1%; 34 estimates), as did P falciparum detected in placental samples (OR 1·95 [1·48–2·57]; I2=33·6%; 31 estimates). P falciparum malaria detected and treated during pregnancy was also associated with stillbirth, but to a lesser extent (OR 1·47 [95% CI 1·13–1·92]; 19 estimates). Plasmodium vivax malaria increased the odds of stillbirth when detected at delivery (2·81 [0·77–10·22]; three estimates), but not when detected and treated during pregnancy (1·09 [0·76–1·57]; four estimates). The association between P falciparum malaria in pregnancy and stillbirth was two times greater in areas of low-to-intermediate endemicity than in areas of high endemicity (ratio of ORs 1·96 [95% CI 1·34–2·89]). Assuming all women with malaria are still parasitaemic at delivery, an estimated 20% of the 1 059 700 stillbirths in malaria-endemic sub-Saharan Africa are attributed to P falciparum malaria in pregnancy; the population attributable fraction decreases to 12%, assuming all women with malaria are treated during pregnancy. Interpretation: P falciparum and P vivax malaria in pregnancy both increase stillbirth risk. The risk of malaria-associated stillbirth is likely to increase as endemicity declines. There is a pressing need for context-appropriate, evidence-based interventions for malaria in pregnancy in low-endemicity settings.</p

Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis

Background: 2·6 million stillbirths occur annually worldwide. The association between malaria in pregnancy and stillbirth has yet to be comprehensively quantified. We aimed to quantify the association between malaria in pregnancy and stillbirth, and to assess the influence of malaria endemicity on the association. Methods: We did a systematic review of the association between confirmed malaria in pregnancy and stillbirth. We included population-based cross-sectional, cohort, or case-control studies (in which cases were stillbirths or perinatal deaths), and randomised controlled trials of malaria in pregnancy interventions, identified before Feb 28, 2017. We excluded studies in which malaria in pregnancy was not confirmed by PCR, light microscopy, rapid diagnostic test, or histology. The primary outcome was stillbirth. We pooled estimates of the association between malaria in pregnancy and stillbirth using meta-analysis. We used meta-regression to assess the influence of endemicity. The study protocol is registered with PROSPERO, protocol number CRD42016038742. Findings: We included 59 studies of 995 records identified, consisting of 141 415 women and 3387 stillbirths. Plasmodium falciparum malaria detected at delivery in peripheral samples increased the odds of stillbirth (odds ratio [OR] 1·81 [95% CI 1·42–2·30]; I2=26·1%; 34 estimates), as did P falciparum detected in placental samples (OR 1·95 [1·48–2·57]; I2=33·6%; 31 estimates). P falciparum malaria detected and treated during pregnancy was also associated with stillbirth, but to a lesser extent (OR 1·47 [95% CI 1·13–1·92]; 19 estimates). Plasmodium vivax malaria increased the odds of stillbirth when detected at delivery (2·81 [0·77–10·22]; three estimates), but not when detected and treated during pregnancy (1·09 [0·76–1·57]; four estimates). The association between P falciparum malaria in pregnancy and stillbirth was two times greater in areas of low-to-intermediate endemicity than in areas of high endemicity (ratio of ORs 1·96 [95% CI 1·34–2·89]). Assuming all women with malaria are still parasitaemic at delivery, an estimated 20% of the 1 059 700 stillbirths in malaria-endemic sub-Saharan Africa are attributed to P falciparum malaria in pregnancy; the population attributable fraction decreases to 12%, assuming all women with malaria are treated during pregnancy. Interpretation: P falciparum and P vivax malaria in pregnancy both increase stillbirth risk. The risk of malaria-associated stillbirth is likely to increase as endemicity declines. There is a pressing need for context-appropriate, evidence-based interventions for malaria in pregnancy in low-endemicity settings. Funding: Australian Commonwealth Government, National Health and Medical Research Council, Australian Research Council