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      Influence of the number and timing of malaria episodes during pregnancy on prematurity and small-for-gestational-age in an area of low transmission

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          Abstract

          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 <32 weeks) and late preterm birth (≥32 and <37 weeks) and international SGA standards were used.

          Results

          Of 50,060 pregnant women followed, 8221 (16%) had malaria during their pregnancy. Of the 50,060 newborns, 10,005 (21%) were SGA, 540 (1%) were very preterm, and 4331 (9%) were late preterm. The rates of falciparum and vivax malaria were highest at 6 and 5 weeks’ gestation, respectively. The odds of SGA increased linearly by 1.13-fold (95% confidence interval: 1.09, 1.17) and 1.27-fold (1.21, 1.33) per episode of falciparum and vivax malaria, respectively. Falciparum malaria at any gestation period after 12–16 weeks and vivax malaria after 20–24 weeks were associated with SGA (falciparum odds ratio, OR range: 1.15–1.63 [ p range: <0.001–0.094]; vivax OR range: 1.12–1.54 [ p range: <0.001–0.138]). Falciparum malaria at any gestation period after 24–28 weeks was associated with either very or late preterm birth (OR range: 1.44–2.53; p range: <0.001–0.001). Vivax malaria at 24–28 weeks was associated with very preterm birth (OR: 1.79 [1.11, 2.90]), and vivax malaria at 28–32 weeks was associated with late preterm birth (OR: 1.23 [1.01, 1.50]). Many of these associations held for asymptomatic malaria.

          Conclusions

          Protection against malaria should be started as early as possible in pregnancy. Malaria control and elimination efforts in the general population can avert the adverse consequences associated with treated asymptomatic malaria in pregnancy.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12916-017-0877-6) contains supplementary material, which is available to authorized users.

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          Most cited references40

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          Pregnancy and infection.

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            Malaria in pregnancy: pathogenesis and immunity.

            Understanding of the biological basis for susceptibility to malaria in pregnancy was recently advanced by the discovery that erythrocytes infected with Plasmodium falciparum accumulate in the placenta through adhesion to molecules such as chondroitin sulphate A. Antibody recognition of placental infected erythrocytes is dependent on sex and gravidity, and could protect from malaria complications. Moreover, a conserved parasite gene-var2csa-has been associated with placental malaria, suggesting that its product might be an appropriate vaccine candidate. By contrast, our understanding of placental immunopathology and how this contributes to anaemia and low birthweight remains restricted, although inflammatory cytokines produced by T cells, macrophages, and other cells are clearly important. Studies that unravel the role of host response to malaria in pathology and protection in the placenta, and that dissect the relation between timing of infection and outcome, could allow improved targeting of preventive treatments and development of a vaccine for use in pregnant women.
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              Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study

              Summary 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 & Melinda Gates Foundation.
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                Author and article information

                Contributors
                kerrynmoore.kam@burnet.edu.au
                julieas@unimelb.edu.au
                sam@shoklo-unit.com
                ayemin@shoklo-unit.com
                ehmoosmru@gmail.com
                mookhopaw@shoklo-unit.com
                jathee@shoklo-unit.com
                yon@tropmedres.ac
                freya.fowkes@burnet.edu.au
                nickwdt@tropmedres.ac
                francois@tropmedres.ac
                rose@shoklo-unit.com
                Journal
                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central (London )
                1741-7015
                21 June 2017
                21 June 2017
                2017
                : 15
                : 117
                Affiliations
                [1 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, , The University of Melbourne, ; Melbourne, VIC Australia
                [2 ]ISNI 0000 0001 2224 8486, GRID grid.1056.2, , Macfarlane Burnet Institute for Medical Research and Public Health, ; Melbourne, VIC Australia
                [3 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, , Mahidol University, ; Mae Sot, Thailand
                [4 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, , Mahidol University, ; Bangkok, Thailand
                [5 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Department of Epidemiology and Preventive Medicine and Department of Infectious Diseases, , Monash University, ; Melbourne, VIC Australia
                [6 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK
                Article
                877
                10.1186/s12916-017-0877-6
                5479010
                28633672
                c78a1795-8b3b-4842-aacf-aa834f8c6370
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 February 2017
                : 16 May 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: WT-106698
                Funded by: FundRef http://dx.doi.org/10.13039/501100000923, Australian Research Council;
                Funded by: Australian Commonwealth Government
                Funded by: FundRef http://dx.doi.org/10.13039/501100004752, State Government of Victoria;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Award ID: 1104975
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: 46589
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Medicine
                malaria in pregnancy,preterm birth,small-for-gestational-age,timing,gestation
                Medicine
                malaria in pregnancy, preterm birth, small-for-gestational-age, timing, gestation

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