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      Risk Factors and Adverse Perinatal Outcomes among Term and Preterm Infants Born Small-for-Gestational-Age: Secondary Analyses of the WHO Multi-Country Survey on Maternal and Newborn Health

      1 , * , 1 , 1 , 2 , 3 , 4 , 3 , 5 , 5 , 1 , on behalf of the WHO Multi-Country Survey on Maternal and Newborn Health Research Network
      PLoS ONE
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          Small for gestational age (SGA) is not only a major indicator of perinatal mortality and morbidity, but also the morbidity risks in later in life. We aim to estimate the association between the birth of SGA infants and the risk factors and adverse perinatal outcomes among twenty-nine countries in Africa, Latin America, the Middle East and Asia in 359 health facilities in 2010–11.


          We analysed facility-based, cross-sectional data from the WHO Multi-country Survey on Maternal and Newborn Health. We constructed multilevel logistic regression models with random effects for facilities and countries to estimate the risk factors for SGA infants using country-specific birthweight reference standards in preterm and term delivery, and SGA’s association with adverse perinatal outcomes. We compared the risks and adverse perinatal outcomes with appropriate for gestational age (AGA) infants categorized by preterm and term delivery.


          A total of 295,829 singleton infants delivered were analysed. The overall prevalence of SGA was highest in Cambodia (18.8%), Nepal (17.9%), the Occupied Palestinian Territory (16.1%), and Japan (16.0%), while the lowest was observed in Afghanistan (4.8%), Uganda (6.6%) and Thailand (9.7%). The risk of preterm SGA infants was significantly higher among nulliparous mothers and mothers with chronic hypertension and preeclampsia/eclampsia (aOR: 2.89; 95% CI: 2.55–3.28) compared with AGA infants. Higher risks of term SGA were observed among sociodemographic factors and women with preeclampsia/eclampsia, anaemia and other medical conditions. Multiparity (> = 3) (AOR: 0.88; 95% CI: 0.83–0.92) was a protective factor for term SGA. The risk of perinatal mortality was significantly higher in preterm SGA deliveries in low to high HDI countries.


          Preterm SGA is associated with medical conditions related to preeclampsia, but not with sociodemographic status. Term SGA is associated with sociodemographic status and various medical conditions.

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          Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia.

          Maternal uteroplacental blood flow increases during pregnancy. Altered uteroplacental blood flow is a core predictor of abnormal pregnancy. Normally, the uteroplacental arteries are invaded by endovascular trophoblast and remodeled into dilated, inelastic tubes without maternal vasomotor control. Disturbed remodeling is associated with maintenance of high uteroplacental vascular resistance and intrauterine growth restriction (IUGR) and preeclampsia. Herein, we review routes, mechanisms, and control of endovascular trophoblast invasion. The reviewed data suggest that endovascular trophoblast invasion involves a side route of interstitial invasion. Failure of vascular invasion is preceded by impaired interstitial trophoblast invasion. Extravillous trophoblast synthesis of nitric oxide is discussed in relation to arterial dilation that paves the way for endovascular trophoblast. Moreover, molecular mimicry of invading trophoblast-expressing endothelial adhesion molecules is discussed in relation to replacement of endothelium by trophoblast. Also, maternal uterine endothelial cells actively prepare endovascular invasion by expression of selectins that enable trophoblast to adhere to maternal endothelium. Finally, the mother can prevent endovascular invasion by activated macrophage-induced apoptosis of trophoblast. These data are partially controversial because of methodological restrictions associated with limitations of human tissue investigations and animal studies. Animal models require special care when extrapolating data to the human due to extreme species variations regarding trophoblast invasion. Basal plates of delivered placentas or curettage specimens have been used to describe failure of trophoblast invasion associated with IUGR and preeclampsia; however, they are unsuitable for these kinds of studies, since they do not include the area of pathogenic events, i.e., the placental bed.
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            Birthweight and mortality in adulthood: a systematic review and meta-analysis.

            Small birth size may be associated with increased risk of cardiovascular diseases (CVD), whereas large birth size may predict increased risk of obesity and some cancers. The net effect of birth size on long-term mortality has only been assessed in individual studies, with conflicting results. The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines for conducting and reporting meta-analysis of observational studies were followed. We retrieved 22 studies that assessed the association between birthweight and adult mortality from all causes, CVD or cancer. The studies were systematically reviewed and those reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs) per kilogram (kg) increase in birthweight were included in generic inverse variance meta-analyses. For all-cause mortality, 36,834 deaths were included and the results showed a 6% lower risk (adjusted HR = 0.94, 95% CI: 0.92-0.97) per kg higher birthweight for men and women combined. For cardiovascular mortality, the corresponding inverse association was stronger (HR = 0.88, 95% CI: 0.85-0.91). For cancer mortality, HR per kg higher birthweight was 1.13 (95% CI: 1.07-1.19) for men and 1.04 (95% CI: 0.98-1.10) for women (P(interaction) = 0.03). Residual confounding could not be eliminated, but is unlikely to account for the main findings. These results show an inverse but moderate association of birthweight with adult mortality from all-causes and a stronger inverse association with cardiovascular mortality. For men, higher birthweight was strongly associated with increased risk of cancer deaths. The findings suggest that birthweight can be a useful indicator of processes that influence long-term health.
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              Socio-economic disparities in pregnancy outcome: why do the poor fare so poorly?

              In this paper, we review the evidence bearing on socio-economic disparities in pregnancy outcome, focusing on aetiological factors mediating the disparities in intrauterine growth restriction (IUGR) and preterm birth. We first summarise what is known about the attributable determinants of IUGR and preterm birth, emphasising their quantitative contributions (aetiological fractions) from a public health perspective. We then review studies relating these determinants to socio-economic status and, combined with the evidence about their aetiological fractions, reach some tentative conclusions about their roles as mediators of the socio-economic disparities. Cigarette smoking during pregnancy appears to be the most important mediating factor for IUGR, with low gestational weight gain and short stature also playing substantial roles. For preterm birth, socio-economic gradients in bacterial vaginosis and cigarette smoking appear to explain some of the socio-economic disparities; psychosocial factors may prove even more important, but their aetiological links with preterm birth require further clarification. Research that identifies and quantifies the causal pathways and mechanisms whereby social disadvantage leads to higher risks of IUGR and preterm birth may eventually help to reduce current disparities and improve pregnancy outcome across the entire socio-economic spectrum.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                13 August 2014
                : 9
                : 8
                : e105155
                [1 ]Department of Health Policy, National Center for Child Health and Development, Tokyo, Japan
                [2 ]Department of Paediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
                [3 ]UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
                [4 ]School of Population Health, University of Western Australia, Perth, Australia
                [5 ]Center for Population Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico
                VU University Medical Center, Netherlands
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: EO TG. Performed the experiments: JPS RM. Analyzed the data: TG EO. Contributed reagents/materials/analysis tools: EO. Wrote the paper: EO. Contributed to the interpretation of the analysis and reviewed the manuscript: NM JPV CP EOP. Reviewed and approved final version of the manuscript: EO TG NM JPV CP EO JPS RM.

                ¶These authors are co-first authors on this work.

                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 3 December 2013
                : 21 July 2014
                Page count
                Pages: 10
                This study is financially supported by the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP); the World Health Organization (WHO); the United States Agency for International Development (USAID); the Ministry of Health, Labour and Welfare of Japan, and Gynuity Health Projects. The sponsors had no role in the data collection, analysis, or interpretation of the data, the writing of the report, or the decision to submit for publication. All authors had access to the analysis plan, the outputs of that analysis and could see the data if they wished to do so. All authors participated in the final discussion and approved the submission.
                Research Article
                Medicine and Health Sciences
                Clinical Epidemiology
                Child Health
                Adverse Reactions
                Public and Occupational Health
                Global Health
                Women's Health
                Maternal Health
                Obstetrics and Gynecology
                People and Places
                Research and Analysis Methods
                Research Design
                Clinical Research Design
                Cross-Sectional Studies
                Survey Research



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