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      Maternal, fetal and perinatal factors associated with necrotizing enterocolitis in Sweden. A national case-control study

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          Abstract

          Objective

          To analyze associations of maternal, fetal, gestational, and perinatal factors with necrotizing enterocolitis in a matched case-control study based on routinely collected, nationwide register data.

          Study design

          All infants born in 1987 through 2009 with a diagnosis of necrotizing enterocolitis in any of the Swedish national health care registers were identified. For each case up to 6 controls, matched for birth year and gestational age, were selected. The resulting study population consisted of 720 cases and 3,567 controls. Information on socioeconomic data about the mother, maternal morbidity, pregnancy related diagnoses, perinatal diagnoses of the infant, and procedures in the perinatal period, was obtained for all cases and controls and analyzed with univariable and multivariable logistic regressions for the whole study population as well as for subgroups according to gestational age.

          Results

          In the study population as a whole, we found independent positive associations with necrotizing enterocolitis for isoimmunization, fetal distress, cesarean section, neonatal bacterial infection including sepsis, erythrocyte transfusion, persistent ductus arteriosus, cardiac malformation, gastrointestinal malformation, and chromosomal abnormality. Negative associations were found for maternal weight, preeclampsia, maternal urinary infection, premature rupture of the membranes, and birthweight. Different patterns of associations were seen in the subgroups of different gestational age.

          Conclusion

          With some interesting exceptions, especially in negative associations, the results of this large, population based study, are in keeping with earlier studies. Although restrained by the limitations of register data, the findings mirror conceivable pathophysiological processes and underline that NEC is a multifactorial disease.

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          Most cited references40

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          The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review

          Background The human gut is the habitat for diverse and dynamic microbial ecosystem. The human microbiota plays a critical role in functions that sustain health and is a positive asset in host defenses. Establishment of the human intestinal microbiota during infancy may be influenced by multiple factors including delivery mode. Present review compiles existing evidences on the effect of delivery mode on the diversity and colonization pattern of infants gut microbiota. Methods Two investigators searched for relevant scientific publications from four databases (Pubmed, Medline, Embase, and Web of Science). The last search was performed on September 21, 2015, using key terms ((delivery mode OR caesarean delivery OR cesarean section OR vaginal delivery) AND (gut microbiota OR gut microbiome OR gut microflora OR intestinal microflora OR microbial diversity) AND (infants OR children)). All included studies described at least two types of gut microbiota in relation to delivery mode (caesarean section vs vaginal delivery) and used fecal samples to detect gut microbiota. Results Seven out of 652 retrieved studies met inclusion criteria, were included in systematic analysis. Caesarean Section (CS) was associated with both lower abundance and diversity of the phyala Actinobacteria and Bacteroidetes, and higher abundance and diversity of the phylum Firmicute from birth to 3 months of life. At the colonization level, Bifidobacterium, and Bacteroides genera seems to be significantly more frequent in vaginally delivered infants compared with CS delivered. These infants were more colonized by the Clostridium, and Lactobacillus genera. From the reports, it is tempting to say that delivery mode has less effect on colonization and diversity of Bifidobacteria, Bacteroides, Clostridium, and Lactobacillus genera from the age of 6 to 12 months of life. Conclusion The diversity and colonization pattern of the gut microbiota were significantly associated to the mode of delivery during the first three months of life, however the observed significant differences disappears after 6 months of infants life. The healthy gut microbiota is considered to promote development and maturation of the immune system while abnormal gut is considered as the major cause of severe gastrointestinal infections during the infancy. Further studies should investigate the diversity and colonization levels of infant gut microbiota in relation to the mode of delivery and its broad impact on infants’ health at each stage of life.
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            Incidence and timing of presentation of necrotizing enterocolitis in preterm infants.

            To examine the variation in the incidence and to identify the timing of the presentation of necrotizing enterocolitis (NEC) in a cohort of preterm infants within the Canadian Neonatal Network (CNN). This was a population-based cohort of 16 669 infants with gestational age (GA) <33 weeks, admitted to 25 NICUs participating in the CNN between January 1, 2003, and December 31(,) 2008. Variations in NEC incidence among the participating NICUs for the study period were examined. We categorized early-onset NEC as occurring at <14 days of age and late-onset NEC occurring at ≥14 days. Multivariate logistic regression analysis was performed to identify risk factors for early-onset NEC. The overall incidence of NEC was 5.1%, with significant variation in the risk adjusted incidence among the participating NICUs in the CNN. Early-onset NEC occurred at a mean of 7 days compared with 32 days for late-onset NEC. Early-onset NEC infants had lower incidence of respiratory distress syndrome, patent ductus treated with indomethacin, less use of postnatal steroids, and shorter duration of ventilation days. Multivariate logistic regression analysis identified that greater GA and vaginal delivery were associated with increased risk of early-onset NEC. Among infants <33 weeks' gestation, NEC appears to present at mean age of 7 days in more mature infants, whereas onset of NEC is delayed to 32 days of age in smaller, lower GA infants. Further studies are required to understand the etiology of this disease process.
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              Intrauterine growth restriction increases morbidity and mortality among premature neonates.

              Intrauterine growth restriction (IUGR) is an important reason for premature delivery and has been reported to be associated with increased mortality, but in some studies paradoxically, improved morbidities. Data on neonatal outcomes for infants with IUGR at each viable gestational age at birth from large numbers of deliveries are lacking. More particularly, data on perinatal outcome related to an antenatal diagnosis of IUGR compared with a neonatal diagnosis are particularly deficient. Therefore, by using a large contemporary database, we evaluated the outcomes of neonates with IUGR and the gestational age-specific associations between growth restriction, morbidity, and mortality. With the use of a database formed from a computer-assisted tool that generates clinical progress notes and discharge summaries on neonatal intensive care unit (NICU) admissions, we reviewed data on neonates discharged from 124 NICUs between January 1, 1997, and December 31, 2001. We evaluated singleton, inborn neonates who delivered between 23 and 34 weeks, excluding major congenital anomalies. We compared 3 measures of IUGR: antenatally diagnosed IUGR; a birth weight below the 10th percentile (small for gestational age [SGA]), and newborn infants with either or both of these diagnoses against a control group of gestational age-matched infants meeting none of these criteria whose birth weights were no greater than the 90th percentile. Our sample included 29,916 prematurely born neonates; 1,451 (4.8%) with IUGR, 2,936 (9.8%) who were SGA, and 3,708 (12.3%) had at least 1 of these 2 markers. There were 22,798 (76%) normally grown control neonates. Within each gestational age group from 25 to 32 weeks, each marker of IUGR was associated with increased mortality, necrotizing enterocolitis, need for respiratory support at 28 days of age, and retinopathy of the premature. When corrected for gestational age, exposure to antenatal steroids, gender, and mode of delivery, these associations remained significant. IUGR remains a serious problem that is associated with increased morbidity and mortality among prematurely born neonates, regardless of the definition used or whether the diagnosis is made antenatally or after birth. These results are important for obstetric counseling and decision making and for the anticipation and treatment of premature newborn infants.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 March 2018
                2018
                : 13
                : 3
                : e0194352
                Affiliations
                [1 ] Department of Radiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
                [2 ] Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
                [3 ] Department of Pediatrics, Institution of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [4 ] Department of Surgery, Ryhov County Hospital, Jönköping, Sweden
                Hopital Robert Debre, FRANCE
                Author notes

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

                Author information
                http://orcid.org/0000-0001-5176-4949
                Article
                PONE-D-17-29090
                10.1371/journal.pone.0194352
                5865724
                29570713
                c3e64912-d7f2-4bdc-87f4-9505e383a79c
                © 2018 Ahle et al

                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.

                History
                : 5 August 2017
                : 1 March 2018
                Page count
                Figures: 0, Tables: 3, Pages: 13
                Funding
                Funded by: Region Östergötland
                Award ID: LiO-107641
                Award Recipient :
                Funded by: Futurum - the Academy of Health Care, Jönköping County Council
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100010805, Forskningsrådet i Sydöstra Sverige;
                Award ID: FORSS 77481
                Award Recipient :
                This study was supported by Region Östergötland, Sweden, https://www.fou.nu/is/lio LiO-107641 (MA); and the Medical Research Council of Southeast Sweden, https://www.fou.nu/is/forss/ FORSS-77481 (MA). Further support was received through non-specific research funding by Futurum – the Academy of Health Care, Jönköping County Council, Jönköping, Sweden http://plus.rjl.se/futurum (RA) and participation in the following grants from Region Östergötland https://www.fou.nu/is/lio: LIO-130291, LIO-204581, LIO-280451, LIO-361481, LIO-449011, and LIO-538881 (MA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Data belong to the Swedish National Board of Health and Welfare in Sweden and the Statistics Sweden, and sharing with a third part is not allowed. All requests to obtain the original data must therefore be addressed to these authorities. The Swedish National Board of Health and Welfare may be contacted at registerservice@ 123456socialstyrelsen.se and Statistics Sweden at mikrodata.individ@ 123456scb.se . The authors are willing to assist in the process.

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