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Effects of Delayed Versus Early Cord Clamping on Healthy Term Infants

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Effects of Delayed Versus Early Cord Clamping on Healthy Term Infants Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 893 Effects of Delayed versus Early Cord Clamping on Healthy Term Infants OLA ANDERSSON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-8647-1 UPPSALA urn:nbn:se:uu:diva-198167 2013 Dissertation presented at Uppsala University to be publicly examined in Rosénsalen, Ingång 95/96, Akademiska Barnsjukhuset, Uppsala, Thursday, May 23, 2013 at 09:30 for the degree of Doctor of Philosophy. The examination will be conducted in English. Abstract Andersson, O. 2013. Effects of Delayed versus Early Cord Clamping on Healthy Term Infants. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 893. 66 pp. Uppsala. ISBN 978-91-554-8647-1. The aim of this thesis was to study maternal and infant effects of delayed cord clamping (≥180 seconds, DCC) compared to early (≤10 seconds, ECC) in a randomised controlled trial. Practice and guidelines regarding when to clamp the cord vary globally, and different meta- analyses have shown contradictory conclusions on benefits and disadvantages of DCC and ECC. The study population consisted of 382 term infants born after normal pregnancies and ran- domised to DCC or ECC after birth. The primary objective was iron stores and iron defi- ciency at 4 months of age, but the thesis was designed to investigate a wide range of sug- gested effects associated with cord clamping. Paper I showed that DCC was associated with improved iron stores at 4 months (45% higher ferritin) and that the incidence of iron deficiency was reduced from 5.7% to 0.6%. Neonatal anaemia at 2-3 days was less frequent in the DCC group, 1.2% vs. 6.3%. There were no differences between the groups in respiratory symptoms, polycythaemia, or hyper- bilirubinaemia. In paper II we demonstrated that DCC versus ECC was not associated with higher risk for maternal post partum haemorrhage and rendered a comparable ratio of valid umbilical artery blood gas samples. In paper III, the Ages and Stages Questionnaire was used to assess neurodevelopment at 4 months. The total scores did not differ, but the DCC group had a higher score in the problem- solving domain and a lower score in the personal-social domain. Immunoglobulin G level was 0.7 g/L higher in the DCC group at 2–3 days, but did not differ at 4 months. Symptoms of infection up to 4 months were comparable between groups. Finally, in paper IV, iron stores and neurodevelopment were similar between groups at 12 months. Gender specific outcome on neurodevelopment at 12 months was discovered, imply- ing positive effects from DCC on boys and negative on girls. We conclude that delaying umbilical cord clamping for 180 seconds is safe and associated with a significantly reduced risk for iron deficiency at 4 months, which may have neurodevel- opmental effects at a later age. Keywords: active management, birth, breast feeding, cord clamping, ferritin, growth, haemoglobin, human infant, infections, iron, iron deficiency, iron deficiency anemia, iron status, morbidity, neurodevelopment, randomised controlled trial, umbilical cord Ola Andersson, Uppsala University, Department of Women's and Children's Health, Pediatrics, Akademiska barnsjukhuset, ing. 95 nbv, Uppsala, Sweden. © Ola Andersson 2013 ISSN 1651-6206 ISBN 978-91-554-8647-1 urn:nbn:se:uu:diva-198167 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-198167) Cover design: Fröken Fokus www.frokenfokus.se Printed by Elanders Sverige AB, 2013 To Cecilia, for providing the spark in real life and in my research To Olle, Måns and Lykke, for being my highly beloved arrows towards the future List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Andersson O, Hellström-Westas L, Andersson D, Domellöf M.(2011) Effect of delayed versus early umbilical cord clamp- ing on neonatal outcomes and iron status at 4 months: a ran- domised controlled trial. BMJ. 343:d7157. II Andersson O, Hellström-Westas L, Andersson D, Clausen J, Domellöf M.(2012) Effects of delayed compared to early um- bilical cord clamping on maternal postpartum hemorrhage and cord blood gas sampling: a randomized trial. Acta Obstetr Gy- necol Scand, 91. doi: 10.1111/j.600-0412.2012.01530.x. [Epub ahead of print]. III Andersson O, Domellöf M, Andersson D, Hellström-Westas L. (2013) Effects of delayed cord clamping on neurodevelopment and infection at four months of age: a randomised trial. Acta Paediatr. 102(5): 525–531. doi: 10.1111/apa.12168 IV Andersson O, Domellöf M, Andersson D, Hellström-Westas L. A randomized trial of delayed versus early cord clamping: iron status and neurodevelopment at 12 months of age. Manuscript. Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 The fetal-placental circulation ............................................................. 12 Early and delayed cord clamping - definitions .................................... 13 Overview of previous research on cord clamping ............................... 14 Active management of third stage of labour ........................................ 16 Guidelines for umbilical cord clamping .............................................. 16 Umbilical cord blood gas sampling ..................................................... 18 Iron deficiency ..................................................................................... 19 Aims of the thesis.......................................................................................... 21 Methods ........................................................................................................ 22 Trial design .......................................................................................... 22 Participants .......................................................................................... 22 Randomisation ..................................................................................... 22 Intervention .......................................................................................... 23 Blinding ............................................................................................... 23 Data collection .......................................................................................... 24 Maternal data ....................................................................................... 24 Neonatal data ....................................................................................... 24 4 and 12 month data ............................................................................. 25 Blood samples ...................................................................................... 26 Ages and Stages Questionnaire (ASQ) ................................................ 27 Sample size .......................................................................................... 27 Statistical analysis .................................................................................... 28 Ethical considerations .............................................................................. 28 Results ........................................................................................................... 31 Maternal characteristics ....................................................................... 31 Newborn characteristics ....................................................................... 31 Per protocol analysis of background characteristics ............................ 32 Main results .............................................................................................. 32 Obstetric outcome (paper II) ................................................................ 32 Neonatal outcome (paper I) ................................................................. 35 Haematological status and iron status (papers I and IV) ..................... 37 Neurodevelopment (papers III and IV) ................................................ 40 Morbidity and IgG at 4 months (paper III) .......................................... 41 Growth and nutrition (papers I, III and IV) ......................................... 42 Discussion ..................................................................................................... 44 Conclusions ................................................................................................... 50 Future perspectives ....................................................................................... 51 Swedish summary ......................................................................................... 52 Acknowledgements ....................................................................................... 55 References ..................................................................................................... 59 Abbreviations ADHD Attention-deficit/hyperactivity disorder AMTSL Active management of third stage labour ASQ Ages and Stages Questionnaire CI Confidence interval CRP C-reactive protein DCC Delayed cord clamping ECC Early umbilical cord clamping ELISA Enzyme-linked immunosorbent assay FIGO International Federation of Obstetrics and Gynaecology Hb Haemoglobin Hct Haematocrit ICM International Confederation of Midwives ID Iron deficiency IDA Iron deficiency anaemia IgG Immunoglobulin G MCHC Mean cell haemoglobin concentration MCV Mean cell volume PPH Maternal postpartum haemorrhage
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