Cerebral and cardiac doppler parameters in the

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Jan 12, 2011 - (Crispi et al., 2010) published that these fetuses have cardiac remodeling and echocardiographic subclinical signs of cardiac dysfunction in ...
Cerebral and cardiac doppler parameters in the identification of fetuses with late-onset intrauterine growth restriction at risk of adverse perinatal and neurobehavioral outcome Rogelio Cruz Martínez

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PhD THESIS Departament d’Obstetrícia i Ginecologia, Pediatria, Radiologia i Anatomía. Programa de Doctorat de Medicina RD 1393/2007

CEREBRAL AND CARDIAC DOPPLER PARAMETERS IN THE IDENTIFICATION OF FETUSES WITH LATE-ONSET INTRAUTERINE GROWTH RESTRICTION AT RISK OF ADVERSE PERINATAL AND NEUROBEHAVIORAL OUTCOME

Submitted by Rogelio Cruz Martínez

For the degree of European Doctor in Medicine November 2010

Director: Professor Eduard Gratacós Solsona Department of Maternal-Fetal Medicine Hospital Clínic, University of Barcelona, Spain

Codirector: Professor Francesc Figueras Retuerta Department of Maternal-Fetal Medicine Hospital Clínic, University of Barcelona, Spain

Professor Eduard Gratacós Solsona Department of Maternal-Fetal Medicine Hospital Clínic, University of Barcelona, Spain

Professor Francesc Figueras Retuerta Department of Maternal-Fetal Medicine Hospital Clínic, University of Barcelona, Spain

We confirm that Rogelio Cruz Martínez has realized under our supervision the studies presented in the thesis “Cerebral and cardiac Doppler parameters in the identification of fetuses with late-onset intrauterine growth restriction at risk of adverse perinatal and neurobehavioral outcome”. The present thesis has been structured following the normative for PhD thesis as a compendium of publications for the degree of Doctor of European Doctor in medicine, and that the mentioned studies are ready to be presented to the Tribunal.

Eduard Gratacós Solsona

Francesc Figueras Retuerta

Barcelona, November 2010.

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ACKNOWLEDGMENTS

ACKNOWLEDGMENTS I would like to express my gratitude to my Professor Eduard who first introduced me into the field of fetal medicine, and has trained me during these years. He has been the best example for improving myself day by day. To all the professors that participated in my training, specially to Josep Maria and Olga, from whom I learned everyday so many new things regarding Fetal Medicine. To all coauthors of the attached papers, who have been indispensable in order to achieve my thesis, in particular to Francesc for his friendship and adopting me as “family”, besides having trained me on fetal Doppler and improved my skills in medical statistics. To Edgar for his friendship and for being always supportive and encouraging me. Thanks to my friends and colleagues; Oscar for trusting me and Fátima for being always ready to help with commitment. I also wish to thank my parents and brothers for being so close despite the distance. Finally, I would like to make a special mention to my wife and my son for all the love and support. Without them this exile would not have been possible.

Acknowledgements for financial support: I also wish to thank the Mexican National Council for Science and Technology (CONACyT), in Mexico City, and the Marie Curie European Program for Early Stage Researchers in Fetal Medicine (FETAL-MED-019707-2) for supporting my predoctoral stay at the Hospital Clinic in Barcelona, Spain.

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CONTENTS

CONTENTS

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CONTENTS TABLE OF CONTENTS 1) Introduction

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1.1 Intrauterine Growth Restriction vs. Small for Gestational Age

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1.2 Early vs. Late-onset Intrauterine Growth Restriction

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1.3 Middle cerebral artery

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1.4 Cerebroplacental ratio

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1.5 Cerebral blood perfusion

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1.6 Aortic isthmus

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1.7 Myocardial performance index

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1.8 Ductus venosus

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1.9 Relevance and justification of the research study

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2) Hypothesis

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3) Objective

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4) Methods

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4.1 Study design

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4.2 Predictive variables

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4.3 Management and outcome variables

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4.4 Ethical approval

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4.5 Statistical analysis

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5) Published papers

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5.1 Study 1: Normal ranges of fetal cerebral blood perfusion

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5.2 Study 2: Normal ranges of fetal myocardial performance index

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5.3 Study 3: Longitudinal changes of cerebral blood perfusion

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5.4 Study 4: Changes of fetal cardiac Doppler parameters

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5.5 Study 5: Prediction of fetal distress and neonatal acidosis

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5.6 Study 6: Prediction of abnormal neonatal neurobehavior

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CONTENTS 6) Results

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5.1 Study 1: Normal ranges of fetal cerebral blood perfusion

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5.2 Study 2: Normal ranges of fetal myocardial performance index

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5.3 Study 3: Longitudinal changes of cerebral blood perfusion

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5.4 Study 4: Changes of fetal cardiac Doppler parameters

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5.5 Study 5: Prediction of fetal distress and neonatal acidosis

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5.6 Study 6: Prediction of abnormal neonatal neurobehavior

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7) Discussion

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8) Conclusion

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9) Bibliography

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10) Abbreviations

128

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INTRODUCTION

1. INTRODUCTION

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INTRODUCTION 1.1 Intrauterine Growth Restriction vs. Small for Gestational Age

A fetus is considered growth-restricted when sonographically measured fetal dimensions, particularly fetal weight estimated from multiple biometric measurements below 10th centile (Ott, 2006, Hadlock et al., 1985, Maulik, 2006). However; this approach can not differentiate constitutional fetal smallness from fetal growth failure. Because fetal growth restriction is a late manifestation of early abnormal placental development, when is confirmed, is necessary to differentiate SGA and IUGR, to identify fetuses who are small due to placental dysfunction and who required early intervention assessing placental function with Doppler ultrasound (Maulik, 2006, Kinzler and Vintzileos, 2008, Tan and Yeo, 2005). SGA fetuses are those identified by a fetal estimated weight below10th centile and a negative screen for abnormal placental or fetal Doppler, or evidence of genetic syndrome or fetal infections. When fetal estimated weight is low together with abnormal placental and fetal Doppler are considered true IUGR due to placental insufficiency(Cruz-Martinez and Figueras, 2009). Recently, with improved ultrasound imaging and the advent of Doppler studies, it has become obvious that, within the descriptive term SGA, there are separate groups with distinct etiologies and prognoses. Therefore, it is generally accepted that normal SGA and IUGR must be considered separately (Soothill et al., 1999). Population birthweight centiles, which account for fetal sex and gestational age at delivery, are typically used to classify size at birth. Unfortunately, due to the wide biologic variability in human size, interplay a number of genetic and physiological factors, such as sex, maternal body mass index, and ethnic group; is necessary to construct normal curves for each population, utilizing a birth weight centile cutoff to identify fetuses at significant risk of compromise more adequately (Groom et al., 2007, McCowan et al., 2005, Figueras et al., 2007, Figueras et al., 2008c). For our population, Figueras et al.(Figueras et al., 2008c) classified no anomalous singleton pregnancies deliveries after 24 weeks gestation as SGA (