Textbook of diabetes and pregnancy, third edition

Textbook of diabetes and pregnancy, third edition trình bày một bài đánh giá toàn diện về khoa học, quản lý lâm sàng, và ý nghĩa y học của bệnh đái tháo đường thai kỳ. Được viết bởi một đội ngũ chuyên gia, cuốn sách cung cấp một cái nhìn toàn diện về bệnh đái tháo đường thai kỳ và sẽ là vô giá đối với các chuyên gia y tế sản khoa, bác sĩ bệnh tiểu đường, bác sĩ nhi khoa và nhiều bác sĩ phụ khoa và bác sĩ đa khoa liên quan đến việc quản lý các bệnh không lây nhiễm trong thai kỳ.

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account You can find more information at https://support.vitalsource.com/ hc/en-us/categories/200139976-Bookshelf-for-Androidand-Kindle-Fire No returns if this code has been revealed N.B The code in the scratch-off panel can only be used once When you have created a Bookshelf account and redeemed the code you will be able to access the ebook online or offline on your smartphone, tablet or PC/Mac SUPPORT If you have any questions about downloading Bookshelf, creating your account, or accessing and using your ebook edition, please visit http://support.vitalsource.com/ SERIES IN MATERNAL-FETAL MEDICINE Published in association with the Journal of Maternal-Fetal & Neonatal Medicine Edited by Gian Carlo Di Renzo and Dev Maulik Howard Carp, Recurrent Pregnancy Loss, ISBN 9780415421300 Vincenzo Berghella, Obstetric Evidence Based Guidelines, ISBN 9780415701884 Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, ISBN 9780415432818 Moshe Hod, Lois Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, Second Edition, ISBN 9780415426206 Simcha Yagel, Norman H Silverman, Ulrich Gembruch, Fetal Cardiology, Second Edition, ISBN 9780415432658 Fabio Facchinetti, Gustaaf A Dekker, Dante Baronciani, George Saade, Stillbirth: Understanding and Management, ISBN 9780415473903 Vincenzo Berghella, Maternal–Fetal Evidence Based Guidelines, Second Edition, ISBN 9781841848228 Vincenzo Berghella, Obstetric Evidence Based Guidelines, Second Edition, ISBN 9781841848242 Howard Carp, Recurrent Pregnancy Loss: Causes, Controversies, and Treatment, Second Edition, ISBN 9781482216141 Moshe Hod, Lois G Jovanovic, Gian Carlo Di Renzo, Alberto De Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, Third Edition, ISBN 9781482213607 Edited by Moshe Hod MD Director, Division of Maternal Fetal Medicine Rabin Medical Center Sackler Faculty of Medicine, Tel-Aviv University Petah-Tiqva, Israel Lois G Jovanovic MD Clinical Professor of Medicine, University of Southern California Keck School of Medicine Adjunct Professor of Biomolecular Science and Engineering University of California at Santa Barbara CEO and Chief Scientific Officer Sansum Diabetes Research Institute, Santa Barbara, CA, USA Gian Carlo Di Renzo MD PhD Professor and Chairman Department of Obstetrics and Gynecology Director, Perinatal and Reproductive Medicine Center and Midwifery School, University Hospital Perugia, Italy Director, Permanent International and European School of Perinatal and Reproductive Medicine (PREIS) Florence, Italy Alberto de Leiva MD PhD Professor of Medicine, Universitat Autònoma de Barcelona Director, Department of Endocrinology, Diabetes and Nutrition Hospital de la Santa Creu i Sant Pau Principal Investigator, EDUAB-HSP, CIBER-BBN, ISCIII Vice President and Scientific Director, Fundación DIABEM Barcelona, Spain Oded Langer MD PhD Former Babcock Professor and Chairman Department of Obstetrics and Gynecology St Luke’s–Roosevelt Hospital 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mothers Maya and Timi For their tolerance, patience, and love—they made it all possible Moshe Hod This page intentionally left blank Contents Preface xi Contributors xvii Introduction: Merging the legacies and hypotheses—Maternal medicine meets fetal medicine Moshe Hod, Kypros Nicolaides, Hamutal Meiri, and Nicky Lieberman History of diabetic pregnancy David R Hadden 11 Metabolism in normal pregnancy Emilio Herrera and Henar Ortega-Senovilla 17 Intermediary metabolism in pregnancies complicated by gestational diabetes Bartolomé Bonet, María Bonet-Alavés, and Isabel Sánchez-Vera 28 Nutrient delivery and metabolism in the fetus William W Hay, Jr., Paul J Rozance, Stephanie R Wesolowski, and Laura D Brown 34 Pathogenesis of gestational diabetes mellitus Yariv Yogev 49 Autoimmunity in gestational diabetes mellitus Alberto de Leiva, Dídac Mauricio, and Rosa Corcoy 57 Epidemiology of gestational diabetes mellitus Yariv Yogev, Avi Ben Haroush, Moshe Hod, and Jeremy Oats 69 Genetics of diabetic pregnancy Komal Bajaj and Susan J Gross 78 10 Animal models in diabetes and pregnancy research Catherine Yzydorczyk, Delphine Mitanchez, and Umberto Simeoni 84 11 Pathologic abnormalities of placental structure and function in diabetes Rhonda Bentley-Lewis, Maria Rosaria Raspollini, and Drucilla Roberts 91 12 The great obstetric syndromes: The roots of disease Rinat Gabbay-Benziv and Ahmet A Baschat 97 13 Placental origins of diabesity and the origin of preeclampsia Gernot Desoye and Berthold Huppertz 100 14 Diagnosis of gestational diabetes mellitus Donald R Coustan and Boyd E Metzger 110 15 Cost-effectiveness of screening and management programs for gestational diabetes mellitus Louise K Weile, James G Kahn, Elliot Marseille, and Nicolai Lohse 119 16 Changing health policy: From study to national policy Ofra Kalter-Leibovici, Nicky Lieberman, Ronni Gamzu, and Moshe Hod 131 17 Ideal weight gain in diabetic pregnancy Gerard H.A Visser and Harold W de Valk 136 18 Medical nutritional therapy for gestational diabetes mellitus Lois Jovanovic 138 19 Pharmacologic treatment of gestational diabetes mellitus: When to start and what agent to use Celeste P Durnwald and Mark B Landon 147 20 Gestational diabetes mellitus: The consequences of not treating Oded Langer 157 vii viii Contents 21 Gestational diabetes mellitus in multiple pregnancies Matteo Andrea Bonomo and Angela Napoli 169 22 Glycemic goals in diabetic pregnancy and defining “good control”: Maternal and fetal perspective Liran Hiersch and Yariv Yogev 179 23 Insulin therapy in pregnancy Lois Jovanovic and John L Kitzmiller 187 24 Use of oral hypoglycemic agents in pregnancy Oded Langer 200 25 The drug dilemma of oral antidiabetic agents in pregnancy: Metformin Yoel Toledano, Moshe Zloczower, and Nicky Lieberman 211 26 Facing noncommunicable diseases’ global epidemic: The battle of prevention starts in utero—The FIGO challenge Luis Cabero and Sabaratnam Arulkumaran 219 27 Links between maternal health and noncommunicable diseases Anil Kapur 226 28 Diabetic pregnancy in the developing world Eran Hadar, Eran Ashwal, and Moshe Hod 234 29 Managing diabetic pregnancy in China Huixia Yang, Weiwei Zhu, and Rina Su 242 30 Gestational diabetes mellitus, obesity, and pregnancy outcomes Harold David McIntyre, Marloes Dekker-Nitert, Helen Lorraine Graham Barrett, and Leonie Kaye Callaway 246 31 Obesity versus glycemic control: Which contributes more to adverse pregnancy outcome? Amir Aviram and Yariv Yogev 253 32 Pharmacological treatment for the obese gestational diabetes mellitus patient Fiona C Denison and Rebecca M Reynolds 259 33 Role of exercise in reducing the risks of gestational diabetes mellitus in obese women Raul Artal 266 34 Role of bariatric surgery in obese women planning pregnancy Ron Charach and Eyal Sheiner 273 35 Fetal lung maturity Gian Carlo Di Renzo, Giulia Babucci, and Graziano Clerici 287 36 Monitoring during the later stage of pregnancy and during labor: Glycemic considerations Harold W de Valk and Gerard H.A Visser 299 37 Timing and mode of delivery Salvatore Alberico and Gianpaolo Maso 305 38 Management of the macrosomic fetus Federico Mecacci, Marianna Pina Rambaldi, and Giorgio Mello 312 39 Congenital malformations in diabetic pregnancy: Prevalence and types Paul Merlob 315 40 Diabetic embryopathy in the preimplantation embryo Asher Ornoy and Noa Bischitz 321 41 Postimplantation diabetic embryopathy Ulf J Eriksson and Parri Wentzel 329 42 Fetal malformations detected with magnetic resonance imaging in the diabetic mother Tuangsit Wataganara 351 43 Continuous glucose monitoring in pregnancy Marlon Pragnell and Aaron Kowalski 362 Effect of breastfeeding  521 that BW ≥4000 g increases twofold the risk for obesity, and this risk is increased about 2.5-fold when BW exceeds the 90th percentile.24 However, the association between higher BW and higher adult BMI may be due to increased lean mass rather than an increase in fat tissue Evidence suggests that although BW is positively associated with BMI, it is not necessarily associated with increased adiposity, and at higher BW, subsequent adiposity may actually be reduced.25 Being large for gestational age (LGA, BW > 90th percentile), in association with GDM or maternal obesity, increases the risk of MS in childhood A longitudinal cohort study analyzed the prevalence of MS in children aged 6–11 years, accordingly they were LGA or adapted for gestational age (AGA, BW 10th–90th percentile), and their mothers had or had no GDM The prevalence at any time of at least two components of MS was higher for the LGA/GDM group (50%), compared to the LGA/control group (29%), AGA/ GDM group (21%), and AGA/control group (18%) The risk of developing MS with time was significantly different between LGA and AGA offspring in the GDM group, with a 3.6-fold greater risk among LGA children by 11 years In this study, children exposed to maternal obesity were also at increased risk of developing MS.26 A recent systematic review on the association between BW and risk of T2D showed that in most populations studied, BW was inversely related to T2D risk There was a positive association between high BW (>4 kg) and risk of T2D only in two native North American populations These populations have an exceptionally high prevalence of T2D and obesity from early ages and a very high prevalence of GDM Therefore, the influence of maternal diabetes/obesity on the BW–T2D association could not be excluded in these populations and may overweight the effect of being LGA alone.27 Effect of maternal glycemic and gestational weight gain control on long-term prognosis in the offspring Treatment of GDM may be an important determinant of offspring outcomes, but there is currently insufficient information to firmly assess the effects of maternal interventions on infant and child health Two trials are available in the literature, with a follow-up of offspring of mothers randomized to either minimal intervention or tight control of diabetes.28,29 They did not demonstrate any differences in the frequency of MS or in the weight of the children according to the intervention provided to their mothers In a large cohort of 9439 mother–child pairs in a diverse US population universally screened for GDM, it was shown that increasing hyperglycemia levels in pregnancy were associated with increased risk of obesity in children at age 5–7 years But this risk was modifiable by treating GDM, as obesity risk was attenuated and no longer significant after multivariate adjustment in the treated GDM group.30 There are significant methodological difficulties in proving an effect of maternal glycemic control over the long term because it may not be sufficient alone to prevent the adverse long-term outcome on the offspring.17 As discussed earlier, other substrates influence fetal growth and probably have long-term metabolic consequences Excess gestational weight gain (GWG) is a factor associated with high BW and subsequent long-term outcomes The comparison of differences in BW between sibling pairs showed that for every additional kilogram an individual woman gained during pregnancy, the BW of her offspring increased by about 25 g.31 In a large prospective multicentric study, excessive GWG was an independent valuable predictor of macrosomia In the subgroup of diabetic mothers, excessive GWG (according to the Institute of Medicine [IOM] recommendations) was related to a 2.6-fold increased risk of developing macrosomia (OR 2.6; 95% CI 1.2–5.5) However, in this population, GWG lower than recommended was not associated with a reduction of macrosomia (OR 0.8; 95% CI 0.3–1.8).32 In a large Swedish prospective cohort, offspring BMI was related to maternal GWG However, in normal-weight women, this positive association was only driven by shared familial risk factors for BMI (genetic/environment) In overweight and obese women, a greater maternal GWG appears to be associated with greater offspring BMI via intrauterine mechanisms and shared familial characteristics.4 Maternal weight gain during pregnancy is probably an important and challenging modifiable risk factor because excessive GWG is associated with higher BW The absence of effect of reduced GWG on fetal growth in diabetic pregnancy, reported in some studies, may be due to the fact that IOM guidelines were not conceived for diabetic mother Then, the challenge is to determine nutritional guidelines specifically devised for women with diabetes, considering the amounts of calories but also the quality of nutrients Other factors of prevention (prepregnancy control of overweight, regular activity, etc.) must be recommended to the mother as part of a comprehensive management plan Effect of breastfeeding Infancy has been suggested as another critical period for future risks in the offspring whatever was the intrauterine environment Breastfeeding compared with formula feeding showed to have beneficial effects on glucose tolerance, HT, dyslipidemia, and obesity.33 The strongest evidence for a protective effect of breastfeeding for later health is for a lower risk of obesity Although unknown, some potential mechanisms by which breastfeeding protects against later risk have been discussed Breastfed babies may control the amount of milk they consume and so learn to self-regulate their energy intakes better than those given formula, although whether this difference persists into adult life is unknown Nutritional benefits of breastfeeding may include differences in nutrients between human milk and formulas (lower glucose and protein, high concentrations in long-chain polyunsaturated fatty acid) Differences in early protein intakes that are greater in formula than in human milk could also affect later adiposity It has been suggested that the benefits of breastfeeding for long-term obesity is of particular 522  Long-term outcomes after gestational diabetes mellitus exposure in the offspring importance in the early postnatal weeks of life This is a critical period for determining levels and distribution of adiposity The benefits of breastfeeding at this time may be due to a slower pattern of growth in breastfed compared with formula-fed infants (the growth acceleration hypothesis).34 Weight gain during the first week of life in healthy formula-fed infants was associated with overweight status two to three decades later After adjustment for important confounding factors, each 100 g increase in absolute weight gain during this period was associated with a 28% increase in the risk of becoming an overweight adult (95% CI  8%–52%).35 A long-term advantage of breastfeeding was further supported by a “dose–response” effect A longer duration of breastfeeding was associated with a lower tendency to later obesity; each month of breastfeeding was associated with a 4% (95% CI −6% to −2%) reduction in obesity risk.36 In diabetic mothers, there are many controversies concerning breastfeeding benefits in their offspring, particularly during the first week of life Some observed a positive dosedependent relation between the volume of diabetic mother milk ingested during the first neonatal week and later risk of overweight.37 But those infants who did not receive breast milk from their diabetic mothers were instead nourished with banked breast milk from nondiabetic donor mothers This created a different “reference exposure” than in all other studies where breastfeeding was tested against formula The mechanisms evoked for such a negative effect of breast milk from diabetic mothers was that it contains increased levels of glucose and insulin as compared with breast milk from healthy mothers but even hormones like insulin and leptin that may be absorbed from milk in the immature gut of an infant.38 However, the composition of milk from diabetic mothers may also be influenced by metabolic control during pregnancy and postpartum, and this may change the impact on the outcome of offspring The same authors found that neither late neonatal intakes of breast milk from diabetic mothers nor the duration of breastfeeding has an independent influence on childhood risk of overweight or glucose intolerance.39 However, others found that adequate breastfeeding (≥6  months) reduces, in childhood, the increase of adiposity levels associated with exposure to diabetes in utero.40 Furthermore, these results were strengthened by the follow-up of a longitudinal cohort It was shown that adequate breastfeeding reduced the overall body size and slowed BMI growth velocity both during infancy and in the childhood period, in offspring of nondiabetic mothers, as well as in offspring of diabetic mothers These effects were independent of sex, race/ethnicity, current childhood diet, and physical activity levels This study indicates that the favorable effects of breastfeeding on BMI growth patterns extend throughout the entire childhood period and are also present in youth at increased risk for obesity due to intrauterine exposure to maternal diabetes.41 Others have reported data that favor the benefit of breastfeeding in offspring of diabetic mothers, either on the risk of obesity42 or on the risk of diabetes.43 Overall, there is no doubt that breastfeeding should be recommended in diabetic mothers, all the more since GDM and T2D are increasingly spreading in emerging countries The controversies concerning the benefit of breastfeeding in diabetic mothers should be reviewed in the light of potential confounders, especially the time point of exposure, exposure quality (exclusive or not exclusive breastfeeding), and duration, but also ethnicity, socioeconomic status, and maternal BMI Breastfeeding may represent an important challenge in preventing long-term disorders in the offspring of diabetic mothers Conclusion More and more indisputable data are evidencing long-term consequences on offspring health in case of gestational diabetes or excess growth at birth Converging results from clinical and epidemiological data, but also from animal models (see Chapter 10), suggest that GDM contributes to the current worldwide T2D pandemic However, the specific mechanisms remain unclear and many aspects, in particular epigenetic, need to be clarified The specific intrauterine metabolic alterations that favor such long-term evolution need to be investigated, and the consequences of overweight and obesity among those of diabetes should be separately evaluated Such comprehensive data will offer major proved opportunities for prevention Meanwhile, obvious preventive measures are indicated like early diagnosis and tight control of maternal diabetes during pregnancy, limited GWG, and promotion of breastfeeding REFERENCES Dabelea D, Pettitt DJ Intrauterine diabetic environment confers risks for type diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility J Pediatr Endocrinol Metab 2001; 14: 1085–1091 Dabelea D The predisposition to obesity and diabetes in offspring of diabetic mothers Diabetes Care 2007; 30(Suppl 2): S169–S174 Dabelea D, Hanson RL, Lindsay RS et al Intrauterine exposure to diabetes conveys risks for type diabetes and obesity: A study of discordant sibships Diabetes 2000; 49: 2208–2211 Lawlor DA, Lichtenstein P, Langstrom N Association of maternal diabetes mellitus in pregnancy with offspring adiposity into early adulthood: Sibling study in a prospective cohort of 280,866 men from 248,293 families Circulation 2011; 123: 258–265 Clausen TD, Mathiesen ER, Hansen T et al High prevalence of type diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type diabetes: The role of intrauterine hyperglycemia Diabetes Care 2008; 31: 340–346 Sobngwi E, Boudou P, Mauvais-Jarvis F et al Effect of a diabetic environment in utero on predisposition to type diabetes Lancet 2003; 361: 1861–1865 Crume TL, Ogden L, Daniels S et al The impact of in utero exposure to diabetes on childhood body mass index growth trajectories: The EPOCH study J Pediatr 2011; 158: 941–946 Bunt JC, Tataranni PA, Salbe AD Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children J Clin Endocrinol Metab 2005; 90: 3225–3229 References 523 West NA, Crume TL, Maligie MA et al Cardiovascular risk factors in children exposed to maternal diabetes in utero Diabetologia 2011; 54: 504–507 10 Aceti A, Santhakumaran S, Logan KM et  al The diabetic pregnancy and offspring blood pressure in childhood: A systematic review and meta-analysis Diabetologia 2012; 55: 3114–3127 11 Taddei S, Virdis A, Mattei P et  al Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with familial history of hypertension J Cardiovasc Pharmacol 1992; 20(Suppl 12): S193–S195 12 Ingram DA, Mead LE, Tanaka H et  al Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood Blood 2004; 104: 2752–2760 13 Ingram DA, Lien IZ, Mead LE et al In vitro hyperglycemia or a diabetic intrauterine environment reduces neonatal endothelial colony-forming cell numbers and function Diabetes 2008; 57: 724–731 14 Blue EK, DiGiuseppe R, Derr-Yellin E et al Gestational diabetes induces alterations in the function of neonatal endothelial colony-forming cells Pediatr Res 2014; 75(2): 266–272 15 Atkins RC, Zimmet P Diabetic kidney disease: Act now or pay later Acta Diabetol 2010; 47(1): 1–4 16 Nelson RG, Morgenstern H, Bennett PH Intrauterine diabetes exposure and the risk of renal disease in diabetic Pima Indians Diabetes 1998; 47: 1489–1493 17 Catalano PM, Hauguel-De Mouzon S Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am J Obstet Gynecol 2011; 204: 479–487 18 Radaelli T, Lepercq J, Varastehpour A et al Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type diabetes mellitus Am J Obstet Gynecol 2009; 201: 209.e1–209.e10 19 Radaelli T, Varastehpour A, Catalano P et al Gestational diabetes induces placental genes for chronic stress and inflammatory pathways Diabetes 2003; 52: 2951–2958 20 Houde AA, Hivert MF, Bouchard L Fetal epigenetic programming of adipokines Adipocyte 2013; 2: 41–46 21 Dabelea D, Mayer-Davis EJ, Lamichhane AP et al Association of intrauterine exposure to maternal diabetes and obesity with type diabetes in youth: The SEARCH Case-Control Study Diabetes Care 2008; 31: 1422–1426 22 Kim SY, England JL, Sharma JA et  al Gestational diabetes mellitus and risk of childhood overweight and obesity in offspring: A systematic review Exp Diabetes Res 2011; 2011: 541308 23 Philipps LH, Santhakumaran S, Gale C et al The diabetic pregnancy and offspring BMI in childhood: A systematic review and meta-analysis Diabetologia 2011; 54: 1957–1966 24 Monasta L, Batty GD, Cattaneo A et  al Early-life determinants of overweight and obesity: A review of systematic reviews Obes Rev 2010; 11: 695–708 25 Rogers I The influence of birthweight and intrauterine environment on adiposity and fat distribution in later life Int J Obes Relat Metab Disord 2003; 27: 755–777 26 Boney CM, Verma A, Tucker R et  al Metabolic syndrome in childhood: Association with birth weight, maternal obesity, and gestational diabetes mellitus Pediatrics 2005; 115: e290–e296 27 Whincup PH, Kaye SJ, Owen CG et al Birth weight and risk of type diabetes: A systematic review J Am Med Assoc 2008; 300: 2886–2897 28 Keely EJ, Malcolm JC, Hadjiyannakis S et al Prevalence of metabolic markers of insulin resistance in offspring of gestational diabetes pregnancies Pediatr Diabetes 2008; 9: 53–59 29 Gillman MW, Oakey H, Baghurst PA et al Effect of treatment of gestational diabetes mellitus on obesity in the next generation Diabetes Care 2010; 33: 964–968 30 Hillier TA, Pedula KL, Schmidt MM et al Childhood obesity and metabolic imprinting: The ongoing effects of maternal hyperglycemia Diabetes Care 2007; 30: 2287–2292 31 Hutcheon JA, Platt RW, Meltzer SJ et al Is birth weight modified during pregnancy? Using sibling differences to understand the impact of blood glucose, obesity, and maternal weight gain in gestational diabetes Am J Obstet Gynecol 2006; 195: 488–494 32 Alberico S, Montico M, Barresi V et al The role of gestational diabetes, pre-pregnancy body mass index and gestational weight gain on the risk of newborn macrosomia: Results from a prospective multicentre study BMC Pregnancy Childbirth 2014; 14: 23 33 Lanigan J, Singhal A Early nutrition and long-term health: A practical approach Proc Nutr Soc 2009; 68: 422–429 34 Singhal A, Lanigan J Breastfeeding, early growth and later obesity Obes Rev 2007; 8(Suppl 1): 51–54 35 Stettler N, Stallings VA, Troxel AB et al Weight gain in the first week of life and overweight in adulthood: A cohort study of European American subjects fed infant formula Circulation 2005; 111: 1897–1903 36 Harder T, Bergmann R, Kallischnigg G et al Duration of breastfeeding and risk of overweight: A meta-analysis Am J Epidemiol 2005; 162: 397–403 37 Plagemann A, Harder T, Franke K et al Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers Diabetes Care 2002; 25: 16–22 38 Plagemann A, Harder T Fuel-mediated teratogenesis and breastfeeding Diabetes Care 2011; 34(3): 779–781 39 Rodekamp E, Harder T, Kohlhoff R et  al Long-term impact of breast-feeding on body weight and glucose tolerance in children of diabetic mothers: Role of the late neonatal period and early infancy Diabetes Care 2005; 28: 1457–1462 40 Crume TL, Ogden L, Maligie M et al Long-term impact of neonatal breastfeeding on childhood adiposity and fat distribution among children exposed to diabetes in utero Diabetes Care 2011; 34: 641–645 41 Crume TL, Ogden LG, Mayer-Davis EJ et al The impact of neonatal breast-feeding on growth trajectories of youth exposed and unexposed to diabetes in utero: The EPOCH Study Int J Obes (Lond) 2012; 36: 529–534 42 Mayer-Davis EJ, Rifas-Shiman SL, Zhou L et al Breast-feeding and risk for childhood obesity: Does maternal diabetes or obesity status matter? Diabetes Care 2006; 29: 2231–2237 43 Pettitt DJ, Knowler WC Long-term effects of the intrauterine environment, birth weight, and breast-feeding in Pima Indians Diabetes Care 1998; 21(Suppl 2): B138–B141 62 Metabolomics and diabetic pregnancy Angelica Dessì, Roberta Carboni, and Vassilios Fanos Introduction Diabetes is one of the diseases that most frequently complicate the course of pregnancy, especially in developed countries where the increased incidence of obesity is one of the risk factors.1 Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset, or which is recognized for the first time, during pregnancy In some cases, it is a pregestational diabetes revealed by investigations during pregnancy, but in other cases it is diabetes with onset during pregnancy; the latter represents 90% of pregnancies complicated by diabetes.2 GDM is a disease that has important repercussions on both the mother and the child, and, therefore, early diagnosis and timely treatment may avoid acute and chronic complications for both.3 At present, the only laboratory method for the diagnosis of gestational diabetes is glycemia measurement However, this is a method that does not take into account the overall metabolic condition of the organism and that is often performed at an advanced stage of pregnancy Moreover, there are still no methods that are useful in singling out women at greater risk of developing GDM and assessing the effectiveness of therapy in single patients Metabolomics, thanks to its capacity to investigate the overall metabolic state of an entire organism, appears to be a promising technique also in the study of GDM and the recognition of possible new biomarkers to reveal at an early stage the women at higher risk of developing this pathological condition Diabetic pregnancy Definition By GDM is meant a condition characterized by a reduced tolerance to glucides, with hyperglycemia of varying seriousness that begins during pregnancy.4 The definition is applied regardless of the use of insulin in the treatment or persistence of the condition following the pregnancy 524 Thus, the possibility that glucose intolerance may be prior to or begin during pregnancy cannot be excluded This pathology has a prevalence of 3%–10% and represents approximately 90% of all pregnancies complicated by diabetes.2,6 Moreover, the increase in maternal age, the high incidence of obesity and diabetes, and the reduction of physical activity with the adoption of modern lifestyles in developing countries have contributed to an increase in the prevalence of GDM.7 Pathophysiology and etiopathogenesis Pregnancy is a condition during which a certain degree of insulin resistance develops physiologically, especially in the muscle and adipose tissues, to ensure fetal growth.8 In the maternal organism, there is a decreased use of insulinmediated glucose that favors an increase in carbohydrates for the fetus.9 In a physiological pregnancy, the basal glycemia remains constant up to the last 3 months and carbohydrate intolerance develops only when β-cell secretion is no longer capable of compensating for peripheral insulin resistance.10 Most of the evidence points to a defect in the β-cell if the GDM is more than acute The hypothesis that the β-cell defect is chronic suggests that when GDM is diagnosed, it includes some women with a preexistent glucose intolerance revealed by tests performed during pregnancy From the etiopathogenetic viewpoint, GDM is considered a type diabetes GDM is frequently characterized by reduced insulin secretion accompanied by an increase in peripheral insulin resistance, two conditions typical of type 2 diabetes During pregnancy, the variations in insulin secretion depend on endocrine alterations that accompany pregnancy Changes in β-cell function take place at the time of development of the fetus and placenta and the production of hormones such as the human chorionic growth hormone, progesterone, cortisol, and prolactin These hormones in a woman with GDM are capable of causing insulin resistance, high triglyceride levels, and lower HDL cholesterol levels compared to what is observed in women with physiological pregnancies.11 In GDM patients, insulin secretion is incapable of compensating for the insulin resistance characteristic of Metabolomics 525 pregnancy Therefore, the loss of the first phase of insulin secretion will cause postprandial hyperglycemia, while the reduced suppression of hepatic production of glucose will be responsible for fasting hyperglycemia Diagnosis As concerns diagnosis, guidelines recommend the measurement of blood sugar at the first appointment in pregnancy for all women with no previous tests to single out those with diabetes prior to becoming pregnant; also recommended is the screening for diabetes in cases of physiological pregnancy using defined risk factors At the 16th–18th week of gestation, an OGTT with 75 g of glucose and a second OGTT with 75 g at 28 weeks of gestational age if the first test gave a normal result should be performed on all women presenting at least one of the following conditions: ●● ●● ●● Gestational diabetes in a previous pregnancy Prepregnancy body mass index (BMI) ≥ 30 The finding of blood sugar values between 100 and 125 mg/dL (5.6–6.9 mmol/L) previous to or at the beginning of pregnancy At the 24th–28th week of gestational age, women presenting at least one of the following conditions must undergo a 75 g OGTT: ●● ●● ●● ●● ●● ●● Age ≥ 35 years Prepregnancy BMI ≥ 25 kg/m2 Fetal macrosomia in a previous pregnancy (≥4.5 kg) GDM in a previous pregnancy (even with a normal result at the 16th–18th week) Family anamnesis of diabetes (first-degree relative with type diabetes) Family from an area with a high rate of diabetes: Southern Asia, the Caribbean, and the Middle East Based on the results of this screening, women with fasting glycemia ≥92 mg/dL, after hour ≥180 mg/dL, and after hours ≥153 mg/dL are defined as affected by GDM The guidelines also specify that in screening for GDM, the following are not to be used: fasting blood sugar, random glycemias, glucose challenge test (GCT) or minicurve, glycosuria, and OGTT 100 g.12 Acute and chronic consequences for mother and child GDM causes an increased risk of morbidity in the fetus and neonate and may be the cause of a later development of type 2 diabetes, in both the mother and the child.13 We can distinguish early and late complications in connection with the maternal pathology that will involve mother and child As concerns the mother, early complications are represented by the risk of spontaneous abortion, polyhydramnios, hypertension in pregnancy, pyelonephritis and other infections, preterm delivery, hypoglycemia, ketoacidosis, and cesarean  delivery The late complications for the mother are in relation to the fact that GDM may be the first manifestation of a type diabetes or a metabolic syndrome; thus after pregnancy, it is important for these women to be followed up.14 The early complications for the neonate are respiratory distress, shoulder dystocia, hyperbilirubinemia, polycythemia, hypocalcemia, macrosomy, and hypoglycemia; the late ones are instead connected with a higher risk of overweight and obesity in the adolescent age as well as the higher risk of developing type diabetes, this too in the adolescent period The reduced action of insulin in GDM causes an excessive increase of nutrients in the blood (glucose, lipids, amino acids), which, on passing through the placenta, determine hyperinsulinism capable of favoring a consequent increase in adipose tissue with fetal organomegaly and macrosomia.10 On passing through the placental barrier, the excess maternal glucose causes a condition of constant hyperglycemia in the fetus that will lead to chronic hyperinsulinism that, on continuing after delivery, will result in neonatal hypoglycemia.15 This reduced glucidic tolerance will tend to persist during growth and into adulthood and consequently will expose the children of diabetic mothers to a higher risk of developing pathologies such as obesity and type diabetes Metabolomics Metabolomics, one of the most recent of the omics sciences, is defined as the study of the complex system of metabolites owing to its capacity of examining an individual’s entire metabolic profile A metabolomic analysis is capable of detecting analytes of relatively low molecular weight (up to 1000 Da), among which amino acids, oligopeptides, sugars, steroids, biliary acids, simple and compound fatty acids, and intermediate compounds of many biochemical pathways.16 The metabolomic approach consists of the sequential application of a surveying technique with the use of nuclear magnetic resonance (NMR) and gas or liquid chromatography coupled with mass spectrometry (LC-MS and GC-MS), by means of which it is possible to measure simultaneously the concentration of a large number of metabolites in the sample The most common biological samples used in metabolomics are urine, plasma, and serum, but other biofluids can be used as well (liquor, saliva, gastric/pancreatic juices, aqueous humor) or tissues Each biological fluid has a unique and characteristic biochemical composition that changes in response to physiological or pathophysiological stimuli to generate a metabolic “fingerprint.” This discipline, based on the use of mathematical and statistical methods to solve multivariate problems, is capable of describing the chemical profile of a biological system in terms of low-molecular-weight metabolites present in cells, tissues, organs, and biological fluids By means of a metabolic approach, it is thus possible to photograph “in real time” the influences on the organism such as biochemical perturbations caused by diseases, drugs, and toxins, thus describing the biochemical phenotype of a biological system.17 526  Metabolomics and diabetic pregnancy In recent years, many clinical studies have been performed on animals, adults, children, and neonates using a metabolomic approach that makes it possible to study important perinatal and postnatal pathologies such as asphyxia and hypoxia, congenital diseases, the state of nutrition, kidney diseases, nephrotoxicity, cardiovascular disease, and other pathologies.18–20 In the medical field, there is growing interest in characterizing at the biochemical and molecular level the different pathophysiological states that mark the lives of human beings in the period from embryonic development to ageing and death “Clinical metabolomics” is proposed as a new multidisciplinary scientific field developed through the interaction of disciplines such as chemistry, physics, biology, and medicine, which to the same extent contribute to the gathering of up-to-now latent information, leading to the identification of new phenotypical characteristics of diseases studied but not yet adequately defined The ultimate objective of such characterization is that of developing “tailored” therapeutic approaches for the single individual and/or group of individuals, where for group is meant persons having a common phenotypical profile deriving from a similar gene–environment interaction.21,22 Gestational diabetes and metabolomics As can be seen in the guidelines, at present the diagnosis of GDM is based solely on the finding of high values of glucose in the blood This kind of investigation does not take into consideration the complete metabolic picture of a woman as well as being, in cases not considered at risk, performed toward the end of the month of pregnancy when, if it is found altered, the fetus is already affected by a series of metabolic influences capable of impacting on its growth For this reason, the application of an “alternative” method is necessary to help in characterizing the overall metabolic state of a pregnant woman Metabolomics in the field of this pathology would appear to be the most suitable method since it is capable of providing a quantitative measurement as a function of time of the metabolic response of a living system to pathophysiological stimuli and/or genetic modifications.16 As concerns GDM, metabolomics proposes to identify biomarkers useful in predicting, already at an early stage of gestation, if a woman is prone to GDM and thus beginning timely treatment so that the disease does not develop and that the fetus does not undergo any of the mother’s metabolic influences that may impact on its metabolism and growth Moreover, thanks to metabolomics, it is possible to study more in depth the metabolic profile of pregnant women Up to the present, few works have been published on the application of metabolomics to the study of women presenting GDM and the assessment of the metabolic state of the children of GDM mothers (Table 62.1), but the results appear promising both as regards the overall metabolic state of women and their risk of developing GDM and as regards the metabolic profile of the neonate.23 In the literature, we find four studies that focused on the metabolomic analysis of maternal biofluids in women presenting GDM and two studies that assessed the metabolome of the children of diabetic mothers The study by Sachse et al.14 examined the urinary metabolic profile by means of NMR of pregnant women for the purpose of identifying biomarkers useful in identifying the women most at risk of developing GDM The urinary metabolic profiles of 823 pregnant women in good health were analyzed Urine samples were taken in the morning while fasting and during three different visits: from the 8th to the 20th week of pregnancy, from the 26th to the 30th week, and from 10 to 16 weeks after delivery The authors highlighted the substantial changes in the composition of the urinary metabolites during and after the pregnancy; in particular, the most important results were the constant increase in lactose and the increasing–decreasing pattern of a plurality of NMR signals between 0.55 and 1.10 ppm, signals that may belong to pregnanediol and estrogens, or more probably, to their sulfates and water-soluble glucuronoids As concerns the possibility of finding biomarkers capable of identifying GDM, the authors concluded that on the basis of their results, it is not possible to find reliable biomarkers for GDM in a large multiethnic population; however, an increase in the citrate excreted in the urine in relation to the seriousness of the cases of GDM was found The work by Diaz et  al.24 was performed on urine and plasma of women in the final 3 months of pregnancy in an Table 62.1  Studies in the literature concerning metabolomics and GDM Population Metabolomic analysis Cord serum Infants 1H-NMR Logan etal.27 Graỗa etal.26 Urine Urine, amniotic fluid Infants Mothers Sachse et al.14 Diaz et al.24 Scioscia et al.25 Urine Urine, plasma Urine Mothers Mothers Mothers 1H-NMR UPLC-MS 1H-NMR 1H-NMR 1H-NMR MS Study Dani et al Sample 28 Metabolites resulting Glucose, pyruvate, histidine, alanine, valine, methionine, arginine, lysine, hypoxanthine Glucose, formate, fumarate, succinate, citrate None Lactose, citrate 3-Hydroxyisovalerate, 2-hydroxyisobutyrate Inositolphosphoglycan P-type References 527 attempt to characterize metabolic changes possibly caused by prenatal disorders and identify possible early biomarkers of diseases The metabolic profile was analyzed by means of NMR and the metabolomic analysis revealed higher levels of 3-hydroxyisovalerate and 2-hydroxyisobutirrate in the urine of women who later developed GDM The work by Scioscia et  al 25 assessed by means of a metabolomic approach performed with MS on the urine of pregnant women if inositolphosphoglycan P-type (P-IPG), a second insulin messenger that correlates with the degree of resistance in diabetic subjects, may have changed during pregnancy The study examined 48 women with GDM and 23 healthy women during pregnancy and revealed an increase in urinary excretion of P-IPG in the GDM women compared to controls The authors also found a correlation between urinary values of P-IPG and blood glucose According to the authors, the metabolomic identification of P-IPG is a potential marker of insulin resistance and may predict fetal growth alteration in GDM patients Finally, the study by Graỗa et al 26 was performed on urine and amniotic liquid of women in the second 3 months of pregnancy with the use of both the UPLC-MS and 1H-NMR methods The authors investigated the possible metabolic effects of fetal malformations, GDM, and preterm delivery In particular, contrary to the other works published, in the metabolome in the case of GDM, no significant changes were found, either in the urine or in the amniotic liquid The other two studies in the literature examined the fetal metabolism of neonates of GDM mothers to assess the consequences of the maternal pathology on the development of their children In their study, Logan et al.27 hypothesized that the metabolic profile of the neonates of diabetic mothers (IDM) was different from that of children of healthy mothers They then studied the metabolome of 18 IDM neonates and 12 term and healthy neonates used as controls Urine was collected within 72 hours from birth using balls of absorbent cotton and then conserved at −80°C; the metabolomic analysis was then performed by means of 1HNMR spectroscopy and the spectra obtained were analyzed using MATLAB® software* The statistical analysis was performed with the principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA) The results obtained in this study made it possible to discriminate between the two groups of neonates: the most important differences in the urinary metabolites were those found for glucose, formate, fumarate, citrate, and succinate, all metabolites involved in the tricarboxylic acid cycle Another similar work was carried out by Dani et  al.,28 who studied the metabolome of newborn children of GDM mothers and compared it with that of the neonates of healthy mothers The purpose of the study was to see if there were differences between the two groups and if such differences remained evident despite close control over the GDM The metabolomic analyses with 1HNMR were performed on the serum of 30 IGDM term neonates and 40 term neonates of healthy mothers used as controls The results of these investigations revealed a lower level of glucose and a higher level of pyruvate, histidine, alanine, valine, methionine, arginine, lysine, hypoxantin, lipoproteins, and lipids in the neonates of GDM mothers compared to the controls Despite these variations, the authors found no differences from the clinical standpoint Conclusions A new challenge in medicine is certainly the application of metabolomics in the study of pathologies originating in the womb that may later lead to both short- and long-term complications, as in the case of GDM The studies published show that metabolomics can be considered a potential and formidable instrument for prevention by identifying women most at risk of developing GDM An evaluation of this kind would make it possible to indicate a therapy, a lifestyle, and diet to follow in pregnancy so as to avoid the frequent complications caused by GDM * MATLAB® is a registered trademark of The MathWorks, Inc For product information, please contact The MathWorks, Inc at Apple Hill Drive Natick, MA 01760-2098, USA; 508-647-7000 (telephone); 508-647-7001 (fax); info@mathworks.com (e-mail); www.mathworks.com (website) REFERENCES Abourawi FI Diabetes mellitus and pregnancy Libyan J Med 2006; 1: 28–41 Lapolla A, Dalfrà MG, Lencioni C et al Epidemiology of diabetes in pregnancy: A review of Italian data Diabetes Nutr Metab 2004; 17: 358–367 Bloomgarden ZT American Diabetes Association 60th Scientific Sessions, 2000: Diabetes and pregnancy Diabetes Care 2000; 23: 1699–1702 Reece EA, Leguizamon G, Wiznitzen A Gestational diabetes: The need for a common ground Lancet 2009; 373: 1789–1797 Lawrence JM, Contreras R, Chen W et al Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999–2005 Diabetes Care 2008; 31: 899–904 King H Epidemiology of glucose intolerance and gestational diabetes in women of childbearing age Diabetes Care 1998; 21: B9–B13 Ferrara A Increasing prevalence of gestational diabetes mellitus Diabetes Care 2007; 30: S141–S146 Kühl C Etiology and pathogenesis of gestational diabetes Diabetes Care 1998; 21: B19–B26 Yamashita H, Shao J, Friedman JE Physiologic and molecular alterations in carbohydrate metabolism during pregnancy and gestational diabetes mellitus Clin Obstet Gynecol 2000; 43: 87–98 10 Di Cianni G, Miccoli R, Volpe L et al Intermediate metabolism in normal pregnancy and in gestational diabetes Diab Met Res Rev 2003; 19: 259–270 11 Ryan EA, Enns L Role of gestational hormones in the induction of insulin resistance J Clin Endocrinol Metab 1998; 67: 341–347 12 Ministero della Salute, Gravidanza Fisiologica, Linea Guida 20 aggiornamento 2011 13 Hod M, Simeoni U Maternal, fetal and neonatal complications of diabetic pregnancy-delivering optimal care while awaiting for cure Semin Fetal Neonatal Med 2009; 14: 63–65 528  Metabolomics and diabetic pregnancy 14 Sachse D, Sletner L, Morkrid K et  al Metabolomic changes in urine during and after pregnancy in a large multiethnics population based cohort study of gestational diabetes PLOS ONE 2012; 7: e52399 15 Lam YY, Hatzinikolas G, Weir JM et al Insulin-stimulated glucose uptake and pathways regulating energy metabolism in skeletal muscle cells: The effects of subcutaneous and visceral fat, and long-chain saturated, n-3 and n-6 polyunsaturated fatty acids Biochim Biophys Acta 2011; 1811: 468–475 16 Nicholson JK, Connelly J, Lindon JC et al Metabonomics: A platform for studying drug toxicity and gene function Nat Rev Drug Discov 2002; 1: 153–161 17 Ellis DI, Dunn WB, Griffin JL et al Metabolic fingerprinting as a diagnostic tool Pharmacogenomics 2007; 8: 1243–1266 18 Fanos V, Antonucci R, Barberini L et al Urinary metabolomics in the newborn and infants Adv Clin Chem 2012; 58: 193–223 19 Fanos V, Antonucci R, Barberini L et  al Clinical application of metabolism in neonatology J Matern Fetal Neonatal Med 2012; 1: 104–109 20 Dessì A, Atzori L, Noto A et  al Metabolomics in newborns with intrauterine growth retardation (IUGR): Urine reveals markers of metabolomic syndrome J Matern Fetal Neonatal Med 2011; 24: 35–39 21 Atzori L, Antonucci R, Barberini L et  al Metabolomics: A new tool for the neonatologist J Matern Fetal Neonatal Med 2009; 22: 50–53 22 Fanos V, Van den Anker J, Noto A et al Metabolomics in neonatology: Fact or fiction? Semin Fetal Neonatal Med 2013; 18: 3–12 23 Dessì A, Puddu M, Ottonello G et  al Metabolomics and fetalneonatal nutrition: Between “not enough” and “too much.” Molecules 2013; 18: 11724–11732 24 Diaz SO, Pinto J, Graỗa G etal Metabolomic biomarkers of prenatal disorders: An exploratory NMR metabonomics study of second trimester maternal urine and blood plasma J Proteome Res 2011; 8: 3732–3742 25 Scioscia M, Kunjara S, Gumaa K et  al Urinary excretion of inositol phosphoglycan P-type in gestational diabetes mellitus Diabetic Med 2007; 24: 13001304 26 Graỗa G, Goodfellow J, Barros AS et al UPLC-MS metabolomic profiling of second trimester amniotic fluid and maternal urine and comparison with NMR spectral profiling for the identification of pregnancy disorder biomarkers Mol Biosyst 2012; 8: 1243–1254 27 Logan KM, Wijeyesekera AD, Perez IG et  al Infants of mothers with diabetes have altered urinary metabolic profile at birth Available from: www.neonatalsociety.ac.uk/abstracts/ logank_2012_diabeticurinaryprofile.shtml, last accessed March 27, 2014 28 Dani C, Bresci C, Berti E et  al Metabolomic profile of term infants of gestational diabetics mothers J Matern Fetal Neonatal Med 2014; 27: 537–542 63 Fetal growth restriction: Evidence-based clinical management Eduard Gratacós and Francesc Figueras Introduction Fetal growth restriction (FGR) is defined as a failure to achieve the endorsed growth potential The diagnosis of fetal “smallness” is currently performed on the basis of an estimated fetal weight below a given threshold, most commonly the 10th centile It is likely that this definition lacks sensitivity, so that it misses cases of growth restriction that not fall below the 10th centile, but it identifies a subset of pregnancies at high risk of poorer perinatal outcome Thus, detection of small fetuses is clinically relevant because as a whole this group of fetuses is associated with poorer perinatal outcome, and this represents opportunities for preventing cases of intrauterine fetal death, perinatal brain injury, and severe intrapartum fetal distress In addition, evidence accumulating over the last 20 years has consistently demonstrated how being born small has important implications for the quality of health during adulthood Population-based studies show that prenatal identification of small for gestational age (SGA) results in a reduction of adverse perinatal outcomes and stillbirth.1,2 However, most SGA babies remain unnoticed until birth, even when routine third trimester ultrasound is performed.3,4 Moreover, according to pregnancy audits, most instances of avoidable stillbirth are related with a failure to antenatally detect SGA.5 However, FGR is probably among the obstetrical entities with the greatest variation in clinical management, resulting from lack of strong supportive evidence, combined with the complexity of the variables and indices for assessing fetal deterioration In this chapter, we will summarize the main aims in the clinical management of FGR, which should be (1) to distinguish “true” FGR from constitutional SGA and (2) to establish whether there is an indication for elective delivery and if not how often monitoring should be performed “Fetal growth restriction” versus “small for gestational age” Overall, a “small fetus” is associated with poorer outcome However, evidence shows that there are, at least, two groups of small fetuses, normally referred to as FGR versus constitutional SGA, also defined as just SGA FGR is associated with poorer perinatal outcome, abnormal Doppler suggesting fetal adaptation to undernutrition/hypoxia, signs of placental disease, and higher risk of preeclampsia (PE) SGA fetuses not present the aforementioned changes and display perinatal outcomes similar to those of normally grown fetuses It is unknown whether SGA fetuses are truly “constitutionally small” or they represent another form of fetal abnormal smallness The distinction between FGR versus SGA is clinically relevant because of the wide consensus that it is reasonable to deliver electively FGR earlier, whereas elective delivery before term offers no benefit in SGA The diagnosis of FGR is currently performed by means of a combination of Doppler and estimated fetal weight For 20 years, the Doppler index widely used to distinguish FGR from SGA was abnormal umbilical artery (UA) Doppler However, UA Doppler identifies severe placental disease but fails to pick up instances of mild placental disease, which in reality constitute the majority of cases of FGR.4,6 Thus, UA Doppler should always be used in combination integrated in the cerebroplacental ratio (CPR) CPR is calculated by dividing the middle cerebral artery (MCA) Doppler pulsatility index (PI) by the UA Doppler PI This index correlates better with adverse outcome.7 Aside from CPR, both the uterine artery Doppler PI (UtA PI)8 and a very low EFW (700 cases determined that 32 weeks at diagnosis and 37 weeks at delivery best classified two groups where the differences in terms of adverse perinatal outcome are maximized.16 Briefly, early-onset FGR represents about 20%–30% of all FGR and it is associated with early PE in up to 50%.4 In early-onset FGR, there is commonly severe placental insufficiency and chronic fetal hypoxia; hence UA Doppler is usually abnormal.17 Fetal condition deteriorates with evolution to decompensated hypoxia and acidosis, which is reflected by progression of abnormalities in the UA into absent and reverse diastolic flow and increased PIs in the ductus venosus (DV), which is used as a reflection of late-stage disease and very high risk of fetal death Fetal deterioration normally lasts weeks18 following a cascade of Doppler changes Management is challenging and aims at achieving the best balance between the risks of leaving the fetus in utero versus the complications of prematurity Late-onset FGR represents 70%–80% of FGR and has a low association (about 10%) with late PE.19 The degree of placental disease is mild;20 thus UA Doppler is below the 95th centile in virtually all cases.6 However, the CPR, which combines changes in the UA and MCA, becomes abnormal at some point before birth in a substantial proportion of cases.6 Changes in the DV are virtually never observed,6,21 and the cascade of sequential fetal deterioration described for early onset does not occur in late FGR However, progression to fetal deterioration may occur suddenly and there is high association with intrapartum fetal distress and neonatal acidosis.22,23 We have proposed24 that this is possibly the consequence of a combination of rapid placental function deterioration, lower tolerance to hypoxia in term fetuses, and the more frequent presence of intense uterine contractions at this pregnancy stage Fetal assessment and correlation with perinatal outcomes Some of the measures and indices discussed later are essentially used for the diagnosis/identification of FGR from SGA, and consequently, they are relevant for the decision as to whether delivery is indicated when pregnancy term is reached Another set of indices have a prognostic value, since they are useful to determine that there is a high risk of deterioration, and consequently, they are used to indicate delivery before term is reached Fetal assessment and correlation with perinatal outcomes  531 Umbilical artery Doppler UA Doppler is the only measure that provides both diagnostic and prognostic information for the management of FGR There is compelling evidence that using UA Doppler in high-risk pregnancies improves perinatal outcomes, with a 29% reduction in perinatal deaths.25 Absent or reversed end-diastolic velocities, the end of the spectrum of the abnormalities of the UA Doppler, have been reported to be present, on average, week before the acute deterioration.26 There is an association between reversed end-diastolic flow in the UA and adverse perinatal outcome (with a sensitivity and specificity of about 60%), which seems to be independent of prematurity.27 After 30 weeks, the risk of stillbirth of a fetus with isolated reversed end-diastolic velocities in the UA Doppler overcomes the risks of prematurity,28,29 and therefore delivery seems justified Middle cerebral artery Doppler/cerebralplacental ratio MCA informs about the existence of brain vasodilation, a surrogate marker of hypoxia There is an association between abnormal MCA-PI and adverse perinatal and neurological outcome, but it is unclear whether delivering before term could add any benefit MCA is particularly valuable for the identification of6 and prediction of adverse outcome among30,31 late-onset FGR, independently of the UA Doppler, which is often normal in these fetuses Fetuses with abnormal MCA-PI had a sixfold risk of emergency cesarean section for fetal distress when compared with SGA fetuses with normal MCA-PI,32 which is particularly relevant because labor induction at term is the current standard of care of late-onset FGR.33–35 Late-FGR with abnormal MCA-PI has poorer neurobehavioral competence at birth and at 2 years of age.23,36 MCA is considered a rather late manifestation, with acceptable specificity but low sensitivity, which is improved by the use of CPR The CPR improves remarkably the sensitivity of UA and MCA alone Thus, the CPR is already decreased when its individual components suffer mild changes but are still within normal ranges.37,38 In late-onset SGA fetuses, abnormal CPR is present before delivery in 20%–25% of the cases,39 and it is associated with a higher risk of adverse outcome at induction, although to a lesser degree than MCA.32 Ductus venosus Doppler DV is the strongest single Doppler parameter to predict the short-term risk of fetal death in early-onset FGR Longitudinal studies have demonstrated that DV flow waveforms become abnormal only in advanced stages of fetal compromise.18,26,27,40 Absent-reversed velocities during atrial contraction are associated with perinatal mortality independently of the gestational age at delivery,41 with a risk ranging from 40% to 100% in early-onset FGR.35,42 Thus, this sign is normally considered sufficient to recommend delivery at any gestational age, after completion of steroids In about 50% of cases, abnormal DV precedes the loss of short-term variability in cCTG, and in about 90% of cases, it is abnormal 48–72 hours before the biophysical profile (BPP).18,40 Hence, it is considered to provide a better window of opportunity for delivering fetuses in critical conditions at very early gestational ages Aortic isthmus Doppler This vessel reflects the balance between the impedance of the brain and systemic vascular systems.43,44 Reverse aortic isthmus (AoI) flow is a sign of advanced deterioration and a further step in the sequence starting with the UA and MCA Doppler AoI has a strong association with both adverse perinatal45 and neurological outcome.46 However, longitudinal studies show that the AoI precedes DV abnormalities by week,21,47 and consequently it is not as good to predict the short-term risk of stillbirth.35 In contrast, AoI seems to improve the prediction of neurological morbidity.30 Fetal heart rate analysis and biophysical profile Early studies on high-risk pregnancies showed that, though highly sensitive, cardiotocography has a 50% rate of false positives for the prediction of adverse outcome.48 In addition, a meta-analysis49 on high-risk pregnancies failed to demonstrate any beneficial effect in reducing perinatal mortality Hence, there is no evidence to support the use of traditional fetal heart rate (FHR) monitoring or “nonstress tests” in FGR fetuses A main limitation of CTG is the subjective interpretation of the FHR, which is extremely challenging in very preterm fetuses with a physiologically reduced variability cCGT has represented a step forward and has provided new insights into the pathophysiology and management of FGR cCGT evaluates short-term variability of the FHR, an aspect that subjective evaluation cannot assess Current evidence suggests that cCGT is sensitive to detect advanced fetal deterioration, and it provides a value similar to DV reverse atrial flow for the short-term prediction of fetal death Shorttem variability becomes abnormal, coinciding with the DV, whereas in about half of cases, abnormal DV precedes the loss of short-term FHR variability; the latter is the first to become abnormal in the other cases.18 Concerning BPP, it is calculated by combining ultrasound assessment of fetal tone and respiratory and body movements, with amniotic fluid index (AFI), and a conventional CTG BPP was designed to improve the performance of FHR Early observational studies reported a very low risk of false positives for acidosis and perinatal death, but more recent studies on early-onset very preterm FGR fetuses raise concerns over the false-positive rate, with up to 23% of instances of IUFD in fetuses with BPP > and 11% in those with BPP > 8.50 A meta-analysis51 showed no significant benefit of BPP in high-risk pregnancies Consequently, whenever Doppler expertise and/or cCTG is available, the incorporation of BPP in management protocols of FGR is questionable 532  Fetal growth restriction Amniotic fluid index AFI is used essentially as part of the BPP Amniotic fluid volume is believed to be a chronic parameter In fact, among the components of BPP, it is the only one that is not considered acute A meta-analysis52 of 18 randomized studies demonstrated that a reduced AFI is associated with an abnormal 5-minute Apgar score, but there was no association with acidosis or perinatal death in SGA (RR 1.6 [95% CI 0.9–2.6]) Longitudinal studies in early-onset FGR fetuses have shown that the AFI fluid index progressively decreases.18 One week before acute deterioration, 20%–30% of cases have oligohydramnios.18,40 There is limited evidence on the role of oligohydramnios to predict perinatal complications in FGR fetuses managed with Doppler so that its inclusion in management protocols is questionable Clinical management of FGR: Follow-up scheme and timing of delivery No treatment has been demonstrated to be of benefit in growth restriction.53–57 Thus, assessment of fetal well-being and timely delivery remain as the main management strategy The aim behind a clinical protocol for managing FGR is to combine existing evidence on various methods for monitoring fetal well-being in order to establish the risks of fetal injury or death and to balance them against the risks of prematurity if the fetus is delivered As we have discussed earlier, the first aim after identifying a “small fetus” is to distinguish between FGR and SGA Once this distinction is established, from a conceptual point of view, the concerns of the clinician are to determine (1)  whether there is an indication for elective delivery, i.e., whether the risks of leaving the fetus in utero exceed those of delivering electively, and (2) if there is not an indication for elective delivery, when should be the next control scheduled Although when considered as groups there are clear differences between early-onset and late-onset forms, on an individual basis there is important overlapping of clinical features at borderline gestational ages In addition, cases with the same gestational age at onset are often detected at different time points during gestation Consequently, we believe it is most practical to define an integrated protocol for the management of FGR As mentioned at the beginning of this chapter, FGR is probably among the obstetrical entities with the greatest variation in clinical practice We have long stated that FGR must be followed according to a stage-based protocol, which integrates the best available evidence to indicate timing of follow-up and delivery In our experience, the application of such protocol facilitates clinical management and communication among doctors about what “severity” means and could largely reduce clinical practice variation Our suggested approach24 is to group in stages those indices or signs that are associated with similar fetal risks, since they should indicate similar follow-up intervals and timing of delivery Thus, we suggest to profile several stages, or prognostic groups, which define different management strategies (Table 63.2): SGA: Excluding infectious and genetic causes, the perinatal results are good Fortnightly Doppler and growth assessment are standard practice Labor induction should be recommended at 40 weeks Fortnightly monitoring is safe Table 63.2  Stage-based classification and management of fetal growth restriction Stage Pathophysiological correlate I Severe smallness or mild placental insufficiency II Severe placental insufficiency III Low-suspicion fetal acidosis IV High-suspicion fetal acidosis Criteria (any of) EFW p95 MCA PI < p5 Uterine artery PI > p95 UA AEDV reverse AoI UA REDV DV-PI > p95 DV reverse atrial flow cCTG 95th centile There is an association between a higher risk of stillbirth and poorer neurological outcome However, since signs suggesting a very high risk of stillbirth within days are not present yet, it seems reasonable to delay elective delivery to reduce as possible the effects of severe prematurity We suggest delivery should be recommended by cesarean section after 30 weeks Monitoring every 24–48 is recommended Stage IV FGR (high suspicion of fetal acidosis and high risk of fetal death): There are spontaneous FHR decelerations, reduced short-term variability (