Budge, Helen

Morrison, Janna L.

Nijland, Mark J.

Regnault, Timothy R.H.

English

Scholarship@Western

Western University Scholarship@Western Paediatrics Publications Paediatrics Department 1-1-2013 Basic experimental and clinical advances in the mechanisms underlying abnormal pregnancy outcomes. Timothy R.H. Regnault Western University, tim.regnault@uwo.ca Mark J. Nijland Helen Budge Janna L. Morrison Follow this and additional works at: https://ir.lib.uwo.ca/paedpub Citation of this paper: Regnault, Timothy R.H.; Nijland, Mark J.; Budge, Helen; and Morrison, Janna L., "Basic experimental and clinical advances in the mechanisms underlying abnormal pregnancy outcomes." (2013). Paediatrics Publications. 1601. https://ir.lib.uwo.ca/paedpub/1601 Hindawi Publishing CorporationJournal of PregnancyVolume 2013, Article ID 327638, 3 pageshttp://dx.doi.org/10.1155/2013/327638EditorialBasic Experimental and Clinical Advances in theMechanismsUnderlying Abnormal Pregnancy OutcomesTimothy R. H. Regnault,1 Mark J. Nijland,2 Helen Budge,3 and Janna L. Morrison41 Departments of Obstetrics and Gynaecology/Physiology and Pharmacology, Children’s Health Research Institute,Western University, London, ON, Canada N6A 5C2Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, School of Medicine,University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3309, USA3Academic Child Health, School of Clinical Sciences, University of Nottingham, Nottingham, UK4 Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research,University of South Australia, GPO Box 2471, Adelaide, SA 5001, AustraliaCorrespondence should be addressed to Timothy R. H. Regnault; tregnaul@uwo.caReceived 2 January 2013; Accepted 2 January 2013Copyright © 2013 Timothy R. H. Regnault et al.is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the originalwork is properly cited.Development and growth of the embryo and fetus arecomplex processes inextricably linked to the ability of theindividual to reach childhood developmental milestones.Insults or stimuli to which the embryo or fetus respondsduring critical periods of intrauterine growth and devel-opment are now understood to alter the genetically dic-tated growth trajectory of the fetus and reprogram thenewborn’s long-term development and physiological path.Basic experimental and clinical human studies demonstratethat intrauterine growth restriction may result from in uteroinsults such as uteroplacental insufficiency and/or hypoxia,preeclampsia, preterm labor, and imbalanced nutrition. efetal responses to these insults manifest as a predispositionto the development of the metabolic syndrome in postnatallife. e “thriy phenotype hypothesis” has been proposedto explain the mechanism by which in utero responsiveadaptations set in motion the series of developmental andphysiological adaptations to maximize the chances of inutero survival [1–3]. While intrauterine growth restrictionresulting in low birth weight is recognized as a major riskfactor for noncommunicable diseases associated with themetabolic syndrome, it is now apparent that both ends ofthe birth weight spectrum are associated with having anincreased risk of adult-onset disease in later life [4, 5]. isfurther highlights the necessity to understand both optimalgrowth patterns that result in optimal birth weight and thecritically important role that they play in setting the stage forhealth and the risk of disease in postnatal life. In this specialissue, we have gathered a number of excellent reviews, eachfocussing upon different facets of how an altered in uteroenvironment results in adaptations in fetal organ systems,expanding our understanding of how perturbations at earlystages of development may have long-term consequences.e placenta represents not only the junction betweenthe maternal and fetal circulatory systems, but also playsan important role in regulating fetal nutritional supply. eregulation of placental nutrient transport is multifactorial.e review by S. Lager and T. L. Powell in this issue focuseson factors regulating placental glucose, amino acid, and fattyacid transporters. Particularly intriguing is the concept thatthe placenta plays a major role in integrating maternal andfetal signals to regulate overall nutrient supply, transport,and thus fetal growth. Keeping with placental function, L.Avagliano et al. discuss the mechanisms controlling placentalamino acid transport in the context of placental insufficiencythat results in I��R. eir review maintains a speci�cemphasis on the human condition and the impact changes inmaternal amino acid concentrations have on placental trans-port and metabolism. e theme of the central role played bythe placenta in fetal growth and development is highlightedin the article by D. T. Yates et al. which examines the topicof placental insufficiency and reduced newbornmuscle mass.In their review, they probe the contribution of reducedfetal oxygen tension during late gestation to modulating2 Journal of Pregnancycirculating catecholamines, as chronic hypercatecholamine-mia reduces both fetal muscle development and growth.ey highlight that developmental programming of skeletalmuscle adrenergic receptors may partially explain how themetabolic and endocrine phenotype of IUGR offspring leadsto differential nutrient utilization, linking skeletal muscledevelopment and later life disease risk. Adipose tissue hasalso been identi�ed as being highly plastic and vulnerable tochanges in the in utero environment, leading to alterationsin postnatal metabolism. Various adipose depots appear tobe sensitive to the in utero environment, such that altered inutero developmentmay provide important linkages to aspectsof the metabolic syndrome in adult life. O. Sarr et al. discusshow IUGR fetuses display increased lipogenic and adipogeniccapacity as offspring and they review the roles factors suchas fetal hypoleptinemia, altered glucocorticoid signaling, andchromatin remodeling may subsequently contribute to anincreased later life obesity risk.An emerging theme in the �eld of developmental pro-gramming stems from observations that different insults inutero result in similar adverse postnatal phenotypes associ-ated with the metabolic syndrome. e idea of a commonfactor acting across the spectrum of in utero insults has beensuggested to explain this phenomenon. Indeed, oxidativestress and activation of in�ammatory pathways have nowbeen proposed as key modulators of fetal growth [6, 7].Oxidative stress in the fetal compartment can be generatedby several conditions, such as prenatal hypoxia, maternalunder- and overnutrition, and inappropriate exposure toglucocorticoids. In their review, L. P. ompson and Y. Al-Hasan discuss possible origins of developmental reprogram-ming as a result of in utero oxidative stress. ey highlightthe important role that oxidant molecules have as signallingfactors in developmental programming and propose thatthese effects are mediated by epigenetic mechanisms. Inaddition to oxidative stress pathways, in�ammatory compli-cations that impact on proin�ammatory cytokines such asIL-1, IL-6, and TNF-𝛼𝛼, as well as increased concentrations ofglucocorticoids also have major roles in the onset of alteredgrowth patterns in utero [8, 9]. R. E. Fisher et al. review theoffspring’s susceptibility to a range of metabolic disorderswhile focusing on the impact of activated in�ammatorypathways and how changes in the neuroendocrine-immunesystem are programmed.e importance of the adrenal gland in fetal physiologyas a master regulator of fetal maturation and the initia-tion of parturition was �rst highlighted in the pioneeringwork of Liggins and colleagues in the 1960 s and 70 s [10].More recently, publications have reported that sustainedor repeated fetal stressors can activate the hypothalamic-pituitary-adrenocortical (HPA) axis resulting in elevated cor-tisol production and early maturation of the adrenal cortexcontributing to fetal growth restriction. In their review,D. A. Myers and C. A. Ducsay have explored the impactof adrenocortical and adipose responses to high altitude-induced, long-term hypoxia in the ovine fetus. ey showthat adaptive responses both at the level of the hypothalamusand anterior pituitary as well as the adrenal cortex contributeto altered adrenal gland function that may be invoked as ageneral adaptive response to intrauterine stress to promotefetal survival. Given the importance of the HPA axis inregulating fetal maturation, glucocorticoids are administeredto pregnant women at risk of preterm labour to promote fetallung surfactant maturation with lifesaving consequences. Anumber of reviews in this issue examine the administrationof antenatal glucocorticoids from a developmental program-ming perspective. L. Bennet et al. report that the overallimpact of glucocorticoid administration on neurodevelop-ment is surprisingly unclear and, worryingly, that there isevidence of postnatal effects associated with impaired braindevelopment following prenatal exposure to glucocorticoids.ey discuss the possibility that maternal glucocorticoidsmay well be both protective and damaging, depending on theprecise timing before the preterm fetus and infant are exposedto an hypoxia/ischemia insult. e authors conclude that,as with so many aspects of prenatal care and neonatology,timing is everything. Further examining the need for carefuluse of glucocorticoids, J. Morrison et al. review the impactof glucocorticoid use in the IUGR fetus and highlight theimportant observation that antenatal glucocorticoidsmaynothave the same effects in IUGR preterm fetuses as they do innormally grown preterm fetuses.Not only does this issue focus upon the direct impactof complications arising from a suboptimal in utero envi-ronment, we also include reviews dealing with how exist-ing maternal conditions may impact the lifelong healthtrajectories of their offspring. Epidemiological studies haveidenti�ed that maternal asthma, during pregnancy, increasesthe risk of a number of poor outcomes for the neonateincluding growth restriction, lower birth weight, pretermdelivery, the need for neonatal resuscitation, and stillbirth.V. L. Clion et al. discuss the evidence currently available tosupport the hypothesis that children of mothers with asthmamay be at risk of lifelong health complications that includediabetes and hypertension. An understudied area of publichealth concern involves treatment ofmaternal conditions andtheir later life implications for the developing offspring. Byway of example, there is considerable uncertainty regardingprescribing practices for pregnant women with severe andpersistent psychiatric disorders. S. Raha et al. discuss theevidence for associating altered birth weight and maternalantipsychotic use, highlighting the role of the placenta andthe possible impact of oxidative stress upon fetal growth.is review sets the stage for further studies to better ourunderstanding of the effects of these drugs on fetal growthand consequences for the long-term health of the offspring.Recently, studies have also begun to highlight how anadverse in utero environment may impact longevity. A keycomponent of longevity is telomere health and a number ofstudies have now identi�ed that telomere development maybe impaired in association with altered fetal development,and the etiology of the diseases associated with the metabolicsyndrome is beginning to be elucidated. In the review by S.E. Hallows et al. the authors suggest that premature agingor cellular senescence through increased oxidative stress andDNA damage to the telomeric ends of chromosomes maybe initiators of disease processes. Finally, treatment at theextremes of the U-shaped birth weight distribution is limitedJournal of Pregnancy 3and prevention of the increased risk of developing metabolicsyndrome in later life is an area of active investigation. Tothis end, N. Ma and D. B. Hardy explore a number ofthe developmental processes contributing to the metabolicsyndrome and discuss possible intervention strategies.is collection of review articles highlights the wide andvaried range of insults that the fetus may experience inutero, to which the fetus can respond through a range ofadaptations which themselves may impact on the life courseof that individual. A better understanding of these wideranging insults and the similarities and differences in the fetalresponses and adaptation will not only allow the predictionof the impact on health in adult life but also guide us in thedevelopment of effective intervention strategies.Timothy R. H. RegnaultMark J. NijlandHelen BudgeJanna L. MorrisonReferences[1] C.N.Hales andD. J. Barker, “e thriy phenotype hypothesis,”British Medical Bulletin, vol. 60, pp. 5–20, 2001.[2] J. C. Wells, “e thriy phenotype as an adaptive maternaleffect,” Biological Reviews, vol. 82, no. 1, pp. 143–172, 2007.[3] M. S. Martin-Gronert and S. E. Ozanne, “Mechanisms underly-ing the developmental origins of disease,” Reviews in Endocrineand Metabolic Disorders, vol. 13, no. 2, pp. 85–92, 2012.[4] D. J. Pettitt and L. Jovanovic, “Birth weight as a predictor oftype 2 diabetes mellitus: the U-shaped curve,” Current DiabetesReports, vol. 1, no. 1, pp. 78–81, 2001.[5] O. Manor and I. Koupil, “Birth weight of infants and mortalityin their parents and grandparents: the Uppsala birth cohortstudy,” International Journal of Epidemiology, vol. 39, no. 5, pp.1264–1276, 2010.[6] B. C. Feltes, J. de Faria Poloni, and D. Bonatto, “e devel-opmental aging and origins of health and disease hypothesesexplained by different protein networks,” Biogerontology, vol.12, no. 4, pp. 293–308, 2011.[7] R. A. Simmons, “Developmental origins of diabetes: the role ofoxidative stress,” Best Practice and Research, vol. 26, no. 5, pp.701–708, 2012.[8] L. K. Rogers and M. �elten, “Maternal in�ammation, growthretardation, and preterm birth: insights into adult cardiovascu-lar disease,” Life Sciences, vol. 89, no. 13-14, pp. 417–421, 2011.[9] A. A. Khan, A. Rodriguez, M. Kaakinen, A. Pouta, A. L.Hartikainen, and M. R. Jarvelin, “Does in utero exposureto synthetic glucocorticoids in�uence birthweight, head cir-cumference and birth length? A systematic review of currentevidence in humans,” Paediatric and Perinatal Epidemiology,vol. 25, no. 1, pp. 20–36, 2011.[10] G. C. Liggins, “e role of cortisol in preparing the fetus forbirth,” Reproduction, Fertility and Development, vol. 6, no. 2, pp.141–150, 1994.Submit your manuscripts athttp://www.hindawi.comStem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014MEDIATORSINFLAMMATIONofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Behavioural NeurologyEndocrinologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Disease MarkersHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalOncologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Oxidative Medicine and Cellular LongevityHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014PPAR ResearchThe Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Journal ofObesityJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Computational and  Mathematical Methods in MedicineOphthalmologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Diabetes ResearchJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Research and TreatmentAIDSHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Gastroenterology Research and PracticeHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Parkinson’s DiseaseEvidence-Based Complementary and Alternative MedicineVolume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Basic experimental and clinical advances in the mechanisms underlying abnormal pregnancy outcomes.

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Basic experimental and clinical advances in the mechanisms underlying abnormal pregnancy outcomes.

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