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Disorders of Pregnancy and Parturition & Biology of Ageing Shreya Mehta sm3622@ic.ac.ukTILO'S COVERED I. Pregnancy physiology: II. Pregnancy disorders: Summarise the key Summarise the major changes in maternal pathology and physiology across the pathophysiology of key course of pregnancy. disorders of pregnancy.LECTURE TIMELINE 1. Foetal growthand 2. Pathophysiology 3. Pre-eclampsia 4. SGA& IUGR placentation 5. Biologyof AgeingFoetal Nutrition Stages What are the two stages of nutrition of the foetus? • Histiotrophic = Foetus takes nutrition from uterine gland secretions and breakdown of endometrial tissue • Haemotrophic = fetus depends on maternal blood supply directly through a haemochorial-type placenta. • Haemochorial = Describes a placenta where the chorion is in direct contactwith the mother’s blood (via chorionic villi)Histiotrophic nutrition What type of nutrition does the placenta use in the first trimester? Why is this appropriate? - Histiotrophic - Low foetal demand on placenta – limited embryo-foetal growth at this stage. What processes is histiotrophic nutrition dependent on? - Breakdown of endometrial tissue - Uterine gland breakdown - Maternal capillaries and endometrium breakdown - Uterine gland secretion What two major cell populations are involved in histiotrophic nutrition, and what are their functions? - Cytotrophoblastsare proliferative, and divide and transform into more syncytiotrophoblastsHaemotrophic nutrition When does the foetus switch to a significantly higher oxygen demand? • ~Week 13 – start of second trimester • Switch from histiotrophic to haemotrophic nutrition via a haemochorial-type placenta What tissue is most important in the switch to haemotrophic nutrition? • Cytotrophoblastsproliferate into chorionic villi What are chorionic villi? • Finger-like extensions of chorionic cytotrophoblasts, which undergo branching, providing substantial SAThe Placenta Structure of the placenta – foetal vein, artery, umbilical cord, chorionic villi, maternal vein, intervillous spaces and maternal artery.Nutrient exchange How are nutrients exchanged in the placenta? - Maternal spiral arteries and veins feed blood into lacunae (intervillousspaces) - Foetal chorionic villi, supplied by foetal capillaries exchange nutrients, gas with intervillous spaces How does the foetus increase its area for exchange? - Branching ofchorionic villi increase with pregnancy progression - + Continued invasion offoetal circulatory system into chorionic villiPhases of CV development Three phases of chorionic villi development • Primary • Outgrowth of cytotrophoblast and branching of these extensions (primary villi) • Secondary • Growth of foetal mesoderm into primary villi • Tertiary • Growth of umbilical artery and vein into villus mesoderm, providing vasculature Microstructure of the terminal villus • Convoluted knot of vessels and vessel dilation • Slows blood flow, enabling exchange of maternal and foetal blood • Coated by trophoblast How do terminal villus microstructures change from early → late pregnancy? • Much smaller villidiameter • Separation distance between capillaries and maternal blood significantly decreases – vessels move closer within villi • Trophoblast layers get thinner with gestationalageSpiral Artery Remodelling What are EVT cells? How do they interact with maternal spiral arteries? • =Extra-villus trophoblast cells • EVT cells coatingvilli invade spiral arteries forming endovascular EVT How are spiral arteries remodelled and what is the physiological effect of this? • Endothelium and smooth muscle broken down, EVT coats inside of blood vessel • Conversion of spiral artery into… • low pressure, high-capacity conduit → increases maternal blood flow How does EVT cell invasion trigger spiral artery remodelling? • Triggers endothelialcells to release chemokines • Attract & recruit immune cells • Endovascular EVT disrupt vesselwalls • Break down normal vessel wall ECM • Replace it w/ fibrionoid (specialised ECM)Failed spiral artery remodelling What does failed conversion of spiral arteries lead to? - Stay spiralised and convoluted – no increase in diameter and low resistance which is needed to increase blood volume to placenta - Smooth muscle remains → increases contractility → higher chance of blockages & reduced perfusion - Immune cells become embedded in vessel walls - Vessels become occluded by RBCs What are maternal unconverted spiral arteries vulnerable to? (3 pathological changes) - Intimal hyperplasia → thickening of wall - Atherosis (due to immune cells remaining within wall) - RBC occlusion What are the local physiological consequences of failed spiral artery remodelling? (x4) - Turbulent and perturbed flow - Local hypoxia - Free radical damage - Inefficient delivery of nutrients to intervillous spaceFailed spiral artery remodellingGrowth factors released by placenta What is VEGF? - Vascular endothelial growth factor (angiogenic factor) What is PLGF? - Placentalgrowth factor (VEGF-related) - Pro-angiogenic factor released in large amounts by placenta What is sFlt1? What is it also known as? What is its role? - Aka soluble VEGFR1 - Soluble receptor for VEGF-like factors which binds soluble angiogenic factors to limit their bioavailability How does the healthy placenta produce FLT1, PLGF, VEGF? What is the effect? - Releases PLGF and VEGF into maternalcirculation - → bind to receptors on endothelial surface → promotes vasodilation, anti-coagulation and healthy maternal endothelial cells Pre-eclampsia – overview Early onset = less than 34 weeks • Affects BOTH fetus & mother • Placental changes DEFINED BY - New onset hypertension (previously normotensive) - BP >140mmHg systolic and/or 90mmgHg diastolic - Must have been normotensive for 20 weeks before pregnancy Late onset - Occurring after 20 weeks gestation = more than 34 weeks • MORE COMMON • Affects mainly mother • Fetus usually OK • Lessplacental changesPre-eclampsia – symptoms & risks Complications of PE: Symptoms : • High BP MOTHER • Oedema • Damage to kidney/liver, other organs • Reduced fetal movements • Increased risk of HELLP syndrome • Risk of eclampsia (seizures/loss of consciousness) • Placental abruption SEVERE Pre-Eclampsia • Detachment ofplacenta from endometrium • Abdominal pain • → bleeding • Headache • → reduced nutrient exchange • Visual disturbances, seizures, loss of consciousness FETUS • Pre-term delivery • Reduced fetal growth • Fetal DeathPre-eclampsia – risk factors Maternal Risk factors: How does pre-eclampsia present on ultrasound? • Previous pregnancy with PE • BMI >30 - Reduced foetal movement • Family history - AND/OR reduced amniotic fluid volume • Increased maternal age (>40), and possibly low - In 30% cases maternal age (<20) • Gestational hypertension, or previous hypertension • Pre-existing conditions (e.g. diabetes, PCOS, renal What is the main clinical difference between pre- disease, subfertility) eclampsia and gestational hypertension? - Proteinuria • Autoimmune disease (antiphospholipid antibodies) • Non-natural cycle IVF – hormonal stimulation to generate mature eggs, or hormonal support to maintain luteal functionPre-eclampsia – placental defects • Failed spiral artery remodelling • Reduced placental perfusion • Placental ischaemia • EVT invasion only in decidual layers • Releases excessive sFLT-1 from distressed placenta (acts like a sponge!) • Mops up PLGF and VEGF • Imbalance between growth factors • → stops endothelial surface receptorbinding → dysfunctional released by placenta (VEGF & sFLT1) endothelial cells • → pro-coagulant factors + vasoconstriction …PLACENTAL DISTRESS & MATERNAL HYPERTENSIONPre-eclampsia – placental defects How does EVT invasion into the myometrium differ in PE? Which form does this normally affect? - Early-onset PE - EVT invasion is limited to the deciduallayer (doesn’t go into myometrium) - → spiralarteries don’t massively increase in capacity (smaller diameter, more resistance) - → reduction in placental perfusionEVs in pre-eclampsia What are EVs? - Extracellular vesicles – nanometre scale - Lipid-bilayer laminated vesicles released by allcelltypes, allthe time - Contain mRNAs, proteins, miRNAs - miRNAs inhibit protein translation at complimentary part of genome - Influence cellbehaviour (locally and at distance) How does PE change EV numbers in the maternal circulation– maternally and placentally derived? - Overall increase in EVs in maternal circulation - Increase in maternalendothelial-derived EVs - Decrease in placenta-derived EVs How do EVs within PE affect physiology? - pro-inflammatory cargoes in PE placenta and maternalendothelium affect: - Trophoblast invasion (inhibits EVT invasion into spiral arteries so only goes into decidual layer and not myometrium) - Maternalendothelial functionTesting for pre-eclampsia When are these results valid? PE: sFLT-1 goes up, PLGF goes down 24-36 weeks Normal: High PLGF Because PLGF goes down naturally and dramatically decreases ~37 weeks as parturition comes closerPre-eclampsia management Management • Key management → Delivery of the placenta Before 34 weeks? Prevention • Preferable to maintain pregnancy if possible for benefit of foetus • Reduce BMI → especially if >35 After 37 weeks? • Exercise throughout pregnancy • Low dose aspirin from 11-14weeks • Delivery preferable How is PE managed between 34-37 weeks? Long-term health impacts • Case by case • Increased risk of pre-eclampsia in next What are the managements for PE before delivery? pregnancy • Regular daily monitoring • Anti-hypertensive therapies • Increased risk of T2DM, CVD & renal issues • Magnesiumsulphate to counteract seizures • Corticosteroids for <34 weeks to promote foetal lung development before deliveryEarly-onset pre-eclampsiaSmall for Gestational Age What is SGA? How is it defined? • Small for gestational age • Foetalweight <10 centile OR 2 SD below population normal What rd severe SGA? • 3 centile or less What are the three clinical course groups of babies who are SGA? • Small throughout pregnancy but otherwise healthy • Early growth normal but slows later in pregnancy (IUGR) • Non-placental growth restriction (genetic, metabolic, infection) SGA vs IUGR (intra-uterine growth restriction) different? • SGA → considers only foetal/neonatal weight without consideration of in-utero growth and physical characteristics at birth • IUGR → clinicaldefinition of foetuses/neonates with clinical features of malnutrition and in-utero growth restriction, irrespective of weight percentile Is it possible to have experienced IUGR and not SGA? - YesIntra-uterine growth restriction Two types – symmetrical & asymmetricalIUGR Implications of IUGR: Symmetrical IUGR Asymmetrical IUGR Earlier in pregnancy Malnutrition disorder in last Cardio part of pregnancy • Foetal cardiac hypertrophy Lesspronounced • brain-sparing foetal- • Re-modelling of foetal vessels due to chronic features of malnutrition growth restriction vasoconstriction (due to hypoxia) • Increases future risk of CVD Poor prognosis More pronounced features of malnutrition Resp Poor maturation of lungs during foetal life Good prognosis • Bronchopulmonary dysplasia • Respiratory compromise (need of corticosteroids towards end of pregnancy) Long term • Motordefects • Cognitive impairmentIUGR and PE relationshipBiology of Ageing Three ‘definitions’ ofageing • a progressive accumulation of changes in the body which occur with the passing of time and which cause the increase in the probability of disease and death of the individual. • the wearing out of the structures and functions that reach a peak or plateau during development and maturations of the individuals of a given species • the time-related deterioration of the physiological functions necessary for survival and reproduction Ageing is notthe same as longevity • Longevity = length oflifespan independent of ageing There are FIVE “damage theories of ageing” • Damage theory of ageing = ageing due to the cumulative impact of assaults (i.e. UV exposure, reactive oxygen species) over the lifecourse • Wear & Tear theory → wearing out of tissues/components → ageing of organism • Rate of living theory --> the basal metabolic rate determines lifespan of the organism (higher rate, shorter lifespan • Cross-linking theory → accumulation of cross-linked proteins over time impairs cellular function → slowing down bodily processes • Free radical theory → reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function. Accumulation of this damage overtime results in aging • Somatic DNA damage theory → accumulation of genetic mutations → breakdown ofgenetic integrity Hallmarks of Ageing Hallmarks ofAgeing= common characteristics of ageing across multiple species To be a “hallmark”, must meet the followingcriteria (i) it should manifest during normal aging; (ii) its experimental aggravation should accelerate aging; (iii) its experimental amelioration shouldretard the normal aging process and, hence, increase healthy lifespan NINE HALLMARKS OF AGEING Genomic hallmarks Cellularhallmarks Biochemical hallmarks • Genomic instability • Stem cell exhaustion • Impaired mitochondrial • Epigenetic changes • Changes in cell signalling function • Impaired proteostasis • Telomere attrition • Cellularsenescence • Impaired nutrient sensingHallmarks of Ageing New modern theory of ageing → “Information theory of ageing” • acquisition of epimutations (harmful epigenetic changes) over the lifecourse leads to aging through loss of 'youthful epigenetic information’ Strategies to preventageing?SBAQ1 Which of the followingis incorrect? A. Maternal extracellular vesicles are upregulated in pre-eclampsia compared to normal B. Pre-eclampsia causes a anti-coagulant state C. Increased free radical damage and local hypoxia occurin maternal blood vessels in pre-eclampsia D. Dysfunction of E-EVT cell invasion of maternal spiral arteries is thought to be the key pathophysiological process in early-onset pre-eclampsia E. Maternal blood vessels are more likely to become occluded by RBCs in pre-eclampsia SBAQ2 Which of the following is not true? A. Pre-eclampsia is more common in the developing world B. Pre-eclampsia is best managed by giving aspirin throughout pregnancy C. After PE, patients are at increased risk of developing diabetes mellitus D. Patients with a history of diabetesmellitus are more likely to develop PE E. Eclampsia isan uncommon complication of PESBAQ3 How many of the followingbabies meet the criteria for small for gestational age? Baby 1: 4 centile; Baby 2: 24 centile; Baby 3: -2.5 SD from mean, Baby 4: 9 centile; Baby 5: 67 centile A. 1 B. 2 C. 3 D. 4 E. 5Please fill out the feedback form :) →