Chestnut Chapter 4- Lesson 5

• The placenta is critical for obstetric anesthesia, involved in cultural rituals, and crucial for fetal well-being.
• It's a dynamic organ performing metabolism, nutrition, and hormonal maintenance during pregnancy.
• Maternal-placental conditions impact the fetus with effects extending into adulthood and future generations.
• Exchange of gases, nutrients, and wastes occurs without significant blood mixing in a fetal-origin structure.

Embryology

• The blastocyst attaches to endometrial pinopodes (uterodomes), expressing receptivity markers.
• Syncytiotrophoblasts and endometrial cells remodel the uterine matrix, invading the decidua and capillaries.
• This leads to the formation of trophoblastic lacunae with maternal blood circulation.
• The vitelline vein system enhances nutrient transport from maternal blood to the chorionic cavity.
• The embryo accelerates growth as diffusion dependence decreases.
• Extra-embryonic mesoderm proliferates into cellular columns carrying syncytiotrophoblast, forming primary villi at 2 weeks.
• Further differentiation leads to secondary and tertiary villi with blood cells and vessels.
• Villi connect within the chorionic plate and the stalk, forming the primitive placenta.
• Cytotrophoblast penetrates the syncytiotrophoblastic layer forming anchoring villi.
• Extensive villous branching enlarges surface area available for exchange.
• Villous maturation reduces cytotrophoblast thickness, shortening diffusion distances.
• Mesodermal components form the allantoic vessels, and the amnion surrounds the connecting stalk and yolk sac.

Placental Development Factors

• Placental development is influenced by nitric oxide, VEGF, TGF-β₁, angiopoietin 1 and 2, and hypoxia.
• eNOS expression in syncytiotrophoblast and endothelium is prominent in the first trimester and increases throughout pregnancy.
• Hypoxia stimulates trophoblast invasion and differentiation via hypoxia-inducible factor-alpha, activating VEGF and eNOS.
• Relative hypoxia is crucial for early placental development as the placental-fetal unit can't tolerate oxidative stress.
• Oxygen levels affect placental vascular sensitivity.
• NOS inhibition and hypoxia independently increase placental perfusion pressure and is prevented by nitric oxide donors.

Preeclampsia & Epigenetics

• Preeclampsia relates to abnormal placental growth and implantation.
• It can result in villous trees with longer capillaries and fewer branches.
• Vascular dysfunction stems from structural changes and nitric oxide synthesis, not altered responses to nitric oxide and vasoconstrictors.
• Expression and control of DNA/genes influence placental/fetal development, phenotype, and clinical diseases.
• Epigenetics explores effects of environmental influences via DNA methylation, histone modification, and noncoding RNA.
• DNA hypomethylation occurs at the blastocyst stage, and placental DNA methylation increases with gestation.
• This causes gene regulation changes for cell cycles and immune response.
• Genomic imprinting silences one allele copy, leading to mosaicism.
• In vitro fertilization, diet, and maternal diseases alter DNA methylation.
• Increased LINE1 methylation and hypomethylation of specific genes associate with early-onset preeclampsia.
• Late-onset preeclampsia links to hypomethylation of only 4 genes.
• DNA regulatory changes influence placental development and pregnancy-related diseases.

Fetal Programming

• Fetal programming means childhood/adult diseases can be influenced by in utero conditions.
• Malnutrition exposure leads to glucose intolerance, atherogenic lipid profiles, and cardiovascular diseases through gene hypomethylation.
• High-fat diets in utero increase diabetes incidence.
• Maternal stress during pregnancy impacts infant neurodevelopment.
• Placental growth correlates with fetal growth.
• At term, the placenta averages 18.5 cm in diameter, 500 g in weight, and 23 mm in thickness.
• The fetal placental weight makes up 6% of maternal weight.

Placental Growth Influences

• Placental and fetal growth are influenced by maternal anabolic status, placental growth hormone, insulin-like growth factor-1, leptin, and glucocorticoids.
• Increased glucocorticoids signal adverse conditions, decreasing glucose and amino acid transfer to the fetus.
• With 12 glucocorticoid receptor subtypes, placental-fetal development alterations can include remodeling, trophoblastic invasion, and angiogenesis inhibition
• Competition between mother and fetus for resources is known as the kinship theory, where imprinted genes affect nutrient allocation.

Comparative Anatomy

• Placentas differ in uterine attachment and tissue layers between circulations and species.
• Grossner classification categorizes placentas by tissue layers in the placental barrier.
• Transfer ability varies among species.
• Sheep have a thicker epitheliochorial placenta (three maternal layers), while human hemochorial placentas lack those layers.

Material Vascular Architecture

• Under corpus luteum hormones, spiral arteries elongate/coil erosion induces lateral looping.
• Late pregnancy, 200 spiral arteries supply 600 mL/min of blood directly to the fetus.
• Vasodilation accommodates increased flow via cytotrophoblastic/fibroid cell replacement.
• This dilates vessel diameter by 10-fold, decreasing blood velocity/pressure.

Preeclampsia

• Inadequate uterine spiral artery development leads to ischemia and preeclampsia.
• Computer models indicate high blood velocity in nondilated spiral arteries damages trophoblast cells.
• The intervillous space develops from trophoblastic lacunae fusion and decidual erosion.
• Basal plate folds form septa, dividing the space into 13–30 compartments for efficient transfer.
• Intervillous space can hold 350 mL of maternal blood.
• Arterial blood enters the intervillous space and moves to low resistance area and terminal villi where exchange predominates.
• Venous blood collects from trees in the perilobular zone and drains from space.

Fetal Vascular Architecture

• Umbilical cord contains two coiled arteries carrying blood to the placenta.
• These divide into chorionic arteries supplying 50 trees in lobules.
• Chorionic arteries split into cotyledonary arteries, then ramulus chorii, and terminal arterioles.
• Arterioles lead to bulbous enlargements with 2-4 capillary loops for exchange.
• The venous end of capillaries returns through collecting venules and chorionic veins.

Barrier Function

• The placenta is an imperfect barrier allowing bidirectional substance transfer, depending on permeability and mechanisms.
• Substances undergo binding in placental tissues, minimizing fetal exposure.
• Cytochrome P450 isoenzymes and transporters alter certain substances.
• Transfer rates of simple substances differ little among species despite placental thickness variations.

Cellular Transfer

• Cellular components cross the barrier via trophoblastic layer disruption or active transmigration.
• Fetal cells, including pluripotent ones, can persist in maternal organs for decades.
• Microchimeric cells may affect immunomodulation and autoimmune diseases and wound healing.
• Placental exosomes and microparticles exert maternal immunosuppressive effects and influence outcomes.
• Syncytial nuclei participate in maternal-fetal signaling and retroviral protein delivery.
• Microparticle excess is seen in early-onset preeclampsia.

Hormonal Function

• Transfer of compounds allows enzymes to convert precursors into estrogen and progesterone.
• Steroidogenic function begins early exceeding corpus luteum output by days 35-47 post-ovulation.
• The placenta produces/stores enzymes, binding proteins, and hormones.
• e.g., human chorionic gonadotropin and human placental lactogen and factors that control hypothalamic function.
• Protein and steroid production allows the placenta to control the environment.

Maternal Blood Flow

• Maternal blood enters the cotyledon space with pressure decreasing in densely packed villi.

Fetal Blood Flow

• Increased flow is through vascular growth not vasodilation.
• The placental vasculature is not sympathetically innervated.
• Adrenomedullin release helps with tone in vessels.
• Fetal blood pressure causes influx/efflux of water that changes volume and perfusion
• Factors such as maternal hyperglycemia and hypoxemia alter regional flow.
• Endothelium-derived relaxing factors are in control of circulation.
• Hypoxia-induced vasoconstriction is similar to that in the lung, re-distributing blood flow.
• The vasculature constricts in response to hypoxia and depends on angiotensin II.

Passive Vs Facilitated Transport

• Molecules can transfer across the placenta via several mechanisms.
• Passive transfer depends on electrochemical differences, molecule size, lipid solubility, ionization, and surface area.
• The mode is driven by concentration gradient through the membrane.
• Drugs with a molecular weight less than 600 Da cross the placenta by passive diffusion.
• Facilitated transport involves carrier-mediated, ATP-independent transport of molecules down gradients.
• This mode occurs with saturation kinetics, inhibition, stereospecificity, and temperature influences.

Active Transport

• Active transport involves an energy-driven transfer of substances across cell membranes.
• It requires a protein carrier, which causes it to exhibits saturation kinetics and competitive inhibition.
• One key version is sodium and potassium translocation through Na+/K+ ATPase.
• The placenta self-generates creatinine to meets metabolic power demands.
• Active transport proteins (P-glycoprotein, proteins, etc.) protect the fetus from foreign/teratogenic compounds.
• Drugs can compete with similar endogenous compounds for active transport.
• P-glycoprotein transports lipophilic drugs and it prevents compounds from leaving the breast milk and entering the maternal blood.
• DNA transcription of transporters may be induced by various factors.

Pinocytosis

• Pinocytosis is a process where the cell membrane invaginates macromolecules with diffusion properties.
• Vesicles move across the cytoplasm and fuse with the membrane at the pole which is how immunoglobulin G is transferred.
• The placenta releases vesicles of multiple sizes and functions.

Placental Environmental Factors

• Other factors that influence exchange include maternal/fetal blood flow, binding affinity, metabolism, diffusion capacity, etc.
• Conditions that alter net transport are lipid solubility, gradients in pregnancy, and plasma protein concentrations.

Oxygen in Detail

• The placenta is the organ for the fetus and provides the body weight of approxomately 8 ml.
• The placental "lung" has ⅕ of the efficiency of the adult lung.
• Oxygen transfer relies on different gradients, area, and oxygen levels.

Carbon Dioxide Transfer

• CO2 transfer occurs through different forms.
• Carbonic anhydrase reaction maintains equilibrium between CO2 and bicarbonate.
• PCO2 gradient drives transfer, facilitated by the rapid movement of CO2 (Chatelier principle.)

Additional Oxygen and CO2 Info

• Placental and fetal glucose depends on a stereospecific system.
• Concentration of amnio acids are highest in the placenta and then drop off after that.
• Fatty acids readily cross the fatty acids through multiple procedures.

Drug Transfer

• Permeability and pharmacokinetics determine fetal exposure to maternal drugs.
• Dual-perfused placenta models can be used to assess placental transfer of anesthetic agents.

Principles

• Transfer data comes from using the use of a transfer index- drug transfer divided by the compound clearance.

Key principles - drug

• A list of some key principles include lipid solubility, protein binding, tissue binding ,the pKa.

Transplacental Anesthetic agents - What drugs readily cross

• Atropine, Nitroglycerin, Nitroprusside, Diazepam, Etomidate, Dexmedetomidine, Halothane, and Ephedrine.

What Drugs DON'T cross?

• Anticholinergic agents, Glycopyrrolate, Heparin, Muscle Relaxants, Sugammadex, Phenylephrine
• Opioids do cross placenta.

Inhalation agents

• Anesthetic agents are quick with easy transfers.

Induction agents

• Induction of Lipophilic also enhances transfer across agents.

Benzodiazepines

• Highly united with lipophilic and protein that has un-ionized has high levels.

Opioids

• These can cross both the placenta and can cause central nervous depression in the the system.

Nonopioid analgesics

• These can cause problems with the hematopoietic.

Local Anesthetics

• Local anesthetics Readily cross.

Anticholinergic Agents

• Agent of what crosses blood is what the correlates.

Vasopressor agents

• Vasopressor agents and other types of agents are administered to affect potential pressure.

Anticoagulants

• These are necessary in all types of pregnancy for women.

Disease states

• Conditions like Diabetes can cause problems with the placenta and high transfer rates.

Infection

• Can cause problems with all types of transfer.

Pathology

• There has been growth in correlations between adverse outcomes, clinic-pathologic, and placental abnormalities.