Lecture 10: The Third Trimester Placenta and Pregnancy Adaptations?

What are the key features of the third-trimester placenta and its vascular structure?

• A term placenta, collected at 37 weeks:

  • Fetal side shows chorionic plate (amniotic membrane removed).

  • Umbilical artery and vein clamped → branching of these vessels into the placenta is visible.

• Placental cast:

  • Demonstrates the vascular network of the villus tree.

  • Umbilical arteries and veins connect to maternal blood spaces within the placenta.

What are the key features of the placenta at term, following immediate delivery?

• Placenta at delivery (from fetal side):

  • Umbilical cord and branching of blood vessels are visible.

  • Blood comes from the maternal intervillous space

    • Initial columns of extravillous trophoblast (EVT) cells invade maternal spiral arteries before the vasculature forms.

• Structure:

  • Discoid, 20–25 cm in diameter, 3 cm thick, 400–750 g.

  • Term: 37–42 weeks’ gestation.

What are the key features of placental development in the first trimester?

• Focus: Placental growth & development:

  • Continuous layer of cytotrophoblast (CT)

    • Extensive and rapid CT proliferation

    • CT fusion to form syncytiotrophoblast (ST)

  • Vascularisation begins

• Proliferation continues throughout pregnancy, but growth slows after the first trimester

What changes occur in the placenta during the third trimester to increase maternal-fetal exchange efficiency?

• Focus: Increased exchange efficiency of placenta

  • Reduced villi diameter → become more branched, and thinner

  • Thinning of STs (50–100 μm → 4–5 μm).

  • CT only cover ~20% of villous

• Highly vascularised → Angiogenesis and development of vascular network promoted by VEGF,

  • Once vascularised → forms tertiary villi (numerous fetal capillaries with fetal RBCs)

• Vasculosyncytial membranes (VS) form, located in terminal villi; the main site of maternal-fetal exchange; acts to reduce diffusion distancebetween maternal blood space and fetal capillaries to 1–2 μm

How does spiral artery remodelling support placental development and fetal nutrition?

• Spiral artery remodelling occurs via extravillous trophoblasts and maternal immune cells, causing a ~30-fold increase in spiral artery diameter and a large increase in blood suplly to the uterus

• Vessels are plugged until ~week 11; the fetus relies on histotrophic nutrition.

• When blood flow begins in the second trimester, it results in a transformation of arteries into low-resistance, high-flow vessels, delivering high-volume, low-pressure maternal blood to the intervillous space.

What are the structural and circulatory features of the third-trimester placenta?

• Highly branched vascular network within the placental villi, covered by syncytiotrophoblasts.

• Optimised for exchange, with:

  • Large surface area (~11 m²)

  • Small diffusion distance (1–5 μm)

  • ~50% of placental volume is occupied by blood vessels

• No mixing of maternal and fetal blood → 2 distinct circulatory systems

  • Fetal blood flows through the umbilical arteries into the placenta and out via the umbilical veins

  • Maternal blood flows into the placenta via remodelled spiral arteries

  • STs act as the interface between the maternal and fetal circulations

What are the Main Functions of the Placenta During Pregnancy?

• Nutrients and gas exchange → responsible for nutrient and gas uptake from mother to developing foetus and removal of waste products, e.g. urea and bilirubin, from the fetal circulation

• Hormone production and secretion → alters maternal physiology to accommodate pregnancy (e.g. insulin resistance and increased fat stores)

• Protective immunological barrier → protection of the hemi-allogenic foetus from maternal immune response (recognised as foreign due to paternal genes)

How do substances cross the placenta into the fetal circulation?

• For substances to enter or leave the fetal circulation, they must cross the placenta and syncytiotrophoblast cells (placental interface)

  • Substances must cross two membranes: microvillus (maternal side) → basal (fetal side)

• This is driven by the electrochemical gradient, exchange surface properties (surface area & diffusion distance), and ST transport properties

  • Large surface area & small diffusion distance provided by the highly branched, vascularised villi (high rate of diffusion)

• Mechanisms of transport:

  1. Diffusion

     • Transcellular: lipophilic substances (e.g., O₂, CO₂)

     • Paracellular: hydrophilic substances

  2. Facilitated diffusion: via transport proteins (glucose, amino acids, ions, small metabolites → hydrophilic substances)

  3. Active transport: nutrient transport via ATP hydrolysis and nutrient transport proteins (glucose, amino acids, ions, small metabolites)

  4. Endocytosis/exocytosis: large molecules (e.g., immunoglobulins)

What are the key hormonal functions of the placenta during pregnancy?

• It is a highly active endocrine organ

• Syncytiotrophoblasts (STs) synthesise and secrete hormones into maternal blood.

• hCG: Peaks at week 7; involved in maternal recognition of pregnancy and maintenance of corpus luteum

• Progesterone:

  • Slowly rises first trimester, production rapidly increases in weeks 8–12 as the placenta takes over from the corpus luteum.

  • Maintains pregnancy: inhibits myometrial contractility (prevents preterm labour) strengthens cervical mucus plug (prevents infection), stimulates breast growth (lactation).

• Oestrogen: Stimulates growth of the myometrium and breasts, and increases uterine blood flow.

• hPL & hPGH: Increase in 2nd–3rd trimester; important for maternal metabolic adaptations.

What Maternal Metabolic Adaptations Occur In Response to Pregnancy?

• Insulin resistance: reduces maternal glucose uptake and promotes gluconeogenesis in maternal liver → increases glucose supply to fetus

  • Mediated by human placental lactogen, placental growth factor (and progesterone)

• Increased maternal fat stores deposition in the 2nd trimester → Mobilised in the 3rd trimester to prioritise glucose transport to the fetus to support rapid fetal growth.

How Does the Syncytiotrophoblast Act As a Protective Barrier?

• It forms the interface between maternal blood (intervillous space) and fetal circulation/tissues.

• Prevents immunological rejection hemi-allogenic fetus and paternal antigens.

• Protects against pathogens, toxins, and drugs.

• Incomplete barrier → some substances can cross it e.g. drugs).

  • Historical example: Thalidomide (maternal antiemetic) in the 1960s caused fetal malformations → crossed the barrier

• Benefits of partial permeability and incomplete barrier - Maternal antibodies (from vaccination, e.g., whooping cough or COVID) can cross and provide a degree of neonatal immunity.

  • Clinical indication: pregnant women routinely vaccinated in the 2^nd/3^rd trimester e.g. whooping cough

What is Antenatal Care?

• A series of appointments that aim to identify the earliest signs of complications in the mother or foetus

• A range of complications can be detected across the trimesters, e.g:

  • 1^st trimester

    • Early miscarriage

  • 2^nd trimester

    • Late miscarriage

  • 3^rd trimester

    • Pre-eclampsia

    • IUGR

    • Prematurity

    • Neonatal disorders

• Most of these conditions in pregnancy and delivery are poorly understood, difficult to predict; have limited treatment options (restricted to delivery) and are of placental origin

What Happens In An Antenatal Care Check?

• A series of measurements are taken, including:

  • Markers of potential placental dysfunction  

    • Blood pressure check

    • Urine check (protein and glucose levels)

    • Assessment of fetal growth

    • Assessment of fetal movement

      • These must be interpreted in terms of normal physiological changes to the maternal body

• Assessments of maternal wellbeing

• Birth preparation

• Education

• Any other issues

What are the major cardiovascular adaptations in pregnancy?

• Maternal blood vessels dilate under the influence of oestrogen and placental and corpus luteum-related factors, reducing vascular resistance.

  • Uterine artery remodelling by extravillous trophoblasts, which replaces smooth muscle cells in the vessel wall, converts spiral arteries from tightly coiled vessels into wide, low-pressure conduits.

• Upregulation of Renin-Angiotensin System → increasing salt and water retention.

  • Results in increased fluid retention and maternal plasma volume to support fetal circulation.

How Do Cardiac and Renal Parameters Change From The 1st to the 3rd Trimester of Pregnancy?

• In the 1st & 2nd trimesters mean arterial pressure decreases.

• In the 3rd trimester, RAS activation increases salt/water retention, causing blood pressure to return toward pre-pregnancy levels.

• Heart rate increases (~10 bpm) by the end of the 1st trimester, maintained with a slight upward drift towards the end of pregnancy to meet increased uterine blood flow demands for oxgen and nutrients

• Glomerular filtration rate (GFR), the amount of water filtered out of the bloodstream by the maternal kidneys, increases throughout pregnancy → increased production of dilute urine.

• Podocytes, lining the glomeruli, remain intact (unaffected) → large proteins should remain absent in urine in a healthy pregnancy

  • small amounts of glucose may occasionally appear in non-diabetic individuals.

What are the markers of placental function, and how are they used in clinical practice

• Markers of placental control are considered based on ease, cost, and routine applicability.

• Common markers:

  • Fetal movement patterns

  • Proteinuria: assessment of proteins in urine

  • Blood pressure: monitoring for hypertension

    • These are low-cost, quick, non-technical assessments

• More complex markers:

  • Fetal growth (requires varying technical expertise)

  • Placental blood flow

  • Placental hormone concentrations

    • Complex tests → require specialised equipment and expertise

    • Usually reserved for individuals at high risk of placental dysfunction

Why is foetal movement considered a marker of foetal wellbeing?

• A low-cost, low-technicality method used to evaluate placental and fetal function.

• Normal pattern: Fetuses move at a constant rate throughout pregnancy, including up to labour; they do not stop or reduce movement in preparation for delivery.

• Suggests that reduced movement may indicate limited oxygen or nutrient supply across the placenta; fetuses make an ‘active decision’ to limit voluntary movements to conserve resources.

  • An accepted sign of foetal wellbeing

• Clinical practice: Asking about fetal movement patterns is a standard part of prenatal care.

How is fetal growth assesed in pregnancy

• Fetal growth is considered a readout of placental function → foetus require adequate nutrients and oxygen to support growth (basic cellular functions, lay down fat and organs)

• Risk assessments are performed at the start of pregnancy by a midwife

• Low-risk pregnancies (the majority of pregnancies): Monitored via symphysiofundal height (SFH)

  • Tape measure from pubic symphysis to fundus (measures length of uterus)

  • Quick, low-cost, widely accessible

  • Plotted on a growth chart (speed of growth compared with normal patterns of growth), deviations may indicate abnormal growth

  • Limitations: Less effective for detecting very small or overgrown babies

• High-risk pregnancies: Monitored via routine ultrasound scans

  • Measures head, abdomen, femur → estimates fetal weight and size using formulas

  • Good sensitivity for detecting small babies, but can overestimate size due to the use of standardised ratio

  • Requires trained personnel (result interpretation), equipment, time and cost

  • Formula limitations: individual variation in body composition → not one-size-fits-all

How Does Ultrasound Work?

• Principle: Sound waves are sent out at a high pitch through maternal tissues, where it will be reflected back by objects beneath the probe (object: fetus)

• Problem: sound waves pass through a number of surfaces (maternal skin, adipose tissue, uterine muscle, abdominal muscle and organ, amniotic fluid and umbilical cord) before reaching the baby

  • Each of these objects and surfaces may reflect the sound waves to the ultrasound probe

• Measure: assess time taken for the sound wave to return to the probe → use known speed of the wave to interpret distance of object from probe

What are the differences between 2D and 3D ultrasound for fetal growth assessment?

• 2D ultrasound: Gold standard for routine fetal growth assessment.

• 3D ultrasound: Constructs a 3D image from sound waves → provides a clear image of the baby

  • It detects fat deposition around the baby → more sensitive to differences in fetal growth.

  • Longer procedure, real-time analysis.

  • Requires expensive equipment and specialised training; mostly used in research centres.

Why is placental function important for fetal growth?

• Adequate placental function ensures the fetus receives sufficient nutrients and oxygen.

• Supports basic cellular functions, fat deposition, muscle and organ development → overall growth.

• Insufficient supply leads to slower growth or growth restriction compared to other fetuses.

What is Doppler Ultrasound

• A modification of previous ultrasound techniques using sound waves:

• Utilises the principle that when sound waves hit a moving object, it will change its frequency (pitch)

• When ultrasound waves pass through the body, they reflect off blood cells in the umbilical and uterine vessels, with each of the RBCs shifting the sound waves

• The probe receives the sound wave at a different pitch and constructs a picture depending on whether the object it is reflected off is moving towards or away from the probe

How is Fetal Placenta Blood Flow Assessed in Pregnancy?

• Doppler ultrasound measures the speed of blood flow in the umbilical and uterine arteries

  • Speed increase in systole; decreases in diastole

• Umbilical artery: Constant blood flow along artery (more frequently assessed)

• Uterine artery: Assessed mainly in high-risk pregnancies (e.g., pre-eclampsia, suspected growth restriction).

  • detects evidence of spiral artery remodelling

• Reduction in resistance to flow as pregnancy progresses → detectable via Doppler ultrasound in uterien artery

How do uterine artery Doppler waveforms change from the non-pregnant state through pregnancy?

• Non-pregnant: Clear marked peak-trough pattern caused by maternal systole and elastic recoil of uterine arteries during diastole

• Early pregnancy: Spiral artery remodelling → less recoil and reduced resistance → reduced notch, showing normal uteroplacental development.

• Mid-2nd to 3rd trimester: Low-pressure, high-flow blood vessels → constant blood supply to intervillous space for oxygen and nutrient delivery.

• Reduction in resistance to flow as pregnancy progresses → detectable via Doppler ultrasound.

How Does the Placenta Function as An Endocrine Organ?

• The placenta produces substances that promote a healthy pregnancy by supporting:

  • Nutrient delivery from maternal stores

  • Vasodilation, improving uteroplacental blood flow and oxygen delivery

  • Placental development and function

  • Immunotolerance, suppressing maternal immune responses to tolerate the fetus

• Some placental substances can be detected in maternal circulation and used as biomarkers of placental function

How are placental biomarkers used to assess placental function in antenatal care

• The placenta produces substances that are released into the maternal circulation and can be measured.

• National screening programmes use placental biomarkers to screen for common chromosomal abnormalities:

  • Down syndrome

  • Edwards syndrome

  • Patau syndrome

• Other placental hormones are also measured in early and late pregnancy:

  • Progesterone levels can be used to interpret bleeding patterns in early pregnancy and estimate the risk of miscarriage.

How are placental hormones used to predict fetal growth restriction in pregnancy?

• Hormones measured in trisomy screening programmes (e.g. hCG and Pregnancy-Associated Plasma Protein A [PAPP-A]) can identify pregnancies at increased risk of fetal growth restriction (FGR).

  • PAPP-A: a protease that cleaves IGF-1 binding proteins, influencing fetal growth.

• Low levels of these hormones in the first trimester reflect placental immaturity and can predict the onset of FGE in later development/pregnancy.

• These hormones, therefore act as early biomarkers of placental function.

How can placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1) be used to assess placental function in the third trimester?

• PlGF: Promotes placental health and angiogenesis of the fetal placental vasculature.

  • Supports the growth and function of placental tissues and cells.

• sFlt-1 (soluble FMS-like tyrosine kinase-1): Acts as an antagonist of PlGF by binding to it and making it biologically unavailable.

  • Regulates placental angiogenesis.

• Clinical relevance: Excess sFlt-1 damages maternal vasculature and kidneys and is associated with placental dysfunction (e.g. pre-eclampsia).

  • The PlGF : sFlt-1 balance is used as a marker of placental function in late pregnancy

How is placental growth factor (PlGF) testing used in the prediction and diagnosis of pre-eclampsia?

• PlGF and PlGF-based tests are actively promoted for the diagnosis and prediction of pre-eclampsia.

• Research interest in its use to help predict small or growth-restricted babies.

• Example of use in early pregnancy → PlGF measurement may estimate an individual's risk of pre-eclampsia and can help identify those who may benefit from aspirin therapy to reduce risk.

• Rationale for use: extensive research into placental dysfunction has defined normal placental patterns, allowing abnormal PlGF levels to be used as markers of pathology.

What are the primary clinical goals of assessing placental biomarkers in Early and Late Pregnancy?

• Early pregnancy:

  • Assess Miscarriage risk.

  • Assess Growth Restriction (FGR) risk.

  • Assess Pre-eclampsia risk.

• Late pregnancy

  • Diagnosis and prediction or prediciton of Pre-eclampsia (and FGR).