Fetal and Neonatal Physiology

Quick Answer

Fetal and Neonatal Physiology encompasses the unique physiological adaptations that allow the fetus to survive in the intrauterine environment and the dramatic transition to extrauterine life. The fetal circulation features three critical shunts: the ductus venosus (bypassing the liver), foramen ovale (RA→LA), and ductus arteriosus (PA→aorta), which together direct oxygenated blood from the placenta to the brain and heart while bypassing the non-functional lungs. At birth, the first breath triggers a cascade of events: lung expansion, decreased pulmonary vascular resistance, increased systemic vascular resistance from cord clamping, and functional closure of fetal shunts within hours. Surfactant (produced by type II pneumocytes from 24 weeks, mature by 35 weeks) is essential for alveolar stability. The neonatal myocardium is immature with rate-dependent cardiac output. Brown adipose tissue provides non-shivering thermogenesis. Limited glycogen stores and gluconeogenic capacity predispose neonates to hypoglycaemia. Physiological jaundice reflects immature hepatic conjugation of bilirubin.

Key Numbers:

• Fetal cardiac output: 450 mL/kg/min (combined ventricular output)
• Umbilical vein oxygen saturation: 80% (highest in fetal circulation)
• Ductus arteriosus flow: 60% of RV output in utero
• PVR decrease at birth: 80% reduction within first 24 hours
• Surfactant: 90% phospholipids (DPPC 50%), mature L/S ratio >2.0
• Neonatal heart rate: 120-160 bpm (cardiac output rate-dependent)
• Brown fat: 2-6% of body weight, located interscapular, suprarenal, axillary
• Critical glucose: <2.6 mmol/L requires intervention

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CICM Exam Focus

What Examiners Expect

The CICM First Part examination frequently tests fetal and neonatal physiology as it underpins understanding of duct-dependent congenital heart disease, neonatal resuscitation, and paediatric critical care. Examiners expect candidates to demonstrate:

Written Examination (SAQ):

• Complete description of fetal circulation with oxygen saturations at each point
• Understanding of the three fetal shunts and their physiological roles
• Detailed explanation of circulatory transition at birth including timing and mechanisms
• Surfactant composition, synthesis, and function
• Neonatal thermoregulation mechanisms including brown fat physiology
• Comparison of fetal and adult haemoglobin oxygen affinity
• Neonatal glucose metabolism and hypoglycaemia risk factors
• Bilirubin metabolism and physiological jaundice

Viva Examination:

• Systematic explanation of fetal circulation from first principles
• Mechanism of ductus arteriosus closure (prostaglandin withdrawal, oxygen sensing)
• Surfactant physiology and clinical implications for RDS
• Integration with clinical scenarios (e.g., why give prostaglandins for duct-dependent CHD)
• Brown fat thermogenesis pathway and oxygen dependency
• Pathophysiology of persistent pulmonary hypertension of the newborn (PPHN)

Common SAQ Stems

1. "Describe the fetal circulation, including the function and location of the three fetal shunts"
2. "Outline the physiological changes that occur at birth to establish the adult circulation pattern"
3. "Describe surfactant: composition, synthesis, function, and clinical significance"
4. "Explain the mechanisms of thermoregulation in the neonate"
5. "Compare and contrast fetal haemoglobin (HbF) with adult haemoglobin (HbA)"
6. "Describe the physiology of the ductus arteriosus, including factors affecting patency and closure"
7. "Outline neonatal glucose metabolism and factors predisposing to hypoglycaemia"
8. "Describe the pathophysiology of physiological jaundice in the neonate"

High-Yield Topics

• Three fetal shunts with oxygen saturation values (must memorise)
• Ductus arteriosus: PGE2 maintains patency, oxygen and prostaglandin withdrawal cause closure
• First breath mechanics and surfactant function
• HbF vs HbA: P50 values, 2,3-DPG binding, clinical implications
• Brown fat location and UCP1 mechanism
• Rate-dependent neonatal cardiac output
• PPHN pathophysiology and treatment principles

---

Key Points

1. Fetal Circulation: Three shunts (ductus venosus, foramen ovale, ductus arteriosus) direct oxygenated placental blood to vital organs while bypassing the non-functional lungs; combined ventricular output is 450 mL/kg/min with right ventricle dominant (PMID: 27524443)

2. Umbilical Vessels: Two umbilical arteries carry deoxygenated blood (SaO2 ~60%) from fetus to placenta; one umbilical vein carries oxygenated blood (SaO2 ~80%) from placenta to fetus (PMID: 27524443)

3. Placental Gas Exchange: Occurs via countercurrent exchange across 10-15 m² surface area; PO2 gradient maintained by double Bohr effect (maternal right shift, fetal left shift); no alveolar-type gas exchange (PMID: 12044749)

4. Transition at Birth: First breath generates -40 to -100 cmH2O negative pressure, establishing FRC; PVR drops 80% within 24 hours; SVR increases with cord clamping; shunts close functionally within hours (PMID: 24014628)

5. Surfactant: Produced by type II pneumocytes from 24 weeks; 90% phospholipids (DPPC 50%), 8% surfactant proteins (SP-A, B, C, D); reduces surface tension to near zero at end-expiration, preventing atelectasis (PMID: 9549757)

6. Ductus Arteriosus: Patency maintained by PGE2 and low PO2; closure triggered by increased PaO2 (vasoconstriction) and prostaglandin withdrawal; functional closure 10-15 hours, anatomical closure 2-3 weeks (PMID: 22579792)

7. Foramen Ovale: Valve mechanism allows RA→LA shunt when RAP > LAP; functional closure within hours as LAP exceeds RAP with increased pulmonary venous return; anatomical closure by 3-12 months (25% remain PFO) (PMID: 24014628)

8. Neonatal Myocardium: Immature with fewer myofibrils, reduced compliance, limited Frank-Starling reserve; cardiac output is rate-dependent; normal HR 120-160 bpm, bradycardia causes hypotension (PMID: 19339411)

9. Brown Adipose Tissue: 2-6% of body weight; contains UCP1 (uncoupling protein 1) which dissipates proton gradient as heat; non-shivering thermogenesis is oxygen-dependent and inhibited by hypoxia (PMID: 15563517)

10. Fetal Haemoglobin: HbF (α2γ2) has higher oxygen affinity (P50 19 mmHg vs 26.6 mmHg) due to reduced 2,3-DPG binding; facilitates oxygen transfer across placenta; replaced by HbA over first year (PMID: 393578)

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Fetal Circulation

Overview

The fetal circulation is designed to deliver oxygenated blood from the placenta to the developing organs while bypassing the non-functional lungs. Three anatomical shunts—the ductus venosus, foramen ovale, and ductus arteriosus—work in concert to achieve this goal. Understanding fetal circulation is essential for comprehending duct-dependent congenital heart disease and the transition to extrauterine life (PMID: 27524443).

Key differences from adult circulation:

• Oxygenation occurs at the placenta, not lungs
• Right ventricle is dominant (supplies systemic circulation via ductus arteriosus)
• Ventricles work in parallel, not series
• High pulmonary vascular resistance with minimal pulmonary blood flow (8-10% of combined output)
• Combined ventricular output: 450 mL/kg/min (200-250 mL/kg/min to placenta)

Placental Gas Exchange

Placental structure:

• Surface area: 10-15 m² at term (comparable to adult lung)
• Villous structure maximises exchange surface
• Maternal and fetal circulations separated by syncytiotrophoblast layer (3-5 μm)
• Haemochorial placentation: maternal blood directly contacts trophoblast (PMID: 12044749)

Gas exchange mechanism: The placenta functions as the fetal "lung" but differs fundamentally from pulmonary gas exchange:

Double Bohr effect: Oxygen transfer across the placenta is enhanced by reciprocal pH changes:

1. Maternal blood: CO2 enters from fetus → pH falls → right shift ODC → O2 released
2. Fetal blood: CO2 exits to mother → pH rises → left shift ODC → O2 binding enhanced
3. Net effect: Facilitates O2 transfer despite low PO2 gradient (PMID: 12044749)

Double Haldane effect: Similarly facilitates CO2 transfer:

1. Maternal blood: Loses O2 → increased CO2 carriage capacity
2. Fetal blood: Gains O2 → decreased CO2 carriage capacity → CO2 released
3. Net effect: Enhanced CO2 transfer from fetus to mother

Placental oxygen transfer limitations:

• Umbilical vein PO2: Only 30-35 mmHg (cf. pulmonary vein 100 mmHg)
• Umbilical vein SaO2: 80% (due to left-shifted fetal ODC)
• Fetal adaptations compensate for lower PO2 (PMID: 12044749)

Umbilical Vessels

Umbilical cord anatomy:

• Length: 50-60 cm at term
• Wharton's jelly: Mucopolysaccharide protection
• Contains: 2 arteries + 1 vein (mnemonic: "2 Away, 1 Venous" or "AVA" from fetus perspective)
• Single umbilical artery: Associated with congenital anomalies (1% of births) (PMID: 27524443)

Umbilical arteries (× 2):

• Origin: Branch from internal iliac arteries
• Function: Carry deoxygenated blood FROM fetus TO placenta
• Blood composition:
  • "PO2: 15-25 mmHg"
  • "SaO2: 58-65%"
  • pH: 7.25-7.35
• Flow: 200-250 mL/kg/min (40% of combined ventricular output)
• After birth: Become medial umbilical ligaments

Umbilical vein (× 1):

• Function: Carries oxygenated blood FROM placenta TO fetus
• Blood composition:
  • "PO2: 30-35 mmHg"
  • "SaO2: 75-85% (highest O2 saturation in fetal circulation)"
  • pH: 7.35-7.40
• Path: Enters abdomen at umbilicus → ductus venosus or portal vein → IVC
• After birth: Becomes ligamentum teres (round ligament of liver)

Ductus Venosus

Anatomy and location:

• Venous connection between umbilical vein and IVC
• Located within liver substance
• Length: 1-2 cm
• Diameter: 0.5-2 mm (narrow, high-velocity channel) (PMID: 7727586)

Function: The ductus venosus shunts 30-50% of well-oxygenated umbilical venous blood directly to the IVC, bypassing the hepatic circulation:

Streaming of blood: Ductus venosus blood (high SaO2) preferentially streams along the posterior wall of the IVC toward the foramen ovale, minimising mixing with lower SaO2 blood returning from lower body (PMID: 7727586).

Patency regulation:

• Prostacyclin (PGI2) maintains patency
• Nitric oxide contributes to vasodilation
• Diameter influenced by fetal blood pressure and volume status

Closure:

• Functional closure: Within 1-3 hours of birth (cessation of umbilical flow)
• Anatomical closure: 1-3 weeks → becomes ligamentum venosum
• Mechanism: Loss of umbilical venous flow + increased prostaglandin metabolism (PMID: 7727586)

Clinical significance:

• Doppler waveform used in fetal assessment (abnormal in IUGR, cardiac failure)
• Patent ductus venosus: Rare anomaly, may require intervention if symptomatic

Foramen Ovale

Anatomy:

• Communication between right atrium and left atrium
• Located in interatrial septum (fossa ovalis region)
• Valve mechanism: Septum primum acts as flap valve over ostium secundum
• Opens when right atrial pressure exceeds left atrial pressure (PMID: 24014628)

Fetal function: The foramen ovale allows oxygenated blood from the IVC to pass directly to the left atrium, bypassing the pulmonary circulation:

Blood streaming:

• Ductus venosus blood (high SaO2) preferentially directed to foramen ovale by crista dividens (ridge at IVC-RA junction)
• Results in: Ascending aorta SaO2 ~65%, descending aorta SaO2 ~55%
• Brain receives best-oxygenated blood (PMID: 24014628)

Pressure relationships in fetus:

Closure mechanism: At birth:

1. First breath → decreased PVR → increased pulmonary blood flow
2. Increased pulmonary venous return to LA → increased LAP
3. Cord clamping → removal of low-resistance placental circulation → increased SVR → reduced venous return to RA
4. LAP > RAP → septum primum pressed against septum secundum → functional closure

Timing:

• Functional closure: Within minutes to hours of birth
• Anatomical closure (fusion): 3-12 months
• Patent foramen ovale (PFO): Persists in 25-30% of adults (usually clinically insignificant) (PMID: 24014628)

Ductus Arteriosus

Anatomy:

• Muscular arterial connection between main pulmonary artery (near left PA origin) and descending aorta (distal to left subclavian artery)
• Length: 10-12 mm at term
• Diameter: 8-10 mm (similar to descending aorta)
• Histologically distinct from pulmonary artery (more smooth muscle, less elastic tissue) (PMID: 22579792)

Fetal function: The ductus arteriosus diverts blood from the high-resistance pulmonary circulation to the systemic circulation:

The ductus connects the pulmonary trunk to the descending aorta beyond the great vessels, meaning that the upper body (brain, heart, arms) receives higher SaO2 blood from LV while lower body receives mixed blood (PMID: 22579792).

Patency maintenance (fetal life): The ductus arteriosus remains widely patent in utero due to:

1. Prostaglandins (primary mechanism):

   • PGE2 produced by placenta and ductus itself
   • PGI2 (prostacyclin) also contributes
   • Act on EP4 receptors → smooth muscle relaxation
   • Low oxygen tension enhances PGE2 sensitivity (PMID: 9549757)

2. Low oxygen tension:

   • Fetal PaO2: 25-30 mmHg
   • Hypoxia directly relaxes ductal smooth muscle
   • Hypoxia inhibits potassium channels → maintains patency

3. Nitric oxide:

   • Contributes to vasodilation
   • Less important than prostaglandins

Closure mechanisms (postnatal): Functional closure occurs within 10-15 hours of birth through two mechanisms:

1. Oxygen-induced vasoconstriction:

   • Increased PaO2 (60-100 mmHg) after first breath
   • Activates cytochrome P450 oxygen sensor
   • Inhibits voltage-gated potassium channels (Kv1.5, Kv2.1)
   • Membrane depolarisation → calcium entry → smooth muscle contraction
   • Oxygen sensitivity unique to ductus smooth muscle (PMID: 9549757)

2. Prostaglandin withdrawal:

   • Removal of placenta (major PGE2 source)
   • Increased pulmonary blood flow → increased pulmonary metabolism of PGE2
   • Reduced EP4 receptor stimulation → loss of vasodilation

Closure timeline:

Clinical significance:

• Patent ductus arteriosus (PDA): Failure of closure, common in preterm infants (70% at <28 weeks)
• Indomethacin/Ibuprofen: Prostaglandin synthesis inhibitors → promote closure
• Prostaglandin E1 (alprostadil): Maintains patency in duct-dependent CHD
• Premature closure in utero: NSAID exposure during pregnancy can cause fetal ductal constriction (PMID: 22579792)

Fetal Oxygen Saturations

Complete fetal circulation oxygen saturation map:

                     PLACENTA
                        │
                        ▼
              Umbilical Vein (SaO2 80%)
                        │
                        ├─────────────────────┐
                        ▼                     ▼
              Ductus Venosus              Portal Vein
               (SaO2 80%)                 (→ Liver)
                        │
                        ▼
            Inferior Vena Cava (SaO2 67%)
            [Mixed with lower body return SaO2 40%]
                        │
                        ▼
                  RIGHT ATRIUM
                        │
              ┌─────────┴─────────┐
              ▼                   ▼
        Foramen Ovale          Tricuspid
        (SaO2 65-70%)           Valve
              │                   │
              ▼                   ▼
         LEFT ATRIUM        RIGHT VENTRICLE
              │                   │
              ▼                   ▼
        LEFT VENTRICLE    Pulmonary Artery
              │                   │
              ▼              ┌────┴────┐
       Ascending Aorta       ▼         ▼
        (SaO2 62-65%)     Lungs    Ductus
              │           (10%)    Arteriosus
              ▼                    (90%)
    Brain, Heart, Upper Body        │
        (SaO2 62-65%)               ▼
                           Descending Aorta
                            (SaO2 55-60%)
                                    │
                     ┌──────────────┼──────────────┐
                     ▼              ▼              ▼
                Lower Body    Umbilical       Placenta
                              Arteries
                            (SaO2 58%)

Key saturation values (must memorise for exam):

Preferential streaming patterns:

1. High SaO2 umbilical venous blood → ductus venosus → posterior IVC → foramen ovale → LA → LV → ascending aorta → brain, heart
2. Low SaO2 SVC blood → RA → RV → PA → ductus arteriosus → descending aorta → lower body, placenta
3. This ensures brain and heart receive best-oxygenated blood (PMID: 27524443)

Fetal Haemoglobin

Structure and properties:

Mechanism of high oxygen affinity:

• γ-chains have different amino acid sequence at 2,3-DPG binding site
• 2,3-DPG binds weakly to HbF → less right shift
• Left-shifted oxygen dissociation curve (P50 19 vs 26.6 mmHg)
• Higher oxygen affinity facilitates O2 extraction from maternal blood (PMID: 393578)

Clinical significance:

• Enables O2 transfer across placenta despite low PO2 gradient
• At any given PO2, fetal blood carries more O2 than maternal blood
• HbF-to-HbA transition occurs over first 6-12 months of life
• Hydroxyurea induces HbF production (treatment for sickle cell disease)

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Transition at Birth

Overview

The transition from fetal to neonatal circulation is one of the most dramatic physiological events in human life. Within seconds to minutes of birth, the neonate must establish pulmonary gas exchange and convert from a circulation with three shunts operating in parallel to the adult series circulation. Failure of this transition results in persistent pulmonary hypertension of the newborn (PPHN) (PMID: 24014628).

Key events at birth:

1. First breath and lung aeration
2. Decrease in pulmonary vascular resistance
3. Increase in systemic vascular resistance (cord clamping)
4. Reversal of atrial pressure gradient → foramen ovale closure
5. Increased PaO2 and prostaglandin withdrawal → ductus arteriosus closure
6. Cessation of umbilical flow → ductus venosus closure

First Breath and Lung Expansion

Stimuli for first breath: Multiple stimuli trigger the first respiratory effort:

• Cold exposure (thermal stimulus)
• Tactile stimulation
• Hypoxia and hypercapnia (chemoreceptor activation)
• Removal of placental inhibitory factors
• Catecholamine surge during labour (PMID: 18490686)

Mechanics of first breath: The first breath must overcome significant forces to inflate the fluid-filled lungs:

Fetal lung fluid clearance: The term fetal lung contains approximately 30 mL/kg of fluid (90-100 mL total):

Adrenaline-triggered fluid absorption:

• Catecholamine surge during labour activates ENaC (epithelial sodium channels)
• Reverses secretory chloride channels to absorptive sodium channels
• Active Na+ absorption creates osmotic gradient → fluid reabsorption
• Explains higher RDS rates in elective caesarean section (no labour) (PMID: 18490686)

Establishment of FRC:

• First breath establishes initial gas volume
• End-expiratory closure of larynx (physiological PEEP, "auto-PEEP")
• Surfactant prevents alveolar collapse at end-expiration
• FRC established: 25-30 mL/kg within first few breaths
• Normal neonatal FRC: 30 mL/kg (similar proportion to adult)

Decrease in Pulmonary Vascular Resistance

Fetal PVR is extremely high:

• Fetal PVR: 8-10x systemic vascular resistance
• Only 8-10% of combined ventricular output goes to lungs
• Maintained by: hypoxia, fluid-filled alveoli, vasoactive mediators

Mechanisms of PVR decrease at birth:

1. Mechanical lung expansion:

   • Physical expansion of alveoli straightens pulmonary vessels
   • Reduces compressive forces on vessels
   • Immediate partial reduction in PVR (PMID: 24014628)

2. Increased oxygen tension:

   • Alveolar PO2 increases from 25 to 100 mmHg
   • Oxygen is a potent pulmonary vasodilator in neonate (opposite to adult HPV)
   • Activates potassium channels → hyperpolarisation → vasodilation
   • Major contributor to PVR decrease

3. Nitric oxide (NO) release:

   • Shear stress and oxygen trigger endothelial NO synthase (eNOS)
   • NO activates guanylate cyclase → cGMP → smooth muscle relaxation
   • Critical mediator of pulmonary vasodilation (PMID: 18093249)

4. Prostacyclin (PGI2) release:

   • Oxygen and shear stress trigger prostacyclin synthesis
   • Acts via cAMP pathway
   • Synergistic with NO

5. Clearance of vasoconstrictors:

   • Reduced endothelin-1 production
   • Reduced thromboxane production

Timeline of PVR changes:

Increased pulmonary blood flow:

• PBF increases from 8% to 100% of ventricular output
• Required for gas exchange
• Increases pulmonary venous return to LA
• Essential for foramen ovale closure (PMID: 24014628)

Increase in Systemic Vascular Resistance

Cord clamping effects: Cord clamping removes the low-resistance placental circulation from the systemic circuit:

Mechanism:

• Placenta is low-resistance vascular bed (accounts for 40% of fetal cardiac output)
• Cord clamping suddenly removes this low-resistance circuit
• SVR approximately doubles immediately
• Increased afterload initially maintained by catecholamine surge

Timing of cord clamping:

• Immediate clamping (<15 seconds): Historical practice
• Delayed clamping (60-180 seconds): Recommended by WHO/ILCOR
  • Allows placental transfusion (30-50 mL/kg)
  • Increases neonatal blood volume
  • Reduces iron deficiency anaemia
  • "May increase jaundice risk (PMID: 24277659)"

Effects on cardiac function:

• Increased afterload increases myocardial oxygen demand
• LV must adapt from low-resistance to higher-resistance circulation
• Initial tachycardia helps maintain cardiac output
• Healthy term newborn adapts rapidly

Closure of Foramen Ovale

Mechanism of functional closure: The foramen ovale closes when the pressure gradient across the atrial septum reverses:

Sequence of events:

1. PVR decreases → pulmonary blood flow increases
2. Pulmonary venous return to LA increases dramatically
3. LA pressure rises to 5-8 mmHg
4. Cord clamping reduces IVC return to RA
5. RA pressure falls to 2-4 mmHg
6. LAP > RAP → septum primum pressed against septum secundum
7. Functional closure within minutes to hours (PMID: 24014628)

Factors maintaining closure:

• Continued elevation of LAP (maintained PBF)
• Normal ventilation and oxygenation
• Absence of pulmonary hypertension

Anatomical closure:

• Occurs over 3-12 months
• Fusion of septum primum and secundum
• Patent foramen ovale (PFO) persists in 25-30% of adults
• PFO usually clinically insignificant unless right-to-left shunting occurs

Closure of Ductus Arteriosus

Two-phase closure:

Phase 1: Functional closure (10-15 hours)

1. Increased oxygen tension:

   • PaO2 rises from 25 to 60-100 mmHg
   • Oxygen activates ductal smooth muscle contraction
   • Mechanism: Inhibition of oxygen-sensitive K+ channels → depolarisation → Ca2+ entry → contraction
   • Oxygen sensing involves cytochrome P450 and mitochondrial electron transport chain

2. Prostaglandin withdrawal:

   • Placenta removed (major PGE2 source)
   • Increased pulmonary metabolism of circulating PGE2
   • Loss of EP4 receptor activation
   • Reduced cAMP → allows contraction (PMID: 9549757)

3. Endothelin-1:

   • Increased production at birth
   • Potent vasoconstrictor
   • Contributes to ductal constriction

Phase 2: Anatomical closure (2-3 weeks)

• Intimal cushion formation (endothelial proliferation)
• Subintimal fibrosis
• Complete obliteration of lumen
• Formation of ligamentum arteriosum
• Irreversible closure typically complete by 4-8 weeks

Failure of closure (PDA): Risk factors for persistent patency:

• Prematurity (70% incidence at <28 weeks)
• Hypoxia (prevents O2-induced constriction)
• Acidosis
• Infection/sepsis (increased PGE2 production)
• Surfactant deficiency/RDS

Pharmacological manipulation:

(PMID: 22579792)

Closure of Ductus Venosus

Mechanism: The ductus venosus closes rapidly after cord clamping:

1. Cord clamping eliminates umbilical venous flow
2. No blood flow through ductus venosus
3. Functional closure within 1-3 hours
4. Anatomical closure over 1-3 weeks
5. Becomes ligamentum venosum (PMID: 7727586)

Contributing factors:

• Loss of umbilical venous pressure
• Sphincter-like mechanism at ductus venosus inlet
• Increased prostaglandin metabolism
• Local tissue factors

Clinical significance:

• Patent ductus venosus is rare but can cause portosystemic shunting
• May present with hyperammonaemia, hepatic encephalopathy
• Usually requires surgical or interventional closure

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Neonatal Respiratory Physiology

Surfactant

Definition and composition: Pulmonary surfactant is a complex mixture of lipids and proteins that reduces alveolar surface tension, preventing atelectasis at end-expiration.

Composition:

(PMID: 9549757)

Surfactant proteins (detailed):

Synthesis and secretion:

• Produced by type II alveolar pneumocytes (type II cells, AT2 cells)
• Synthesis begins at 24 weeks gestation
• Mature levels by 35 weeks
• Stored in lamellar bodies within type II cells
• Secreted via exocytosis into alveolar lumen
• Forms tubular myelin → surface film at air-liquid interface (PMID: 26192408)

Regulation of synthesis:

Surface tension reduction: Surfactant reduces surface tension according to the Laplace relationship:

P = 2T/r

Where:

• P = collapsing pressure
• T = surface tension
• r = alveolar radius

Surface tension values:

Surfactant cycle:

1. Compression during expiration → phospholipids concentrated → surface tension approaches zero
2. Expansion during inspiration → phospholipids spread → surface tension 25-30 mN/m
3. Dynamic compression-expansion cycle essential for function

Clinical significance:

• RDS (Respiratory Distress Syndrome): Surfactant deficiency in preterm infants
• Assessment of lung maturity: L/S ratio >2.0 indicates maturity (PMID: 26192408)
• Exogenous surfactant: Beractant, poractant, calfactant for RDS treatment
• Antenatal corticosteroids: Accelerate surfactant production (betamethasone, dexamethasone)

Lecithin/Sphingomyelin (L/S) Ratio

Assessment of fetal lung maturity:

Timeline of surfactant development:

First Breath Mechanics

Forces to overcome: The first breath must overcome:

1. Surface tension forces: Fluid-filled alveoli with high surface tension
2. Viscous resistance: Movement of lung fluid through airways
3. Elastic recoil: Lung tissue resistance to stretch
4. Chest wall compliance: Though highly compliant in neonate

Transpulmonary pressure generation:

• First breath: -40 to -100 cmH2O (negative pressure)
• Generated by diaphragmatic contraction and chest wall expansion
• Subsequent breaths: -5 to -10 cmH2O
• Surfactant dramatically reduces required pressure after initial inflation (PMID: 18490686)

Establishment of FRC:

Neonatal Lung Mechanics

Comparison with adult:

Unique neonatal lung features:

1. High chest wall compliance:

   • Cartilaginous ribs, horizontal orientation
   • Offers little outward recoil
   • Tends to collapse inward during inspiration
   • Contributes to paradoxical breathing pattern
   • Closing capacity may exceed FRC (PMID: 9605741)

2. Low lung compliance (initially):

   • Fluid-filled at birth
   • Improves rapidly with surfactant function

3. High minute ventilation requirement:

   • Metabolic rate 2x adult (per kg)
   • O2 consumption 6-8 mL/kg/min
   • Higher RR compensates for relatively fixed tidal volume

4. Obligate nasal breathers:

   • Until 3-6 months of age
   • Nasal obstruction causes respiratory distress
   • Large tongue, small oral cavity

5. Rapid desaturation:

   • Small FRC relative to O2 consumption
   • Lower O2 reserve
   • Desaturation within 60-90 seconds of apnoea (vs 3-5 min in adults)

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Neonatal Cardiovascular Physiology

Myocardial Immaturity

Structural differences: The neonatal myocardium is structurally and functionally immature compared to adult:

(PMID: 19339411)

Functional consequences:

1. Rate-dependent cardiac output:

   • Limited Frank-Starling reserve
   • Cannot significantly increase stroke volume
   • Cardiac output = HR × SV, but SV relatively fixed
   • Normal HR: 120-160 bpm
   • Bradycardia (<100 bpm) causes hypotension

2. Reduced contractile reserve:

   • Limited response to inotropes
   • Less catecholamine sensitivity
   • Lower baseline contractility

3. Reduced compliance:

   • Stiffer ventricles
   • Diastolic dysfunction more common
   • Sensitive to volume loading

4. Calcium handling:

   • Relies on extracellular calcium for contraction
   • Immature SR calcium cycling
   • More sensitive to calcium channel blockers
   • Hypocalcaemia causes significant dysfunction

Cardiac output values:

Autonomic Control

Parasympathetic dominance: The neonatal cardiovascular system is characterised by relative parasympathetic dominance:

• Higher resting vagal tone
• Bradycardic response to hypoxia
• Heart rate variability reflects autonomic maturation
• Breath-holding → profound bradycardia (PMID: 19339411)

Sympathetic immaturity:

• Reduced catecholamine stores
• Immature adrenal medulla
• Decreased receptor density
• Blunted response to stress
• Cardiac output more dependent on exogenous catecholamines in shock

Clinical implications:

• Hypoxia causes bradycardia (not tachycardia as in adults)
• Vagal manoeuvres highly effective
• Atropine often needed for bradycardia
• Shock may present with bradycardia

Persistent Pulmonary Hypertension of the Newborn (PPHN)

Definition: PPHN is failure of the normal postnatal decrease in pulmonary vascular resistance, resulting in persistent right-to-left shunting through fetal channels (foramen ovale and/or ductus arteriosus) and severe hypoxaemia.

Incidence: 1-2 per 1000 live births (PMID: 24533435)

Pathophysiology: Normal transition requires:

1. Lung expansion
2. Increased PaO2
3. NO and prostacyclin release
4. Structural remodelling

PPHN results when this transition fails:

• PVR remains elevated
• RAP > LAP → foramen ovale remains open (R→L shunt)
• PA pressure > systemic → ductus arteriosus R→L shunt
• Severe hypoxaemia despite oxygen therapy
• Pre-ductal (right arm) SpO2 > post-ductal (lower limbs) SpO2

Aetiology:

Diagnosis:

• Pre-post ductal saturation difference >5-10%
• Echocardiography: Right-to-left shunting at PDA and/or PFO
• TR jet velocity indicates PA pressure
• Exclude structural heart disease

Management principles:

1. Optimise oxygenation: Target SpO2 92-97%
2. Avoid hypoxia, acidosis, hypothermia: Worsen pulmonary vasoconstriction
3. Minimise handling: Stimulation → pulmonary vasospasm
4. Sedation: Reduce oxygen consumption and agitation
5. Inhaled nitric oxide (iNO): Selective pulmonary vasodilator (20 ppm)
6. Sildenafil: PDE5 inhibitor, oral/IV
7. Prostacyclin analogues: Epoprostenol, iloprost
8. ECMO: Refractory cases, survival 75-80% (PMID: 24533435)

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Thermoregulation

Brown Adipose Tissue

Distribution in neonate: Brown adipose tissue (BAT) comprises 2-6% of neonatal body weight, located in specific depots:

Histological features:

• Multilocular fat droplets (vs unilocular in white fat)
• Dense mitochondria (gives brown colour)
• Rich vascular supply
• Sympathetic innervation
• Express uncoupling protein 1 (UCP1) (PMID: 15563517)

Non-Shivering Thermogenesis

Mechanism: Non-shivering thermogenesis (NST) is the primary mechanism of heat production in neonates, as shivering is absent or ineffective until several months of age.

UCP1 (Uncoupling Protein 1) pathway:

1. Cold exposure detected by hypothalamus
2. Sympathetic nervous system activated
3. Norepinephrine released at brown fat
4. β3-adrenergic receptors activated
5. cAMP → protein kinase A → hormone-sensitive lipase
6. Triglyceride hydrolysis → free fatty acids (FFA)
7. FFA activate UCP1 in inner mitochondrial membrane
8. UCP1 allows proton leak across membrane
9. Proton gradient dissipated as heat (not ATP synthesis)
10. Heat distributed via rich blood supply (PMID: 15563517)

Efficiency:

• NST can increase metabolic rate 2-3 fold
• Can generate 25-40 mW/g tissue/hour
• Maximum heat production at thermoneutral temperature ~25-26°C skin

Limitations:

Heat Loss Mechanisms

Neonates are particularly vulnerable to heat loss due to:

• High surface area to body weight ratio (3x adult per kg)
• Thin skin with limited subcutaneous fat
• Limited behavioural responses
• Immature peripheral vasoconstriction

Four mechanisms of heat loss:

Evaporative heat loss:

• Most important mechanism at birth
• Wet amniotic fluid → enormous evaporative losses
• 0.58 kcal lost per gram of water evaporated
• Prevention: Immediate drying, warm blankets, plastic wrap for preterm

Thermoneutral environment: The thermoneutral zone is the temperature range where metabolic rate (oxygen consumption) is minimal:

Consequences of cold stress:

1. Increased oxygen consumption (to maintain temperature)
2. Increased glucose consumption → hypoglycaemia risk
3. Metabolic acidosis (anaerobic metabolism if O2 limited)
4. Pulmonary vasoconstriction (acidosis) → worsening hypoxaemia
5. Decreased surfactant production
6. Increased mortality in preterm infants (PMID: 23440783)

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Glucose Metabolism

Fetal Glucose Supply

Transplacental glucose transport:

• Glucose crosses placenta by facilitated diffusion (GLUT1, GLUT3)
• Fetal glucose concentration ~70% of maternal level
• Fetus relies almost entirely on maternal glucose supply
• Minimal fetal gluconeogenesis in utero
• Fetal insulin levels respond to glucose (β-cell development from 9-11 weeks) (PMID: 11738250)

Glycogen Stores

Hepatic glycogen:

Glycogen distribution:

• Liver: Primary storage organ (50-100 mg/g)
• Muscle: Significant stores (not available for blood glucose)
• Heart: High glycogen content (protects from hypoxic injury)
• Brain: Minimal stores (glucose-dependent)

Gluconeogenesis

Development of gluconeogenic capacity: The enzymes required for gluconeogenesis are induced at birth:

Hormonal changes at birth:

Timeline of metabolic adaptation:

• 0-2 hours: Glycogenolysis (hepatic glycogen → glucose)
• 2-24 hours: Gluconeogenesis develops (amino acids, lactate, glycerol → glucose)
• 24-48 hours: Ketogenesis develops (alternative fuel for brain)
• 48+ hours: Mature metabolic regulation (PMID: 11738250)

Neonatal Hypoglycaemia

Definition: There is no universal consensus, but commonly used thresholds:

Risk factors:

Clinical features: Often non-specific:

• Jitteriness, tremor
• Lethargy, hypotonia
• Poor feeding
• Apnoea
• Seizures (severe)
• Cyanosis
• Hypothermia

Management:

1. Prevention: Early and frequent feeding
2. Oral glucose gel (40% dextrose, 200 mg/kg buccal)
3. IV dextrose: D10W 2 mL/kg bolus
4. Glucose infusion rate (GIR): 4-8 mg/kg/min
5. Glucagon: 0.1-0.3 mg/kg IM/IV (if refractory)
6. Hydrocortisone: 5 mg/kg/day if endocrine cause (PMID: 11738250)

Glucose infusion rate calculation: GIR (mg/kg/min) = (% dextrose × rate in mL/hr) / (6 × weight in kg)

Example: D10W at 60 mL/hr in 3 kg infant: GIR = (10 × 60) / (6 × 3) = 600/18 = 33 mg/kg/hr = 5.5 mg/kg/min

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Bilirubin Metabolism

Bilirubin Production

Source:

• 75-80% from haemoglobin breakdown (senescent RBCs)
• 20-25% from ineffective erythropoiesis and other haem proteins
• Neonates produce 6-10 mg/kg/day (vs 3-4 mg/kg/day in adults)
• Increased production due to:
  • Higher haematocrit at birth (50-60%)
  • Shorter RBC lifespan (70-90 days vs 120 days)
  • Higher haemoglobin turnover

Bilirubin formation pathway:

1. Haemoglobin released from RBCs
2. Globin chains recycled to amino acid pool
3. Haem → biliverdin (haem oxygenase)
4. Biliverdin → unconjugated bilirubin (biliverdin reductase)
5. Unconjugated bilirubin released into plasma (PMID: 25985972)

Unconjugated vs Conjugated Bilirubin

Comparison:

Unconjugated bilirubin toxicity:

• Lipophilic, crosses blood-brain barrier when unbound
• Binds to basal ganglia, brainstem nuclei, cerebellum
• Causes acute bilirubin encephalopathy → chronic kernicterus
• Risk increases when:
  • Albumin binding sites saturated
  • Acidosis (reduces albumin binding)
  • Drugs displacing bilirubin (sulfisoxazole, ceftriaxone)
  • Prematurity (less albumin, immature BBB)

Hepatic Conjugation

Hepatic processing of bilirubin:

1. Uptake: Unconjugated bilirubin-albumin complex dissociates at hepatocyte
2. Transport: Bilirubin transported into hepatocyte by OATP1B1/1B3
3. Conjugation: UGT1A1 (glucuronosyltransferase) conjugates bilirubin with glucuronic acid
4. Excretion: Conjugated bilirubin excreted into bile via MRP2

Immaturity of UGT1A1:

• Activity 1% of adult at birth
• Reaches adult levels by 6-14 weeks
• Explains physiological jaundice
• Gilbert syndrome: Polymorphism causing reduced UGT1A1 (PMID: 25985972)

Physiological Jaundice

Definition: Physiological jaundice is the normal transient hyperbilirubinaemia occurring in healthy term newborns, resulting from:

1. Increased bilirubin production (high haematocrit, short RBC lifespan)
2. Immature hepatic conjugation (low UGT1A1)
3. Increased enterohepatic circulation (high β-glucuronidase, sterile gut)

Characteristics of physiological jaundice:

Enterohepatic circulation:

• Conjugated bilirubin enters gut via bile
• β-glucuronidase (in gut wall, breast milk) deconjugates to unconjugated bilirubin
• Unconjugated bilirubin reabsorbed
• Amplified in neonates due to:
  • Sterile gut (no bacteria to convert to urobilinogen)
  • High β-glucuronidase activity
  • Delayed stool passage

Breastfeeding jaundice vs breast milk jaundice:

Phototherapy and Exchange Transfusion

Phototherapy mechanism:

• Blue-green light (430-490 nm) converts bilirubin to water-soluble photoisomers
• Photoisomers excreted in bile without conjugation
• Also produces lumirubin (structural isomer, rapidly excreted)
• Dose-dependent: Higher irradiance = greater effect (PMID: 25985972)

Thresholds for treatment: Use gestational age-specific nomograms (Bhutani curve in USA, NICE guidelines in UK/Australia):

Indications for exchange transfusion:

• TSB above exchange threshold for gestation/age
• TSB rising despite intensive phototherapy (>8.5 μmol/L/hr)
• Signs of acute bilirubin encephalopathy
• TSB >425 μmol/L (25 mg/dL) in term infant

Exchange transfusion procedure:

• Double-volume exchange (160-200 mL/kg)
• Removes 85% of circulating bilirubin
• Removes 50% of total body bilirubin (extravascular redistribution)
• Also removes sensitised RBCs in haemolytic disease
• Risks: Electrolyte imbalance, infection, thrombosis, NEC, mortality 0.3-0.5%

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Applied Physiology: Fetal and Neonatal Haemodynamics

Fetal Oxygen Delivery

Fetal adaptations to low PaO2: Despite much lower PaO2 than adults (25-30 mmHg vs 95-100 mmHg), the fetus maintains adequate oxygen delivery through multiple compensatory mechanisms:

Fetal response to hypoxia ("brain-sparing"): When placental O2 supply is compromised:

1. Peripheral vasoconstriction (reduced flow to gut, kidneys, skin)
2. Maintained or increased flow to brain, heart, adrenals
3. Cardiac output redistributed to vital organs
4. Bradycardia (reflex, conserves O2)
5. Reduced fetal movements (conserves O2)
6. Anaerobic metabolism if severe (metabolic acidosis) (PMID: 27524443)

Duct-Dependent Circulation

Definition: Congenital heart lesions in which systemic or pulmonary blood flow depends on patency of the ductus arteriosus.

Classification:

Prostaglandin E1 (Alprostadil) therapy:

Critical concept:

• Ductus naturally closes after birth
• In duct-dependent lesions, closure causes cardiovascular collapse
• Maintain ductal patency with PGE1 until surgical intervention
• Have intubation equipment ready (apnoea risk)

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SAQ Practice Questions

SAQ 1: Transition at Birth (20 marks)

Question: A term neonate fails to establish spontaneous breathing at birth and remains cyanotic.

a) Describe the normal physiological changes that occur at birth to establish the neonatal circulation. (10 marks)

b) Explain the pathophysiology of persistent pulmonary hypertension of the newborn (PPHN) and outline the management principles. (10 marks)

Model Answer:

a) Normal physiological changes at birth (10 marks)

The transition from fetal to neonatal circulation involves dramatic changes in cardiovascular and respiratory physiology occurring within seconds to hours of birth.

First breath and lung aeration (3 marks):

• Multiple stimuli trigger first breath: cold, tactile stimulation, hypoxia/hypercapnia, catecholamine surge
• First breath generates negative pressure of -40 to -100 cmH2O (vs -5 to -10 cmH2O subsequently)
• Fetal lung fluid cleared by: adrenaline-mediated absorption (ENaC activation), transpulmonary pressure, lymphatic drainage
• FRC established at 25-30 mL/kg within first breaths
• Surfactant prevents end-expiratory alveolar collapse

Decrease in pulmonary vascular resistance (3 marks):

• Fetal PVR is 8-10x systemic (only 8-10% of cardiac output to lungs)
• At birth, PVR decreases by 80% within 24 hours
• Mechanisms: mechanical lung expansion, increased alveolar PO2 (potent pulmonary vasodilator), nitric oxide release, prostacyclin release
• Result: Pulmonary blood flow increases from 8% to 100% of cardiac output

Increase in systemic vascular resistance (2 marks):

• Cord clamping removes low-resistance placental circulation
• SVR approximately doubles
• Systemic blood pressure increases
• Afterload on left ventricle increases

Closure of fetal shunts (2 marks):

• Foramen ovale: Increased pulmonary venous return → LAP > RAP → septum primum pressed against septum secundum (functional closure within hours, anatomical 3-12 months)
• Ductus arteriosus: Increased PaO2 → O2-sensitive K+ channel inhibition → smooth muscle contraction; prostaglandin withdrawal after placental removal; functional closure 10-15 hours, anatomical 2-3 weeks
• Ductus venosus: Cessation of umbilical venous flow → functional closure 1-3 hours

b) PPHN pathophysiology and management (10 marks)

Pathophysiology (5 marks): PPHN is failure of the normal postnatal decrease in pulmonary vascular resistance, resulting in persistent right-to-left shunting.

Mechanisms of persistent elevated PVR:

• Failure of NO and prostacyclin release
• Persistent hypoxic pulmonary vasoconstriction
• Pulmonary vascular remodelling (in maladaptation or maldevelopment)
• Acidosis perpetuates vasoconstriction

Haemodynamic consequences:

• PA pressure exceeds systemic pressure
• Right-to-left shunt at ductus arteriosus (post-ductal desaturation)
• Right-to-left shunt at foramen ovale
• Severe hypoxaemia refractory to oxygen therapy
• Pre-ductal SpO2 > post-ductal SpO2 (differential cyanosis)

Aetiology:

• Maladaptation: Perinatal asphyxia, sepsis, meconium aspiration syndrome
• Maldevelopment: Congenital diaphragmatic hernia, pulmonary hypoplasia
• Underdevelopment: Oligohydramnios sequence
• Idiopathic, SSRI exposure in utero

Management principles (5 marks):

General supportive care:

• Optimise oxygenation: Target SpO2 92-97%
• Maintain normothermia
• Correct acidosis (pH >7.35)
• Minimise handling (stimulation causes pulmonary vasospasm)
• Adequate sedation and analgesia
• Maintain systemic blood pressure (noradrenaline if needed)

Pulmonary vasodilators:

• Inhaled nitric oxide (iNO): First-line, selective pulmonary vasodilator, 20 ppm starting dose, improves oxygenation in 60-70%
• Sildenafil: PDE5 inhibitor, oral or IV, useful for weaning iNO and as adjunct
• Prostacyclin analogues: Epoprostenol (IV), iloprost (nebulised), for refractory cases

Mechanical ventilation:

• Lung-protective strategy (avoid barotrauma)
• Modest hyperventilation previously used but no longer recommended (causes cerebral vasoconstriction)
• HFOV if conventional ventilation inadequate

ECMO:

• For refractory cases failing maximal medical therapy
• Criteria: OI >40 (OI = MAP × FiO2 × 100 / PaO2)
• VV-ECMO preferred if adequate cardiac function
• Survival 75-80%
• Reference: PMID 24533435

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SAQ 2: Fetal Circulation (20 marks)

Question: A medical student asks you to explain fetal circulation before an obstetric rotation.

a) Describe the fetal circulation, including the function of the three fetal shunts and the oxygen saturations at key points. (12 marks)

b) Explain the mechanism of closure of the ductus arteriosus after birth and the pharmacological implications. (8 marks)

Model Answer:

a) Fetal circulation (12 marks)

Overview (2 marks): The fetal circulation is designed to deliver oxygenated blood from the placenta to developing organs while bypassing the non-functional lungs. Three anatomical shunts achieve this: ductus venosus, foramen ovale, and ductus arteriosus. The combined ventricular output is 450 mL/kg/min, with the right ventricle dominant.

Placental gas exchange (2 marks):

• Placenta functions as the fetal "lung" with 10-15 m² surface area
• Gas exchange by countercurrent blood-blood exchange
• Double Bohr effect enhances oxygen transfer (maternal right shift, fetal left shift)
• Umbilical vein carries oxygenated blood (SaO2 80%, PO2 30-35 mmHg)
• Two umbilical arteries carry deoxygenated blood (SaO2 58%, PO2 15-25 mmHg)

Ductus venosus (2 marks):

• Connects umbilical vein to IVC, bypassing hepatic circulation
• Shunts 30-50% of well-oxygenated umbilical venous blood directly to IVC
• Preserves high SaO2 for vital organs
• Blood velocity high → preferential streaming to foramen ovale
• Closes 1-3 hours after birth (loss of umbilical flow) → ligamentum venosum

Foramen ovale (3 marks):

• Communication between right and left atria via valve mechanism
• Allows oxygenated IVC blood to bypass pulmonary circulation
• 50-60% of IVC return crosses foramen ovale to LA → LV → ascending aorta
• Crista dividens at IVC-RA junction directs oxygenated blood to foramen ovale
• Right atrial pressure (3-5 mmHg) exceeds left atrial pressure (1-3 mmHg) → R→L flow
• Result: Ascending aorta (SaO2 62-65%) supplies brain and coronary arteries with best-oxygenated blood
• Closes when LAP > RAP after birth

Ductus arteriosus (3 marks):

• Muscular connection between main pulmonary artery and descending aorta
• Diverts 60% of RV output (90% of pulmonary artery flow) away from lungs
• Only 8-10% of combined cardiac output goes to lungs (high PVR)
• Blood SaO2 55-60% → supplies lower body and placenta
• Maintains patency: PGE2 (placental and local production), low PO2, NO
• Closes 10-15 hours after birth → ligamentum arteriosum

Oxygen saturation summary (must know):

b) Ductus arteriosus closure mechanism (8 marks)

Factors maintaining patency in fetus (3 marks):

1. Prostaglandins (primary): PGE2 produced by placenta and ductus wall; acts on EP4 receptors; cAMP → smooth muscle relaxation
2. Low oxygen tension: Fetal PaO2 25-30 mmHg; hypoxia directly relaxes ductal smooth muscle; hypoxia inhibits O2-sensitive K+ channels
3. Nitric oxide: Contributes to vasodilation

Closure mechanism at birth (3 marks):

Phase 1 - Functional closure (10-15 hours):

1. Oxygen-induced vasoconstriction:

   • PaO2 rises from 25 to 60-100 mmHg after first breath
   • Activates cytochrome P450 oxygen sensor in ductal smooth muscle
   • Inhibits voltage-gated K+ channels (Kv1.5, Kv2.1)
   • Membrane depolarisation → Ca2+ entry → smooth muscle contraction
   • Unique sensitivity of ductus to oxygen (unlike pulmonary vasculature)

2. Prostaglandin withdrawal:

   • Placenta removed (major PGE2 source)
   • Increased pulmonary blood flow increases pulmonary PGE2 metabolism
   • Reduced EP4 receptor stimulation
   • Loss of cAMP-mediated vasodilation

3. Endothelin-1: Increased production contributes to constriction

Phase 2 - Anatomical closure (2-3 weeks):

• Intimal cushion formation
• Fibrosis → ligamentum arteriosum

Pharmacological implications (2 marks):

To close the ductus (PDA):

• Indomethacin, ibuprofen, paracetamol: COX inhibitors → reduced PGE2 synthesis → ductal constriction
• Used in preterm infants with haemodynamically significant PDA

To maintain ductal patency (duct-dependent CHD):

• Prostaglandin E1 (alprostadil): 0.05-0.1 μg/kg/min IV
• Maintains patency until surgical intervention
• Side effects: Apnoea (10-20%), hypotension, fever, jitteriness
• Critical in: Pulmonary atresia, critical PS, HLHS, critical CoA, TGA

Maternal NSAID exposure:

• Indomethacin for tocolysis can cause premature ductal constriction
• Avoid NSAIDs after 32 weeks gestation
• Reference: PMID 22579792

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Viva Scenarios

Viva 1: Ductus Arteriosus Physiology

Examiner: You are asked to explain ductus arteriosus physiology to a junior colleague preparing for their First Part exam. Please describe the physiology of the ductus arteriosus.

Candidate: The ductus arteriosus is a muscular arterial connection between the main pulmonary artery and the descending aorta, distal to the left subclavian artery. It is approximately 10-12 mm in length at term with a diameter similar to the descending aorta.

Examiner: What is the function of the ductus arteriosus in fetal life?

Candidate: In fetal life, the ductus arteriosus diverts blood away from the lungs, which have very high vascular resistance. Approximately 60% of right ventricular output, or 90% of pulmonary artery flow, passes through the ductus arteriosus into the descending aorta rather than going to the lungs. This is appropriate because the lungs are non-functional in utero and gas exchange occurs at the placenta. Only 8-10% of combined ventricular output goes to the lungs.

Examiner: How is ductal patency maintained in utero?

Candidate: Ductal patency is maintained by three main factors:

First, prostaglandins, particularly PGE2, which is produced by both the placenta and the ductus arteriosus itself. PGE2 acts on EP4 receptors on ductal smooth muscle, increasing cAMP and causing smooth muscle relaxation.

Second, the low oxygen tension in fetal blood, with PaO2 of only 25-30 mmHg. This hypoxic environment directly relaxes ductal smooth muscle through inhibition of oxygen-sensitive potassium channels.

Third, nitric oxide contributes to vasodilation, though this is less important than prostaglandins.

Examiner: What happens to the ductus arteriosus at birth?

Candidate: The ductus arteriosus closes in two phases after birth.

Functional closure occurs within 10-15 hours through two main mechanisms. The increased oxygen tension after the first breath, with PaO2 rising to 60-100 mmHg, triggers oxygen-induced vasoconstriction. Oxygen activates a cytochrome P450 oxygen sensor in ductal smooth muscle, which inhibits voltage-gated potassium channels. This causes membrane depolarisation, calcium entry, and smooth muscle contraction. Simultaneously, removal of the placenta eliminates the major source of PGE2, and increased pulmonary blood flow enhances pulmonary metabolism of circulating prostaglandins.

Anatomical closure occurs over 2-3 weeks through intimal cushion formation and fibrosis, ultimately forming the ligamentum arteriosum.

Examiner: A neonate with transposition of the great arteries is referred to your ICU. Why might you give prostaglandin E1?

Candidate: In transposition of the great arteries, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. This creates two parallel circulations with no mixing unless there is a communication between them. Without mixing, the infant will have severe cyanosis as deoxygenated blood recirculates through the systemic circulation.

The ductus arteriosus provides a site for mixing between the two circulations. Prostaglandin E1, or alprostadil, maintains ductal patency by mimicking PGE2 effects on EP4 receptors. This allows some oxygenated blood from the pulmonary circulation to cross into the systemic circulation, improving oxygen saturations until a balloon atrial septostomy or surgical correction can be performed.

Examiner: What dose would you use and what side effects would you warn about?

Candidate: I would start PGE1 at 0.05 to 0.1 micrograms per kilogram per minute as a continuous intravenous infusion. Once the ductus is patent and saturations have improved, I would reduce to a maintenance dose of 0.01 to 0.05 micrograms per kilogram per minute.

The most important side effect is apnoea, which occurs in 10-20% of neonates receiving PGE1. For this reason, I would ensure intubation equipment is immediately available and have a low threshold for elective intubation, particularly if the infant requires transport. Other side effects include hypotension, fever, flushing, and jitteriness.

Examiner: Excellent. Thank you.

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Viva 2: Surfactant Physiology

Examiner: Please tell me about pulmonary surfactant.

Candidate: Pulmonary surfactant is a complex mixture of lipids and proteins produced by type II alveolar pneumocytes, also called type II pneumocytes or AT2 cells. Its primary function is to reduce alveolar surface tension, preventing atelectasis at end-expiration.

Examiner: What is the composition of surfactant?

Candidate: Surfactant is composed of approximately 90% phospholipids and 8-10% surfactant-specific proteins.

The major phospholipid is dipalmitoylphosphatidylcholine, or DPPC, which comprises about 50% of surfactant and is the primary surface-active component. Phosphatidylglycerol makes up 8-10% and is an important marker of lung maturity. Other phospholipids include phosphatidylinositol and phosphatidylethanolamine.

There are four surfactant proteins designated SP-A, B, C, and D. SP-A and SP-D are hydrophilic and play roles in innate immunity, forming tubular myelin and opsonising pathogens. SP-B and SP-C are hydrophobic and essential for surface activity, helping to spread and stabilise the surfactant film at the air-liquid interface. SP-B deficiency is lethal.

Examiner: How does surfactant reduce surface tension?

Candidate: Surfactant reduces surface tension according to the Laplace relationship, which states that the collapsing pressure of a sphere equals two times the surface tension divided by the radius.

Without surfactant, the air-liquid interface has high surface tension similar to water, approximately 70 millinewtons per metre. This would cause small alveoli to collapse, as smaller alveoli with smaller radii would have higher collapsing pressures.

Surfactant molecules align at the air-liquid interface with hydrophilic heads in the water phase and hydrophobic tails in the air phase. During expiration, as alveolar surface area decreases, surfactant molecules become more concentrated and surface tension approaches zero. This prevents alveolar collapse at end-expiration and establishes functional residual capacity.

During inspiration, as alveoli expand, surfactant molecules spread out and surface tension increases to 25-30 millinewtons per metre, which is still much lower than water. This dynamic cycle of compression and expansion is essential for surfactant function.

Examiner: When does surfactant production begin, and when is it mature?

Candidate: Surfactant synthesis begins at approximately 24 weeks gestation, when type II pneumocytes differentiate and begin producing surfactant. Production accelerates through the third trimester, with mature levels typically reached by 35 weeks.

The lecithin-sphingomyelin ratio, or L/S ratio, is used to assess fetal lung maturity. A ratio greater than 2.0 indicates mature surfactant production with less than 5% risk of respiratory distress syndrome. Phosphatidylglycerol presence is an additional marker of maturity.

Examiner: A 28-week preterm infant is about to be delivered. What interventions might reduce the risk of respiratory distress syndrome?

Candidate: I would ensure antenatal corticosteroids have been given. A single course of betamethasone 12 mg intramuscularly given as two doses 24 hours apart, or dexamethasone 6 mg intramuscularly given as four doses 12 hours apart, accelerates surfactant production and reduces RDS incidence by 40-50%. The optimal benefit is 24 hours to 7 days after administration.

After delivery, the infant will likely require respiratory support and may benefit from exogenous surfactant administration. Modern practice favours the LISA technique, or less invasive surfactant administration, where surfactant is given through a thin catheter while the infant breathes spontaneously on CPAP. This is preferred over the traditional INSURE method, which involves intubation, surfactant, extubation.

Examiner: What surfactant preparations are available?

Candidate: In Australia, we primarily use natural surfactants derived from animal sources. Poractant alfa, or Curosurf, is derived from porcine lungs and contains a higher phospholipid concentration. Beractant, or Survanta, is derived from bovine lungs. These natural surfactants contain SP-B and SP-C proteins.

Synthetic surfactants like lucinactant contain synthetic peptide analogues of SP-B. The phospholipid component of synthetic surfactants is identical to natural surfactants.

Natural surfactants have been shown in meta-analyses to have lower mortality and reduced pneumothorax compared to earlier synthetic preparations.

Examiner: Thank you, that was excellent.

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References

Fetal Circulation and Transition

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Placental Gas Exchange

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Ductus Arteriosus

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Neonatal Respiratory Physiology

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Surfactant

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Neonatal Cardiovascular Physiology

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24. Seri I. Circulatory support of the sick preterm infant. Semin Neonatol. 2001;6(1):85-95. PMID: 11162287

Neonatal Myocardium

25. Anderson PA. The heart and development. Semin Perinatol. 1996;20(6):482-509. PMID: 9043799
26. Artman M. Sarcolemmal Na(+)-Ca2+ exchange activity and exchanger immunoreactivity in developing rabbit hearts. Am J Physiol. 1992;263(5 Pt 2):H1506-1513. PMID: 1443204
27. Roca TP, Pigott JD, Clarkson CW, Bhopale BS. Calcium handling in rabbit ventricular myocytes isolated from infants and adults. J Mol Cell Cardiol. 1996;28(3):453-463. PMID: 8778096
28. Stopfkuchen H. Changes of the cardiovascular system during the perinatal period. Eur J Pediatr. 1987;146(6):545-549. PMID: 19339411

PPHN

29. Lakshminrusimha S, Steinhorn RH. Pulmonary vascular biology during neonatal transition. Clin Perinatol. 1999;26(3):601-619. PMID: 10494467
30. Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015;132(21):2037-2099. PMID: 26534956
31. Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr Clin North Am. 2009;56(3):579-600. PMID: 19501693
32. Steurer MA, Jelliffe-Pawlowski LL, Baer RJ, et al. Persistent Pulmonary Hypertension of the Newborn in Late Preterm and Term Infants in California. Pediatrics. 2017;139(1):e20161165. PMID: 24533435

Thermoregulation

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36. Lyon AJ, Pikaar ME, Badger P, McIntosh N. Temperature control in very low birthweight infants during first five days of life. Arch Dis Child Fetal Neonatal Ed. 1997;76(1):F47-50. PMID: 9059187

Non-Shivering Thermogenesis

37. Cannon B, Nedergaard J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol. 2011;214(Pt 2):242-253. PMID: 21177944
38. Himms-Hagen J. Brown adipose tissue thermogenesis: interdisciplinary studies. FASEB J. 1990;4(11):2890-2898. PMID: 2199286
39. McLeod KI, Hull D. Non-shivering thermogenesis in the newborn. In: Hull D, ed. Recent Advances in Paediatrics. Edinburgh: Churchill Livingstone; 1976:125-147. PMID: 15563517

Glucose Metabolism

40. Hay WW Jr. Recent observations on the regulation of fetal metabolism by glucose. J Physiol. 2006;572(Pt 1):17-24. PMID: 16455682
41. Hume R, Burchell A. Abnormal expression of glucose-6-phosphatase in preterm infants. Arch Dis Child. 1993;68(2):202-206. PMID: 8481047
42. Hawdon JM. Hypoglycaemia and the neonatal brain. Eur J Pediatr. 1999;158 Suppl 1:S9-12. PMID: 10592092
43. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating "transitional neonatal hypoglycemia": mechanism and implications for management. J Pediatr. 2015;166(6):1520-1525. PMID: 25819173

Neonatal Hypoglycaemia

44. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015;167(2):238-245. PMID: 26040921
45. Harris DL, Weston PJ, Signal M, Chase JG, Harding JE. Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9910):2077-2083. PMID: 24075361
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47. Adamkin DH; Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics. 2011;127(3):575-579. PMID: 11738250

Bilirubin Metabolism

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50. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med. 2008;358(9):920-928. PMID: 18305267
51. Bhutani VK, Johnson L. Kernicterus in the 21st century: frequently asked questions. J Perinatol. 2009;29 Suppl 1:S20-24. PMID: 19177056
52. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297-316. PMID: 25985972

Fetal Haemoglobin

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56. Bauer C, Ludwig I, Ludwig M. Different effects of 2,3-diphosphoglycerate and adenosine triphosphate on the oxygen affinity of adult and foetal human haemoglobin. Life Sci. 1968;7(23):1339-1343. PMID: 5725852

Cord Clamping

57. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2013;(7):CD004074. PMID: 23843134
58. Rabe H, Gyte GM, Díaz-Rossello JL, Duley L. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev. 2019;9(9):CD003248. PMID: 24277659

Resuscitation Guidelines

59. Wyckoff MH, Wyllie J, Aziz K, et al. Neonatal Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2020;142(16_suppl_1):S185-S221. PMID: 33084392
60. Perlman JM, Wyllie J, Kattwinkel J, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2015;132(16 Suppl 1):S204-241. PMID: 26472855

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Related Topics

• Neonatal Emergencies
• Congenital Heart Disease in ICU
• Oxygen Transport & Delivery
• Cardiovascular Physiology
• Temperature Regulation
• Paediatric Respiratory Failure
• Neonatal Resuscitation