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ESSAY 1 (April 2011 / May 2019 / General)

Carbohydrate Metabolism in Pregnancy / Discuss Screening Tests for Diabetes in Pregnancy

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KEYWORD BOX Accelerated starvation | Facilitated anabolism | Insulin resistance | Human Placental Lactogen (hPL) | Progesterone | Gluconeogenesis | OGTT | GDM | Disposition Index | Freinkel's concept

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I. Introduction

1. Ensuring continuous glucose supply to the fetoplacental unit
2. Providing energy reserves for the mother

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II. Normal (Non-Pregnant) Carbohydrate Metabolism

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III. Changes in Carbohydrate Metabolism During Pregnancy

A. EARLY PREGNANCY (1st Trimester - Phase of Facilitated Anabolism)

• Enhanced insulin secretion (beta cell hyperplasia)
• Increased peripheral glucose utilisation
• Enhanced glycogen synthesis in liver and muscle
• Increased fat deposition

• Fasting blood glucose falls (by ~10 mg/dL) due to plasma volume expansion and increased fetoplacental consumption
• Increased insulin sensitivity (paradoxically, to build maternal energy stores)
• Enhanced fat storage (maternal adiposity increases)

B. LATE PREGNANCY (2nd-3rd Trimester - Phase of Accelerated Starvation)

┌─────────────────────────────────────────────────────────┐
│         DIABETOGENIC FACTORS IN PREGNANCY               │
│                                                         │
│  Human Placental Lactogen (hPL) ─── anti-insulin effect│
│  Progesterone ─────────────────── impairs insulin action│
│  Oestrogen ─────────────────────── modulates sensitivity│
│  Prolactin ──────────────────────── insulin antagonist  │
│  Cortisol ───────────────────────── gluconeogenesis ↑   │
│  Glucagon ───────────────────────── hepatic glucose ↑   │
└─────────────────────────────────────────────────────────┘

1. Insulin Resistance: 50-60% reduction in insulin sensitivity by 3rd trimester (measured by hyperinsulinemic-euglycemic clamp). Affects primarily skeletal muscle and adipose tissue.
2. Hepatic glucose production: 30% increase in basal hepatic glucose output by third trimester (Catalano et al., 1992 - Creasy & Resnik).
3. Post-prandial hyperglycaemia: Blunted insulin response to glucose load; post-prandial glucose levels rise progressively.
4. Fasting hypoglycaemia: Prolonged fasting in late pregnancy leads to rapid decline in blood glucose (exaggerated starvation), accompanied by ketonaemia.
5. Lipolysis: Insulin resistance promotes FFA mobilisation, hepatic ketogenesis - "accelerated starvation."

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IV. Mechanism of Insulin Resistance in Pregnancy

Placenta secretes hPL, Progesterone, Cortisol
           |
           ▼
  Impaired post-receptor insulin signalling
  (IRS-1 phosphorylation defect, PI3-kinase pathway)
           |
           ▼
  ↓ GLUT-4 translocation to cell membrane
           |
           ▼
  ↓ Glucose uptake by muscle + adipose
           |
     ┌─────┴──────┐
     ▼            ▼
Compensatory   If compensation
beta-cell      fails → GDM
hyperplasia

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V. Glucose Transport in Pregnancy

• GLUT-1: Predominant transporter in placenta - constitutive, insulin-independent; ensures fetal glucose supply even during maternal hypoglycaemia
• GLUT-4: Skeletal muscle/adipose - insulin-dependent; downregulated in pregnancy (contributes to insulin resistance)
• GLUT-2: Liver and pancreatic beta cells - high-capacity, bidirectional

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VI. Protein and Lipid Metabolism (Brief)

• Protein: Positive nitrogen balance in early pregnancy; anabolism favours fetal growth. In late pregnancy, gluconeogenesis from amino acids increases.
• Lipid: Hypertriglyceridaemia is physiological. Increased lipolysis in late pregnancy provides FFA as maternal fuel, sparing glucose for the fetus. Ketones cross placenta freely and can be teratogenic in excess.

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VII. Screening Tests for Diabetes in Pregnancy

A. WHO to Screen?

B. When to Screen?

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C. Screening and Diagnostic Tests

1. One-Step Approach: 75g OGTT (IADPSG 2010 / WHO 2013)

• Done at 24-28 weeks, fasting
• Diagnosis of GDM if ANY one of the following is met:

2. Two-Step Approach (Carpenter-Coustan / ACOG)

• Non-fasting, 50g glucose load
• 1-hour plasma glucose measured
• Threshold: ≥130 or ≥140 mg/dL (sensitivity 80-90%)
• Positive result → proceed to Step 2

• Diagnosis requires ≥2 abnormal values:

3. DIPSI Test (India - Diabetes in Pregnancy Study Group India)

• Non-fasting 75g OGTT
• 2-hour plasma glucose
• GDM: ≥ 140 mg/dL
• Overt DM: ≥ 200 mg/dL
• Advantage: single-step, non-fasting, applicable in primary care

4. HbA1c

• Not recommended for GDM screening (poor sensitivity)
• Useful for detecting pre-existing diabetes at booking: HbA1c ≥ 6.5% = diabetes

5. Fasting Plasma Glucose (FPG)

• Screening at first visit
• FPG 92-125 mg/dL at 1st visit = GDM (IADPSG)
• FPG ≥ 126 mg/dL = overt diabetes

6. Urine Glucose (Glycosuria)

• Unreliable due to physiologically lowered renal threshold in pregnancy
• Not recommended as primary screening tool

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VIII. Summary Diagram

ALL PREGNANT WOMEN
       |
First antenatal visit
       |
       ├── FPG ≥ 126 mg/dL or RBS ≥ 200 mg/dL ──→ OVERT DIABETES
       ├── FPG 92-125 mg/dL ────────────────────→ GDM (IADPSG)
       └── Normal → retest at 24-28 weeks
                          |
               75g OGTT (IADPSG) or
               50g GCT → 100g OGTT (ACOG)
                          |
            Any 1 value above threshold = GDM

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ESSAY 2 (April 2011)

"Pregnancy is a Diabetogenic State" - Discuss

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KEYWORD BOX Freinkel | Facilitated anabolism | Accelerated starvation | hPL | Insulin resistance | GDM | Counter-regulatory hormones | Disposition Index | Exaggerated starvation | Post-prandial hyperglycaemia

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I. Introduction

• Insulin resistance increases 50-60% by late gestation
• Post-prandial glucose is higher than in non-pregnant state
• Fasting glucose is LOWER (due to increased fetoplacental use and plasma volume expansion)
• 7-10% of pregnancies result in overt GDM when beta cells cannot compensate

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II. Evidence That Pregnancy is Diabetogenic

A. Hormonal Counter-Regulatory Forces

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B. Insulin Resistance in Late Pregnancy

MECHANISM OF INSULIN RESISTANCE

  hPL / Progesterone / Cortisol
            |
            ▼
   Impaired insulin receptor
   post-binding signalling
            |
            ▼
   ↓ PI3-kinase activation
   ↓ Akt/PKB phosphorylation
            |
            ▼
   ↓ GLUT-4 translocation
   ↓ Glucose uptake in muscle
            |
            ▼
   Peripheral insulin resistance
   (50-60% decrease by 3rd trimester)

• Measured by hyperinsulinemic-euglycemic clamp studies (Catalano et al.)
• Hepatic glucose production increases 30% in 3rd trimester despite elevated insulin
• Post-prandial glucose excursions are broader and more prolonged

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C. Altered Glucose Dynamics

• Fetal glucose consumption = 30-50% of maternal post-absorptive glucose disposal
• Maternal FFA and ketone bodies rise rapidly with brief fasting (12-18h)
• This "accelerated starvation" mimics diabetic ketosis

• Blunted first-phase insulin secretion
• Prolonged hyperglycaemia post-meal
• Glucose freely crosses placenta → fetal hyperinsulinism → macrosomia

NON-PREGNANT STATE vs PREGNANT STATE (Blood Glucose Curve)

mg/dL
200 |                    Pregnant (2nd-3rd trimester)
    |         /‾‾‾‾‾‾‾‾‾‾‾\
180 |        /              \
    |       /                \_______________
140 |      /                                 \___
    | ____/ Non-Pregnant                         ‾‾‾___
100 |─────────────────────────────────────────────────
    |
 70 |─── Fasting (pregnant = lower due to fetal use)
    |________________________________________
         0      1hr     2hr     3hr   time

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D. Beta Cell Response - The Compensatory Mechanism

• Beta cell hyperplasia (increased islet mass ~25-50%)
• Enhanced glucose-stimulated insulin secretion
• First-phase insulin response may be blunted but compensated by second phase

• Normal pregnancy: DI maintained despite reduced sensitivity
• GDM: DI falls - beta cells cannot compensate sufficiently

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E. When Compensation Fails: GDM

• Obesity (pre-existing insulin resistance)
• Advanced maternal age
• Family history of T2DM
• Previous GDM
• PCOS

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III. Two Phases of Pregnancy (Freinkel's Concept)

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IV. Maternal and Fetal Consequences of the Diabetogenic State

• Macrosomia (Pedersen hypothesis: maternal hyperglycaemia → fetal hyperinsulinism → growth)
• Shoulder dystocia, birth trauma
• Neonatal hypoglycaemia
• Increased risk of T2DM in mother (50% within 10 years)
• Increased risk of obesity and DM in offspring

• Lower maternal fasting glucose benefits fetal growth
• Mild post-prandial excursions contribute to normal fetal adiposity

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V. Conclusion

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ESSAY 3 (May 2019)

Compare Carbohydrate Metabolism in Pregnant and Non-Pregnant Women

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KEYWORD BOX Facilitated anabolism | Accelerated starvation | hPL | Insulin resistance | GLUT-4 | Hepatic glucose production | Glycogen synthesis | Post-prandial hyperglycaemia | Fasting hypoglycaemia | Pedersen hypothesis

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I. Introduction

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II. Comparative Table

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III. Early Pregnancy: Facilitated Anabolism

• Rising oestrogen and progesterone cause beta cell hyperplasia → increased insulin secretion
• Enhanced insulin sensitivity → increased glucose uptake, glycogen synthesis, fat deposition
• Maternal adiposity increases (fat stored for late pregnancy energy demands)
• Fasting glucose FALLS (hemodilution from plasma volume expansion; increased renal glucose excretion due to lowered threshold)
• Post-prandial glucose and insulin levels show exaggerated first-phase response - rapid glucose clearance

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IV. Late Pregnancy: Accelerated Starvation

A. Insulin Resistance (most important change)

COMPARISON: Insulin Action

NON-PREGNANT:
  Insulin → Receptor → IRS-1 → PI3K → GLUT-4 → Muscle/Adipose
  Normal glucose uptake

LATE PREGNANCY:
  Insulin → Receptor → IRS-1 (impaired by hPL/Progesterone)
  ↓ PI3K activation
  ↓ GLUT-4 translocation
  50-60% REDUCED glucose uptake

B. Hepatic Glucose Production

• Non-pregnant: Insulin fully suppresses hepatic glucose output post-prandially
• Late pregnancy: 30% INCREASE in basal hepatic glucose production
• Insulin resistance at hepatocyte level = increased gluconeogenesis and glycogenolysis
• This maintains glucose delivery to fetus during maternal fasting

C. Post-Prandial State

D. Fasting State: Accelerated Starvation

Non-Pregnant Fasting:
  12h fast → mild hypoglycaemia → mild ketosis

Pregnant (Late) Fasting:
  6-8h fast → significant hypoglycaemia (fetal glucose drain)
            → rapid FFA mobilisation
            → RAPID ketogenesis
  = "Starvation Ketosis" appears earlier and more severely

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V. Key Hormonal Differences

NON-PREGNANT                    PREGNANT (Late)
                                ________________________
Insulin: PRIMARY regulator      Insulin: IMPAIRED action
                                hPL: Rising (peaks 36-38 wk)
Glucagon: Suppressed post-meal  Glucagon: Less suppressed
Cortisol: Normal                Cortisol: Elevated 2-3x
Progesterone: Cyclic            Progesterone: Persistently high
hPL: Absent                     hPL: HIGH (insulin antagonist)

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VI. Glucose Transport: Comparison

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VII. Summary Diagram: The Two Phases

PREGNANCY TIMELINE
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
|  1st Trimester        |  2nd-3rd Trimester      |
|  FACILITATED          |  ACCELERATED            |
|  ANABOLISM            |  STARVATION             |
|                       |                         |
|  ↑ Insulin sensitivity|  ↓ Insulin sensitivity  |
|  ↑ Glycogen synthesis |  ↑ Lipolysis            |
|  ↑ Fat deposition     |  ↑ Hepatic glucose      |
|  ↓ Fasting glucose    |  ↑ Post-prandial glucose|
|  ↑ Beta cell response |  ↑↑ Beta cell response  |
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
                                    |
                               If beta cells
                               cannot compensate
                                    |
                                   GDM

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VIII. Conclusion

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ESSAY 4 (April 2013)

Glucose Transport in Cells and Ketoacidosis

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KEYWORD BOX GLUT transporters | Facilitated diffusion | SGLT | Insulin signalling | IRS-1 | GLUT-4 | DKA | Anion gap | Kussmaul breathing | Bicarbonate | Ketone bodies | Counter-regulatory hormones

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I. Glucose Transport in Cells

A. Overview

GLUCOSE TRANSPORT SYSTEMS
        |
   ┌────┴────┐
   ▼         ▼
FACILITATED  ACTIVE
DIFFUSION    TRANSPORT
(GLUTs)      (SGLTs)
 - Down       - Against
   gradient    gradient
 - No energy   - Na+ cotransport
   required     (energy via Na/K ATPase)

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B. GLUT Family (Facilitated Diffusion Transporters)

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C. Mechanism of Insulin-Stimulated GLUT-4 Translocation

INSULIN-STIMULATED GLUCOSE UPTAKE

  Insulin
    |
    ▼
Insulin Receptor (tyrosine kinase)
    |
    ▼
IRS-1 phosphorylation
    |
    ▼
PI3-Kinase activation
    |
    ▼
PIP3 accumulates → Akt (PKB) phosphorylation
    |
    ▼
AS160 phosphorylation → Rab GTPase activation
    |
    ▼
GLUT-4 vesicles translocate to plasma membrane
    |
    ▼
Glucose enters cell (facilitated diffusion)
    |
    ▼
Glucose → Glucose-6-phosphate (Hexokinase)
    |
    ├─→ Glycolysis → ATP
    ├─→ Glycogen synthesis
    └─→ Pentose phosphate pathway

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D. SGLT (Sodium-Glucose Co-Transporters)

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E. Glucose Entry into Cells: Summary by Tissue

TISSUE-SPECIFIC GLUCOSE UPTAKE

Brain ──────── GLUT-1, GLUT-3 ─── Insulin-independent (priority supply)
   |
Liver ──────── GLUT-2 ────────── Insulin-independent uptake
               (high Km - acts as glucose buffer)
   |
Muscle ─────── GLUT-4 ────────── INSULIN-DEPENDENT (major site)
   |
Adipose ─────── GLUT-4 ────────── INSULIN-DEPENDENT
   |
RBCs ────────── GLUT-1 ────────── Insulin-independent
   |
Placenta ─────── GLUT-1, GLUT-3 ── Insulin-independent
                                   (fetal glucose supply)

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II. Ketoacidosis (DKA)

A. Definition

1. Hyperglycaemia (blood glucose >250 mg/dL, may be lower in euglycaemic DKA)
2. Metabolic acidosis (pH <7.3, bicarbonate <15 mEq/L)
3. Ketonaemia/ketonuria

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B. Pathophysiology

PRECIPITATING EVENT (infection, omitted insulin, new DM, physiological stress)
            |
            ▼
  INSULIN DEFICIENCY + COUNTER-REGULATORY HORMONE EXCESS
  (Glucagon↑, Cortisol↑, Catecholamines↑, GH↑)
            |
     ┌──────┴──────┐
     ▼             ▼
HYPERGLYCAEMIA   KETOGENESIS
     |             |
     |    FFA mobilised from adipose
     |    (lipolysis uninhibited)
     |             |
     |    FFA → Liver
     |             |
     |    Acetyl-CoA cannot enter TCA
     |    (oxaloacetate depleted by
     |     gluconeogenesis)
     |             |
     |    Acetyl-CoA → HMG-CoA
     |             |
     |    ├→ Acetoacetate
     |    ├→ Beta-hydroxybutyrate (predominant)
     |    └→ Acetone (fruity breath)
     |             |
     |       KETOACIDAEMIA
     |             |
     └─────────────┘
         METABOLIC ACIDOSIS
         (HIGH ANION GAP)

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C. Biochemical Features of DKA

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D. DKA in Pregnancy

• Fetal mortality up to 30-90% (if untreated)
• Can occur at lower blood glucose levels (euglycaemic DKA - may occur at BG 200 mg/dL)
• Faster onset due to:
  • Pregnancy-related respiratory alkalosis (lower CO2 buffer reserve)
  • Increased insulin resistance
  • Increased ketogenic tendency
  • Reduced bicarbonate buffering

• Infection/sepsis (commonest)
• Omitted insulin
• Beta-mimetic tocolysis (ritodrine/terbutaline)
• Corticosteroids for lung maturity
• Hyperemesis gravidarum
• Undiagnosed T1DM

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E. Clinical Features

DKA CLINICAL FEATURES

Symptoms:                   Signs:
• Polyuria, polydipsia      • Dehydration, dry mucosa
• Nausea, vomiting          • Kussmaul breathing
• Abdominal pain              (deep, rapid - CO2 blowoff)
• Confusion, drowsiness     • Fruity (acetone) breath
• Weakness                  • Tachycardia, hypotension
                            • Hypothermia (despite infection)

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F. Management of DKA (Key Principles)

DKA MANAGEMENT

1. FLUIDS: 0.9% NaCl 1L/hr × 2h → 0.5L/hr × 4h → 0.25L/hr
   (Switch to 5% dextrose when BG <250 mg/dL)

2. INSULIN: IV regular insulin 0.1 U/kg bolus → 0.1 U/kg/hr infusion
   Target: BG fall of 50-75 mg/dL/hr

3. POTASSIUM: Replace early (K+ <3.5 mEq/L → replace BEFORE insulin)
   (Insulin drives K+ into cells - fatal hypokalaemia possible)

4. BICARBONATE: Only if pH <6.9 (controversial)

5. PHOSPHATE: Replace if <1 mg/dL

6. TREAT PRECIPITANT: Antibiotics, etc.

7. In PREGNANCY: Continuous fetal monitoring, obstetric team involvement

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G. Differentiation: DKA vs HHS vs Starvation Ketosis

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ESSAY 5 (November 2024)

Iron Metabolism / Laboratory Investigations / Principles of Iron Therapy in Anaemia in Pregnancy

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KEYWORD BOX Ferritin | Transferrin | TIBC | Hepcidin | Ferroportin | DMT-1 | HIF-2α | Elemental iron | Oral vs parenteral | IV iron sucrose | Ferrous sulphate | WHO criteria | Megaloblastic vs IDA

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I. Introduction

• Expansion of maternal red cell mass (requires ~500 mg Fe)
• Fetal iron requirement (~300 mg Fe)
• Placental iron (~50 mg)
• Total additional requirement: ~800-1000 mg during pregnancy

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II. Normal Iron Metabolism

A. Iron Distribution in the Body (70 kg adult)

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B. Iron Absorption

1. Non-haem iron (Fe3+ / Fe2+): Most dietary iron; Fe3+ must be reduced to Fe2+ by duodenal cytochrome B (DcytB) and gastric acid before absorption
2. Haem iron (Fe2+): From meat; absorbed intact via haem carrier protein-1 (HCP-1); superior bioavailability (15-35%)

IRON ABSORPTION IN ENTEROCYTE

Lumen            Enterocyte          Blood
  |                   |                |
Fe3+ → (DcytB)        |                |
Fe2+ ─(DMT-1)──→ Fe2+ pool            |
                      |                |
Haem ─(HCP-1)──→ Released iron        |
                      |                |
            ┌─────────┘                |
            ▼                         |
      Stored as ferritin               |
            OR                        |
      Exported via FERROPORTIN──→ Fe2+│
                      |               |
                   Hephaestin         |
                   (oxidises to Fe3+) │
                      |               │
                   TRANSFERRIN binds Fe3+
                      |
                   Delivered to bone marrow,
                   liver, other tissues

• High iron stores → high hepcidin → degrades ferroportin → blocks iron export → absorption falls
• Low iron/anaemia/hypoxia → low hepcidin → ferroportin preserved → absorption increases
• Pregnancy: hepcidin falls in 2nd-3rd trimester → facilitates increased iron absorption

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C. Iron Transport

• Iron travels in plasma bound to Transferrin (beta-1 globulin)
• Each transferrin molecule carries 2 Fe3+ ions
• Transferrin saturation = iron/TIBC × 100% (normal 20-45%)
• Transferrin receptor (TfR1) on cell surface internalises Fe-transferrin complex by receptor-mediated endocytosis

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D. Iron Storage

• Ferritin: Soluble storage protein; each ferritin molecule stores up to 4500 Fe3+ atoms
  • Serum ferritin = best marker of iron stores (1 ng/mL = ~10 mg stored iron)
  • < 12 ng/mL = iron deficiency; < 30 ng/mL = depleted stores in pregnancy
• Haemosiderin: Insoluble ferritin aggregates; seen in iron overload

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E. Iron Recycling

• 20-25 mg/day of iron is recycled from senescent RBCs by macrophages in reticuloendothelial system
• This far exceeds the 1-2 mg/day absorbed from diet
• Macrophage ferroportin exports recycled iron back to transferrin

---

F. Iron Losses

• Normal daily loss: 1 mg/day (GI, skin, urinary)
• Menstruation adds 1-2 mg/day
• Pregnancy adds ~3-5 mg/day additional requirement in 3rd trimester

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III. Iron Metabolism in Pregnancy (Special Considerations)

PREGNANCY IRON DEMANDS

1st Trimester:  Minimal (menstruation stops - actually iron spared)
2nd Trimester:  Moderate (expanding red cell mass begins)
3rd Trimester:  MAXIMUM - 5-6 mg/day required
                Fetus draws iron actively (active transport)
                Even anaemic mothers deliver iron to fetus

Total extra need: 800-1000 mg
Normal diet provides: ~1-2 mg/day absorbed
Gap met by: Mobilising stores + supplementation

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IV. Laboratory Investigations for Iron Deficiency Anaemia

A. Full Blood Count

• 1st/3rd trimester: Hb <11 g/dL
• 2nd trimester: Hb <10.5 g/dL

• Mild: Hb 10-10.9 g/dL
• Moderate: Hb 7-9.9 g/dL
• Severe: Hb <7 g/dL
• Very severe: Hb <4 g/dL

---

B. Iron Studies

---

C. Peripheral Blood Smear

• Microcytic, hypochromic RBCs
• Target cells
• Pencil cells (elliptocytes)
• Anisocytosis, poikilocytosis

PERIPHERAL SMEAR IN IDA

Normal RBC         IDA
  [○○○○]           [∘∘∘∘]
  Normo-           Microcytic
  chromic          Hypochromic
                   Pencil cells
                   Target cells

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D. Additional Tests

• Reticulocyte count: Low in IDA; rises with treatment (reticulocytosis at day 7-10 = treatment response)
• Bone marrow: Gold standard - absent stainable iron (Perl's stain); rarely needed
• Stool for occult blood: Rule out chronic blood loss
• Urine routine: Rule out haematuria
• Serum B12 and folate: Rule out megaloblastic anaemia (dimorphic blood picture = combined deficiency)

E. Differentiating IDA from Other Microcytic Anaemias

---

V. Principles of Iron Therapy in Anaemia in Pregnancy

A. Prophylactic Supplementation (All Pregnant Women)

• WHO/India: 60 mg elemental iron + 500 mcg folic acid daily from 12-16 weeks onward for 6 months
• IFA supplementation (GoI): 100 mg elemental iron + 500 mcg folic acid daily

---

B. Oral Iron Therapy

1. Give on empty stomach (best absorption) - but if intolerant, give with meals
2. Avoid tea, coffee, phytates, calcium (inhibit absorption)
3. Vitamin C (ascorbic acid) enhances absorption (reduces Fe3+ to Fe2+)
4. Expected Hb rise: 1-2 g/dL per week (Hb should rise 2 g/dL in 3-4 weeks)
5. Reticulocytosis peaks at day 7-10 = response indicator
6. Side effects: nausea, constipation, black stools, epigastric discomfort (change to alternate formulation or enteric-coated)

---

C. Parenteral Iron Therapy

1. Oral iron intolerance/non-compliance
2. Malabsorption (Crohn's, coeliac, post-bariatric surgery)
3. Very severe anaemia (Hb <7 g/dL) with >8 weeks to term
4. Last trimester with Hb <8 g/dL when oral therapy insufficient
5. Need for rapid Hb correction before surgery/delivery

Total iron deficit = Weight (kg) × (Target Hb - Actual Hb) × 2.4 + 500 mg stores

Example: 60 kg, Hb 7 g/dL, Target 11 g/dL
= 60 × (11-7) × 2.4 + 500 = 576 + 500 = 1076 mg
= 5-6 infusions of 200 mg each

• Rapid Hb response (1-2 g/dL per week)
• Bypasses GI absorption issues
• Replenishes stores rapidly

• Anaphylaxis risk (rare with sucrose)
• Phlebitis, staining (IM)
• Cost

---

D. Blood Transfusion

• Severe anaemia (Hb <6 g/dL) near term or at delivery
• Haemodynamic compromise
• Expected surgical blood loss
• Hb <7 g/dL with <4 weeks to delivery

---

E. Response Monitoring

IRON THERAPY MONITORING TIMELINE

Day 7-10: Reticulocytosis (first sign of response)
Week 3-4: Hb rises 1-2 g/dL
Month 2:  Hb approaches target (10-11 g/dL)
Month 3:  Continue to replenish stores
Monitor: Hb, MCV, serum ferritin at 4-6 weeks

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ESSAY 6 (April 2010)

Pharmacotherapy of Anaemia in Pregnancy

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KEYWORD BOX Oral iron | Parenteral iron | IV iron sucrose | Ferric carboxymaltose | Folic acid | Vitamin B12 | Erythropoietin | Blood transfusion | Haematinic agents | WHO classification

---

I. Introduction

---

II. Pharmacotherapy of IDA

A. Oral Iron (First-Line)

• Treatment dose: 120-200 mg elemental iron/day in divided doses
• Prophylaxis: 60-100 mg elemental iron/day from 12 weeks

ENHANCERS vs INHIBITORS OF ORAL IRON ABSORPTION

Enhancers:                  Inhibitors:
• Vitamin C (ascorbic acid) • Tea (tannins)
• Citric acid               • Coffee
• Meat factor               • Phytates (cereals)
• Acidic gastric pH         • Calcium (milk, antacids)
                            • Tetracyclines
                            • PPIs/H2 blockers

• Constipation → increase fluids, dietary fibre; switch to carbonyl iron
• Nausea → take with food or switch to ferrous gluconate
• Black stools → reassure patient

---

B. Parenteral Iron

---

C. Erythropoietin (EPO)

• Used in renal anaemia in pregnancy and aplastic anaemia
• Dose: 50-300 units/kg SC 3 times/week
• Must supplement with IV iron (demand-driven erythropoiesis)
• Rarely used in IDA alone

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III. Pharmacotherapy of Megaloblastic Anaemia

A. Folic Acid Therapy

• Inadequate dietary intake (most common)
• Increased requirement (multiple pregnancy, haemolysis)
• Malabsorption
• Antifolate drugs (methotrexate, trimethoprim, anticonvulsants)

• DNA synthesis (thymidylate synthesis)
• Cell division (rapidly dividing cells: bone marrow, neural tube)
• Methionine synthesis (methyl donation)

---

B. Vitamin B12 Therapy

• Hydroxocobalamin or Cyanocobalamin 1000 mcg IM weekly × 6 weeks, then monthly
• Oral B12 (methylcobalamin 1000-2000 mcg/day) if compliant

---

IV. Blood Transfusion

• Hb <6 g/dL before term
• Symptomatic anaemia near delivery
• Surgical anaemia, haemorrhage

---

V. Treatment Summary Algorithm

ANAEMIA IN PREGNANCY - PHARMACOTHERAPY

ALL: 
├── Dietary advice (iron-rich foods, vitamin C)
└── Haematinics supplementation

IDA MILD/MODERATE (Hb 7-11 g/dL, >8 weeks to delivery):
├── Oral iron 200 mg elemental/day
├── Check response at 4 weeks
└── Reticulocytosis by day 10 = adequate response

IDA MODERATE-SEVERE or near term / oral failure:
├── IV Iron Sucrose (200 mg/infusion)
├── OR Ferric Carboxymaltose (1000 mg single dose)
└── Weekly Hb monitoring

IDA SEVERE (Hb <6-7 g/dL, <4 weeks to term):
└── Blood transfusion + IV iron

MEGALOBLASTIC (folate deficient):
└── Folic acid 5 mg/day

MEGALOBLASTIC (B12 deficient):
└── B12 IM + folate

MIXED/DIMORPHIC:
└── Both iron + folate + B12 as appropriate

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ESSAY 7 (October 2011)

Role of Folic Acid in Metabolism

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KEYWORD BOX Tetrahydrofolate (THF) | One-carbon transfer | Thymidylate synthase | Methionine synthase | Neural tube defect | Dihydrofolate reductase | Homocysteine | Megaloblastic anaemia | 5-methylTHF | Methotrexate

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I. Introduction

• DNA synthesis and repair
• Amino acid metabolism
• Methylation reactions
• Cell division

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II. Structure and Activation

DIETARY FOLATE (polyglutamate)
         |
    Conjugase (gut)
         |
    MONOGLUTAMATE FOLATE
         |
    Absorbed in jejunum
         |
    DIHYDROFOLATE REDUCTASE (DHFR)
         |
    DIHYDROFOLATE (DHF)
         |
    DHFR again
         |
    TETRAHYDROFOLATE (THF) ← ACTIVE FORM
         |
    THF modified by serine hydroxymethyltransferase
         |
    5,10-methyleneTHF (key intermediate)
         |
    ┌────┴─────────────┐
    ▼                  ▼
5-methylTHF    5,10-methyleneTHF
(methionine     (thymidylate
 cycle)          synthesis)

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III. Key Metabolic Roles of Folic Acid

A. DNA Synthesis: Thymidylate Synthesis

dUMP ──(Thymidylate synthase + 5,10-methyleneTHF)──→ dTMP
                                                      |
                                               Incorporated into DNA

When THF deficient:
dUMP not converted → uracil misincorporated into DNA
                   → Megaloblastic changes
                   → Large, dysfunctional RBCs

B. Purine Synthesis

• 5,10-methyleneTHF and 10-formylTHF provide carbon atoms for purine ring formation (position 2 and 8 of purine ring)
• Purines are essential for DNA AND RNA synthesis
• Folate deficiency → impaired purine synthesis → impaired DNA replication

C. Amino Acid Metabolism

1. METHIONINE SYNTHESIS (via methionine cycle):

Homocysteine + 5-methylTHF ──(Methionine synthase + Vit B12)──→ Methionine + THF
                                                                   |
                                                               SAM (S-adenosyl methionine)
                                                               Universal methyl donor

   Folate deficiency → THF not regenerated → Homocysteine accumulates
   → HYPERHOMOCYSTEINAEMIA (cardiovascular risk, NTD risk)

2. SERINE ↔ GLYCINE interconversion (serine hydroxymethyltransferase)

3. HISTIDINE catabolism (formiminoglutamate → glutamate needs THF)

D. Neural Tube Development

Day 21-28 post-conception: Neural tube closure

Folic acid required for:
• Rapid cell division of neural epithelium
• DNA synthesis
• Methylation of genes controlling neural differentiation

DEFICIENCY → Neural tube fails to close:
• Anencephaly (cranial)
• Spina bifida (spinal)
• Encephalocele

Prevention: Folic acid 400 mcg/day from BEFORE CONCEPTION (periconcept)
High-risk: 4-5 mg/day (previous NTD, anticonvulsants, diabetes)

E. Methylation Reactions (via SAM)

• SAM (derived from methionine, which requires folate for synthesis) is the universal methyl donor for:
  • DNA methylation (epigenetic control)
  • Histone methylation (gene expression)
  • Myelin synthesis (important for B12/folate interplay)
  • Neurotransmitter synthesis (dopamine, serotonin, noradrenaline)
  • Phospholipid synthesis

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IV. Folate and Vitamin B12 Interaction

FOLATE-B12 METABOLIC LINK

METHYLATION TRAP:
5-methylTHF (majority of plasma folate)
         |
Must donate methyl group to homocysteine to regenerate THF
         |
Enzyme: Methionine synthase (REQUIRES B12 as cofactor)
         |
If B12 DEFICIENT:
→ 5-methylTHF cannot be converted back to THF
→ Folate is TRAPPED as 5-methylTHF
→ Functional folate deficiency (despite normal folate levels)
→ Megaloblastic anaemia + Neurological damage (B12 deficiency)

⚠ Treating B12 deficiency with folate alone:
→ Haematological response improves
→ BUT neurological damage CONTINUES (SACD)
→ ALWAYS TREAT BOTH

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V. Causes of Folic Acid Deficiency in Pregnancy

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VI. Clinical Consequences of Deficiency in Pregnancy

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VII. Recommended Doses

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VIII. Summary Diagram: Folic Acid in Metabolism

FOLIC ACID (THF)
       |
  ┌────┼─────────────┬──────────────┐
  ▼    ▼             ▼              ▼
DNA   Purine       Methionine     Amino Acid
synthesis synthesis synthesis    Metabolism
(dTMP)  (purines)  (+ B12)      (serine/glycine
  |        |          |           histidine)
  ▼        ▼          ▼
DNA    RNA/DNA     SAM (methyl   Homocysteine
replication     donor for     controlled
             epigenetics,
             myelin, NT)

DEFICIENCY EFFECTS:
→ Megaloblastic anaemia
→ Neural tube defects
→ Hyperhomocysteinaemia
→ Impaired DNA repair
→ Poor fetal growth

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MASTER KEYWORD INDEX (for quick revision)